U.S. patent application number 12/382787 was filed with the patent office on 2009-08-20 for benzofuran derivatives.
Invention is credited to Hidenori Akatsuka, Toru Iijima, Takayuki Kawaguchi, Takashi Mitsui, Jun Murakami, Yasunori Tsuboi.
Application Number | 20090209511 12/382787 |
Document ID | / |
Family ID | 28677558 |
Filed Date | 2009-08-20 |
United States Patent
Application |
20090209511 |
Kind Code |
A1 |
Kawaguchi; Takayuki ; et
al. |
August 20, 2009 |
Benzofuran Derivatives
Abstract
The present invention provides a benzofuran derivative of the
formula [1]: ##STR00001## wherein x is a group of the formula:
--N.dbd. or --CH.dbd.; Y is an optionally substituted amino group,
an optionally substituted cycloalkyl group or an optionally
substituted saturated heterocyclic group; A is a single bond, a
carbon chain optionally having a double bond within or at the
end(s) of the chain, or an oxygen atom; R.sup.1 is a hydrogen atom
or a halogen atom; Ring B is an optionally substituted benzene
ring; and R.sup.3 is a hydrogen atom, or a pharmaceutically
acceptable salt thereof, which is useful as a medicament,
especially as an activated blood coagulation factor X
inhibitor.
Inventors: |
Kawaguchi; Takayuki;
(Tokyo-to, JP) ; Akatsuka; Hidenori; (Toda-shi,
JP) ; Iijima; Toru; (Toda-shi, JP) ; Tsuboi;
Yasunori; (Ashiya-shi, JP) ; Mitsui; Takashi;
(Tokyo-to, JP) ; Murakami; Jun; (Saitama-shi,
JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Family ID: |
28677558 |
Appl. No.: |
12/382787 |
Filed: |
March 24, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10508512 |
Sep 21, 2004 |
7531537 |
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PCT/JP03/03807 |
Mar 27, 2003 |
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12382787 |
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Current U.S.
Class: |
514/210.2 ;
514/237.2; 514/337; 514/376; 544/124; 546/284.1; 548/229 |
Current CPC
Class: |
C07D 413/14 20130101;
C07D 307/85 20130101; C07D 405/14 20130101; A61P 7/00 20180101;
C07D 417/14 20130101; C07D 405/12 20130101; A61P 7/02 20180101 |
Class at
Publication: |
514/210.2 ;
514/237.2; 514/337; 514/376; 544/124; 546/284.1; 548/229 |
International
Class: |
A61K 31/397 20060101
A61K031/397; A61K 31/535 20060101 A61K031/535; A61K 31/4439
20060101 A61K031/4439; A61K 31/421 20060101 A61K031/421; C07D
413/14 20060101 C07D413/14; C07D 405/12 20060101 C07D405/12; C07D
263/00 20060101 C07D263/00 |
Foreign Application Data
Date |
Code |
Application Number |
Mar 28, 2002 |
JP |
2002-91686 |
Dec 26, 2002 |
JP |
2002-376158 |
Claims
1. A benzofuran derivative of the formula [1]: ##STR00894## wherein
x is a group of the formula: --N.dbd. or the formula: --CH.dbd.; Y
is an optionally substituted amino group, an optionally substituted
cycloalkyl group or an optionally substituted saturated
heterocyclic group; A is a single bond, a carbon chain optionally
having a double bond within or at the end(s) of the chain, or an
oxygen atom; R.sup.1 is a hydrogen atom, a halogen atom, a lower
alkyl group, a lower alkoxy group, a cyano group or an amino group
optionally substituted by a lower alkyl group; Ring B of the
formula: ##STR00895## is an optionally substituted benzene ring;
and R.sup.3 is a hydrogen atom or a lower alkyl group, or a
pharmaceutically acceptable salt thereof.
2. The compound according to claim 1, wherein Ring B is a benzene
ring optionally substituted by a group(s) selected independently
from a halogen atom, an optionally substituted lower alkyl group, a
hydroxy group, an optionally substituted lower alkoxy group, an oxy
group substituted by an optionally substituted saturated
heterocyclic group, a substituted carbonyl group, an optionally
substituted amino group, a nitro group, a cyano group, a
4,5-dihydroxazolyl group or a group of the formula: ##STR00896##
and the "optionally substituted cycloalkyl group" for Y is a
cycloalkyl group optionally substituted by a group selected from an
optionally substituted amino group, an optionally substituted group
of a formula selected from the formulas: ##STR00897## and an
optionally substituted lower alkyl group.
3. The compound according to claim 2, wherein the "optionally
substituted saturated heterocyclic group" for Y is a saturated
heterocyclic group optionally substituted by a group selected from
the followings: (1) a lower alkyl group, (2) a lower alkyl group
substituted by a pyridyl group, (3) a piperidyl group substituted
by a lower alkyl group, (4) a piperidyl group, (5) a piperidyl
group substituted by a lower alkoxycarbonyl group, (6) an
unsaturated heterocyclic group selected from a pyridyl group, a
pyrimidinyl group, a 4,5-dihydroxazolyl group and a thiazolyl
group, (7) a lower alkanoyl group, (8) a lower alkanoyl group
substituted by a di-lower alkylamino group, (9) a carbonyl group
substituted by a pyridyl group, (10) a lower alkylsulfonyl group,
(11) a lower alkoxycarbonyl group, (12) a lower alkyl group
substituted by a di-lower alkylamino group, and (13) an oxo group;
the "optionally substituted amino group" for Y is an amino group
optionally substituted by a group selected from the followings: (1)
a piperidyl group substituted by a lower alkyl group, (2) a lower
alkyl group, and (3) a lower alkoxycarbonyl group; the "optionally
substituted amino group" as a substituent on the cycloalkyl group
for Y is an amino group optionally substituted by a group selected
from the followings: (1) a lower alkyl group, (2) a cycloalkyl
group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group
substituted by a lower alkyl group, (5) a lower alkyl group
substituted by an amino group optionally substituted by a group
selected from (a) a lower alkyl group, (b) a lower alkanoyl group,
(c) a lower alkanoyl group substituted by an amino group
substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl
group, (6) a lower alkyl group substituted by a cyano group, (7) a
lower alkyl group substituted by a lower alkoxycarbonyl group, (8)
a lower alkyl group substituted by a carboxyl group, (9) a lower
alkyl group substituted by a carbamoyl group optionally substituted
by a lower alkyl group, (10) a lower alkyl group substituted by an
aryl group, (11) a lower alkyl group substituted by a pyridyl
group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl
group substituted by a di-lower alkyl amino group, (14) a lower
alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl
group substituted by a morpholinyl group, (17) a lower
alkylsulfonyl group, (18) a carbamoyl group substituted by a lower
alkyl group, (19) a carbonyl group substituted by an aryl group,
(20) a lower alkanoyl group substituted by a lower alkoxy group,
(21) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (22) an aryl group substituted by a hydroxyl group, and (23)
a hydroxy-lower alkanoyl group; the "optionally substituted group
of a formula selected from the formulas: ##STR00898## as a
substituent on the cycloalkyl group for Y is a group selected from
the groups of the formulas: ##STR00899## that is optionally
substituted by an oxo group; the "optionally substituted lower
alkyl group" as a substituent on the cycloalkyl group for Y is a
lower alkyl group optionally substituted by a group selected from
the followings: (1) an oxopyrrolidinyl group, and (2) an
oxomorpholinyl group, and (3) an amino group optionally substituted
by a group selected from (a) a lower alkyl group, (b) a lower
alkoxycarbonyl group, and (c) a lower alkanoyl group; the
"optionally substituted lower alkyl group" as a substituent for
Ring B is a lower alkyl group optionally substituted by a group
selected from the followings: (1) a lower alkoxycarbonyl group, (2)
a carboxyl group, (3) a carbamoyl group optionally substituted by a
group selected from (a) a lower alkyl group, (b) a lower
alkoxy-lower alkyl group, (c) a lower alkyl group substituted by a
hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group
substituted by a morpholinyl group, (5) a piperidylcarbonyl group
substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; the
"optionally substituted lower alkoxy group" as a substituent for
Ring B is a lower alkoxy group optionally substituted by a group
selected from the followings: (1) a carboxyl group, (2) a lower
alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl
group, (5) an aminooxy group optionally substituted by a lower
alkoxycarbonyl group, (6) a lower alkoxy group substituted by a
lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; the "oxy group substituted by an
optionally substituted saturated heterocyclic group" as a
substituent for Ring B is an oxy group substituted by a
heterocyclic group optionally substituted by an aryl group; the
"substituted carbonyl group" as a substituent for Ring B is a
carbonyl group substituted by a group selected from the followings:
(1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group
optionally substituted by (a) a lower alkyl group, (b) a lower
alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a
hydroxy-lower alkyl group, (e) a lower alkyl group substituted by
an amino group optionally substituted by a lower alkyl group, (f) a
lower alkyl group substituted by an aryl group, and (g) a lower
alkyl group substituted by a pyridyl group, (4) a morpholinyl
group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl
group, (5) a hydroxypiperidyl group, (6) a piperidyl group
substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl
group substituted by a hydroxy-lower alkyl group, and (8) a lower
alkyl-piperazinyl group; the "optionally substituted amino group"
as a substituent for Ring B is an amino group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkoxy-lower alkyl group, (3) a
hydroxy-lower alkyl group, (4) a lower alkanoyl group, (5) a lower
alkoxy-lower alkanoyl group, (6) a hydroxy-lower alkanoyl group,
(7) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (8) a lower alkanoyl group substituted by an amino group
optionally substituted by a group selected from (a) a lower alkyl
group and (b) a lower alkanoyl group, (9) a lower alkoxycarbonyl
group, (10) a lower alkoxycarbonyl group substituted by an aryl
group, (11) a carbamoyl group substituted by a lower alkyl group,
(12) a lower alkylsulfonyl group, and (13) a lower alkylsulfonyl
group substituted by a morpholinyl group.
4. The compound according to claim 3, wherein B is an unsubstituted
benzene ring; and Y is a saturated heterocyclic group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkyl group substituted by a pyridyl group
(3) a piperidyl group substituted by a lower alkyl group, (4) a
piperidyl group, (5) a piperidyl group substituted by a lower
alkoxycarbonyl group, (6) an unsaturated heterocyclic group
selected from a pyridyl group, a pyrimidinyl group, a
4,5-dihydroxazolyl group and a thiazolyl group, (7) a lower
alkanoyl group, (8) a lower alkanoyl group substituted by a
di-lower alkylamino group, (9) a carbonyl group substituted by a
pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group.
5. The compound according to claim 3, wherein B is an unsubstituted
benzene ring; and Y is an amino group optionally substituted by a
group selected from the followings: (1) a piperidyl group
substituted by a lower alkyl group, (2) a lower alkyl group, and
(3) a lower alkoxycarbonyl group.
6. The compound according to claim 3, wherein B is an unsubstituted
benzene ring; and Y is a cycloalkyl group optionally substituted by
the followings: A) an amino group optionally substituted by the
followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a
hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by
a lower alkyl group, (5) a lower alkyl group substituted by an
amino group optionally substituted by a group selected from (a) a
lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl
group substituted by an amino group substituted by a lower alkyl
group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl
group substituted by a cyano group, (7) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (8) a lower alkyl
group substituted by a carboxyl group, (9) a lower alkyl group
substituted by a carbamoyl group optionally substituted by a lower
alkyl group, (10) a lower alkyl group substituted by an aryl group,
(11) a lower alkyl group substituted by a pyridyl group, (12) a
lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted
by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15)
a pyrimidinyl group, (16) a lower alkanoyl group substituted by a
morpholinyl group, (17) a lower alkylsulfonyl group, (18) a
carbamoyl group substituted by a lower alkyl group, (19) a carbonyl
group substituted by an aryl group, (20) a lower alkanoyl group
substituted by a lower alkoxy group, (21) a lower alkanoyl group
substituted by a lower alkanoyloxy group, (22) an aryl group
substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl
group; B) a group of a formula selected from the formulas:
##STR00900## that is optionally substituted by an oxo group; or C)
a lower alkyl group optionally substituted by a group selected from
the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group.
7. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkyl group optionally substituted by a
group selected from the followings: (1) a lower alkoxycarbonyl
group, (2) a carboxyl group, (3) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl
group substituted by a morpholinyl group, (5) a piperidylcarbonyl
group substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; and Y
is a saturated heterocyclic group optionally substituted by a group
selected from the followings: (1) a lower alkyl group, (2) a lower
alkyl group substituted by a pyridyl group (3) a piperidyl group
substituted by a lower alkyl group, (4) a piperidyl group, (5) a
piperidyl group substituted by a lower alkoxycarbonyl group, (6) an
unsaturated heterocyclic group selected from a pyridyl group, a
pyrimidinyl group, a 4,5-dihydroxaolyl group and a thiazolyl group,
(7) a lower alkanoyl group, (8) a lower alkanoyl group substituted
by a di-lower alkylamino group, (9) a carbonyl group substituted by
a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group.
8. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkyl group optionally substituted by a
group selected from the followings: (1) a lower alkoxycarbonyl
group, (2) a carboxyl group, (3) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl
group substituted by a morpholinyl group, (5) a piperidylcarbonyl
group substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; and Y
is an amino group optionally substituted by a group selected from
the followings: (1) a piperidyl group substituted by a lower alkyl
group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl
group.
9. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkyl group optionally substituted by a
group selected from the followings: (1) a lower alkoxycarbonyl
group, (2) a carboxyl group, (3) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl
group substituted by a morpholinyl group, (5) a piperidylcarbonyl
group substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; and Y
is a cycloalkyl group optionally substituted by the followings: A)
an amino group optionally substituted by the followings: (1) a
lower alkyl group, (2) a cycloalkyl group, (3) a hydroxy-lower
alkyl group, (4) a 1,3-dioxanyl group substituted by a lower alkyl
group, (5) a lower alkyl group substituted by an amino group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkanoyl group, (c) a lower alkanoyl group
substituted by an amino group substituted by a lower alkyl group,
and (d) a lower alkoxycarbonyl group, (6) a lower alkyl group
substituted by a cyano group, (7) a lower alkyl group substituted
by a lower alkoxycarbonyl group, (8) a lower alkyl group
substituted by a carboxyl group, (9) a lower alkyl group
substituted by a carbamoyl group optionally substituted by a lower
alkyl group, (10) a lower alkyl group substituted by an aryl group,
(11) a lower alkyl group substituted by a pyridyl group, (12) a
lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted
by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15)
a pyrimidinyl group, (16) a lower alkanoyl group substituted by a
morpholinyl group, (17) a lower alkylsulfonyl group, (18) a
carbamoyl group substituted by a lower alkyl group, (19) a carbonyl
group substituted by an aryl group, (20) a lower alkanoyl group
substituted by a lower alkoxy group, (21) a lower alkanoyl group
substituted by a lower alkanoyloxy group, (22) an aryl group
substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl
group; B) a group of a formula selected from the formulas:
##STR00901## that is optionally substituted by an oxo group; or C)
a lower alkyl group optionally substituted by a group selected from
the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group.
10. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkoxy group optionally substituted by
a group selected from the followings: (1) a carboxyl group, (2) a
lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a
hydroxyl group, (5) an aminooxy group optionally substituted by a
lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by
a lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; and Y is a saturated heterocyclic
group optionally substituted by a group selected from the
followings: (1) a lower alkyl group, (2) a lower alkyl group
substituted by a pyridyl group (3) a piperidyl group substituted by
a lower alkyl group, (4) a piperidyl group, (5) a piperidyl group
substituted by a lower alkoxycarbonyl group, (6) an unsaturated
heterocyclic group selected from a pyridyl group, a pyrimidinyl
group, a 4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower
alkanoyl group, (8) a lower alkanoyl group substituted by a
di-lower alkylamino group, (9) a carbonyl group substituted by a
pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group.
11. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkoxy group optionally substituted by
a group selected from the followings: (1) a carboxyl group, (2) a
lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a
hydroxyl group, (5) an aminooxy group optionally substituted by a
lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by
a lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; and Y is an amino group optionally
substituted by a group selected from the followings: (1) a
piperidyl group substituted by a lower alkyl group, (2) a lower
alkyl group, and (3) a lower alkoxycarbonyl group.
12. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a lower alkoxy group optionally substituted by
a group selected from the followings: (1) a carboxyl group, (2) a
lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a
hydroxyl group, (5) an aminooxy group optionally substituted by a
lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by
a lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; and Y is a cycloalkyl group optionally
substituted by the followings: A) an amino group optionally
substituted by the followings: (1) a lower alkyl group, (2) a
cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a
1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower
alkyl group substituted by an amino group optionally substituted by
a group selected from (a) a lower alkyl group, (b) a lower alkanoyl
group, (c) a lower alkanoyl group substituted by an amino group
substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl
group, (6) a lower alkyl group substituted by a cyano group, (7) a
lower alkyl group substituted by a lower alkoxycarbonyl group, (8)
a lower alkyl group substituted by a carboxyl group, (9) a lower
alkyl group substituted by a carbamoyl group optionally substituted
by a lower alkyl group, (10) a lower alkyl group substituted by an
aryl group, (11) a lower alkyl group substituted by a pyridyl
group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl
group substituted by a di-lower alkyl amino group, (14) a lower
alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl
group substituted by a morpholinyl group, (17) a lower
alkylsulfonyl group, (18) a carbamoyl group substituted by a lower
alkyl group, (19) a carbonyl group substituted by an aryl group,
(20) a lower alkanoyl group substituted by a lower alkoxy group,
(21) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (22) an aryl group substituted by a hydroxy group, and (23)
a hydroxy-lower alkanoyl group; B) a group of a formula selected
from the formulas: ##STR00902## that is optionally substituted by
an oxo group; or C) a lower alkyl group optionally substituted by a
group selected from the followings: (1) an oxopyrrolidinyl group,
(2) an oxomorpholinyl group, and (3) an amino group optionally
substituted by (a) a lower alkyl group, (b) a lower alkoxycarbonyl
group, and (c) a lower alkanoyl group.
13. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a carbonyl group substituted by a group
selected from the followings: (1) a lower alkoxy group, (2) a
hydroxyl group, (3) an amino group optionally substituted by (a) a
lower alkyl group, (b) a lower alkoxy group, (c) a lower
alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a
lower alkyl group substituted by an amino group optionally
substituted by a lower alkyl group, (f) a lower alkyl group
substituted by an aryl group, and (g) a lower alkyl group
substituted by a pyridyl group, (4) a morpholinyl group, a
pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,
(5) a hydroxypiperidyl group, (6) a piperidyl group substituted by
a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted
by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl
group; and Y is a saturated heterocyclic group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkyl group substituted by a pyridyl group
(3) a piperidyl group substituted by a lower alkyl group, (4) a
piperidyl group, (5) a piperidyl group substituted by a lower
alkoxycarbonyl group, (6) an unsaturated heterocyclic group
selected from a pyridyl group, a pyrimidinyl group, a
4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl
group, (8) a lower alkanoyl group substituted by a di-lower
alkylamino group, (9) a carbonyl group substituted by a pyridyl
group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group.
14. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a carbonyl group substituted by a group
selected from the followings: (1) a lower alkoxy group, (2) a
hydroxyl group, (3) an amino group optionally substituted by (a) a
lower alkyl group, (b) a lower alkoxy group, (c) a lower
alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a
lower alkyl group substituted by an amino group optionally
substituted by a lower alkyl group, (f) a lower alkyl group
substituted by an aryl group, and (g) a lower alkyl group
substituted by a pyridyl group, (4) a morpholinyl group, a
pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,
(5) a hydroxypiperidyl group, (6) a piperidyl group substituted by
a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted
by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl
group; and Y is an amino group optionally substituted by a group
selected from the followings: (1) a piperidyl group substituted by
a lower alkyl group, (2) a lower alkyl group, and (3) a lower
alkoxycarbonyl group.
15. The compound according to claim 3, wherein Ring B is a benzene
ring substituted by a carbonyl group substituted by a group
selected from the followings: (1) a lower alkoxy group, (2) a
hydroxyl group, (3) an amino group optionally substituted by (a) a
lower alkyl group, (b) a lower alkoxy group, (c) a lower
alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl group, (e) a
lower alkyl group substituted by an amino group optionally
substituted by a lower alkyl group, (f) a lower alkyl group
substituted by an aryl group, and (g) a lower alkyl group
substituted by a pyridyl group, (4) a morpholinyl group, a
pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,
(5) a hydroxypiperidyl group, (6) a piperidyl group substituted by
a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted
by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl
group; and Y is a cycloalkyl group optionally substituted by the
followings: A) an amino group optionally substituted by the
followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a
hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by
a lower alkyl group, (5) a lower alkyl group substituted by an
amino group optionally substituted by a group selected from (a) a
lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl
group substituted by an amino group substituted by a lower alkyl
group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl
group substituted by a cyano group, (7) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (8) a lower alkyl
group substituted by a carboxyl group, (9) a lower alkyl group
substituted by a carbamoyl group optionally substituted by a lower
alkyl group, (10) a lower alkyl group substituted by an aryl group,
(11) a lower alkyl group substituted by a pyridyl group, (12) a
lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted
by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15)
a pyrimidinyl group, (16) a lower alkanoyl group substituted by a
morpholinyl group, (17) a lower alkylsulfonyl group, (18) a
carbamoyl group substituted by a lower alkyl group, (19) a carbonyl
group substituted by an aryl group, (20) a lower alkanoyl group
substituted by a lower alkoxy group, (21) a lower alkanoyl group
substituted by a lower alkanoyloxy group, (22) an aryl group
substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl
group; B) a group of a formula selected from the formulas:
##STR00903## that is optionally substituted by an oxo group; or C)
a lower alkyl group optionally substituted by a group selected from
the followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group.
16. The compound according to any one of claims 1, 2, 3, 4, 7, 10
and 13, wherein the saturated heterocyclic ring is a saturated 4-
to 7-membered heterocyclic group containing 1 to 4 hetero atoms
selected independently from the group consisting of nitrogen atom,
oxygen atom and sulfur atom.
17. The compound according to any one of claims 1, 2, 3, 4, 7, 10
and 13, wherein the saturated heterocyclic group is imidazolidinyl,
piperazolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, homopiperazinyl, homopiperidyl, pyrrolidinyl,
oxazolidinyl or 1,3-dioxanyl.
18. The compound according to claim 3, wherein the group of the
formula: ##STR00904## is the group of the formula: ##STR00905## and
the group of the formula: ##STR00906## is a group of the formula:
##STR00907## R.sup.1 is a halogen atom or a lower alkyl group;
R.sup.2 is a group selected from the followings: A) a hydrogen
atom, B) a lower alkyl group optionally substituted by a group
selected from the followings: (1) a lower alkoxycarbonyl group, (2)
a carboxyl group, (3) a carbamoyl group optionally substituted by a
group selected from (a) a lower alkyl group, (b) a lower
alkoxy-lower alkyl group, (c) a lower alkyl group substituted by a
hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group
substituted by a morpholinyl group, (5) a piperidylcarbonyl group
substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; C) a
lower alkoxy group optionally substituted by a group selected from
the followings: (1) a carboxyl group, (2) a lower alkoxycarbonyl
group, (3) a lower alkoxy group, (4) a hydroxyl group, (5) an
aminooxy group optionally substituted by a lower alkoxycarbonyl
group, (6) a lower alkoxy group substituted by a lower alkoxy
group, (7) a carbonyl group substituted by a morpholinyl group, a
piperidyl group or a pyrrolidinyl group, (8) a carbonyl group
substituted by a hydroxypiperidyl group, (9) a piperidylcarbonyl
group substituted by a hydroxy-lower alkyl group, (10) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by a group selected from (a) a lower alkyl group, (b) a lower
alkoxycarbonyl group, and (c) a lower alkanoyl group, (13) a
carbamoyl group optionally substituted by a group selected from (a)
a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a
lower alkyl group substituted by a hydroxyl group, and (d) a lower
alkyl group substituted by a di-lower alkylamino group, and (14) a
group of the formula: --O--NH--C(.dbd.NH)NH.sub.2; or D) a carbonyl
group substituted by a group selected from the followings: (1) a
lower alkoxy group, (2) a hydroxyl group, (3) an amino group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkoxy group, (c) a lower alkoxy-lower alkyl
group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl group
substituted by an amino group optionally substituted by a lower
alkyl group, (f) a lower alkyl group substituted by an aryl group,
and (g) a lower alkyl group substituted by a pyridyl group, (4) a
morpholinyl group, a pyrrolidinyl group, a piperidyl group or a
thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a
piperidyl group substituted by a hydroxy-lower alkyl group, (7) a
pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and
(8) a lower alkyl-piperazinyl group; A is a single bond; and
R.sup.3 is a hydrogen atom.
19. The compound according to claim 18, wherein Y is a group
selected from the followings: (1) a piperidyl group substituted by
a lower alkyl group, (2) a cycloalkyl group substituted by an amino
group optionally substituted by a group selected from (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group, (3) a cycloalkyl group substituted by a group of a
formula selected from the formulas: ##STR00908## that is optionally
substituted by an oxo group, (4) a cycloalkyl group substituted by
an amino group substituted by a lower alkyl group substituted by an
amino group optionally substituted by a group selected from (a) a
lower alkanoyl group and (b) a lower alkoxycarbonyl group, and (5)
a cycloalkyl group substituted by a lower alkyl group substituted
by an amino group optionally substituted by a lower alkyl group;
and R.sup.2 is a group selected from the followings: (1) a hydrogen
atom, (2) a cyano group, (3) an amino group optionally substituted
by a lower alkyl group, (4) a hydroxyl group, (5) a lower alkoxy
group, (6) a lower alkoxy group substituted by a lower alkoxy
group, (7) a lower alkoxy group substituted by a hydroxyl group,
(8) a lower alkoxy group substituted by an amino group optionally
substituted by a lower alkyl group, (9) a lower alkoxycarbonyl
group, (10) a carboxyl group, (11) an aminocarbonyl group
optionally substituted by a group selected from (a) lower alkyl
group, and (b) a hydroxy-lower alkyl group, (12) a
morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a
piperidylcarbonyl group or a thiomorpholinylcarbonyl group, (13) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group
or a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (14) a lower alkyl group, (15) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (16) a carboxy-lower
alkyl group, (17) a lower alkyl group substituted by a carbamoyl
group optionally substituted by a group selected from (a) lower
alkyl group and (b) a hydroxy-lower alkyl group, (18) a lower alkyl
group substituted by a morpholinylcarbonyl group, (19) a lower
alkyl group substituted by a piperidylcarbonyl group substituted by
a hydroxy-lower alkyl group, or a lower alkyl group substituted by
a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, or (20) a hydroxy-lower alkyl group.
20. The compound according to claim 18, wherein Y is a cycloalkyl
group substituted by a group of a formula selected from the
formulas: ##STR00909## that is optionally substituted by an oxo
group, or a cycloalkyl group substituted by an amino group
optionally substituted by a group selected from (a) a lower alkyl
group and (b) a lower alkanoyl group; and R.sup.2 is a group
selected from the followings: (1) a hydrogen atom, (2) an amino
group-substituted carbonyl group optionally substituted by a group
selected from (a) a lower alkyl group and (b) a lower alkoxy-lower
alkyl group, (3) a lower alkoxycarbonyl group, (4) a
morpholinylcarbonyl group, a pyrrolidinylcarbonyl group, a
piperidylcarbonyl group or a thiomorpholinylcarbonyl group, (5) a
lower alkyl group substituted by a lower alkyl group-substituted
carbamoyl group, (6) a carboxy-lower alkyl group, (7) a lower alkyl
group substituted by a morpholinylcarbonyl group, and (8) a
hydroxy-lower alkyl group.
21. The compound according to claim 18, wherein Y is a cycloalkyl
group substituted by an oxopyrrolidinyl group, a cycloalkyl group
substituted by an oxomorpholinyl group or a cycloalkyl group
substituted by an amino group optionally substituted by a group
selected from (a) a lower alkyl group and (b) a lower alkanoyl
group; and R.sup.2 is a group selected from the followings: (1) a
hydrogen atom, (2) a hydroxy-lower alkyl group, (3) a carboxy-lower
alkyl group, (4) a lower alkoxy group substituted by a lower alkoxy
group, or (5) a carbonyl group substituted by a group selected from
(a) an amino group optionally substituted by a lower alkyl group
and (b) a morpholinyl group.
22. The compound according to claim 18, wherein Y is a group
selected from the followings: (1) a cycloalkyl group substituted by
an amino group substituted by a lower alkyl group having 1 to 3
carbon atoms, (2) a cycloalkyl group substituted by an amino group
substituted by a lower alkanoyl group having 1 to 2 carbon atoms,
(3) a cycloalkyl group substituted by a pyrrolidin-1-yl group
optionally substituted by an oxo group, (4) a cycloalkyl group
substituted by a piperidin-1-yl group optionally substituted by an
oxo group, (5) a cycloalkyl group substituted by a morpholin-4-yl
group optionally substituted by an oxo group, (6) a cycloalkyl
group substituted by a lower alkyl group substituted by an amino
group substituted by a lower alkyl group having 1 to 3 carbon
atoms, or (7) a cycloalkyl group substituted by a lower alkyl group
substituted by an amino group substituted by a lower alkanoyl group
having 1 to 2 carbon atoms.
23. A compound selected from
trans-5-Dimethylaminocarbonyl-3-[4-(N-formyl-N-methylamino)cyclohexylcarb-
onylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;
trans-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonylamino]-5-(2-hydroxye-
thyl)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide;
trans-5-(morpholine-4-ylcarbonyl)-3-[4-(2-oxo-pyrroridin-1-yl)cyclohexylc-
arbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; and
trans-3-(4-dimethylaminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)-
benzofuran-2-carboxamide, or a pharmaceutically acceptable salt
thereof. ##STR00910## wherein the symbols are the same as defined
above, or a salt thereof.
24. A pharmaceutical composition, which comprises as an active
ingredient a compound according to any one of claims 1 to 24, or a
pharmaceutically acceptable salt thereof.
25. A method for treatment of thrombosis, which comprises
administering an effective amount of a compound according to any
one of claims 1 to 24, or a pharmaceutically acceptable salt
thereof, to a patient in need thereof
26. Use of a compound according to any one of claims 1 to 24 above
or a pharmaceutically acceptable salt thereof in treatment of
patients suffering from thrombosis.
27. A medicament for treatment of thrombosis substantially free of
phospholipidosis, which comprises as an active ingredient a factor.
Xa (FXa) inhibitor showing a distribution volume of 0.1-3.0 L/kg
and an FXa inhibitory effect with the IC.sub.50 value of 100 nM or
below.
28. A medicament for treatment of thrombosis substantially free of
hepatotoxicity, which comprises as an active ingredient an FXa
inhibitor showing a distribution volume of 0.1-3.0 L/kg or below
and an FXa inhibitory effect with the IC.sub.50 value of 100 nM or
below.
29. A medicament for oral administration for treatment of
thrombosis substantially free of phospholipidosis, which comprises
as an active ingredient a factor Xa (FXa) inhibitor showing a
distribution volume of 0.1-3.0 L/kg and an FXa inhibitory effect
with the IC.sub.50 value of 100 nM or below.
30. A medicament for oral administration for treatment of
thrombosis substantially free of hepatotoxicity, which comprises as
an active ingredient an FXa inhibitor showing a distribution volume
of 0.1-3.0 L/kg or below and an FXa inhibitory effect with the
IC.sub.50 value of 100 nM or below.
31. A medicament for treatment of thrombosis substantially free of
phospholipidosis, which comprises as an active ingredient an FXa
inhibitor having a partial structure of the formula: ##STR00911##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
32. A medicament for treatment of thrombosis substantially free of
hepatotoxicity, which comprises as an active ingredient an FXa
inhibitor having a partial structure of the formula: ##STR00912##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
33. A medicament for oral administration for treatment of
thrombosis substantially free of phospholipidosis, which comprises
as an active ingredient an FXa inhibitor having a partial structure
of the formula: ##STR00913## and showing a distribution volume of
0.1-3.0 L/kg and an FXa inhibitory effect with the IC.sub.50 value
of 100 nM or below.
34. A medicament for oral administration for treatment of
thrombosis substantially free of hepatotoxicity, which comprises as
an active ingredient an FXa inhibitor having a partial structure of
the formula: ##STR00914## and showing a distribution volume of
0.1-3.0 L/kg and an FXa inhibitory effect with the IC.sub.50 value
of 100 nM or below.
Description
[0001] This Application is a Divisional of co-pending application
Ser. No. 10/508,512, filed on Sep. 21, 2004, and claims priority
thereto PCT International Application No. PCT/JP03/03807 filed Mar.
27, 2003 under 35 U.S.C. .sctn. 120. This Application also claims
priority under 35 U.S.C. .sctn. 119 on Japanese Application Nos. JP
2002-091686 and JP 2002-376158, each filed on Mar. 28, 2002 and
Dec. 26, 2002, respectively. The entire contents of which are
hereby incorporated by reference in their entirety.
TECHNICAL FIELD
[0002] The present invention relates to a benzofuran derivative
useful as a medicament, particularly as an inhibitor of activated
blood coagulation factor X, or pharmaceutically acceptable salt
thereof.
BACKGROUND ART
[0003] In late years, as the westernization of living habit and the
aging of populations, thromboembolic diseases such as myocardial
infarction, cerebral infarction and peripheral arterial thrombosis
increase year by year, and social importance of treatment thereof
has risen more and more.
[0004] Among therapies of thromboembolic diseases, anticoagulant
therapy, as well as fibrinolytic therapy and antiplatelet therapy,
takes part in medical therapy for treatment and prevention of
thrombosis (Sogorinsho 41: 2141-2145, 1989). In particular, the
safety sustainable to chronic administration and the reliable and
appropriate expression of anticoagulant activity are essential in
the prevention of thrombosis. A coumarin derivative, especially
warfarin potassium, has often been used all over the world as only
anticoagulant available orally. However, owing to the
characteristics arisen from the mechanism of action, it requires
long time until the drug efficacy manifests and has very long
half-life in blood, although the concentration range for expression
of drug efficacy is relatively narrow, and also shows significant
differences in the effective dose among individuals. For these
reasons, the anticoagulant ability can hardly be controlled
(Journal of Clinical Pharmacology, 1992, vol. 32, pp. 196-209; NEW
ENGLAND JOURNAL OF MEDICINE, 1991, vol. 324, no. 26, pp.
1865-1875). In addition, there may be adverse drug reactions such
as risk of bleeding, nausea, vomiting, diarrhea, depilation, etc.,
and therefore the clinical application thereof is very difficult
and the development of anticoagulants that are useful and easy to
handle has been demanded.
[0005] In addition, enhancement of blood clotting ability is one of
significant causative factors of unstable angina, cerebral
infarction, cerebral embolism, myocardial infarction, pulmonary
infarction, pulmonary embolism, Buerger's disease, deep vein
thrombosis, disseminated intravascular coagulation, thrombogenesis
after artificial heart valve displacement, reocclusion after blood
circulation reconstruction and thrombogenesis during extracorporeal
circulation, etc. Therefore, a distinguished anticoagulant that
shows good dose response and lower risk of hemorrhage with few
side-effects, and can exert sufficient effects upon oral
administration has been desired (Thrombosis Research, 1992, vol.
68, pp. 507-512). Thrombin participates not only in the conversion
of fibrinogen to fibrin, which is the final stage of the
coagulation cascade, but also deeply in the activation and
aggregation of blood platelets (Matsuo, O., "t-PA and Pro-UK",
Gakusaikikaku, 1986, pp. 5-40), and an inhibitor thereof has long
been the center of the research in anticoagulants as a target of
development of new drugs. However, a thrombin inhibitor shows low
bioavailability upon oral administration and also has drawbacks in
regard to safety such as bleeding tendency as one of side effects
(Biomedica Biochimica Acta, 1985, Vol. 44, p. 1201-1210), and there
have been no thrombin inhibitors marketed so far, which can be
orally administered.
[0006] The activated blood coagulation factor X is a key enzyme
located in the position of the common pathway of both extrinsic and
intrinsic coagulation cascade reactions. The factor Xa is located
upstream from thrombin in the coagulation cascade. Therefore, the
inhibition of the factor Xa is possibly more effective and specific
in the inhibition of coagulation system compared to the inhibition
of thrombin (Thrombosis Research, 1980, Vol. 19, pp. 339-349).
[0007] Thus, among inhibitors of activated blood coagulation factor
X, a substance, which inhibits blood coagulation factor Xa and
shows distinguished enzyme selectivity and high bioavailability, is
expected to undergo control of its anticoagulant activity for a
long period of time and can express superior therapeutic effect
upon oral administration compared to the existing anticoagulants.
Accordingly, the development of a novel inhibitor of activated
blood coagulation factor X (FXa inhibitor) that can be administered
orally has been earnestly demanded.
[0008] Examples of known compounds having inhibitory effect on
activated blood coagulation factor X include thiobenzamide
compounds that are useful in prevention or treatment of thrombosis
(WO99/42439).
[0009] The following benzofuran compounds have also been known
(Indian Journal of Hetero Cyclic Chemistry, 1994, Vol. 3, pp.
3247-3252), but said literature does not mention about the
inhibitory effect of the compounds on activated blood coagulation
factor X.
##STR00002##
[0010] Condensed bicyclic amide compounds of the formula:
##STR00003##
which has an activity of suppressing the growth of activated
lymphocytes and are useful as a drug for preventing or treating
autoimmune diseases are also known (WO02/12189). The WO02/12189
does not mention about the inhibitory effect on activated blood
coagulation factor X either. In the pamphlet, compounds having a
condensed ring of pyridine and furan to which ring an amide and a
carbamoyl groups are di-substituted are disclosed; however, said
compounds all have a benzene ring on the nitrogen atom of the
carbamoyl group, said benzene ring being substituted by X and Y
simultaneously.
DISCLOSURE OF INVENTION
[0011] The present invention provides a novel benzofuran derivative
having excellent inhibitory effect on activated blood coagulation
factor X, or a pharmaceutically acceptable salts thereof.
[0012] The present inventors have intensively studied and have
found that a benzofuran derivative of the formula below has
excellent inhibitory effect on activated blood coagulation factor X
and have accomplished the present invention.
[0013] That is, the present invention is as follows:
(i) A benzofuran derivative of the formula [1]:
##STR00004##
wherein x is a group of the formula: --N.dbd. or the formula:
--CH.dbd.; Y is an optionally substituted amino group, an
optionally substituted cycloalkyl group or an optionally
substituted saturated heterocyclic group; A is a single bond, a
carbon chain optionally having a double bond within or at the
end(s) of the chain, or an oxygen atom; R.sup.1 is a hydrogen atom,
a halogen atom, a lower alkyl group, a lower alkoxy group, a cyano
group or an amino group optionally substituted by a lower alkyl
group; Ring B of the formula:
##STR00005##
is an optionally substituted benzene ring; and R.sup.3 is a
hydrogen atom or a lower alkyl group, or a pharmaceutically
acceptable salt thereof. (ii) The compound according to (i),
wherein Ring B is a benzene ring optionally substituted by a
group(s) selected independently from a halogen atom, an optionally
substituted lower alkyl group, a hydroxy group, an optionally
substituted lower alkoxy group, an oxy group substituted by an
optionally substituted saturated heterocyclic group, a substituted
carbonyl group, an optionally substituted amino group, a nitro
group, a cyano group, a 4,5-dihydroxazolyl group or a group of the
formula:
##STR00006##
and the "optionally substituted cycloalkyl group" for Y is a
cycloalkyl group optionally substituted by a group selected from an
optionally substituted amino group, an optionally substituted group
of a formula selected from the formulas:
##STR00007##
and an optionally substituted lower alkyl group. (iii) The compound
according to (ii), wherein the "optionally substituted saturated
heterocyclic group" for Y is a saturated heterocyclic group
optionally substituted by a group selected from the followings: (1)
a lower alkyl group, (2) a lower alkyl group substituted by a
pyridyl group, (3) a piperidyl group substituted by a lower alkyl
group, (4) a piperidyl group, (5) a piperidyl group substituted by
a lower alkoxycarbonyl group, (6) an unsaturated heterocyclic group
selected from a pyridyl group, a pyrimidinyl group, a
4,5-dihydroxazolyl group and a thiazolyl group, (7) a lower
alkanoyl group, (8) a lower alkanoyl group substituted by a
di-lower alkylamino group, (9) a carbonyl group substituted by a
pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group; the "optionally
substituted amino group" for Y is an amino group optionally
substituted by a group selected from the followings: (1) a
piperidyl group substituted by a lower alkyl group, (2) a lower
alkyl group, and (3) a lower alkoxycarbonyl group; the "optionally
substituted amino group" as a substituent on the cycloalkyl group
for Y is an amino group optionally substituted by a group selected
from the followings: (1) a lower alkyl group, (2) a cycloalkyl
group, (3) a hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group
substituted by a lower alkyl group, (5) a lower alkyl group
substituted by an amino group optionally substituted by a group
selected from (a) a lower alkyl group, (b) a lower alkanoyl group,
(c) a lower alkanoyl group substituted by an amino group
substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl
group, (6) a lower alkyl group substituted by a cyano group, (7) a
lower alkyl group substituted by a lower alkoxycarbonyl group, (8)
a lower alkyl group substituted by a carboxyl group, (9) a lower
alkyl group substituted by a carbamoyl group optionally substituted
by a lower alkyl group, (10) a lower alkyl group substituted by an
aryl group, (11) a lower alkyl group substituted by a pyridyl
group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl
group substituted by a di-lower alkyl amino group, (14) a lower
alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl
group substituted by a morpholinyl group, (17) a lower
alkylsulfonyl group, (18) a carbamoyl group substituted by a lower
alkyl group, (19) a carbonyl group substituted by an aryl group,
(20) a lower alkanoyl group substituted by a lower alkoxy group,
(21) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (22) an aryl group substituted by a hydroxyl group, and (23)
a hydroxy-lower alkanoyl group; the "optionally substituted group
of a formula selected from the formulas:
##STR00008##
as a substituent on the cycloalkyl group for Y is a group selected
from the groups of the formulas:
##STR00009##
that is optionally substituted by an oxo group; the "optionally
substituted lower alkyl group" as a substituent on the cycloalkyl
group for Y is a lower alkyl group optionally substituted by a
group selected from, the followings: (1) an oxopyrrolidinyl group,
(2) an oxomorpholinyl group, and (3) an amino group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxycarbonyl group, and (c) a lower alkanoyl group; the
"optionally substituted lower alkyl group" as a substituent for
Ring B is a lower alkyl group optionally substituted by a group
selected from the followings: (1) a lower alkoxycarbonyl group, (2)
a carboxyl group, (3) a carbamoyl group optionally substituted by a
group selected from (a) a lower alkyl group, (b) a lower
alkoxy-lower alkyl group, (c) a lower alkyl group substituted by a
hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl group
substituted by a morpholinyl group, (5) a piperidylcarbonyl group
substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; the
"optionally substituted lower alkoxy group" as a substituent for
Ring B is a lower alkoxy group optionally substituted by a group
selected from the followings: (1) a carboxyl group, (2) a lower
alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl
group, (5) an aminooxy group optionally substituted by a lower
alkoxycarbonyl group, (6) a lower alkoxy group substituted by a
lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; the "oxy group substituted by an
optionally substituted saturated heterocyclic group" as a
substituent for Ring B is an oxy group substituted by a
heterocyclic group optionally substituted by an aryl group; the
"substituted carbonyl group" as a substituent for Ring B is a
carbonyl group substituted by a group selected from the followings:
(1) a lower alkoxy group, (2) a hydroxyl group, (3) an amino group
optionally substituted by (a) a lower alkyl group, (b) a lower
alkoxy group, (c) a lower alkoxy-lower alkyl group, (d) a
hydroxy-lower alkyl group, (e) a lower alkyl group substituted by
an amino group optionally substituted by a lower alkyl group, (f) a
lower alkyl group substituted by an aryl group, and (g) a lower
alkyl group substituted by a pyridyl group, (4) a morpholinyl
group, a pyrrolidinyl group, a piperidyl group or a thiomorpholinyl
group, (5) a hydroxypiperidyl group, (6) a piperidyl group
substituted by a hydroxy-lower alkyl group, (7) a pyrrolidinyl
group substituted by a hydroxy-lower alkyl group, and (8) a lower
alkyl-piperazinyl group; the "optionally substituted amino group"
as a substituent for Ring B is an amino group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkoxy-lower alkyl group, (3) a
hydroxy-lower alkyl group, (4) a lower alkanoyl group, (5) a lower
alkoxy-lower alkanoyl group, (6) a hydroxy-lower alkanoyl group,
(7) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (8) a lower alkanoyl group substituted by an amino group
optionally substituted by a group selected from (a) a lower alkyl
group and (b) a lower alkanoyl group, (9) a lower alkoxycarbonyl
group, (10) a lower alkoxycarbonyl group substituted by an aryl
group, (11) a carbamoyl group substituted by a lower alkyl group,
(12) a lower alkylsulfonyl group, and (13) a lower alkylsulfonyl
group substituted by a morpholinyl group. (iv) The compound
according to (iii), wherein B is an unsubstituted benzene ring; and
Y is a saturated heterocyclic group optionally substituted by a
group selected from the followings: (1) a lower alkyl group, (2) a
lower alkyl group substituted by a pyridyl group (3) a piperidyl
group substituted by a lower alkyl group, (4) a piperidyl group,
(5) a piperidyl group substituted by a lower alkoxycarbonyl group,
(6) an unsaturated heterocyclic group selected from a pyridyl
group, a pyrimidinyl group, a 4,5-dihydroxazolyl group and a
thiazolyl group, (7) a lower alkanoyl group, (8) a lower alkanoyl
group substituted by a di-lower alkylamino group, (9) a carbonyl
group substituted by a pyridyl group, (10) a lower alkylsulfonyl
group, (11) a lower alkoxycarbonyl group, (12) a lower alkyl group
substituted by a di-lower alkylamino group, and (13) an oxo group.
(v) The compound according to (iii), wherein B is an unsubstituted
benzene ring; and Y is an amino group optionally substituted by a
group selected from the followings: (1) a piperidyl group
substituted by a lower alkyl group, (2) a lower alkyl group, and
(3) a lower alkoxycarbonyl group. (vi) The compound according to
(iii), wherein B is an unsubstituted benzene ring; and Y is a
cycloalkyl group optionally substituted by the followings:
[0014] A) an amino group optionally substituted by the
followings:
(1) a lower alkyl group, (2) a cycloalkyl group, (3) a
hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by
a lower alkyl group, (5) a lower alkyl group substituted by an
amino group optionally substituted by a group selected from (a) a
lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl
group substituted by an amino group substituted by a lower alkyl
group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl
group substituted by a cyano group, (7) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (8) a lower alkyl
group substituted by a carboxyl group, (9) a lower alkyl group
substituted by a carbamoyl group optionally substituted by a lower
alkyl group, (10) a lower alkyl group substituted by an aryl group,
(11) a lower alkyl group substituted by a pyridyl group, (12) a
lower alkoxycarbonyl group, (13) a lower alkanoyl group substituted
by a di-lower alkyl amino group, (14) a lower alkanoyl group, (15)
a pyrimidinyl group, (16) a lower alkanoyl group substituted by a
morpholinyl group, (17) a lower alkylsulfonyl group, (18) a
carbamoyl group substituted by a lower alkyl group, (19) a carbonyl
group substituted by an aryl group, (20) a lower alkanoyl group
substituted by a lower alkoxy group, (21) a lower alkanoyl group
substituted by a lower alkanoyloxy group, (22) an aryl group
substituted by a hydroxy group, and (23) a hydroxy-lower alkanoyl
group; B) a group of a formula selected from the formulas:
##STR00010##
that is optionally substituted by an oxo group; or C) a lower alkyl
group optionally substituted by a group selected from the
followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group. (vii) The compound according to (iii), wherein Ring
B is a benzene ring substituted by a lower alkyl group optionally
substituted by a group selected from the followings: (1) a lower
alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkoxy-lower alkyl group, (c) a lower alkyl
group substituted by a hydroxyl group, and (d) a lower alkoxy
group, (4) a carbonyl group substituted by a morpholinyl group, (5)
a piperidylcarbonyl group substituted by a hydroxy-lower alkyl
group, (6) a pyrrolidinylcarbonyl group substituted by
.alpha.-hydroxy-lower alkyl group, (7) a carbonyl group substituted
by a hydroxyl group-substituted piperidyl group, and (8) a hydroxyl
group; and Y is a saturated heterocyclic group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkyl group substituted by a pyridyl group
(3) a piperidyl group substituted by a lower alkyl group, (4) a
piperidyl group, (5) a piperidyl group substituted by a lower
alkoxycarbonyl group, (6) an unsaturated heterocyclic group
selected from a pyridyl group, a pyrimidinyl group, a
4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl
group, (8) a lower alkanoyl group substituted by a di-lower
alkylamino group, (9) a carbonyl group substituted by a pyridyl
group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group. (viii) The
compound according to (iii), wherein Ring B is a benzene ring
substituted by a lower alkyl group optionally substituted by a
group selected from the followings: (1) a lower alkoxycarbonyl
group, (2) a carboxyl group, (3) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkoxy group, (4) a carbonyl
group substituted by a morpholinyl group, (5) a piperidylcarbonyl
group substituted by a hydroxy-lower alkyl group, (6) a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (7) a carbonyl group substituted by a hydroxyl
group-substituted piperidyl group, and (8) a hydroxyl group; and Y
is an amino group optionally substituted by a group selected from
the followings: (1) a piperidyl group substituted by a lower alkyl
group, (2) a lower alkyl group, and (3) a lower alkoxycarbonyl
group. (ix) The compound according to (iii), wherein Ring B is a
benzene ring substituted by a lower alkyl group optionally
substituted by a group selected from the followings: (1) a lower
alkoxycarbonyl group, (2) a carboxyl group, (3) a carbamoyl group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkoxy-lower alkyl group, (c) a lower alkyl
group substituted by a hydroxyl group, and (d) a lower alkoxy
group, (4) a carbonyl group substituted by a morpholinyl group, (5)
a piperidylcarbonyl group substituted by a hydroxy-lower alkyl
group, (6) a pyrrolidinylcarbonyl group substituted by a
hydroxy-lower alkyl group, (7) a carbonyl group substituted by a
hydroxyl group-substituted piperidyl group, and (8) a hydroxyl
group; and Y is a cycloalkyl group optionally substituted by the
followings: A) an amino group optionally substituted by the
followings: (1) a lower alkyl group, (2) a cycloalkyl group, (3) a
hydroxy-lower alkyl group, (4) a 1,3-dioxanyl group substituted by
a lower alkyl group, (5) a lower alkyl group substituted by an
amino group optionally substituted by a group selected from (a) a
lower alkyl group, (b) a lower alkanoyl group, (c) a lower alkanoyl
group substituted by an amino group substituted by a lower alkyl
group, and (d) a lower alkoxycarbonyl group, (6) a lower alkyl
group substituted by a cyano group, (7) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (8) a lower alkyl
group substituted by a carboxyl group, (9) a lower alkyl group
substituted by a carbamoyl group optionally substituted by a lower
alkyl, group, (10) a lower alkyl group substituted by an aryl
group, (11) a lower alkyl group substituted by a pyridyl group,
(12) a lower alkoxycarbonyl group, (13) a lower alkanoyl group
substituted by a di-lower alkyl amino group, (14) a lower alkanoyl
group, (15) a pyrimidinyl group, (16) a lower alkanoyl group
substituted by a morpholinyl group, (17) a lower alkylsulfonyl
group, (18) a carbamoyl group substituted by a lower alkyl group,
(19) a carbonyl group substituted by an aryl group, (20) a lower
alkanoyl group substituted by a lower alkoxy group, (21) a lower
alkanoyl group substituted by a lower alkanoyloxy group, (22) an
aryl group substituted by a hydroxy group, and (23) a hydroxy-lower
alkanoyl group; B) a group of a formula selected from the
formulas:
##STR00011##
that is optionally substituted by an oxo group; or C) a lower alkyl
group optionally substituted by a group selected from the
followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group. (x) The compound according to (iii), wherein Ring B
is a benzene ring substituted by a lower alkoxy group optionally
substituted by a group selected from the followings: (1) a carboxyl
group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group,
(4) a hydroxyl group, (5) an aminooxy group optionally substituted
by a lower alkoxycarbonyl group, (6) a lower alkoxy group
substituted by a lower alkoxy group, (7) a carbonyl group
substituted by a morpholinyl group, a piperidyl group or a
pyrrolidinyl group, (8) a carbonyl group substituted by a
hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted
by a hydroxy-lower alkyl group, (10) a pyrrolidinylcarbonyl group
substituted by a hydroxy-lower alkyl group, (11) a carbonyl group
substituted by a lower alkyl-piperazinyl group, (12) an amino group
optionally substituted by (a) a lower alkyl group, (b) a lower
alkoxycarbonyl group, and (c) a lower alkanoyl group, (13) a
carbamoyl group optionally substituted by a group selected from (a)
a lower alkyl group, (b) a lower alkoxy-lower alkyl group, (c) a
lower alkyl group substituted by a hydroxyl group, and (d) a lower
alkyl group substituted by a di-lower alkylamino group; and (14) a
group of the formula: --O--NH--C(.dbd.NH)NH.sub.2; and Y is a
saturated heterocyclic group optionally substituted by a group
selected from the followings: (1) a lower alkyl group, (2) a lower
alkyl group substituted by a pyridyl group (3) a piperidyl group
substituted by a lower alkyl group, (4) a piperidyl group, (5) a
piperidyl group substituted by a lower alkoxycarbonyl group, (6) an
unsaturated heterocyclic group selected from a pyridyl group, a
pyrimidinyl group, a 4,5-dihydroxaolyl group and a thiazolyl group,
(7) a lower alkanoyl group, (8) a lower alkanoyl group substituted
by a di-lower alkylamino group, (9) a carbonyl group substituted by
a pyridyl group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group. (xi) The compound
according to (iii), wherein Ring B is a benzene ring substituted by
a lower alkoxy group optionally substituted by a group selected
from the followings: (1) a carboxyl group, (2) a lower
alkoxycarbonyl group, (3) a lower alkoxy group, (4) a hydroxyl
group, (5) an aminooxy group optionally substituted by a lower
alkoxycarbonyl group, (6) a lower alkoxy group substituted by a
lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; and Y is an amino group optionally
substituted by a group selected from the followings: (1) a
piperidyl group substituted by a lower alkyl group, (2) a lower
alkyl group, and (3) a lower alkoxycarbonyl group. (xii) The
compound according to (iii), wherein Ring B is a benzene ring
substituted by a lower alkoxy group optionally substituted by a
group selected from the followings: (1) a carboxyl group, (2) a
lower alkoxycarbonyl group, (3) a lower alkoxy group, (4) a
hydroxyl group, (5) an aminooxy group optionally substituted by a
lower alkoxycarbonyl group, (6) a lower alkoxy group substituted by
a lower alkoxy group, (7) a carbonyl group substituted by a
morpholinyl group, a piperidyl group or a pyrrolidinyl group, (8) a
carbonyl group substituted by a hydroxypiperidyl group, (9) a
piperidylcarbonyl group substituted by a hydroxy-lower alkyl group,
(10) a pyrrolidinylcarbonyl group substituted by a hydroxy-lower
alkyl group, (11) a carbonyl group substituted by a lower
alkyl-piperazinyl group, (12) an amino group optionally substituted
by (a) a lower alkyl group, (b) a lower alkoxycarbonyl group, and
(c) a lower alkanoyl group, (13) a carbamoyl group optionally
substituted by a group selected from (a) a lower alkyl group, (b) a
lower alkoxy-lower alkyl group, (c) a lower alkyl group substituted
by a hydroxyl group, and (d) a lower alkyl group substituted by a
di-lower alkylamino group; and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; and Y is a cycloalkyl group optionally
substituted by the followings: A) an amino group optionally
substituted by the followings: (1) a lower alkyl group, (2) a
cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a
1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower
alkyl group substituted by an amino group optionally substituted by
a group selected from (a) a lower alkyl group, (b) a lower alkanoyl
group, (c) a lower alkanoyl group substituted by an amino group
substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl
group, (6) a lower alkyl group substituted by a cyano group, (7) a
lower alkyl group substituted by a lower alkoxycarbonyl group, (8)
a lower alkyl group substituted by a carboxyl group, (9) a lower
alkyl group substituted by a carbamoyl group optionally substituted
by a lower alkyl group, (10) a lower alkyl group substituted by an
aryl group, (11) a lower alkyl group substituted by a pyridyl
group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl
group substituted by a di-lower alkyl amino group, (14) a lower
alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl
group substituted by a morpholinyl group, (17) a lower
alkylsulfonyl group, (18) a carbamoyl group substituted by a lower
alkyl group, (19) a carbonyl group substituted by an aryl group,
(20) a lower alkanoyl group substituted by a lower alkoxy group,
(21) a lower alkanoyl group substituted by a lower alkanoyloxy
group, (22) an aryl group substituted by a hydroxy group, and (23)
a hydroxy-lower alkanoyl group; B) a group of a formula selected
from the formulas:
##STR00012##
that is optionally substituted by an oxo group; or C) a lower alkyl
group optionally substituted by a group selected from the
followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group. (xiii) The compound according to (iii), wherein
Ring B is a benzene ring substituted by a carbonyl group
substituted by a group selected from the followings: (1) a lower
alkoxy group, (2) a hydroxyl group, (3) an amino group optionally
substituted by (a) a lower alkyl group, (b) a lower alkoxy group,
(c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower alkyl
group, (e) a lower alkyl group substituted by an amino group
optionally substituted by a lower alkyl group, (f) a lower alkyl
group substituted by an aryl group, and (g) a lower alkyl group
substituted by a pyridyl group, (4) a morpholinyl group, a
pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,
(5) a hydroxypiperidyl group, (6) a piperidyl group substituted by
a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted
by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl
group; and Y is a saturated heterocyclic group optionally
substituted by a group selected from the followings: (1) a lower
alkyl group, (2) a lower alkyl group substituted by a pyridyl group
(3) a piperidyl group substituted by a lower alkyl group, (4) a
piperidyl group, (5) a piperidyl group substituted by a lower
alkoxycarbonyl group, (6) an unsaturated heterocyclic group
selected from a pyridyl group, a pyrimidinyl group, a
4,5-dihydroxaolyl group and a thiazolyl group, (7) a lower alkanoyl
group, (8) a lower alkanoyl group substituted by a di-lower
alkylamino group, (9) a carbonyl group substituted by a pyridyl
group, (10) a lower alkylsulfonyl group, (11) a lower
alkoxycarbonyl group, (12) a lower alkyl group substituted by a
di-lower alkylamino group, and (13) an oxo group. (xiv) The
compound according to (iii), wherein Ring B is a benzene ring
substituted by a carbonyl group substituted by a group selected
from the followings: (1) a lower alkoxy group, (2) a hydroxyl
group, (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower
alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl
group substituted by an amino group optionally substituted by a
lower alkyl group, (f) a lower alkyl group substituted by an aryl
group, and (g) a lower alkyl group substituted by a pyridyl group,
(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or
a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a
piperidyl group substituted by a hydroxy-lower alkyl group, (7) a
pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and
(8) a lower alkyl-piperazinyl group; and Y is an amino group
optionally substituted by a group selected from the followings: (1)
a piperidyl group substituted by a lower alkyl group, (2) a lower
alkyl group, and (3) a lower alkoxycarbonyl group. (xv) The
compound according to (iii), wherein Ring B is a benzene ring
substituted by a carbonyl group substituted by a group selected
from the followings: (1) a lower alkoxy group, (2) a hydroxyl
group, (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxy group, (c) a lower alkoxy-lower
alkyl group, (d) a hydroxy-lower alkyl group, (e) a lower alkyl
group substituted by an amino group optionally substituted by a
lower alkyl group, (f) a lower alkyl group substituted by an aryl
group, and (g) a lower alkyl group substituted by a pyridyl group,
(4) a morpholinyl group, a pyrrolidinyl group, a piperidyl group or
a thiomorpholinyl group, (5) a hydroxypiperidyl group, (6) a
piperidyl group substituted by a hydroxy-lower alkyl group, (7) a
pyrrolidinyl group substituted by a hydroxy-lower alkyl group, and
(8) a lower alkyl-piperazinyl group; and Y is a cycloalkyl group
optionally substituted by the followings: A) an amino group
optionally substituted by the followings: (1) a lower alkyl group,
(2) a cycloalkyl group, (3) a hydroxy-lower alkyl group, (4) a
1,3-dioxanyl group substituted by a lower alkyl group, (5) a lower
alkyl group substituted by an amino group optionally substituted by
a group selected from (a) a lower alkyl group, (b) a lower alkanoyl
group, (c) a lower alkanoyl group substituted by an amino group
substituted by a lower alkyl group, and (d) a lower alkoxycarbonyl
group, (6) a lower alkyl group substituted by a cyano group, (7) a
lower alkyl group substituted by a lower alkoxycarbonyl group, (8)
a lower alkyl group substituted by a carboxyl group, (9) a lower
alkyl group substituted by a carbamoyl group optionally substituted
by a lower alkyl group, (10) a lower alkyl group substituted by an
aryl group, (11) a lower alkyl group substituted by a pyridyl
group, (12) a lower alkoxycarbonyl group, (13) a lower alkanoyl
group substituted by a di-lower alkyl amino group, (14) a lower
alkanoyl group, (15) a pyrimidinyl group, (16) a lower alkanoyl
group substituted by a morpholinyl group, (17) a lower
alkylsulfonyl group, (18) a carbamoyl group substituted by a lower
alkyl group, (19) a carbonyl group substituted by an aryl group,
(20) a lower alkanoyl group substituted by lower alkoxy group, (21)
a lower alkanoyl group substituted by a lower alkanoyloxy group,
(22) an aryl group substituted by a hydroxy group, and (23) a
hydroxy-lower alkanoyl group; B) a group of a formula selected from
the formulas:
##STR00013##
that is optionally substituted by an oxo group; or C) a lower alkyl
group optionally substituted by a group selected from the
followings: (1) an oxopyrrolidinyl group, (2) an oxomorpholinyl
group, and (3) an amino group optionally substituted by (a) a lower
alkyl group, (b) a lower alkoxycarbonyl group, and (c) a lower
alkanoyl group. (xvi) The compound according to (i), (ii), (iii),
(iv), (vii), (x) or (xiii), wherein the saturated heterocyclic ring
is a saturated 4- to 7-membered heterocyclic group containing 1 to
4 hetero atoms selected independently from the group consisting of
nitrogen atom, oxygen atom and sulfur atom. (xvii) The compound
according to (i), (ii), (iii), (iv), (vii), (x) or (xiii), wherein
the saturated heterocyclic group is imidazolidinyl,
piperazolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, homopiperazinyl, homopiperidyl, pyrrolidinyl,
oxazolidinyl or 1,3-dioxanyl. (xviii) The compound according to
(111), wherein the group of the formula:
##STR00014##
is the group of the formula:
##STR00015##
and the group of the formula:
##STR00016##
is a group of the formula:
##STR00017##
R.sup.1 is a halogen atom or a lower alkyl group; R.sup.2 is a
group selected from the followings: A) a hydrogen atom, B) a lower
alkyl group optionally substituted by a group selected from the
followings: (1) a lower alkoxycarbonyl group, (2) a carboxyl group,
(3) a carbamoyl group optionally substituted by a group selected
from (a) a lower alkyl group, (b) a lower alkoxy-lower alkyl group,
(c) a lower alkyl group substituted by a hydroxyl group, and (d) a
lower alkoxy group, (4) a carbonyl group substituted by a
morpholinyl group, (5) a piperidylcarbonyl group substituted by a
hydroxy-lower alkyl group, (6) a pyrrolidinylcarbonyl group
substituted by a hydroxy-lower alkyl group, (7) a carbonyl group
substituted by a hydroxyl group-substituted piperidyl group, and
(8) a hydroxyl group; C) a lower alkoxy group optionally
substituted by a group selected from the followings: (1) a carboxyl
group, (2) a lower alkoxycarbonyl group, (3) a lower alkoxy group,
(4) a hydroxyl group, (5) an aminooxy group optionally substituted
by a lower alkoxycarbonyl group, (6) a lower alkoxy group
substituted by a lower alkoxy group, (7) a carbonyl group
substituted by a morpholinyl group, a piperidyl group or a
pyrrolidinyl group, (8) a carbonyl group substituted by a
hydroxypiperidyl group, (9) a piperidylcarbonyl group substituted
by a hydroxy-lower alkyl group, (10) a pyrrolidinylcarbonyl group
substituted by a hydroxy-lower alkyl group, (11) a carbonyl group
substituted by a lower alkyl-piperazinyl group, (12) an amino group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl
group, (13) a carbamoyl group optionally substituted by a group
selected from (a) a lower alkyl group, (b) a lower alkoxy-lower
alkyl group, (c) a lower alkyl group substituted by a hydroxyl
group, and (d) a lower alkyl group substituted by a di-lower
alkylamino group, and (14) a group of the formula:
--O--NH--C(.dbd.NH)NH.sub.2; or D) a carbonyl group substituted by
a group selected from the followings: (1) a lower alkoxy group, (2)
a hydroxyl group, (3) an amino group optionally substituted by a
group selected from (a) a lower alkyl group, (b) a lower alkoxy
group, (c) a lower alkoxy-lower alkyl group, (d) a hydroxy-lower
alkyl group, (e) a lower alkyl group substituted by an amino group
optionally substituted by a lower alkyl group, (f) a lower alkyl
group substituted by an aryl group, and (g) a lower alkyl group
substituted by a pyridyl group, (4) a morpholinyl group, a
pyrrolidinyl group, a piperidyl group or a thiomorpholinyl group,
(5) a hydroxypiperidyl group, (6) a piperidyl group substituted by
a hydroxy-lower alkyl group, (7) a pyrrolidinyl group substituted
by a hydroxy-lower alkyl group, and (8) a lower alkyl-piperazinyl
group; A is a single bond; and R.sup.3 is a hydrogen atom. (xix)
The compound according to (xviii), wherein Y is a group selected
from the followings: (1) a piperidyl group substituted by a lower
alkyl group, (2) a cycloalkyl group substituted by an amino group
optionally substituted by a group selected from (a) a lower alkyl
group, (b) a lower alkoxycarbonyl group, and (c) a lower alkanoyl
group, (3) a cycloalkyl group substituted by a group of a formula
selected from the formulas:
##STR00018##
that is optionally substituted by an oxo group, (4) a cycloalkyl
group substituted by an amino group substituted by a lower alkyl
group substituted by an amino group optionally substituted by a
group selected from (a) a lower alkanoyl group and (b) a lower
alkoxycarbonyl group, and (5) a cycloalkyl group substituted by a
lower alkyl group substituted by an amino group optionally
substituted by a lower alkyl group; and R.sup.2 is a group selected
from the followings: (1) a hydrogen atom, (2) a cyano group, (3) an
amino group optionally substituted by a lower alkyl group, (4) a
hydroxyl group, (5) a lower alkoxy group, (6) a lower alkoxy group
substituted by a lower alkoxy group, (7) a lower alkoxy group
substituted by a hydroxyl group, (08) a lower alkoxy group
substituted by an amino group optionally substituted by a lower
alkyl group, (9) a lower alkoxycarbonyl group, (10) a carboxyl
group, (11) an aminocarbonyl group optionally substituted by a
group selected from (a) lower alkyl group, and (b) a hydroxy-lower
alkyl group, (12) a morpholinylcarbonyl group, a
pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a
thiomorpholinylcarbonyl group, (13) a piperidylcarbonyl group
substituted by a hydroxy-lower alkyl group or a
pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, (14) a lower alkyl group, (15) a lower alkyl group
substituted by a lower alkoxycarbonyl group, (16) a carboxy-lower
alkyl group, (17) a lower alkyl group substituted by a carbamoyl
group optionally substituted by a group selected from (a) lower
alkyl group and (b) a hydroxy-lower alkyl group, (18) a lower alkyl
group substituted by a morpholinylcarbonyl group, (19) a lower
alkyl group substituted by a piperidylcarbonyl group substituted by
a hydroxy-lower alkyl group, or a lower alkyl group substituted by
a pyrrolidinylcarbonyl group substituted by a hydroxy-lower alkyl
group, or (20) a hydroxy-lower alkyl group. (xx) The compound
according to (xviii), wherein Y is a cycloalkyl group substituted
by a group of a formula selected from the formulas:
##STR00019##
that is optionally substituted by an oxo group, or a cycloalkyl
group substituted by an amino group optionally substituted by a
group selected from (a) a lower alkyl group and (b) a lower
alkanoyl group; and R.sup.2 is a group selected from the
followings: (1) a hydrogen atom, (2) an amino group-substituted
carbonyl group optionally substituted by a group selected from (a)
a lower alkyl group and (b) a lower alkoxy-lower alkyl group, (3) a
lower alkoxycarbonyl group, (4) a morpholinylcarbonyl group, a
pyrrolidinylcarbonyl group, a piperidylcarbonyl group or a
thiomorpholinylcarbonyl group, (5) a lower alkyl group substituted
by a lower alkyl group-substituted carbamoyl group, (6) a
carboxy-lower alkyl group, (7) a lower alkyl group substituted by a
morpholinylcarbonyl group, and (8) a hydroxy-lower alkyl group.
(xxi) The compound according to (xviii), wherein Y is a cycloalkyl
group substituted by an oxopyrrolidinyl group, a cycloalkyl group
substituted by an oxomorpholinyl group or a cycloalkyl group
substituted by an amino group optionally substituted by a group
selected from (a) a lower alkyl group and (b) a lower alkanoyl
group; and R.sup.2 is a group selected from the followings: (1) a
hydrogen atom, (2) a hydroxy-lower alkyl group, (3) a carboxy-lower
alkyl group, (4) a lower alkoxy group substituted by a lower alkoxy
group, or (5) a carbonyl group substituted by a group selected from
(a) an amino group optionally substituted by a lower alkyl group
and (b) a morpholinyl group. (xxii) The compound according to
(xviii), wherein Y is a group selected from the followings: (1) a
cycloalkyl group substituted by an amino group substituted by a
lower alkyl group having 1 to 3 carbon atoms, (2) a cycloalkyl
group substituted by an amino group substituted by a lower alkanoyl
group having 1 to 2 carbon atoms, (3) a cycloalkyl group
substituted by a pyrrolidin-1-yl group optionally substituted by an
oxo group, (4) a cycloalkyl group substituted by a piperidin-1-yl
group optionally substituted by an oxo group, (5) a cycloalkyl
group substituted by a morpholin-4-yl group optionally substituted
by an oxo group, (6) a cycloalkyl group substituted by a lower
alkyl group substituted by an amino group substituted by a lower
alkyl group having 1 to 3 carbon atoms, or (7) a cycloalkyl group
substituted by a lower alkyl group substituted by an amino group
substituted by a lower alkanoyl group having 1 to 2 carbon atoms.
(xxiii) A compound selected from [0015]
trans-5-Dimethylaminocarbonyl-3-[4-(N-formyl-N-methylamino)cyclohexylcarb-
onylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; [0016]
trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-(2-hydroxy-
ethyl)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; [0017]
trans-S-(morpholine-4-ylcarbonyl)-3-[4-(2-oxo-pyrroridin-1-yl)cyclohexylc-
arbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide; and
[0018]
trans-3-(4-dimethylaminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)-
benzofuran-2-carboxamide, or a pharmaceutically acceptable salt
thereof. (xxiv) A benzofuran derivative having a partial structure
of the formula [1-1]:
##STR00020##
[0018] wherein the symbols are the same as defined above, or a
pharmaceutically acceptable salt thereof. (xxv) A benzofuran
derivative of the formula [2]:
##STR00021##
wherein the symbols are the same as defined above, or a salt
thereof. (xxvi) A pharmaceutical composition, which comprises as an
active ingredient a compound according to any one of (i) to (xxiv)
above or a pharmaceutically acceptable salt thereof. (xxvii) A
method for treatment of thrombosis, which comprises administering
an effective amount of a compound according to any one of (i) to
(xxiv) above or a pharmaceutically acceptable salt thereof, to a
patient in need thereof (xxviii) Use of a compound according to any
one of (i) to (xxiv) above or a pharmaceutically acceptable salt
thereof in treatment of patients suffering from thrombosis. (xxix)
A medicament for treatment of thrombosis substantially free of
phospholipidosis, which comprises as an active ingredient a factor
Xa (FXa) inhibitor showing a distribution volume of 0.1-3.0 L/kg
and an FXa inhibitory effect with the IC.sub.50 value of 100 nM or
below. (xxx) A medicament for treatment of thrombosis substantially
free of hepatotoxicity, which comprises as an active ingredient an
FXa inhibitor showing a distribution volume of 0.1-3.0 L/kg or
below and an FXa inhibitory effect with the IC.sub.50 value of 100
nM or below. (xxxi) A medicament for oral administration for
treatment of thrombosis substantially free of phospholipidosis,
which comprises as an active ingredient a factor Xa (FXa) inhibitor
showing a distribution volume of 0.1-3.0 L/kg and an FXa inhibitory
effect with the IC.sub.50 value of 100 nM or below. (xxxii) A
medicament for oral administration for treatment of thrombosis
substantially free of hepatotoxicity, which comprises as an active
ingredient an FXa inhibitor showing a distribution volume of
0.1-3.0 L/kg or below and an FXa inhibitory effect with the
IC.sub.50 value of 100 nM or below. (xxxiii) A medicament for
treatment of thrombosis substantially free of phospholipidosis,
which comprises as an active ingredient an FXa inhibitor having a
partial structure of the formula:
##STR00022##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
(xxxiv) A medicament for treatment of thrombosis substantially free
of hepatotoxicity, which comprises as an active ingredient an FXa
inhibitor having a partial structure of the formula:
##STR00023##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
(xxxv) A medicament for oral administration for treatment of
thrombosis, which causes substantially no phospholipidosis and
comprises as an active ingredient an FXa inhibitor having a partial
structure of the formula:
##STR00024##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
(xxxvi) A medicament for oral administration for treatment of
thrombosis substantially free of hepatotoxicity, which comprises as
an active ingredient an FXa inhibitor having a partial structure of
the formula:
##STR00025##
and showing a distribution volume of 0.1-3.0 L/kg and an FXa
inhibitory effect with the IC.sub.50 value of 100 nM or below.
BEST MODE FOR CARRYING OUT THE INVENTION
[0019] The compound [1] of the present invention will be
hereinafter described in detail.
[0020] The term "lower" used in the definition of the formulas
herein described means unless otherwise noted a straight- or
branched-carbon chain having 1 to 6 carbon atoms.
[0021] Thus, examples of "lower alkyl group" include methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl,
1,2-dimethylpropyl, hexyl, isohexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl,
1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl, 2-ethylbutyl,
1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,
1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, etc. Among them,
alkyl groups having 1 to 4 carbon atoms are preferred, and methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl
are especially preferred.
[0022] The term "lower alkoxy group" means a substituent wherein an
oxygen atom is bound to the above-mentioned alkyl group. Among
them, alkoxy groups having 1 to 4 carbon atoms are preferred, and
methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy
and tert-butoxy groups are especially preferred.
[0023] Examples of "carbon chain optionally having a double bond
within or at the end(s) of the chain" include "lower alkylene
group", "lower alkenylene group" and "lower alkenylidene
group".
[0024] Examples of "lower alkylene group" include a straight- or
branched-chain alkylene group having 1 to 6 carbon atoms,
specifically, methylene, ethylene, trimethylene, tetramethylene,
pentamethylene, hexamethylene, etc. Among them, an alkylene group
having 1 to 5 carbon atoms is preferred.
[0025] Examples of "lower alkenylene group" include a straight- or
branched-chain alkenylene group having 2 to 6 carbon atoms,
specifically, vinylene, propenylene, butenylene, pentenylene, etc.
Among them, an alkenylene group having 2 to 5 carbon atoms is
preferred.
[0026] Examples of "lower alkenylidene group" include alkenylidenes
having 2 to 6 carbon atoms, specifically, vinylidene,
propenylidene, butenylidene, pentenylidene, etc.
[0027] Examples of "lower alkanoyl group" include alkanoyl groups
formed by removing a "OH" group from the carboxyl group of a lower
carboxylic acid, specifically, formyl, acetyl, propionyl, butyryl,
etc.
[0028] The "saturated heterocyclic group" means a saturated
heterocyclic group containing 1 to 4 hetero atoms selected
independently from the group consisting of nitrogen atom, oxygen
atom and sulfur atom, preferably a 4- to 7-membered heterocyclic
group containing 1 to 4 hetero atoms selected independently from
the group consisting of nitrogen atom, oxygen atom and sulfur atom.
A condensed heterocyclic ring is included. Specific examples
include imidazolidinyl, pyrazolidinyl, piperidyl, piperazinyl,
morpholinyl, thiomorpholinyl, homopiperazinyl, homopiperidyl,
pyrrolidinyl, oxazolidinyl, 1,3-dioxanyl, etc. Above all,
piperidyl, piperazinyl, homopiperazinyl and pyrrolidinyl are
preferred.
[0029] The "unsaturated heterocyclic group" means an unsaturated
heterocyclic group containing 1 to 4 hetero atoms selected
independently from the group consisting of nitrogen atom, oxygen
atom and sulfur atom, preferably a 4 to 7-membered heterocyclic
group containing 1 to 4 hetero atoms selected independently from
the group consisting of nitrogen atom, oxygen atom and sulfur atom.
A condensed heterocyclic ring is included. Specific examples
include pyridyl, pyrimidinyl, pyrazinyl, furyl, thienyl, pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 4,5-dihydro-oxazolyl,
thiazolyl, isothiazolyl, etc. Above all, pyridyl, pyrimidinyl,
pyrazinyl, thienyl, oxazolyl, 4,5-dihydro-oxazolyl and thiazolyl
are preferred.
[0030] Examples of "halogen atom" include fluorine, chlorine,
bromine or iodine atom. Above all, fluorine, chlorine or bromine
atom is preferred.
[0031] The term "cycloalkyl group" means a cyclic lower alkyl
group, preferably a cyclohexyl group.
[0032] The term "aryl group" means a phenyl or a naphthyl group,
preferably phenyl group.
[0033] The symbol "Y", when A and Y are bound via a double bond,
refers to the corresponding bivalent group.
[0034] The pharmaceutically acceptable salt of the compound [1]
includes a salt with an inorganic acid such as hydrochloric acid,
hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid,
phosphoric acid, etc.; a salt with an organic acid such as formic
acid, acetic acid, propionic acid, oxalic acid, malonic acid,
succinic acid, fumaric acid, maleic acid, lactic acid, malic acid,
tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic
acid, benzenesulfonic acid, etc.; salt with an acidic amino acid
such as aspartic acid, glutamic acid, etc.; salt with a metal such
as sodium, potassium, magnesium, calcium, aluminium, etc.; salt
with an organic base such as methylamine, ethylamine, ethanolamine,
etc.; or a salt with a basic amino acid such as lysine, ornithine,
etc.
[0035] The compound [1] of the present invention can be in the form
of quaternary ammonium salt and such a quaternary ammonium salt
falls within the scope of the present compound [1].
[0036] Further, the compound [1] of the present invention includes
a intramolecular salt hydrate, solvate or crystalline polymorphism,
etc.
[0037] Besides, when the compound [1] has a double bond(s), it may
exist in the form of a geometrical isomer (cis, trans), when the
compound [1] has an unsaturated bond such as carbonyl, it may exist
in the from of a tautomerism, when the compound [1] has an
asymmetric carbon atom(s), it can exist as an optical isomer, and
the present invention encompass these isomers and a mixture
thereof.
[0038] Additionally, the compound [1] of the present invention
encompasses a prodrug of a compound as mentioned above. Examples of
a prodrug include those prepared by protecting a functional group
such as an amino or carboxy group of a compound above with a
conventional protecting group.
[0039] The compound of the present invention may be prepared by the
following processes.
[Process A]
[0040] Among the compound [1] of the present invention, a compound
wherein A is a single bond or a carbon chain optionally having a
double bond within or at the end(s) of the chain, i.e., a compound
of the formula [1-A]:
##STR00026##
wherein A.sup.1 is a single bond or a carbon chain optionally
having a double bond within or at the end(s) of the chain, and the
other symbols are the same as defined above, can be prepared by
reacting an amino compound of the formula [2]:
##STR00027##
wherein the symbols are the sane as defined above, with a
carboxylic acid compound of the formula [3-A]:
YA.sup.1-COOH [3-A]
wherein the symbols are the same as defined above, or a reactive
derivative thereof at its carboxyl group.
[Process B]
[0041] Among the compound [1] of the present invention, a compound
wherein A is an oxygen atom, or A is a single bond, and Y is an
optionally substituted amino group, i.e., a compound of the formula
[1-B]:
##STR00028##
wherein A.sup.2 is an oxygen atom and the other symbols are the
same as defined above, or wherein A.sup.2 is a single bond and the
other symbols are the same as defined above, can be prepared by
reacting the compound [2] above with a compound of the formula
[3-B1]:
YA.sup.2-H [3-B1]
wherein the symbols are the same as defined above, and a compound
of the formula [3-B2]:
L.sup.1-CO-L.sup.2 [3-B2]
wherein L.sup.1 and L.sup.2 are the same or different and each a
leaving group.
[0042] The compound [1] can also be prepared, if necessary, through
the mutual conversion, wherein the residue Y and/or the substituent
for Ring B (R.sup.2) of resulting compound [1-A] or [1-B] is
adequately converted into a compound [1] through the mutual
conversion by alkylation, reductive alkylation, amidation,
sulfonyl-amidation, amidino-etherification, arylation, reduction,
dealkylation, hydrolysis, quaternary amination, formylation,
pyrrolylation, protection of amino or carboxyl group and
deprotection, etc.
[Manufacturing Process for Starting Materials: Preparation of
compound [2]]
[0043] The compound [2] can be prepared by a process
comprising:
converting the aldehyde group of a compound of the formula
[10]:
##STR00029##
wherein the symbols are the same as defined above, into cyano group
to give a compound of the formula [9]:
##STR00030##
wherein the symbols are the same as defined above, reacting the
compound [9] with a compound of the formula [8]:
##STR00031##
wherein L.sup.3 is a leaving group and P.sup.1 is a protecting
group for carboxyl group, to give a compound of the formula
[7]:
##STR00032##
wherein the symbols are the same as defined above, deprotecting the
protecting group P.sup.1 of the compound [7] to give a compound of
the formula [6]:
##STR00033##
wherein the symbols are the same as defined above, reacting the
compound [6], if necessary, after converting into a reactive
derivative at the carboxyl group thereof, with a compound [5]:
##STR00034##
wherein the symbols are the same as defined above, to give a
compound of the formula [4]:
##STR00035##
and subjecting the compound [4] to cyclization.
[0044] Further, the compound [4] can also be prepared by reacting a
compound of the formula [9] with a compound of the formula
[12]:
##STR00036##
wherein L.sup.4 is a leaving group and the other symbols are the
same as defined above.
[0045] The compound [4] can also be prepared by reacting a compound
of the formula [13]:
##STR00037##
wherein L.sup.5 is a leaving group and the other symbols are the
same as defined above with a compound of the formula [14]:
##STR00038##
wherein the symbols are the same as defined above.
[0046] Further, the compound of the formula [10] can be prepared by
formylating a compound of the formula [11]:
##STR00039##
wherein the symbols are the same as defined above.
[0047] The Processes [A] and [B] above can be carried out in the
following manner.
[Process A]
[0048] The reaction where a compound [1-A] is prepared using a
compound [2] and a compound [3-A] can be carried out in a
conventional manner for amidation. That is, the reaction can be
carried out by reacting a compound [2] with a compound [3-A], a
reactive derivative thereof, or a salt thereof in the presence or
absence of a condensing agent, and if necessary, in the presence of
an acid scavenger, in an appropriate solvent.
[0049] The condensing agent includes conventional agents such as
N,N-dicyclohexylcarbodiimide (DCC),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) or a
hydrochloride thereof, carbonyldiimidazole (CDI),
diphenylphosphoryl-azide (DPPA), diethyl cyanophosphonate (DEPC),
etc. Above all, DCC, EDC or a hydrochloride thereof is
preferred.
[0050] Examples of the reactive derivative of the compound [3-A]
include those conventionally used such as an acid halide, a mixed
anhydride, a reactive ester, etc. Examples of an activator that can
be used for converting the compound [3-A] into the reactive
derivative thereof include thionyl chloride, thionyl bromide,
oxalyl chloride, N-hydroxylamines such as 1-hydroxysuccinimide,
1-hydroxybenzotriazole, etc., and phenols such as p-nitrophenol,
etc. Above all, thionyl chloride, oxalyl chloride,
1-hydroxysuccinimide and 1-hydroxybenzotriazole are preferred. The
acid chloride method is especially preferable.
[0051] Examples of the salt of a compound [3-A] or a reactive
derivative of the compound [3-A] include a salt with an inorganic
acid such as hydrochloric acid, hydrobromic acid, sulfuric acid,
etc. An acid scavenger is also usable depending on the method to be
employed, which includes inorganic or organic bases.
[0052] The present reaction may be facilitated when it is carried
out in the presence of a base or by using such a base as a solvent.
Examples of inorganic bases include inorganic bases such as alkali
metal carbonates (sodium carbonate, potassium carbonate, cesium
carbonate, etc.), alkali earth metal carbonates (calcium carbonate,
etc.), alkali metal hydrogen carbonates (sodium hydrogen carbonate,
potassium hydrogen carbonate, etc.), alkali metal hydroxides
(sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.).
Examples of organic bases include tri-lower alkylamines
(triethylamine, tributylamine, diisopropylethylamine, etc.),
tertiary-amines (1,4-diazabicyclo[2.2.2]octane,
1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all,
triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, or
pyridine is preferred for carrying out the reaction. The present
reaction can be carried out in the presence or absence of a
solvent, preferably in the presence of a solvent.
[0053] Examples of the solvent include any inert solvent which does
not disturb the reaction, such as halogenated hydrocarbons
(chloroform, dichloromethane, dichloroethane, etc.), aromatic
hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), esters (ethyl acetate, etc.), amides
(N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitrites (acetonitrile,
etc.), dimethylsulfoxide, pyridine, 2,6-luthidine, etc., a mixed
solvent comprising two or more of these solvents, if necessary, and
also a mixture of any one(s) of these solvents and water. It is
preferred to select any appropriate solvent depending on the method
used. Above all, dichloromethane, chloroform, toluene, xylene,
tetrahydrofuran, dioxane, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, pyridine,
and the like are preferred, and dichloromethane, chloroform,
N,N-dimethylformamide and pyridine are especially preferred. The
present reaction can be carried out in a wide range of temperature
from a temperature of under cooling to under heating. For example,
the reaction can be preferably carried out at a temperature of
-10.degree. C. to the boiling point of the reaction mixture,
especially from under ice-cooling to 60.degree. C.
[Process B]
[0054] The process wherein the compound [1-B] is prepared by
reacting a compound [2] with compounds of the formulas [3-B1] and
[3-B2], respectively, can be carried out in accordance: with a
conventional method for carbonylation in the presence of an
appropriate acid scavenger in an appropriate solvent.
[0055] Examples of a leaving group for a compound of the formula
[3-B2] include a halogen atom. Examples of a compound [3-B2]
include phosgene, triphosgene, CDI, etc., and triphosgene is
preferred.
[0056] Examples of acid scavenger used in the reaction include both
the inorganic and organic bases. Examples of inorganic bases
include alkali metal carbonates (sodium carbonate, potassium
carbonate, cesium carbonate, etc.) and alkali metal hydrogen
carbonates (sodium hydrogen carbonate, potassium hydrogen
carbonate, etc.). Examples of organic bases include tri-lower
alkylamines (triethylamine, tributylamine, diisopropylethylamine,
etc.), tertiary-amines (1,4-diazabicyclo[2.2.2]octane,
1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]-undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all,
triethylamine, diisopropylethylamine, 4-dimethylaminopyridine and
pyridine are preferred.
[0057] Examples of the solvent include any inert solvent which does
not disturb the reaction, such as halogenated hydrocarbons
(chloroform, dichloromethane, dichloroethane, etc.), ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), esters (ethyl acetate, etc.), amides
(N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitriles (acetonitrile,
etc.), pyridine, 2,6-luthidine, etc., and a mixed solvent
comprising two or more of these solvents, if necessary. It is
preferred to select any appropriate solvent depending on the method
used. Above all, dichloromethane, tetrahydrofuran,
N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, pyridine, and the like are
preferred, and dichloromethane and N,N-dimethylformamide are
especially preferred. The present reaction can be carried out in a
wide range of temperature from -78.degree. C. to the boiling point
of the reaction mixture. For example, the reaction can be
preferably carried out at a temperature of -10.degree. C. to the
boiling point of the reaction mixture, especially at a temperature
of under ice-cooling to room temperature.
[0058] Furthermore, after carrying out the Processes [A] and [B],
the objective compound [1] can also be obtained, if necessary,
through a mutual conversion by conducting the following
reaction(s), on condition that the resulting compounds of the
formula [1-A] and/or [1-B] has one or more moieties available to a
further reaction(s) in the substituent(s) for group Y and/or Ring B
(mainly referring to, for example, a protecting group for amine,
alcoholic or phenolic OH, ester, carboxylic acid, nitro, halogen,
etc.)
[0059] The reactions for alkylation, reductive alkylation,
amidation, sulfonyl-amidation, amidino-etherification, arylation,
reduction, dealkylation, hydrolysis, quaternary amination,
pyrrolylation, protection and deprotection of amino or carboxyl
group, which are conducted when needed, can be carried out as
follows.
[0060] The alkylation can be carried out in a conventional manner,
when needed. For example, this reaction can be carried out by
reacting a compound [1] with an alkyl halide such as alkyl
chloride, alkyl bromide, alkyl iodide, etc. in the presence or
absence of a base in an appropriate solvent.
[0061] Examples of the bases usable include inorganic and organic
bases. The inorganic bases include alkali metal carbonates (sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal hydrogen carbonates (sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.), alkali metal hydroxides (sodium
hydroxide, potassium hydroxide, lithium hydroxide, etc.). Examples
of organic bases include tri-lower alkylamines (triethylamine,
tributylamine, diisopropylethylamine, etc.), tertiary-amines
(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), pyridine, lutidine,
collidine, etc. Above all, alkali metal carbonates such as sodium
carbonate, potassium carbonate and cesium carbonate, triethylamine,
diisopropylethylamine, pyridine, etc. are preferred.
[0062] An alkali metal iodide such as lithium iodide, sodium
iodide, potassium iodide, etc. can also be added, which may
facilitate the reaction.
[0063] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitriles (acetonitrile, etc.), alcohols (methanol, ethanol,
propanol, etc.), dimethylsulfoxide, pyridine, 2,6-luthidine, etc.,
and a mixed solvent comprising two or more of these solvents, if
necessary. It is preferred to select any appropriate solvent
depending on the method used. Above all, tetrahydrofuran,
N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, acetonitrile, ethanol,
dimethylsulfoxide, etc., are preferred and N,N-dimethylformamide,
acetonitrile, ethanol, and a mixed solvent thereof are more
preferred.
[0064] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating,
preferably at -10.degree. C. to the boiling point of the reaction
mixture.
[0065] The reductive alkylation can be carried out in a
conventional manner, when needed. For example, this reaction can be
carried out by reacting a compound (1) with a corresponding
carbonyl compound in the presence of an appropriate metal hydride
reducing agent, or under the condition for catalytic reduction in
the presence of an appropriate metal catalyst, in an appropriate
solvent.
[0066] In the reaction, any conventional metal hydride reducing
agents can be used without limitation; however, reducing agents
which do not affect the amide bonds etc., such as sodium
borohydride, sodium triacetoxy borohydride, sodium cyano
borohydride, etc. are preferred.
[0067] Besides, organic acids such as acetic acid, etc. or mineral
acids such as hydrochloric acid, etc. can also be added to the
present reaction, which may facilitate the reaction.
[0068] Furthermore, when the compound [1] used is an amine in the
form of a salt with a mineral acid such as hydrochloric acid, etc.,
an appropriate neutralizing agent such as an organic base (e.g.,
triethylamine) or an alkali metal acetate (e.g., sodium acetate)
may be added to the reaction, which may facilitate the
reaction.
[0069] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include halogenated
hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.),
ethers (diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitriles (acetonitrile, etc.), aromatic hydrocarbons (benzene,
toluene, xylene, etc.), alcohols (methanol, ethanol, propanol,
etc.), water, and a mixed solvent comprising two or more of these
solvents, if necessary. It is preferred to select any appropriate
solvent depending on the method used. Above all, dichloromethane,
dichloroethane, tetrahydrofuran, 1,2-dimethoxyethane, methanol,
ethanol, propanol, etc. are preferred, and dichloromethane,
dichloroethane and tetrahydrofuran are especially preferred.
[0070] The reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of -10.degree. C. to the boiling point of the reaction
mixture, especially from under ice-cooling to the boiling point of
the mixture.
[0071] The present reaction can similarly be carried out according
to the catalytic hydrogenation in the presence of a metal catalyst.
Examples of the metal catalyst include palladium-carbon,
platinum-carbon, platinum oxide, Raney Nickel, etc.
[0072] Besides, organic acids such as acetic acid, etc. or mineral
acids such as hydrochloric acid, etc. can also be added to the
present reaction, which may facilitate the reaction.
[0073] Furthermore, when the compound [1] used is an amine in the
form of a salt with a mineral acid such as hydrochloric acid, etc.,
an appropriate neutralizing agent such as an organic base (e.g.,
triethylamine) or an alkali metal acetate (e.g., sodium acetate)
may be added to the reaction, which may facilitate the
reaction.
[0074] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
aromatic hydrocarbons (benzene, toluene, xylene, etc.), alcohols
(methanol, ethanol, propanol, etc.), water, and a mixed solvent
comprising two or more of these solvents, if necessary. It is
preferred to select any appropriate solvent depending on the method
used. Above all, tetrahydrofuran, N,N-dimethylformamide, methanol,
ethanol, etc. are preferred, and tetrahydrofuran, methanol,
ethanol, etc. are especially preferred.
[0075] The reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of -10.degree. C. to the boiling point of the reaction
mixture, especially from under ice-cooling to room temperature.
[0076] The amidation can be carried out in a manner similar to the
above-mentioned reaction between a compound [2] and a compound
[3-A], when needed.
[0077] The sulfonylamidation can be carried out in a conventional
manner, when needed. For example, this reaction can be carried out
by reacting a compound [1] with an optionally substituted
alkylsulfonic acid halide in the presence or absence of a base in
an appropriate solvent. For the reaction, similar acid scavenger,
solvent and reaction temperature to those used in the amidation
reaction between a compound [2] and a compound [3-A] above can be
employed.
[0078] The amidino-etherification can be carried out in a
conventional manner, when needed. For example, the reaction can be
carried out by reacting a compound [1] with 2-bromoethyl isocyanate
or 2-chloroethyl isocyanate in the presence or absence of an
appropriate acid scavenger in an appropriate solvent.
[0079] Examples of the bases usable include inorganic and organic
bases. The inorganic bases include alkali metal carbonates (sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal hydrogen carbonates (sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.), etc. Examples of organic bases include
tri-lower alkylamines (triethylamine, tributylamine,
diisopropylethylamine, etc.), tert-amines
(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethyl-aminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all, triethylamine
and diisopropylethylamine are preferred.
[0080] The present reaction can be carried out in the presence or
absence of a solvent, preferably in the presence of a solvent.
[0081] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include halogenated
hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.),
aromatic hydrocarbons (benzene, toluene, xylene, etc.), ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitrites (acetonitrile, etc.), dimethylsulfoxide, pyridine,
2,6-luthidine, etc., and a mixed solvent comprising two or more of
these solvents, if necessary. Above all, dichloromethane,
tetrahydrofuran, N,N-dimethylformamide, etc. are preferred and
tetrahydrofuran is more preferred.
[0082] The reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of -10.degree. C. to the boiling point of the reaction
mixture, especially from under ice-cooling to room temperature.
[0083] The arylation can be carried out in a conventional manner,
when needed. For example, the reaction can be carried out by
reacting a compound [1] with a halogenated aryl compound in the
presence or absence of an appropriate base in an appropriate
solvent.
[0084] Examples of the bases usable include inorganic and organic
bases. The inorganic bases include alkali metal carbonates (sodium
carbonate, potassium carbonate, cesium carbonate, etc.), alkali
metal hydrogen carbonates (sodium hydrogen carbonate, potassium
hydrogen carbonate, etc.), etc. Examples of organic bases include
tri-lower alkylamines (triethylamine, tributylamine,
diisopropylethylamine, etc.), tert-amines
(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]-non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all,
triethylamine, diisopropylethylamine, potassium carbonate, etc. are
preferred.
[0085] The present reaction can be carried out in the presence or
absence of a solvent, preferably in the presence of a solvent.
[0086] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include aromatic
hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitriles (acetonitrile, etc.), alcohols (methanol, ethanol,
propanol, 2-butanol, etc.), dimethylsulfoxide, pyridine,
2,6-luthidine, etc., and a mixed solvent comprising two or more of
these solvents, if necessary. Above all, xylene, tetrahydrofuran,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, ethanol,
2-butanol, etc. are preferred and tetrahydrofuran,
N,N-dimethylacetamide and 2-butanol are more preferred.
[0087] The reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of -10.degree. C. to the boiling point of the reaction
mixture, especially from room temperature to the boiling point of
the reaction mixture.
[0088] The reduction can be carried out in a conventional manner,
when needed. For example, the reaction can be carried out by
reacting a compound [1] with an appropriate reducing agent, or with
hydrogen in the presence of a metal catalyst in an appropriate
solvent.
[0089] In the reaction, any conventional reducing agents can be
used without limitation; however, metal hydride reducing agents
such as lithium aluminium hydride, lithium borohydride, sodium
borohydride, etc., metals such as zinc, iron, stannum, etc., and
metal salts such as tin chloride, etc. are preferred, and metals
such as stannum, etc. and metal salts such as tin chloride, etc.
are more preferred. In the catalytic hydrogenation, any
conventional metal catalysts can be used without limitation;
however, palladium-carbon, Raney Nickel, Raney Cobalt, platinum
oxide, etc. are preferred and metals such as Raney Nickel, etc. are
more preferred. Furthermore, depending on the method used, the
reaction can sometimes be facilitated when it is carried out under
an acidic condition in the co-existence of a mineral acid such as
hydrochloric acid, etc.
[0090] In the reaction where a metal hydride reducing agent is
used, any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
aromatic hydrocarbons (benzene, toluene, xylene, etc.), alcohols
(methanol, ethanol, propanol, etc.), water, etc., and a mixed
solvent comprising two or more of these solvents, if necessary. It
is preferred to select any appropriate solvent depending on the
method used.
[0091] In the reaction where a metal such as zinc, iron, stannum,
etc., or a metal salt such as tin chloride, etc. is used, any inert
solvents which do not disturb the reaction can be used without
limitation, and examples thereof include water, alcohols (methanol,
ethanol, propanol etc.), esters (ethyl acetate, etc.), ethers
(diethyl ether, diisopropyl ether, tetrahydrofuran,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitriles (acetonitrile, etc.), aromatic hydrocarbons (benzene,
toluene, xylene, etc.), and a mixed solvent comprising two or more
of these solvents, if necessary. It is preferred to select any
appropriate solvent depending on the method used. Above all, ethyl
acetate, water, or a mixed solvent comprising water and an alcohol,
an ether, an amide, a nitrile etc. is preferred.
[0092] In the reaction where hydrogenation is carried out in the
presence of a metal catalyst, any inert solvents which do not
disturb the reaction can be used without limitation, and examples
thereof include alcohols, ethers, aliphatic hydrocarbons, aromatic
hydrocarbons, amides, esters (ethyl acetate, etc.), organic acids
formic acid, acetic acid, propionic acid, trifluoroacetic acid,
etc.), and a mixed solvent comprising two or more of these
solvents, if necessary. It is preferred to select any appropriate
solvent depending on the method used.
[0093] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of -10.degree. C. to the boiling point of the reaction
mixture.
[0094] The hydrogen pressure used in the catalytic hydrogenation
reaction is generally about 1-100 atm.
[0095] The reaction time for the present reaction varies depending
on the kind of the reducing agent or the activity of the catalyst
used; however, it is generally between about 10 minutes and 24
hours.
[0096] The dealkylation can be carried out in a conventional
manner, when needed. For example, this reaction can be carried out
by reacting a compound [1] with an appropriate dealkylating agent
in an appropriate solvent or without solvent.
[0097] Any conventional dealkylating agents can be used without
limitation, and preferred examples thereof include boron
tribromide, boron trichloride, iodotrimethylsilane, aluminium (III)
chloride, pyridinium chloride, etc., and boron tribromide,
iodotrimethylsilane, etc. are preferred.
[0098] Any inert solvents which do not disturb the reaction can be
used without limitation, and examples thereof include halogenated
hydrocarbons (chloroform, dichloromethane, dichloroethane, etc.),
amides (N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitrites (acetonitrile,
etc.), and a mixed solvent comprising two or more of these
solvents, if necessary. It is preferred to select any appropriate
solvent depending on the method used.
[0099] The reaction can be carried out in a wide, range of
temperature from a temperature of under cooling to under heating,
preferably from -78.degree. C. to the boiling point of the reaction
mixture.
[0100] The hydrolysis can be carried out in a conventional manner,
when needed.
[0101] The quaternary amination can be carried out in a
conventional manner, when needed. This reaction can be conducted in
a similar manner to the above-mentioned alkylation.
[0102] The pyrrolylation can be carried out by, for example,
reacting a compound having an amino group with
tetrahydro-2,5-dimethoxyfuran in the presence of an acid in an
appropriate solvent.
[0103] Examples of the acids include an organic acid such as formic
acid, acetic acid, propionic acid, trifluoroacetic acid, etc., and
a mineral acid such as hydrochloric acid, etc, which acids can also
be used as a solvent.
[0104] Any inert solvents, in addition to the above-mentioned
organic acids and mineral acids, which do not disturb the reaction
can be used without limitation, and examples thereof include
halogenated hydrocarbons (chloroform, dichloromethane,
dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene,
xylene, etc.), ethers (diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), amides
(N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitrites (acetonitrile,
etc.), etc., and organic acids are preferred.
[0105] The reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating,
preferably from -78.degree. C. to the boiling point of the reaction
mixture.
[0106] The protection of an amino or a carboxy group, or
deprotection of the protected group can be carried out, when
needed, according to any of known methods.
[Manufacturing Process for Starting Materials: Preparation of
Compound [2]]
[0107] (1) The reaction for converting the aldehyde group of the
compound [10] into a cyano group to give the compound [9] can be
carried out by reacting the compound [10] with a hydroxylamine or
hydrochloride thereof in the presence or absence of sodium formate
in an appropriate solvent. A dehydrating agent may be added. The
solvent available includes an organic lower fatty acid such as
formic acid; however, it is preferred to select an appropriate
solvent depending on the method used.
[0108] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of under ice-cooling to the boiling point of the
reaction mixture, especially at the boiling point of the react on
mixture.
[0109] (2) The next reaction between the resulting compound [9] and
the compound [8] to give the compound [7] can be carried out in a
conventional manner for O-alkylation of a phenol compound. The
present reaction can be carried out by reacting the compound [9]
with the compound [8] in an appropriate solvent in the presence of
a base or by using such a base as the solvent.
[0110] The leaving group in the compound [8] can be preferably, for
example, a halogen atom. Examples of a preferred protecting group
for the carboxyl group of the compound [8] include a lower alkyl
group and a phenyl-lower alkyl group.
[0111] Examples of the base usable include both the inorganic and
organic bases such as alkali metal carbonates (sodium carbonate,
potassium carbonate, etc.), alkali metal hydrogen carbonates
(sodium hydrogen carbonate, potassium hydrogen carbonate, etc.),
alkali metal hydroxides (sodium hydroxide, potassium hydroxide,
lithium hydroxide, etc.), alkali metal hydrides (sodium hydride,
etc.), alkali metal alkoxides (sodium methoxide, potassium
t-butoxide, etc.), tri-lower alkylamines (triethylamine,
tributylamine, diisopropylethylamine, etc.), tertiary-amines
(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all, alkali metal
carbonate, diisopropylethylamine, pyridine, etc. are preferred.
[0112] Examples of the solvent include any inert solvent which does
not disturb the reaction, such as ketones (e.g., acetone,
methylethyl ketone, etc.), aromatic hydrocarbons (benzene, toluene,
xylene, etc.), ethers (diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), amides
(N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitrites (acetonitrile,
etc.), alcohols (methanol, ethanol, propanol, 2-butanol, etc.),
dimethylsulfoxide, pyridine, 2,6-luthidine, etc., and a mixed
solvent comprising two or more of these solvents, if necessary.
Above all, ketones such as acetone, methylethyl ketone, etc., and
amides such as N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc. are preferred.
[0113] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating.
For example, the reaction can be preferably carried out at a
temperature of under ice-cooling to the boiling point of the
reaction mixture.
[0114] An alkali metal iodide such as lithium iodide, sodium
iodide, potassium iodide, etc. can also be added, which may
facilitate the reaction.
[0115] (3) The reaction for removing a protecting group from the
compound [7] to give the compound [6] can be carried out by a
method generally used for the deprotection of carboxyl group.
[0116] (4) The reaction for condensing the compound [5] with the
compound [6] to give the compound [4] can be carried out in a
manner similar to that for reacting the compound [2] with the
compound [3-A].
(5) The reaction for cyclizing the compound [4] to give the
compound [2] can be carried out by treating the compound [4] with a
base in an appropriate solvent.
[0117] Examples of the base usable include both the inorganic and
organic bases such as alkali metal carbonates (sodium carbonate,
potassium carbonate, etc.), alkali metal hydroxides (sodium
hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkali
metal hydrides (sodium hydride, etc.), alkali metal alkoxides
(sodium methoxide, potassium t-butoxide, etc.), tri-lower
alkylamines (triethylamine, tributylamine, diisopropylethylamine,
etc.), tert-amines (1,4-diazabicyclo[2.2.2]octane,
1,5-diazabicyclo[4.3.0]-non-5-ene,
1,8-diazabicyclo[5.4.0]undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine, collidine, etc. Above all, alkali metal
carbonate, alkali metal alkoxides, diisopropylethylamine, pyridine,
etc. are preferred.
[0118] The present reaction can be carried out in the presence or
absence of a solvent, preferably in the presence of a solvent.
Examples of the solvent include any inert solvent which does not
disturb the reaction, such as aromatic hydrocarbons (benzene,
toluene, xylene, etc.), ethers (diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), amides
(N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitriles (acetonitrile,
etc.), alcohols (methanol, ethanol, propanol, 2-butanol, etc.),
dimethylsulfoxide, pyridine, 2,6-luthidine, etc., and a mixed
solvent comprising two or more of these solvents, if necessary.
Above all, xylene, tetrahydrofuran, N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, methanol,
pyridine, etc. are preferred, and N,N-dimethylacetamide and
1,3-dimethyl-2-imidazolidinone are especially preferred.
[0119] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating,
preferably at a temperature of under ice-cooling to the boiling
point of the reaction mixture.
[0120] (6) The reaction between the compound [9] and the compound
[12) to give the compound (4] can be carried out in the presence of
a base in an appropriate solvent, if necessary. The leaving group
in the compound [12] can be preferably, for example, a halogen
atom.
[0121] Examples of the base usable in the present reaction include
the inorganic and organic bases. The inorganic bases include alkali
metal carbonates (sodium carbonate, potassium carbonate, etc.),
alkali metal hydrogen carbonates (sodium hydrogen carbonate,
potassium hydrogen carbonate, etc.), alkali metal hydroxides
(sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.),
alkali metal hydrides (sodium hydride, etc.). A mixture of cesium
carbonate and sodium iodide can also be used. The organic bases
include alkali metal alkoxides (sodium methoxide, potassium
t-butoxide, etc.), tri-lower alkylamines (triethylamine,
tributylamine, diisopropylethylamine, etc.), tert-amines
(1,4-diazabicyclo[2.2.2]octane, 1,5-diazabicyclo[4.3.0]non-5-ene,
1,8-diazabicyclo[5.4.0]-undec-7-ene, etc.), amines
(N,N-dimethylaniline, N,N-diethylaniline, 4-dimethylaminopyridine,
etc.), pyridine, lutidine and collidine, etc. above all, alkali
metal carbonates, diisopropylethylamine, pyridine, etc. are
preferred. In the present reaction, the bases above can also be
used as a solvent.
[0122] Examples of the solvent usable in the present reaction
include any inert solvent which does not disturb the reaction, such
as ketones (e.g., acetone, methylethyl ketone, etc.), aromatic
hydrocarbons (benzene, toluene, xylene, etc.), ethers (diethyl
ether, diisopropyl ether, tetrahydrofuran, dioxane,
1,2-dimethoxyethane, etc.), amides (N,N-dimethylformamide,
N,N-dimethylacetamide, 1,3-dimethyl-2-imidazolidinone, etc.),
nitriles (acetonitrile, etc.), alcohols (methanol, ethanol,
propanol, 2-butanol, etc.), dimethylsulfoxide, pyridine,
2,6-luthidine, etc. A mixed solvent comprising two or more of these
solvents can also be used. Above all, ketones and amides are
preferred.
[0123] The present reaction can generally be carried out at a
temperature of under ice-cooling to the reflux temperature of the
solvent.
[0124] The reaction time for the present reaction is generally
between 30 minutes and 24 hours; however, longer or shorter
reaction time can be selected appropriately, if necessary. Further,
an alkali metal iodide such as lithium iodide, sodium iodide,
potassium iodide, etc. can also be added, which may facilitate the
reaction.
[0125] The reaction between the compound [13] and the compound [14]
can be carried out in the presence of a base in an appropriate
solvent, if necessary. The leaving group in the compound [13] can
be preferably, for example, a halogen atom or a nitro group.
[0126] Examples of the base usable in the present reaction include
alkali metal carbonates (sodium carbonate, potassium carbonate,
cesium carbonate, etc.), alkali metal hydrides (sodium hydride,
etc.) and alkali metal alkoxides (sodium methoxide, potassium
t-butoxide, etc.). Above all, sodium hydride is preferred.
[0127] Examples of the solvent usable in the present reaction
include amides (N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.) and ethers (diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane,
etc.), and N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc. are preferred.
[0128] The reaction for formylation of the compound [11] to give
the compound [10] can be carried out in a conventional manner, if
necessary. For example, the reaction can be carried out by reacting
a formylating agent in accordance with the method for Duff
reaction, Gatterman-Koch reaction, Vilsmeier reaction, etc. in an
appropriate solvent.
[0129] Any conventional formylating agent can be used without
limitation, and hexamethylenetetramine, etc. are preferred.
[0130] Examples of the solvent include any inert solvent which does
not disturb the reaction, such as organic acids (acetic acid,
propionic acid, trifluoroacetic acid, methanesulfonic acid, etc.),
halogenated hydrocarbons (chloroform, dichloromethane,
dichloroethane, etc.), aromatic hydrocarbons (benzene, toluene,
xylene, etc.), ethers (diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, 1,2-dimethoxyethane, etc.), ketones
(acetone, methylethyl ketone, etc.), esters (ethyl acetate, etc.),
amides (N,N-dimethylformamide, N,N-dimethylacetamide,
1,3-dimethyl-2-imidazolidinone, etc.), nitriles (acetonitrile,
etc.), water, and a mixed solvent comprising two or more of these
solvents, if necessary. It is preferred to select any appropriate
solvent depending on the method used.
[0131] The present reaction can be carried out in a wide range of
temperature from a temperature of under cooling to under heating,
preferably at -78.degree. C. to the boiling point of the reaction
mixture.
[0132] The resulting compounds of the present invention thus
produced can be isolated and purified by a procedure well known in
the field of organic chemistry such as recrystallization, column
chromatography, etc.
[0133] The present compound [1] or a pharmaceutically acceptable
salt thereof has an excellent inhibitory effect on activated blood
coagulation factor X, and hence is useful in the prevention and
treatment of various disorders caused by thrombi and emboli in a
mammal (e.g., human, monkey, rabbit, dog, cat, pig, horse, bull,
mouse, rat, guinea pig, etc.), which disorders include, for
example, stable angina pectoris, unstable angina pectoris, cerebral
thrombosis, cerebral infarction, cerebral embolism, transient
ischemic attack (TIA), ischemic cerebrovascular disease such as
cerebrovascular spasm after subarachnoid hemorrhage, ischemic heart
disease caused by coronary artery thrombogenesis, congestive
chronic heart failure, myocardial infarction, acute myocardial
infarction, pulmonary infarction, pulmonary embolism, pulmonary
vascular disorders, economy-class syndrome, kidney disease
(diabetic renal disease, chronic glomerulonephritis is, IgA
nephropathy, etc.), thrombogenesis with atherosclerosis, peripheral
arterial occlusion, peripheral venous occlusion, Buerger's disease,
deep vein thrombosis, disseminated intravascular coagulation (DIC),
thrombogenesis after implantation of a synthetic vascular
prosthesis or replacement of artificial heart valve or joint,
intermittent claudication, thrombogenesis and reocclusion after
blood circulation reconstruction such as percutaneous transluminal
coronary angioplasty (PTCA) or percutaneous transluminal coronary
artery recanalization (PTCR), systemic inflammatory response
syndrome (SIRS), multiple organ failure (MODS), thrombogenesis in
extracorporeal circulation, blood coagulation in case of blood
drawing, diabetic circulatory disturbance, graft rejection, organ
protection and improvement of function in case of transplantation,
etc.
[0134] The present compound is characterized in that it shows
excellent inhibitory effect on activated blood coagulation factor
X, decreased toxicity, and causes few side effects (bleeding, etc.)
that are seen in the existing anticoagulants.
[0135] When a FXa inhibitor has a small distribution volume
(internal medicine/blood concentration), it would be substantially
free of side effects such as phospholipidosis, hepatotoxicity, etc.
Accordingly, FXa inhibitors, especially those having the
distribution volume of 0.1-3.0 L/kg and the FXa inhibitory effect
with the IC.sub.50 value of 100 nM or below are substantially free
of side effects such as phospholipidosis, hepatotoxicity, etc., and
useful as a medicament for treating thrombosis. For example,
trans-5-dimethylaminocarbonyl-3-[4-(N-formyl-N-methylamino)-cyclohexylcar-
bonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide has
the distribution volume of 0.8 L/kg and the FXa inhibitory effect
with the IC.sub.50 value of less than 100 nM, and can be an
excellent medicine being substantially free of side effects such as
phospholipidosis, hepatotoxicity, etc.
[0136] FXa inhibitors having small distribution volume have
preferably the following partial structure:
##STR00040##
and more preferably the following partial structure:
##STR00041##
[0137] The present compound (1) or a pharmaceutically acceptable
salt thereof can be formulated into a pharmaceutical composition
comprising a therapeutically effective amount of the compound (1)
and a pharmaceutically acceptable carrier therefor. The
pharmaceutically acceptable carriers include diluents, binders
(e.g., syrup, gum arabic, gelatine, sorbit, tragacanth,
polyvinylpyrrolidone), excipients (e.g., lactose, sucrose, corn
starch, potassium phosphate, sorbit, glycine) lubricants (e.g.,
magnesium stearate, talc, polyethylene glycol, silica),
disintegrants (e.g., potato starch) and wetting agents (e.g.,
sodium lauryl sulfate), etc.
[0138] The compound [1] of the present invention or a
pharmaceutically acceptable salt thereof can be administered orally
or parenterally, and be used as an appropriate pharmaceutical
preparation. Examples of an appropriate preparation for oral
administration include solid preparations (tablets, granules,
capsules, powders, etc.), solutions, suspensions and emulsions.
Examples of an appropriate preparation for parenteral
administration include suppository, injections or preparation for
continuous infusion prepared using distilled water for injection,
physiological saline or aqueous glucose solution, etc., or
inhalant.
[0139] The dose of the compound [1] or a pharmaceutically
acceptable salt thereof of the present invention may vary depending
on the administration routes, and the age, weight and condition of
the patient, or the kind or severity of the disease, it is usually
in the range of about 0.1 to 50 mg/kg/day, preferably about 0.1 to
30 mg/kg/day.
EXAMPLES
[0140] The present invention will be illustrated in detail by
Examples and Reference Examples, but should not be construed to be
limited thereto.
Example 1
Trans-5-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino-
]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
##STR00042##
[0142] Trans-4-(2-oxopyrrolidin-1-yl)cyclohexanecarboxylic acid
(634 mg) obtained in Reference Example 113 is dissolved in thionyl
chloride (10 ml), and the mixture stirred at room temperature for 4
hours. The reaction solution is concentrated under reduced
pressure, and the residue is dissolved in chloroform (5 ml). The
mixture is added drop-wise into a suspension of
3-amino-5-methoxy-carbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxami-
de (691 mg) obtained in Reference Example 72 in pyridine (15 ml)
under ice-cooling. After the addition, the reaction solution is
warmed to room temperature, and then stirred for 17 hours. To the
reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with chloroform.
The organic layer is washed with a saturated brine, dried over
sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: chloroform) to give the title compound (785
mg).
[0143] APCI-MS M/Z: 539/541 [M+H].sup.+
Example 2
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-methoxycarb-
onylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00043##
[0145] Trans-4-(N-acetyl-N-methylamino)cyclohexanecarboxylic acid
(1.80 g) obtained in Reference Example 114 is dissolved in thionyl
chloride (20 ml), and the mixture is stirred at room temperature
for 12 hours. The reaction solution is concentrated under reduced
pressure, and the residue is dissolved in chloroform (70 ml), and
thereto is added
3-amino-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carb-
oxamide (2.20 g) obtained in Reference Example 73 under
ice-cooling. To the mixture is further added pyridine (4.95 ml),
and the reaction solution is warmed to room temperature, and
stirred for 3 hours. To the reaction solution is poured a saturated
aqueous sodium hydrogen carbonate solution, and the mixture is
extracted with chloroform. The organic layer is washed successively
with water and a saturated brine, dried over sodium sulfate, and
the solvent is evaporated under reduced pressure. The resulting
residue is purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/1, then ethyl acetate only) to give the
title compound (2.97 g).
[0146] APCI-MS M/Z: 541/543 [M+H].sup.+
Example 3
3-[2-(1-Isopropylpiperidin-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzo-
furan-2-carboxamide dihydrochloride
##STR00044##
[0148] (1-Isopropylpiperidin-4-yl)acetic acid hydrochloride (432
mg) obtained in Reference Example 129 is dissolved in thionyl
chloride (5 ml), and the mixture is stirred at room temperature for
3 hours. The thionyl chloride is evaporated under reduced pressure,
and the resulting residue is dissolved in dichloromethane (10 ml),
and cooled with ice. To this solution are added
3-amino-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide (374 mg)
obtained in Reference Example 74 and pyridine (420 .mu.l), and the
reaction solution is warmed to room temperature, and stirred for 3
hours. To the reaction solution was added water and a saturated
aqueous sodium hydrogen carbonate solution, and the mixture is
extracted with ethyl acetate. The organic layer is washed with
water and a saturated brine, dried over sodium sulfate, and the
solvent was evaporated under reduced pressure. The resulting
residue is purified by silica gel column chromatography (eluent:
chloroform, then chloroform/methanol=10/1, further 6/1) to give
3-[2-(1-isopropylpiperidin-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benz-
ofuran-2-carboxamide (489 mg), which is further dissolved in
dichloromethane (10 ml), and thereto is added 4N hydrogen chloride
in dioxane (5 ml), and the mixture is stirred at room temperature
for 30 minutes. The reaction solution is concentrated under reduced
pressure, and the resulting residue is suspended in
methanol-chloroform. The precipitates are collected by filtration
to give the title compound (423 mg).
[0149] APCI-MS M/Z: 455/457 [M+H].sup.+
Examples 4-75
[0150] The corresponding amino compounds and carboxylic acid
compounds are treated in a similar manner to Example 1, Example 2
or Example 3 to give the following compounds in a free form, which
are further treated with hydrogen chloride to give hydrochlorides
thereof.
TABLE-US-00001 ##STR00045## Ex. Physicochemical No. --R.sup.2 -AY
properties 4 ##STR00046## ##STR00047## APCI-MS M/Z: 511/513 [M +
H].sup.+ 5 ##STR00048## ##STR00049## APCI-MS M/Z: 369/571 [M +
H].sup.+ 6 ##STR00050## ##STR00051## APCI-MS M/Z: 506/508 [M +
H].sup.+ 7 ##STR00052## ##STR00053## APCI-MS M/Z: 497/499 [M +
H].sup.+ 8 ##STR00054## ##STR00055## APCI-MS M/Z: 555/557 [M +
H].sup.+ 9 ##STR00056## ##STR00057## APCI-MS M/Z: 568/570 [M +
H].sup.+ Hydrochloride 10 ##STR00058## ##STR00059## APCI-MS M/Z:
673/675 [M + NH.sub.4].sup.+ 11 ##STR00060## ##STR00061## APCI-MS
M/Z: 541/543 [M + H].sup.+ 12 ##STR00062## ##STR00063## APCI-MS
M/Z: 499/501 [M + H].sup.+ 13 ##STR00064## ##STR00065## APCI-MS
M/Z: 499/501 [M + H].sup.+ Dihydrochloride 14 ##STR00066##
##STR00067## APCI-MS M/Z: 513/515 [M + H].sup.+ Hydrochloride 15
##STR00068## ##STR00069## APCI-MS M/Z: 475/477 [M + H].sup.+ 16
##STR00070## ##STR00071## APCI-MS M/Z: 519/521 [M + H].sup.+ 17
##STR00072## ##STR00073## APCI-MS M/Z: 455/457 [M + H].sup.+
Dihydrochloride 18 ##STR00074## ##STR00075## APCI-MS M/Z: 486/488
[M + H].sup.+ Hydrochloride 19 ##STR00076## ##STR00077## APCI-MS
M/Z: 471/473 [M + H].sup.+ Hydrochloride 20 ##STR00078##
##STR00079## APCI-MS M/Z: 529/531 [M + H].sup.+ 21 ##STR00080##
##STR00081## APCI-MS M/Z: 584/586 [M + H].sup.+ 22 ##STR00082##
##STR00083## APCI-MS M/Z: 604/606 [M + H].sup.+ Hydrochloride Ex.
Physicochemical No. Structure Properties 23 ##STR00084## APCI-MS
M/Z: 471/473 [M + H].sup.+ Hydrochloride 24 ##STR00085## APCI-MS
M/Z: 519/521 [M + H].sup.+ Dihydrochloride 25 ##STR00086## APCI-MS
M/Z: 455/457 [M + H].sup.+ Dihydrochloride 26 ##STR00087## APCI-MS
M/Z: 512/514 [M + H].sup.+ Dihydrochloride 27 ##STR00088## APCI-MS
M/Z: 471/473 [M + H].sup.+ Dihydrochloride 28 ##STR00089## APCI-MS
M/Z: 455/457 [M + H].sup.+ Dihydrochloride 29 ##STR00090## APCI-MS
M/Z: 471/473 [M + H].sup.+ Hydrochloride ##STR00091## Ex.
Physicochemical No. --R.sup.2 -AY Properties 30 ##STR00092##
##STR00093## APCI-MS M/Z: 466/468 [M + H].sup.+ Hydrochloride 31
##STR00094## ##STR00095## APCI-MS M/Z: 571/573 [M + H].sup.+ 32
##STR00096## ##STR00097## APCI-MS M/Z: 515/517 [M + H].sup.+
Dihydrochloride 33 ##STR00098## ##STR00099## APCI-MS M/Z: 528/530
[M + H].sup.+ Trihydrochloride 34 ##STR00100## ##STR00101## APCI-MS
M/Z: 559/561 [M + H].sup.+ Dihydrochloride 35 ##STR00102##
##STR00103## APCI-MS M/Z: 619/621 [M + H].sup.+ 36 ##STR00104##
##STR00105## APCI-MS M/Z: 614/616 [M + H].sup.+ Ex. Physicochemical
No. Structure Properties 37 ##STR00106## APCI-MS M/Z: 485/487 [M +
H].sup.+ 38 ##STR00107## APCI-MS M/Z: 421 [M + H].sup.+
Hydrochloride 39 ##STR00108## APCI-MS M/Z: 479 [M + H].sup.+
Dihydrochloride 40 ##STR00109## APCI-MS M/Z: 484/486 [M + H].sup.+
41 ##STR00110## APCI-MS M/Z: 420 [M + H].sup.+ 42 ##STR00111##
APCI-MS M/Z: 424 [M + H].sup.+ 43 ##STR00112## APCI-MS M/Z: 436 [M
+ H].sup.+ ##STR00113## Ex. Physicochemical No. --R.sup.2 -AY
Properties 44 ##STR00114## ##STR00115## APCI-MS M/Z: 525/527 [M +
H].sup.+ Dihydrochloride 45 ##STR00116## ##STR00117## APCI-MS M/Z:
539/541 [M + H].sup.+ Dihydrochloride 46 ##STR00118## ##STR00119##
APCI-MS M/Z: 555/557 [M + H].sup.+ 47 ##STR00120## ##STR00121##
APCI-MS M/Z: 541/543 [M + H].sup.+ Dihydrochloride 48 ##STR00122##
##STR00123## APCI-MS M/Z: 555/557 [M + H].sup.+ Hydrochloride 49
--H ##STR00124## APCI-MS M/Z: 455/456 [M + H].sup.+ Dihydrochloride
50 ##STR00125## ##STR00126## APCI-MS M/Z: 489/491 [M + H].sup.+
Hydrochloride 51 ##STR00127## ##STR00128## APCI-MS M/Z: 533/535 [M
+ H].sup.+ Hydrochloride 52 ##STR00129## ##STR00130## APCI-MS M/Z:
500/502 [M + H].sup.+ Hydrochloride 53 ##STR00131## ##STR00132##
APCI-MS M/Z: 485/487 [M + H].sup.+ Hydrochloride Ex.
Physicochemical No. Structure Properties 54 ##STR00133## APCI-MS
M/Z: 485/487 [M + H].sup.+ Dihydrochloride 55 ##STR00134## APCI-MS
M/Z: 469/471 [M + H].sup.+ Hydrochloride ##STR00135## Ex.
Physicochemical No. --R.sup.2 -AY Properties 56 ##STR00136##
##STR00137## APCI-MS M/Z: 475/477 [M + H].sup.+ Dihydrochloride 57
##STR00138## ##STR00139## APCI-MS M/Z: 519/521 [M + H].sup.+
Dihydrochloride 58 ##STR00140## ##STR00141## APCI-MS M/Z: 486/488
[M + H].sup.+ Dihydrochloride 59 ##STR00142## ##STR00143## APCI-MS
M/Z: 471/473 [M + H].sup.+ Dihydrochloride Ex. Physicochemical No.
Structure Properties 60 ##STR00144## APCI-MS M/Z: 471/473 [M +
H].sup.+ Dihydrochloride 61 ##STR00145## APCI-MS M/Z: 512/514 [M +
H].sup.+ Trihydrochloride 62 ##STR00146## APCI-MS M/Z: 471/473 [M +
H].sup.+ Dihydrochloride 63 ##STR00147## APCI-MS M/Z: 455/457 [M +
H].sup.+ Dihydrochloride 64 ##STR00148## APCI-MS M/Z: 440 [M +
H].sup.+ ##STR00149## Ex. Physicochemical No. --R.sup.2 -AY
properties 65 ##STR00150## ##STR00151## APCI-MS M/Z: 533/535 [M +
H].sup.+ Dihydrochloride 66 ##STR00152## ##STR00153## APCI-MS M/Z:
485/487 [M + H].sup.+ Dihydrochloride Ex. Physicochemical No.
Structure Properties 67 ##STR00154## APCI-MS M/Z: 485/487 [M +
H].sup.+ Dihydrochloride 68 ##STR00155## APCI-MS M/Z: 469/471 [M +
H].sup.+ Dihydrochloride ##STR00156## Ex. Physicochemical No.
--R.sup.2 -AY Properties 69 --H ##STR00157## APCI-MS M/Z: 469/471
[M + H].sup.+ Dihydrochloride 70 --H ##STR00158## APCI-MS M/Z:
467/468 [M + H].sup.+ Hydrochloride 71 --H ##STR00159## APCI-MS
M/Z: 476 [M + H].sup.+ 72 --H ##STR00160## APCI-MS M/Z: 490 [M +
H].sup.+ 73 --H ##STR00161## APCI-MS M/Z: 505/507 [M + H].sup.+
Dihydrochloride 74 --H ##STR00162## APCI-MS M/Z: 456/458 [M +
H].sup.+ Trihydrochloride 75 --H ##STR00163## APCI-MS M/Z: 470/472
[M + H].sup.+ Trihydrochloride
Example 76
3-[(1-Isopropylpiperidin-4-yl)carbonylamino]-3-N-(5-chloropyridin-2-yl)ben-
zofuran-2-carboxamide
##STR00164##
[0152] 3-Amino-N-(S-chloropyridin-2-yl)benzofuran-2-carboxamide
(201 mg) obtained in Reference Example 74 is dissolved in
N,N-dimethylformamide (6 ml), and thereto are successively added
(1-isopropylpiperidin-4-yl)carboxylic acid hydrochloride (1.99 mg)
obtained in Reference Example 130, 4-dimethylaminopyridine (137 mg)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(203 mg), and the mixture is stirred at 60.degree. C. for 4 hours.
The reaction solution is diluted with ethyl acetate, and water and
a saturated aqueous sodium hydrogen carbonate solution are poured
thereto, and the mixture is extracted with ethyl acetate. The
organic layer is washed with water and a saturated brine, dried
over sodium sulfate, and charged onto NH-silica gel pad. The
solvent is evaporated under reduced pressure, and the resulting
residue is purified recycled HPLC and suspended in diethyl
ether/n-hexane. The precipitates are collected by filtration to
give the title compound (174 mg).
[0153] APCI-MS M/Z: 441 [M+H].sup.+
Example 77
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbonylamino]-N-(5--
chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00165##
[0155] Trans-5-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)
cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamid-
e (710 mg) obtained in Example 1 is suspended in
tetrahydrofuran-methanol (1:1, 10 ml), and thereto is added 4N
aqueous sodium hydroxide solution (2 ml) under ice-cooling. The
mixture is warmed to room temperature, and stirred for 18 hours.
The reaction solution is concentrated under reduced pressure, and
thereto is poured ice-water, and the mixture is neutralized with
10% hydrochloric acid. The precipitates are collected by
filtration, washed with water, and dried to give the title compound
(655 mg).
[0156] ESI-MS M/Z: 523/525 [M-H].sup.-
Examples 78-86
[0157] The corresponding carboxylic acid esters are treated in a
similar manner to Example 77 to give the following compounds in a
free form, which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00002 ##STR00166## Ex. Physicochemical No. --R.sup.2 -AY
Properties 78 ##STR00167## ##STR00168## APCI-MS M/Z: 483/485 [M -
H].sup.- Ex. Physicochemical No. Structure Properties 79
##STR00169## ESI-MS M/Z: 463 [M - H].sup.- ##STR00170## Ex.
Physicochemical No. --R.sup.2 -AY Properties 80 ##STR00171##
##STR00172## ESI-MS M/Z: 509/511 [M - H].sup.- 81 ##STR00173##
##STR00174## APCI-MS M/Z: 527/529 [M + H].sup.+ 82 ##STR00175##
##STR00176## ESI-MS M/Z: 537/539 [M - H].sup.- 83 ##STR00177##
##STR00178## ESI-MS M/Z: 525/527 [M - H].sup.- 84 ##STR00179##
##STR00180## ESI-MS M/Z: 497/499 [M - H].sup.- 85 ##STR00181##
##STR00182## ESI-MS M/Z: 523/525 [M - H].sup.- 86 ##STR00183##
##STR00184## ESI-MS M/Z: 541/543 [M + H].sup.-
Example 87
Trans-5-(morpholin-4-ylcarbonyl)-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcar-
bonylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00185##
[0159]
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino-
]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (830 mg)
obtained in Example 77 is suspended in
N,N-dimethylformamide-pyridine (1:1, 30 ml), and thereto are added
successively morpholine (196 mg), 1-hydroxybenzotriazole (406 mg)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(576 mg) under ice-cooling, and the mixture is stirred at room
temperature for 17 hours. To the reaction solution are poured
ice-water and a saturated aqueous sodium hydrogen carbonate
solution, and the mixture is extracted with ethyl acetate, washed
with water and a saturated brine, and dried over sodium sulfate.
The solvent is evaporated under reduced pressure, and the resulting
residue is purified by NH-silica gel column chromatography (eluent:
chloroform). The resulting residue is suspended in ethyl
acetate-n-hexane, and the precipitates are collected by filtration,
and dried to give the title compound (805 mg).
[0160] APCI-MS M/Z: 594/596 [MH].sup.+
Examples 88-143
[0161] The corresponding compounds are treated in a similar manner
to Example 87 to give the following compounds in a free form, which
are further treated with hydrogen chloride to give hydrochlorides
thereof.
TABLE-US-00003 ##STR00186## Ex. Physicochemical No. --R.sup.2 -AY
Properties 88 ##STR00187## ##STR00188## APCI-MS M/Z: 552/554 [M +
H].sup.+ 89 ##STR00189## ##STR00190## APCI-MS M/Z: 596/599 [M +
H].sup.+ 90 ##STR00191## ##STR00192## APCI-MS M/Z: 582/584 [M +
H].sup.+ 91 ##STR00193## ##STR00194## APCI-MS M/Z: 578/580 [M +
H].sup.+ 92 ##STR00195## ##STR00196## APCI-MS M/Z: 622/624 [M +
H].sup.+ 93 ##STR00197## ##STR00198## APCI-MS M/Z: 566/568 [M +
H].sup.+ 94 ##STR00199## ##STR00200## APCI-MS M/Z: 610/612 [M +
H].sup.+ 95 ##STR00201## ##STR00202## APCI-MS M/Z: 596/598 [M +
H].sup.+ 96 ##STR00203## ##STR00204## APCI-MS M/Z: 608/610 [M +
H].sup.+ 97 ##STR00205## ##STR00206## APCI-MS M/Z: 554/556 [M +
H].sup.+ 98 ##STR00207## ##STR00208## APCI-MS M/Z: 596/598 [M +
H].sup.+ 99 ##STR00209## ##STR00210## APCI-MS M/Z: 624/626 [M +
H].sup.+ 100 ##STR00211## ##STR00212## APCI-MS M/Z: 512/514 [M +
H].sup.+ Dihydrochloride Ex. Physicochemical No. Structure
Properties 101 ##STR00213## APCI-MS M/Z: 492 [M + H].sup.+
Hydrochloride ##STR00214## Ex. Physicochemical No. --R.sup.2 -AY
properties 102 ##STR00215## ##STR00216## APCI-MS M/Z: 498/500 [M +
H].sup.+ Dihydrochloride 103 ##STR00217## ##STR00218## APCI-MS M/Z:
484/486 [M + H].sup.+ Dihydrochloride 104 ##STR00219## ##STR00220##
APCI-MS M/Z: 540/542 [M + H].sup.+ Hydrochloride 105 ##STR00221##
##STR00222## APCI-MS M/Z: 528/530 [M + H].sup.+ Hydrochloride Ex.
Physicochemical No. Structure Properties 106 ##STR00223## APCI-MS
M/Z: 536 [M + H].sup.+ Dihydrochloride ##STR00224## Ex.
Physicochemical No. --R.sup.2 -AY Properties 107 ##STR00225##
##STR00226## APCI-MS M/Z: 542/544 [M + H].sup.+ Dihydrochloride 108
##STR00227## ##STR00228## APCI-MS M/Z: 542/544 [M + H].sup.+
Hydrochloride 109 ##STR00229## ##STR00230## APCI-MS M/Z: 528/530 [M
+ H].sup.+ Dihydrochloride 110 ##STR00231## ##STR00232## APCI-MS
M/Z: 558/560 [M + H].sup.+ 111 ##STR00233## ##STR00234## APCI-MS
M/Z: 558/560 [M + H].sup.+ Dihydrochloride 112 ##STR00235##
##STR00236## APCI-MS M/Z: 555/557 [M + H].sup.+ Trihydrochloride
113 ##STR00237## ##STR00238## APCI-MS M/Z: 554/556 [M + H].sup.+
Dihydrochloride 114 ##STR00239## ##STR00240## APCI-MS M/Z: 552/554
[M + H].sup.+ Dihydrochloride 115 ##STR00241## ##STR00242## APCI-MS
M/Z: 538/540 [M + H].sup.+ Dihydrochloride 116 ##STR00243##
##STR00244## APCI-MS M/Z: 582/584 [M + H].sup.+ Dihydrochloride 117
##STR00245## ##STR00246## APCI-MS M/Z: 568/570 [M + H].sup.+
Dihydrochloride 118 ##STR00247## ##STR00248## APCI-MS M/Z: 568/570
[M + H].sup.+ Hydrochloride 119 ##STR00249## ##STR00250## APCI-MS
M/Z: 567/569 [M + H].sup.+ Trihydrochloride 120 ##STR00251##
##STR00252## APCI-MS M/Z: 526/528 [M + H].sup.+ Hydrochloride 121
##STR00253## ##STR00254## APCI-MS M/Z: 542/544 [M + H].sup.+
Hydrochloride 122 ##STR00255## ##STR00256## APCI-MS M/Z: 556/558 [M
+ H].sup.+ 123 ##STR00257## ##STR00258## APCI-MS M/Z: 568/570 [M +
H].sup.+ Hydrochloride 124 ##STR00259## ##STR00260## APCI-MS M/Z:
596/598 [M + H].sup.+ Hydrochloride 125 ##STR00261## ##STR00262##
APCI-MS M/Z: 582/584 [M + H].sup.+ Hydrochloride 126 ##STR00263##
##STR00264## APCI-MS M/Z: 582/584 [M + H].sup.+ Hydrochloride 127
##STR00265## ##STR00266## APCI-MS M/Z: 538/540 [M + H].sup.+ 128
##STR00267## ##STR00268## APCI-MS M/Z: 538/540 [M + H].sup.+
Hydrochloride 129 ##STR00269## ##STR00270## APCI-MS M/Z: 580/582 [M
+ H].sup.+ Dihydrochloride 130 ##STR00271## ##STR00272## APCI-MS
M/Z: 608/610 [M + H].sup.+ Dihydrochloride 131 ##STR00273##
##STR00274## APCI-MS M/Z: 552/554 [M + H].sup.+ Dihydrochloride 132
##STR00275## ##STR00276## APCI-MS M/Z: 596/598 [M + H].sup.+
Dihydrochloride 133 ##STR00277## ##STR00278## APCI-MS M/Z: 582/584
[M + H].sup.+ 134 ##STR00279## ##STR00280## APCI-MS M/Z: 594/596 [M
+ H].sup.+ Dihydrochloride 135 ##STR00281## ##STR00282## APCI-MS
M/Z: 554/556 [M + H].sup.+ Dihydrochloride 136 ##STR00283##
##STR00284## APCI-MS M/Z: 598/600 [M + H].sup.+ 137 ##STR00285##
##STR00286## APCI-MS M/Z: 584/586 [M + H].sup.+ 138 ##STR00287##
##STR00288## APCI-MS M/Z: 596/598 [M + H].sup.+ 139 ##STR00289##
##STR00290## APCI-MS M/Z: 624/626 [M + H].sup.+ 140 ##STR00291##
##STR00292## APCI-MS M/Z: 568/570 [M + H].sup.+ 141 ##STR00293##
##STR00294## APCI-MS M/Z: 612/614 [M + H].sup.+ Hydrochloride 142
##STR00295## ##STR00296## APCI-MS M/Z: 598/600 [M + H].sup.+ 143
##STR00297## ##STR00298## APCI-MS M/Z: 610/612 [M + H].sup.+
Hydrochloride
Example 144
Trans-5-(4,5-dihydroxazol-2-yl)-3-[4-(dimethylamino)cyclohexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00299##
[0163]
Trans-5-carboxy-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-N-(5--
chloropyridin-2-yl)benzofuran-2-carboxamide (220 mg) obtained in
Example 78 is suspended in pyridine (3 ml), and thereto are added
successively 2-bromoethylammonium bromide (125 mg), 1.0M
1-hydroxy-benzotriazole-N,N-dimethylformamide solution (600 .mu.l)
and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(115 mg) under ice-cooling, and the mixture is stirred at room
temperature for 2.5 days. To the reaction solution are poured
ice-water and a saturated aqueous sodium hydrogen carbonate
solution, and the mixture is extracted with chloroform, dried over
sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: chloroform, then chloroform/ethyl
acetate=4/1), and the resulting residue is suspended in diisopropyl
ether. The precipitates are collected by filtration, and dried to
give the title compound (117 mg).
[0164] APCI-MS M/Z: 510/512 [M+H].sup.+
Example 145
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-(2-hydroxye-
thyl)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
##STR00300##
[0166]
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-meth-
oxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(2.95 g) obtained in Example 2 is suspended in tetrahydrofuran (65
ml), and thereto is added lithium borohydride (238 mg), and the
mixture is stirred at room temperature for 12 hours. To the
reaction solution is poured 10% hydrochloric acid under
ice-cooling, and the mixture is stirred at room temperature for 15
minutes. Subsequently, the reaction solution is neutralized with a
saturated aqueous sodium hydrogen carbonate solution, and extracted
with ethyl acetate. The organic layer is washed with a saturated
brine, dried over sodium sulfate, and the solvent is evaporated
under reduced pressure. The resulting residue is purified by
NH-silica gel column chromatography (eluent: ethyl acetate, then
chloroform/methanol=40/1), and the resulting residue is suspended
in diethyl ether. The precipitates are collected by filtration to
give the title compound (2.24 g).
[0167] APCI-MS M/Z: 513/515 [M+H].sup.+
Examples 146-149
[0168] The corresponding compounds are treated in a similar manner
to Example 145 to give the following compounds in a free form,
which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00004 ##STR00301## Ex. Physicochemical No. -R.sup.2 -AY
Properties 146 ##STR00302## ##STR00303## APCI-MS M/Z: 525/527 [M +
H].sup.+ 147 ##STR00304## ##STR00305## APCI-MS M/Z: 541/543 [M +
H].sup.+ 148 ##STR00306## ##STR00307## APCI-MS M/Z: 485/487 [M +
H].sup.+ Hydrochloride 149 ##STR00308## ##STR00309## APCI-MS M/Z:
501/503 [M + H].sup.+
Example 150
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-hydroxymethyl-N-(5-c-
hloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride
##STR00310##
[0170]
Trans-5-carboxy-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-N-(5--
chloropyridin-2-yl)benzofuran-2-carboxamide (243 mg) obtained in
Example 78 is suspended in thionyl chloride (2.5 ml), and the
mixture is stirred at room temperature for 10 minutes, then stirred
at 50.degree. C. for 10 minutes. The mixture is cooled to room
temperature and stirred for one hour. The reaction solution is
concentrated to dryness under reduced pressure. The resulting
residue is suspended in tetrahydrofuran/chloroform (2:1, 15 ml),
and thereto is added sodium borohydride (150 mg), and the mixture
is stirred at room temperature overnight. To the reaction solution
is poured 1N hydrochloric acid under ice-cooling, and the mixture
is stirred for 0.5 hour. A saturated aqueous sodium hydrogen
carbonate solution is further poured thereto, and the mixture is
extracted with chloroform. The organic layer is washed with a
saturated aqueous sodium hydrogen carbonate solution and a
saturated brine, dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent:
chloroform, then chloroform/methanol=200/1) to give
trans-3-[4-(dimethylamino)
cyclohexylcarbonylamino]-5-hydroxymethyl-N-(5-chloro-pyridin-2-yl)benzofu-
ran-2-carboxamide (46 mg) This product is dissolved in chloroform
(1 ml), and thereto is added 2N hydrogen chloride in methanol (0.1
ml), and the reaction solution is concentrated under reduced
pressure. The resulting residue is suspended in ethyl
acetate-methanol, and the precipitates are collected by filtration,
and dried to give the title compound (45 mg).
[0171] APCI-MS M/Z: 471/473 [M+H].sup.+
Example 151
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-6-hydroxy-N-(5-chlorop-
yridin-2-yl)benzofuran-2-carboxamide hydrochloride
##STR00311##
[0173] To a suspension of
trans-3-[4-(dimethylamino)cyclo-hexylcarbonylamino]-6-methoxy-N-(5-chloro-
pyridin-2-yl)-benzofuran-2-carboxamide (473 mg) obtained in Example
23 in dichloromethane (20 ml) is added dropwise boron tribromide
(3.5 g) over 2 minutes at -78.degree. C. The mixture is stirred at
room temperature for 4 days, and the reaction solution is poured
into ice-water, neutralized with a saturated aqueous sodium
hydrogen carbonate solution, and extracted with a mixed solvent of
ethyl acetate-tetrahydrofuran. The organic layer is washed with a
saturated brine, dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
suspended in chloroform/diethyl ether, and the precipitates are
collected by filtration, and dried to give
trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-chlorop-
yridin-2-yl)benzofuran-2-carboxamide (335 mg). This product (48 mg)
is suspended In methanol and treated with 4N hydrogen chloride in
dioxane to give the title compound (54 mg).
[0174] APCI-MS M/Z: 457/459 [M+H].sup.+
Example 152
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-hydroxy-N-(5-chlorop-
yridin-2-yl)benzofuran-2-carboxamide hydrochloride
##STR00312##
[0176]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-methyloxy-N-(5-
-chloropyridin-2-yl)benzofuran-2-carboxamide (473 mg) obtained in
Example 19 is treated in a similar manner to Example 151 to give
the title compound (33 mg).
[0177] APCI-MS M/Z: 457/459 (M+H)+
Example 153
Trans-6-t-butoxycarbonylmethoxy-3-[4-(dimethylamino)cyclohexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00313##
[0179]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-c-
hloropyridin-2-yl)benzofuran-2-carboxamide (90 mg) obtained in
Example 151 is dissolved in N,N-dimethylformamide (2 ml), and
thereto are added cesium carbonate (110 mg) and t-butyl
bromoacetate (35.5 .mu.l). The mixture is stirred at room
temperature for 12 hours, and further stirred at 5.0.degree. C. for
2.5 hours. The reaction solution is allowed to stand for cooling,
and diluted with water, and extracted with ethyl acetate. The
organic layer is concentrated under reduced pressure, and the
resulting residue is purified by NH-silica gel column
chromatography (eluent: hexane/ethyl acetate=1/1, then ethyl
acetate) to give the title compound (21 mg).
[0180] APCI-MS M/Z: 571/573 [M+H].sup.+
Examples 154-155
[0181]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-6-hydroxy-N-(5-c-
hloropyridin-2-yl)benzofuran-2-carboxamide obtained in Example 151
and the corresponding starting compounds are treated in a similar
manner to Example 153 to give the following compounds in a free
form, or which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00005 Ex. Physicochemical No. Structure properties 154
##STR00314## APCI-MS M/Z: 528/530 [M + H].sup.+ Dihydrochloride 155
##STR00315## APCI-MS M/Z: 542/544 [M + H].sup.+ Dihydrochloride
Example 156
Trans-6-carboxymethyloxy-3-(4-(dimethylamino)-cyclohexylcarbonylamino)-N-(-
5-chloropyridin-2-yl)benzo-furan-2-carboxamide hydrochloride
##STR00316##
[0183]
Trans-6-t-butoxycarbonylmethyloxy-3-[4-(dimethyl-amino)cyclohexylca-
rbonylamino]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide (21
mg) obtained in Example 153 is suspended in 4N hydrogen chloride in
dioxane (8 ml), and the mixture is stirred at room temperature for
28 hours. The reaction solution is diluted with diethyl ether, and
the precipitates are collected by filtration, washed several times
with diethyl ether, and dried to give the title compound (17
mg).
[0184] APCI-MS M/Z: 515/517 [M+H].sup.+
Example 157
Trans-5-carboxymethyloxy-3-[4-(dimethyl-amino)cyclohexylcarbonylamino]-N-(-
5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride
##STR00317##
[0186]
Trans-5-t-butoxycarbonylmethoxy-3-[4-(dimethylamino)-cyclohexylcarb-
onylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (1.92
g) obtained in Example 31 is dissolved in 6N hydrochloric acid (40
ml), and the mixture is stirred at room temperature for 2 hours. To
the reaction solution is added isopropanol (100 ml), and the
precipitated solid is collected by filtration, washed with
isopropanol and diethyl ether, and dried under reduced pressure to
give the title compound (1.86 g).
[0187] APCI-MS M/Z: 515/517 [M+H].sup.+
Examples 158-179
[0188]
Trans-5-carboxymethyloxy-3-[4-(dimethylamino)cyclo-hexylcarbonylami-
no]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride
obtained in Example 157 and the corresponding starting compounds
are treated in a similar manner to Example 87 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00006 ##STR00318## Ex. Physicochemical No. -R.sup.2 -AY
properties 158 ##STR00319## ##STR00320## APCI-MS M/Z: 542/544 [M +
H].sup.+ Hydrochloride 159 ##STR00321## ##STR00322## APCI-MS M/Z:
528/530 [M + H].sup.+ Hydrochloride 160 ##STR00323## ##STR00324##
APCI-MS M/Z: 514/516 [M + H].sup.+ Hydrochloride 161 ##STR00325##
##STR00326## APCI-MS M/Z: 572/574 [M + H].sup.+ Hydrochloride 162
##STR00327## ##STR00328## APCI-MS M/Z: 572/574 [M + H].sup.+
Hydrochloride 163 ##STR00329## ##STR00330## APCI-MS M/Z: 558/560 [M
+ H].sup.+ Hydrochloride 164 ##STR00331## ##STR00332## APCI-MS M/Z:
572/574 [M + H].sup.+ Hydrochloride 165 ##STR00333## ##STR00334##
APCI-MS M/Z: 630/632 [M + H].sup.+ Hydrochloride 166 ##STR00335##
##STR00336## APCI-MS M/Z: 572/574 [M + H].sup.+ Hydrochloride 167
##STR00337## ##STR00338## APCI-MS M/Z: 572/574 [M + H].sup.+
Hydrochloride 168 ##STR00339## ##STR00340## APCI-MS M/Z: 572/574 [M
+ H].sup.+ Hydrochloride 169 ##STR00341## ##STR00342## APCI-MS M/Z:
572/574 [M + H].sup.+ Hydrochloride 170 ##STR00343## ##STR00344##
APCI-MS M/Z: 586/588 [M + H].sup.+ Hydrochloride 171 ##STR00345##
##STR00346## APCI-MS M/Z: 588/590 [M + H].sup.+ Hydrochloride 172
##STR00347## ##STR00348## APCI-MS M/Z: 585/587 [M + H].sup.+
Dihydrochloride 173 ##STR00349## ##STR00350## APCI-MS M/Z: 584/586
[M + H].sup.+ Hydrochloride 174 ##STR00351## ##STR00352## APCI-MS
M/Z: 582/584 [M + H].sup.+ Hydrochloride 175 ##STR00353##
##STR00354## APCI-MS M/Z: 568/570 [M + H].sup.+ Hydrochloride 176
##STR00355## ##STR00356## APCI-MS M/Z: 598/600 [M + H].sup.+
Hydrochloride 177 ##STR00357## ##STR00358## APCI-MS M/Z: 612/614 [M
+ H].sup.+ Hydrochloride 178 ##STR00359## ##STR00360## APCI-MS M/Z:
598/600 [M + H].sup.+ Hydrochloride 179 ##STR00361## ##STR00362##
APCI-MS M/Z: 597/599 [M + H].sup.+ Dihydrochloride
Example 180
Trans-5-amino-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-N-(5-chloropyr-
idin-2-yl)benzofuran-2-carboxamide dihydrochloride
##STR00363##
[0190]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-nitro-N-(5-chl-
oropyridin-2-yl)benzofuran-2-carboxamide (3.00 g) obtained in
Example 18 is suspended in ethanol (100 ml), and thereto are added
tin(II) chloride (anhydrous) (7.02 g) and water (1.0 ml). The
mixture is heated under reflux for 7 hours, and allowed to stand
for cooling. To the reaction solution are added 10% aqueous sodium
hydroxide solution (30 ml) and tetrahydrofuran (200 ml), and the
mixture is stirred at room temperature for one hour. The insoluble
materials are filtered on celite, and the filtrate is concentrated
under reduced pressure, and purified by silica gel column
chromatography (eluent: n-hexane/ethyl acetate=1/1, then
chloroform/ethyl acetate=1/1). The resulting residue is suspended
in ethyl acetate/n-hexane, and the precipitates are collected by
filtration and dried to give
trans-5-amino-3-[4-(dimethyl-amino)cyclohexylcarbonylamino]-N-(5-chloropy-
ridin-2-yl)-benzofuran-2-carboxamide (1.43 g). This product (35 mg)
is dissolved in ethanol, and treated with 4N hydrogen
chloride/ethyl acetate to give the title compound (43 mg).
[0191] APCI-MS M/Z: 456/458 [M+H].sup.+
Example 181
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-methylamino-N-(5-chl-
oropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride
##STR00364##
[0193] To
trans-5-[N-(benzyloxycarbonyl)-N-methylamino]-3-[4-(dimethylamin-
o)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamid-
e (100 mg) obtained in Example 22 is added 30% hydrogen bromide in
acetic acid (2 ml), and the mixture is stirred at room temperature
for 2 hours. To the reaction solution is added diethyl ether (20
ml), and the precipitates are collected by filtration, and
suspended in a saturated aqueous sodium hydrogen carbonate
solution, and extracted with ethyl acetate. The organic layer is
washed with a saturated brine, dried over sodium sulfate, and the
solvent is evaporated under reduced pressure to give
trans-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-5-methylamino-N--
(5-chloropyridin-2-yl)benzo-furan-2-carboxamide. Subsequently, this
product is dissolved in ethanol, and treated with 4N hydrogen
chloride in ethyl acetate to give the title compound (88 mg).
[0194] APCI-MS M/Z: 470/472 [M+H].sup.+
Example 182
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-(2-methylaminoethoxy-
)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
trihydrochloride
##STR00365##
[0196]
Trans-5-[2-(N-t-butoxycarbonyl-N-methylamino)ethoxy]-3-[4-(dimethyl-
amino)cyclohexylcarbonylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carbo-
xamide (300 mg) obtained in Example 36 is dissolved in dioxane (5
ml), and thereto is added 4N hydrogen chloride in dioxane (10 ml),
and the mixture stirred at room temperature for 5 hours. The
reaction solution is concentrated under reduced pressure, and the
resulting residue is suspended in diethyl ether. The precipitates
are collected by filtration, and dried to give the title compound
(301 mg).
[0197] APCI-MS M/Z: 514/516 [M+H].sup.+
Example 183
Trans-5-(2-aminoxyethoxy)-3-[4-(2-oxo-pyrrolidine-1-yl)cyclohexylcarbonyla-
mino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
dihydrochloride
##STR00366##
[0199]
Trans-5-[2-(t-butoxycarbonylaminoxy)ethoxy]-3-[4-(2-oxopyrrolidine--
1-yl)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxa-
mide (250 mg) obtained in Example 10 is treated in a similar manner
to Example 182 to give the title compound (334 mg).
[0200] APCI-MS M/Z: 556/558 [M+H].sup.+
Example 184
Trans-5-methoxyacetylamino-3-[4-(dimethyl-amino)cyclohexylcarbonylamino]-N-
-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride
##STR00367##
[0202]
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in
Example 180 is suspended in N,N-dimethylformamide (6 ml), and
thereto are added successively methoxyacetic acid (23 mg),
1-hydroxybenzo-triazole (39 mg) and
1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (55
mg) under ice-cooling, and the mixture is stirred at room
temperature for 17 hours. To the reaction solution is poured a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture is extracted with chloroform. The organic layer is washed
with a saturated brine, and dried over sodium sulfate. The solvent
is evaporated under reduced pressure, and the resulting residue is
purified by NH-silica gel column chromatography (eluent:
chloroform, then chloroform/methanol=30/1) to give
trans-5-methoxyacetylamino-3-[4-(dimethylamino)cyclohexylcarbonylami-
no]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. Subsequently,
this product is dissolved in ethanol, and treated with 4N hydrogen
chloride in ethyl acetate to give the title compound (84 mg).
[0203] APCI-MS M/Z: 528/530 [M+H].sup.+
Examples 185-188
[0204]
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide obtained in Example 180
and the corresponding starting compounds are treated in a similar
manner to Example 184 to the compounds in a free form, or which are
further treated with hydrogen chloride to give hydrochlorides
thereof.
TABLE-US-00007 ##STR00368## Ex. Physicochemical No. -R.sup.2 -AY
properties 185 ##STR00369## ##STR00370## APCI-MS M/Z: 542/544 [M +
H].sup.+ Hydrochloride 186 ##STR00371## ##STR00372## APCI-MS M/Z:
541/543 [M + H].sup.+ Dihydrochloride 187 ##STR00373## ##STR00374##
APCI-MS M/Z: 569/571 [M + H].sup.+ Dihydrochloride 188 ##STR00375##
##STR00376## APCI-MS M/Z: 555/557 [M + H].sup.+ Hydrochloride
Example 189
Trans-5-acetoxyacetylamino-3-[4-(dimethyl-amino)cyclohexylcarbonylamino]-N-
-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride
##STR00377##
[0206]
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide (100 mg) obtained in
Example 180 is dissolved in dichloromethane (8 ml), and thereto are
added acetoxy acetylchloride (36 mg) and pyridine (36 .mu.l) under
ice-cooling, and the mixture is stirred at room temperature for 17
hours. To the reaction solution is poured a saturated aqueous
sodium hydrogen carbonate solution, and the mixture is extracted
with chloroform. The organic layer is washed with a saturated
brine, dried over sodium sulfate, and the solvent is evaporated
under reduced pressure. The resulting residue is purified by
NH-silica gel column chromatography (eluent: chloroform, then
chloroform/methanol=50/1) to give
trans-5-acetoxyacetylamino-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-
-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (110 mg). A portion
of this product is dissolved in ethanol, and treated with 4N
hydrogen chloride in ethyl acetate to give the title compound (16
mg).
[0207] APCI-MS M/Z: 556/558 [M+H].sup.+
Examples 190-196
[0208] The corresponding compounds are treated in a similar manner
to Example 189 to give the following compounds in a free form, or
which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00008 ##STR00378## Ex. Physicochemical No. -R.sup.2 -AY
properties 190 ##STR00379## ##STR00380## APCI-MS M/Z: 498/500 [M +
H].sup.+ Hydrochloride 191 ##STR00381## ##STR00382## APCI-MS M/Z:
528/530 [M + H].sup.+ Hydrochloride 192 ##STR00383## ##STR00384##
APCI-MS M/Z: 527/529 [M + H].sup.+ Hydrochloride 193 ##STR00385##
##STR00386## APCI-MS M/Z: 534/536 [M + H].sup.+ Hydrochloride 194
##STR00387## ##STR00388## APCI-MS M/Z: 647/649 [M + H].sup.+
Dihydrochloride 195 ##STR00389## ##STR00390## APCI-MS M/Z: 548/550
[M + H].sup.+ Hydrochloride 196 ##STR00391## ##STR00392## APCI-MS
M/Z: 556/558 [M + H].sup.+ Dihydrochloride
Example 197
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-hydroxyacetylamino-N-
-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide hydrochloride
##STR00393##
[0210]
Trans-5-acetoxyacetylamino-3-[4-(dimethylamino)-cyclohexylcarbonyla-
mino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (70 mg)
obtained in Example 189 is dissolved in tetrahydrofuran/methanol
(1:1, 8 ml), and thereto is added potassium carbonate (5 mg), and
the mixture is stirred at room temperature for 48 hours. The
reaction solution is concentrated under reduced pressure, and the
resulting residue is purified by silica gel column chromatography
(eluent: chloroform/methanol=30/1). The resulting
trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-hydroxyac-
etylamino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide is
dissolved in ethanol, and treated with 4N hydrogen chloride in
ethyl acetate to give the title compound (46 mg).
[0211] APCI-MS M/Z: 514 [M+H].sup.+
Example 198
Trans-5-dimethylamino-3-[4-(dimethylamino)-cyclohexylcarbonylamino]-N-(5-c-
hloropyridin-2-yl)benzo-furan-2-carboxamide dihydrochloride
##STR00394##
[0213]
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide (50 mg) obtained in
Example 180 is suspended in dichloromethane (3 ml), and thereto are
added successively 35% aqueous formaldehyde solution (82 .mu.l) and
sodium triacetoxy borohydride (70 mg) under ice-cooling. The
reaction solution is warmed to room temperature, and stirred for
11.5 hours. To the reaction solution is poured a saturated aqueous
sodium hydrogen carbonate solution under ice-cooling, and the
mixture is extracted with dichloromethane. The organic layer is
washed with a saturated brine, dried over sodium sulfate, and the
solvent is evaporated under reduced pressure. The resulting residue
is purified by NH-silica gel column chromatography (eluent: ethyl
acetate) to give
trans-5-dimethylamino-3-[4-(dimethylamino)cyclohexyl-carbonylamino]-N-(5--
chloropyridin-2-yl)benzofuran-2-carboxamide (44 mg). This product
is suspended in methanol, and treated with 4N hydrogen chloride in
ethyl acetate to give the title compound (49 mg).
[0214] APCI-MS M/Z: 528/530 [M+H].sup.+
Examples 199-200
[0215]
Trans-5-amino-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide obtained in Example 180
and the corresponding starting compounds are treated in a similar
manner to Example 198 to give the following compounds in a free
form, or which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00009 ##STR00395## Ex. Physicochemical No. -R.sup.2 -AY
properties 199 ##STR00396## ##STR00397## APCI-MS M/Z: 600/602 [M +
H].sup.+ Dihydrochloride 200 ##STR00398## ##STR00399## APCI-MS M/Z:
544/546 [M + H].sup.+ Dihydrochloride
Example 201
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-5-(2-hydroxy-1-hydroxy-
methylethoxy)-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
dihydrochloride
##STR00400##
[0217]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-5-(2-phenyl-[1,3-
]dioxan-5-yloxy)-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
(200 mg) obtained in Example 35 is dissolved in tetrahydrofuran (5
ml), and thereto is added 2N hydrochloric acid (5 ml), and the
mixture is stirred at room temperature for 3 hours. The reaction
solution is basified with a saturated aqueous sodium hydrogen
carbonate solution and potassium carbonate, and extracted with
chloroform. The organic layer is washed with a saturated brine,
dried over sodium sulfate, and the solvent is evaporated under
reduced pressure. The resulting residue is purified by NH-silica
gel column chromatography (eluent: methanol/ethyl
acetate=1/20.fwdarw.methanol/ethyl acetate=1/5) to give
trans-3-[(4-(dimethylamino)cyclohexyl-carbonylamino]-5-(2-hydroxy-1-hydro-
xymethylethoxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(162 mg). This product is dissolved in methanol, and thereto is
added 4N hydrogen chloride in ethyl acetate (1 ml). The solvent is
evaporated under reduced pressure, and the resulting residue is
suspended in diethyl ether, and the precipitates are collected by
filtration to give the title compound (141 mg).
[0218] APCI-MS M/Z: 531/533 [M+H].sup.+
Example 202
Trans-3-[4-(N-t-butoxycarbonyl-N-methylamino)-cyclohexylcarbonylamino]-5-m-
ethoxycarbonyl-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00401##
[0220]
Trans-4-(N-t-butoxycarbonyl-N-methylamino)cyclohexane-carboxylic
acid (4.12 g) obtained in Reference Example 115 is dissolved in
dichloromethane (80 ml), and thereto is added pyridine (7.9 ml). To
the mixture is added dropwise thionyl chloride (1.04 ml) under
ice-cooling, and the mixture is stirred at room temperature for 3
hours. The reaction solution is concentrated, and to the resulting
residue are added successively pyridine (80 ml),
3-amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamid-
e (2.76 g) obtained in Reference Example 72, and
4-dimethylaminopyridine (195 mg) under ice-cooling. The reaction
solution is warmed to room temperature, and stirred for 17 hours.
To the reaction solution is poured a saturated aqueous sodium
hydrogen carbonate solution, and the precipitates are collected by
filtration, washed successively with water and diethyl ether, and
dried to give the title compound (4.63 g).
[0221] APCI-MS M/Z: 585 [M+H].sup.+
Example 203
Trans-3-[4-(t-butoxycarbonylamino)cyclohexyl-carbonylamino]-N-(5-chloropyr-
idin-2-yl)benzofuran-2-carboxamide
##STR00402##
[0223] Trans-4-(t-butoxycarbonylamino)cyclohexanecarboxylic acid
(2.54 g) obtained in Reference Example 116 is dissolved in
dichloromethane (50 ml), and thereto is added pyridine (4.22 ml),
and the mixture is cooled with ice. To the mixture is added
dropwise thionyl chloride (0.76 ml), and the mixture is stirred at
room temperature for 5 hours. The reaction solution is cooled again
with ice, and thereto are added
3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.00 g)
obtained in Reference Example 74 and dichloromethane (20 ml), and
the mixture is stirred at room temperature for 15 hours. To the
reaction solution is poured water, and the mixture is extracted
with chloroform. The organic layer is washed successively with
water, 5% aqueous citric acid solution, water, a saturated aqueous
sodium hydrogen carbonate solution and a saturated brine, dried
over sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by silica gel column
chromatography (eluent: chloroform) and suspended in diethyl ether.
The precipitates are collected by filtration to give the title
compound (2.94 g).
[0224] APCI-MS M/Z: 513/515 [M+H].sup.+
Examples 204-217
[0225] The corresponding starting compounds are treated in a
similar manner to Example 202 or Example 203 to give the following
compounds.
TABLE-US-00010 ##STR00403## Ex. Physicochemical No. -R.sup.2 -AY
properties 204 --H ##STR00404## APCI-MS M/Z: 527/529 [M + H].sup.+
205 ##STR00405## ##STR00406## APCI-MS M/Z: 616/618 [M +
NH.sub.4].sup.+ 206 ##STR00407## ##STR00408## APCI-MS M/Z: 601/603
[M + H].sup.+ 207 ##STR00409## ##STR00410## APCI-MS M/Z: 614/616 [M
+ H].sup.+ Ex. Physicochemical No. Structure properties 208
##STR00411## APCI-MS M/Z: 512/514 [M + H].sup.+ ##STR00412## Ex.
Physicochemical No. -R.sup.2 -AY properties 209 ##STR00413##
##STR00414## APCI-MS M/Z: 588/590 [M + H].sup.+ 210 --H
##STR00415## APCI-MS M/Z: 527/529 [M + H].sup.+ 211 --H
##STR00416## APCI-MS M/Z: 499/501 [M + H].sup.+ 212 --H
##STR00417## APCI-MS M/Z: 513/515 [M + H].sup.+ 213 --H
##STR00418## APCI-MS M/Z: 527/529 [M + H].sup.+ 214 --H
##STR00419## APCI-MS M/Z: 511/513 [M + H].sup.+ 215 --H
##STR00420## APCI-MS M/Z: 487/489 [M + H].sup.+ 216 --H
##STR00421## APCI-MS M/Z: 501/503 [M + H].sup.+ 217 --H
##STR00422## APCI-MS M/Z: 513 [M + H].sup.+
Example 218
Trans-5-methoxycarbonyl-3-[4
(methylamino)-cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzo-fura-
n-2-carboxamide hydrochloride
##STR00423##
[0227]
Trans-3-[4-(N-t-butoxycarbonyl-N-methylamino)cyclo-hexylcarbonylami-
no]-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(4.60 g) obtained in Example 202 is dissolved in dioxane (20 ml),
and thereto is added 4N hydrogen chloride in dioxane (10 ml), and
the mixture is stirred at room temperature for 48 hours. The
reaction solution is diluted with diethyl ether, and the
precipitates are collected by filtration, washed several times with
diethyl ether and dried to give the title compound (4.02 g).
[0228] APCI-MS M/Z: 485/487 [M+H].sup.+
Example 219
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloropyridin-2-yl)benzofura-
n-2-carboxamide dihydrochloride
##STR00424##
[0230]
Trans-3-[4-(t-butoxycarbonylamino)cyclohexylcarbonyl-amino]-N-(5-ch-
loropyridin-2-yl)benzofuran-2-carboxamide (10.70 g) obtained in
Example 203 is dissolved in dioxane (150 ml), and thereto is added
4N hydrogen chloride in dioxane (150 ml). The mixture is stirred at
room temperature for 12 hours, and concentrated under reduced
pressure. The residue is crushed in diethyl ether, and collected by
filtration to give the title compound (9.80 g).
[0231] APCI-MS M/Z: 412/414 [M+H].sup.+
Example 220
3-[2-(piperidin-4-yl)acetylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-ca-
rboxamide
##STR00425##
[0233]
3-[2-(1-t-Butoxycarbonylpiperidin-4-yl)acetylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide (2.34 g) obtained in Example 212
is suspended in ethyl acetate (30 ml), and thereto is added 2.6N
hydrogen chloride in ethyl acetate (30 ml), and the mixture is
stirred at room temperature for 5 hours. The reaction solution is
concentrated under reduced pressure, and to the resulting residue
are added chloroform and an aqueous sodium hydrogen carbonate
solution. The precipitates are collected by filtration to give the
title compound (1.47 g).
[0234] APCI-MS M/Z: 413/415 [M+H].sup.+
Examples 221-233
[0235] The corresponding starting compounds are treated in a
similar manner to Example 218, Example 219 or Example 220 to give
the following compounds in a free form, or which are further
treated with hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00011 ##STR00426## Ex. Physicochemical No. -R.sup.2 -AY
properties 221 --H ##STR00427## APCI-MS M/Z: 427/429 [M + H].sup.+
222 ##STR00428## ##STR00429## APCI-MS M/Z: 499/501 [M + H].sup.+
Dihydrochloride 223 ##STR00430## ##STR00431## APCI-MS M/Z: 501/503
[M + H].sup.+ Dihydrochloride 224 ##STR00432## ##STR00433## APCI-MS
M/Z: 514/516 [M + H].sup.+ Trihydrochloride Ex. Physicochemical No.
Structure properties 225 ##STR00434## APCI-MS M/Z: 412/414 [M +
H].sup.+ Hydrochloride ##STR00435## Ex. Physicochemical No.
-R.sup.2 -AY properties 226 ##STR00436## ##STR00437## APCI-MS M/Z:
471/473 [M + H].sup.+ Hydrochloride 227 --H ##STR00438## APCI-MS
M/Z: 427/429 [M + H].sup.+ Dihydrochloride 228 --H ##STR00439##
APCI-MS M/Z: 399/401 [M + H].sup.+ 229 --H ##STR00440## APCI-MS
M/Z: 427/429 [M + H].sup.+ 230 --H ##STR00441## APCI-MS M/Z:
411/413 [M + H].sup.+ Dihydrochloride 231 --H ##STR00442## APCI-MS
M/Z: 387/389 [M + H].sup.+ 232 --H ##STR00443## APCI-MS M/Z:
401/403 [M + H].sup.+ 233 --H ##STR00444## APCI-MS M/Z: 413/415 [M
+ H].sup.+ Dihydrochloride
Example 234
Trans-3-[4-(N-formyl-N-methylamino)cyclohexyl-carbonylamino]-5-methoxycarb-
onyl-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
##STR00445##
[0237] To a solution of imidazole (783 mg) and triethylamine (2.41
ml) in chloroform (80 ml) is added dropwise formic acid (709 .mu.l)
with stirring under ice-cooling. Oxalyl chloride (1.00 ml) in
chloroform (10 ml) is further added thereto, and the mixture is
stirred at room temperature for 0.5 hour. The reaction solution is
cooled again with ice, and thereto is added
trans-5-methoxycarbonyl-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-c-
hloropyridine-2-yl)benzofuran-2-carboxamide hydrochloride (1.50 g)
obtained in Example 218. The mixture is warmed to room temperature
and stirred for 3 hours. To the reaction solution are poured
ice-water and a saturated aqueous sodium hydrogen carbonate
solution, and the mixture is extracted with chloroform. The extract
is washed with a saturated brine, and dried over sodium sulfate.
The solvent is evaporated under reduced pressure, and the resulting
residue is purified by NH-silica gel column chromatography (eluent:
chloroform) to give the title compound (1.45 g).
[0238] APCI-MS M/Z: 513/515 [M+H].sup.+
Examples 235-238
[0239] The corresponding starting compounds are treated in a
similar manner to Example 234 to give the following compounds.
TABLE-US-00012 ##STR00446## Ex. Physicochemical No. -R.sup.2 -AY
properties 235 ##STR00447## ##STR00448## APCI-MS M/Z: 527 [M +
H].sup.+ 236 --H ##STR00449## APCI-MS M/Z: 455/457 [M + H].sup.+
237 ##STR00450## ##STR00451## APCI-MS M/Z: 485/487 [M + H].sup.+
238 ##STR00452## ##STR00453## APCI-MS M/Z: 529/531 [M +
H].sup.+
Example 239
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-methoxycarb-
onyl-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
##STR00454##
[0241]
Trans-5-methoxycarbonyl-3-[4-(methylamino)cyclohexyl-carbonylamino]-
-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride
(1.50 g) obtained in Example 218 is suspended in dichloromethane
(80 ml), and thereto are added acetyl chloride (307 .mu.l) and
triethylamine (1.60 ml) under ice-cooling. The mixture is warmed to
room temperature, and stirred for 2 hours. To the reaction solution
is soured a saturated aqueous sodium hydrogen carbonate solution,
and the mixture is extracted with chloroform, washed with water and
a saturated brine, and dried over sodium sulfate. The solvent is
evaporated under reduced pressure, and the resulting residue is
purified by NH-silica gel column chromatography (eluent:
chloroform) to give the title compound (1.51 g).
[0242] APCI-MS M/Z: 527/520, [M+H].sup.+
Example 240
3-[(1-Acetylpiperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofur-
an-2-carboxamide
##STR00455##
[0244]
3-(Piperidin-4-yl)carbonylamino-3-N-(5-chloropyridin-2-yl)benzofura-
n-2-carboxamide (140 mg) obtained in Example 228 is suspended in
dichloromethane (10 ml), and thereto are added acetyl chloride (30
.mu.l) and triethylamine (74 .mu.l) under ice-cooling, and the
mixture is stirred at room temperature for 6 hours. The reaction
solution is diluted with chloroform, washed successively with
water, 5% aqueous citric acid solution, a saturated aqueous sodium
hydrogen carbonate solution and a saturated brine, and dried over
sodium sulfate. The solvent is evaporated under reduced pressure,
and the resulting residue is dissolved in ethyl acetate, and
treated with activated carbon. The resulting residue is
recrystallized from ethyl acetate to give the title compound (38
mg).
[0245] APCI-MS M/Z: 441/443 [M+H].sup.+
Examples 241-245
[0246] The corresponding starting compounds are treated in a
similar manner to Example 239 or Example 240 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00013 ##STR00456## Ex. Physicochemical No. -R.sup.2 -AY
properties 241 --H ##STR00457## APCI-MS M/Z: 483/485 [M + H].sup.+
242 --H ##STR00458## APCI-MS M/Z: 496/498 [M + H].sup.+ 243 --H
##STR00459## APCI-MS M/Z: 497/499 [M + H].sup.+ 244 --H
##STR00460## APCI-MS M/Z: 511/513 [M + H].sup.+ 245 --H
##STR00461## APCI-MS M/Z: 477/479 [M + H].sup.+
Example 246
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexyl-carbonylamino]-5-(2-methoxye-
thoxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00462##
[0248]
Trans-5-(2-methoxyethoxy)-3-[4-(methylamino)cyclo-hexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride
(110 mg) obtained in Example 223 is suspended in
N,N-dimethylformamide (5 ml), and thereto are added successively
acetic acid (13.2 .mu.l), 1-hydroxybenzotriazole (31 mg),
triethylamine (80 .mu.l) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (44
mg), and the mixture is stirred at room temperature for 15 hours.
To the reaction solution are added acetic acid (8.2 .mu.l),
1-hydroxybenzotriazole (20 mg), triethylamine (67 .mu.l) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (28
mg), and the mixture is further stirred at room temperature for 20
hours. To the reaction solution is poured a saturated aqueous
sodium hydrogen carbonate solution, and the mixture is extracted
with chloroform. The organic layer is washed with a saturated
brine, dried over sodium sulfate, and the solvent is evaporated
under reduced pressure. The resulting residue is purified by
NH-silica gel column chromatography (eluent: n-hexane/ethyl
acetate=1/1, then ethyl acetate). The obtained solid is suspended
in n-hexane/diisopropyl ether, and collected by filtration to give
the title compound (42 mg).
[0249] APCI-MS M/Z: 54.3/545 [M+H].sup.+
Example 247
3-[1-((Pyridin-3-yl)carbonyl)piperidin-4-yl-carbonylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide dihydrochloride
##STR00463##
[0251]
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofura-
n-2-carboxamide (100 mg) obtained in Example 228 is dissolved in
N,N-dimethylformamide (3 ml), and thereto are added successively
nicotinic acid (34 mg), 1-hydroxybenzotriazole (37 mg) and
1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (53
mg), and the mixture is stirred at room temperature for 4 hours. To
the reaction solution are poured a saturated aqueous sodium
hydrogen carbonate solution and water, and the precipitates are
collected by filtration, washed with chloroform, and dried to give
3-[1-((pyridin-3-yl)carbonyl)piperidin-4-ylcarbonylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide (103 mg). This product is treated
with hydrogen chloride in dioxane to give the title compound (115
mg).
[0252] APCI-MS M/Z: 504/506 [M+H].sup.+
Examples 248-257
[0253] The corresponding starting compounds are treated in a
similar manner to Example 246 or Example 247 to give the following
compounds in a free form, or which are treated with hydrogen
chloride to give hydrochlorides thereof.
TABLE-US-00014 ##STR00464## Ex. Physicochemical No. -R.sup.2 -AY
properties 248 --H ##STR00465## APCI-MS M/Z: 469/471 [M + H].sup.+
249 ##STR00466## ##STR00467## APCI-MS M/Z: 556/568 [M + H].sup.+
Dihydrochloride 250 --H ##STR00468## APCI-MS M/Z: 512/514 [M +
H].sup.+ 251 --H ##STR00469## APCI-MS M/Z: 554/556 [M + H].sup.+
252 --H ##STR00470## APCI-MS M/Z: 455/457 [M + H].sup.+ 253 --H
##STR00471## APCI-MS M/Z: 483/485 [M + H].sup.+ 254 --H
##STR00472## APCI-MS M/Z: 498/500 [M + H].sup.+ Dihydrochloride 255
--H ##STR00473## APCI-MS M/Z: 484/486 [M + H].sup.+ 256 --H
##STR00474## APCI-MS M/Z: 504/506 [M + H].sup.+ 257 --H
##STR00475## APCI-MS M/Z: 504/506 [M + H].sup.+ Dihydrochloride
Example 258
Trans-5-carboxy-3-[4-(N-formyl-N-methylamino)-cyclohexylcarbonylamino]-N-(-
5-chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00476##
[0255]
Trans-3-[4-(N-formyl-N-methylamino)cyclohexyl-carbonylamino]-5-meth-
oxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (1.90
g) obtained in Example 234 is suspended in tetrahydrofuran/methanol
(1:1, 50 ml), and thereto is added 4N aqueous sodium hydroxide
solution (5 ml) under ice-cooling. The mixture is warmed to room
temperature, and stirred for 17 hours. The reaction solution is
concentrated under reduced pressure, and to the residue is poured
ice-water, and the mixture is neutralized with 10% hydrochloric
acid. The precipitates are collected by filtration, washed
successively with water and tetrahydrofuran, and dried to give the
title compound (1.59 g).
[0256] ESI-MS M/Z: 497/499 [M-H].sup.-
Examples 259-260
[0257] The corresponding starting compounds are treated in a
similar manner to Example 258 to give the following compounds in a
free form, or which are treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00015 ##STR00477## Ex. Physicochemical No. --R.sup.2 --AY
properties 259 ##STR00478## ##STR00479## ESI-MS M/Z: 511/513 [M -
H].sup.- 260 ##STR00480## ##STR00481## ESI-MS M/Z: 511/513 [M -
H].sup.-
Example 261
Trans-5-dimethylaminocarbonyl-3-[4-(N-formyl-N-methylamino)cyclohexylcarbo-
nylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00482##
[0259]
Trans-5-carboxy-3-[4-(N-formyl-N-methylamino)cycl-hexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (196 mg)
obtained in Example 258 is suspended in
N,N-dimethylformamide/pyridine (1:1, 8 ml), and thereto are added
successively dimethylamine hydrochloride (49 mg),
1-hydroxybenzotriazole (108 mg) and
1-ethyl-3-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (153
mg) under ice-cooling, and the mixture is stirred at room
temperature for 48 hours. To the reaction solution is poured a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture is extracted with ethyl acetate. The extract is washed with
water and a saturated brine, dried over sodium sulfate. The solvent
is evaporated under reduced pressure, and the resulting residue is
purified by NH-silica gel column chromatography (eluent: ethyl
acetate). The resulting residue is suspended in diethyl
ether/n-hexane, and the precipitates are collected by filtration to
give the title compound (141 mg).
[0260] APCI-MS M/Z: 526/528 [M+H].sup.+
Examples 262-275
[0261] The corresponding starting compounds are treated in a
similar manner to Example 261 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00016 ##STR00483## Physicochemical Ex. No. --R.sup.2 --AY
properties 262 ##STR00484## ##STR00485## APCI-MS M/Z: 568/570 [M +
H].sup.+ 263 ##STR00486## ##STR00487## APCI-MS M/Z: 552/554 [M +
H].sup.+ 264 ##STR00488## ##STR00489## APCI-MS M/Z: 570/572 [M +
H].sup.+ 265 ##STR00490## ##STR00491## APCI-MS M/Z: 556/558 [M +
H].sup.+ 266 ##STR00492## ##STR00493## APCI-MS M/Z: 596/598 [M +
H].sup.+ 267 ##STR00494## ##STR00495## APCI-MS M/Z: 540/542 [M +
H].sup.+ 268 ##STR00496## ##STR00497## APCI-MS M/Z: 582/584 [M +
H].sup.+ 269 ##STR00498## ##STR00499## APCI-MS M/Z: 610/612 [M +
H].sup.+ 270 ##STR00500## ##STR00501## APCI-MS M/Z: 540/542 [M +
H].sup.+ 271 ##STR00502## ##STR00503## APCI-MS M/Z: 582/584 [M +
H].sup.+ 272 ##STR00504## ##STR00505## APCI-MS M/Z: 566/568 [M +
H].sup.+ 273 ##STR00506## ##STR00507## APCI-MS M/Z: 584/586 [M +
H].sup.+ 274 ##STR00508## ##STR00509## APCI-MS M/Z: 570/572 [M +
H].sup.+ 275 ##STR00510## ##STR00511## APCI-MS M/Z: 610/612 [M +
H].sup.+
Examples 276-277
[0262] The corresponding starting compounds are treated in a
similar manner to Example 145 to give the following compounds.
TABLE-US-00017 ##STR00512## Ex. Physicochemical No. --R.sup.2 --AY
properties 276 ##STR00513## ##STR00514## APCI-MS M/Z: 499/501 [M +
H].sup.+ 277 ##STR00515## ##STR00516## APCI-MS M/Z: 499/501 [M +
H].sup.+
Example 278
Trans-3-[4-(N-(2-hydroxyethyl)-N-methylamino)-cyclohexylcarbonylamino]-N-(-
5-chloropyridin-2-yl)benzo-furan-2-carboxamide dihydrochloride
##STR00517##
[0264] Trans-3-[4-(methylamino)cyclohexylcarbonyl
amino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide. (125 mg)
obtained in Example 221 is suspended in ethanol (5 ml), and thereto
are added 2-iodo-ethanol (105 .mu.l) and sodium carbonate (57 mg),
and the mixture is stirred at 50.degree. C. for 15 hours. To the
mixture is further added 2-iodo-ethanol (53 .mu.l), and the mixture
is further stirred at 80.degree. C. for 6 hours. Again,
2-iodo-ethanol (53 .mu.l) is added thereto, and the mixture is
stirred at 80.degree. C. for 24 hours. The reaction solution is
concentrated under reduced pressure, and to the residue is poured a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture is extracted with chloroform. The organic layer is washed
with water, a saturated brine, dried over sodium sulfate, and the
solvent is evaporated under reduced pressure. The resulting residue
is purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/2, then ethyl acetate) to give
trans-3-[4-(N-(2-hydroxyethyl)-N-methylamino)cyclo-hexylcarbonylamino]-N--
(5-chloropyridin-2-yl)benzofuran-2-carboxamide (53 mg).
Subsequently, this product is dissolved in chloroform/methanol
(5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl
acetate (1 ml). The solvent is evaporated under reduced pressure.
The resulting residue is suspended in diethyl ether, and collected
by filtration to give the title compound (55 mg).
[0265] APCI-MS M/Z: 471/473 [(M+H].sup.+
Example 279
3-[[1-((Pyridin-4-yl)methyl)piperidin-4-yl]-carbonylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide
##STR00518##
[0267]
3-((Pipiperidin-4-yl)carbonylamino)-N-(5-chloropyridin-2-yl)benzofu-
ran-2-carboxamide (100 mg) obtained in Example 228 is suspended in
N,N-dimethylacetamide (3 ml), and thereto are added
4-(chloromethyl)pyridine hydrochloride (45 mg), sodium carbonate
(80 mg) and sodium iodide (41 mg), and the mixture is stirred at
room temperature for 12 hours. To the reaction solution is poured a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture is extracted with ethyl acetate. The organic layer is
washed with water and a saturated brine, and dried over sodium
sulfate. The solvent is evaporated under reduced pressure, and the
resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate=2/1, then 1/1) to
give the title compound (109 mg).
[0268] APCI-MS M/Z: 490/492 [M+H].sup.+
Examples 280-289
[0269] The corresponding starting compounds are treated in a
similar manner to Example 278 or Example 279 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00018 ##STR00519## Ex. Physicochemical No. --R.sup.2 --AY
properties 280 --H ##STR00520## APCI-MS M/Z: 455/457 [M + H].sup.+
Dihydrochloride 281 --H ##STR00521## APCI-MS M/Z: 469/471 [M +
H].sup.+ Dihydrochloride Ex. Physicochemical No. Structure
properties 282 ##STR00522## APCI-MS M/Z: 468/470 [M + H].sup.+
Hydrochloride 283 ##STR00523## APCI-MS M/Z: 441/443 [M + H].sup.+
Dihydrochloride 284 ##STR00524## APCI-MS M/Z: 440/442 [M + H].sup.+
Hydrochloride ##STR00525## Ex. Physicochemical No. --R.sup.2 --AY
properties 285 --H ##STR00526## APCI-MS M/Z: 518/520 [M + H].sup.+
Trihydrochloride 286 --H ##STR00527## APCI-MS M/Z: 518/520 [M +
H].sup.+ Trihydrochloride 287 --H ##STR00528## APCI-MS M/Z: 517/519
[M + H].sup.+ Dihydrochloride 288 --H ##STR00529## APCI-MS M/Z:
490/492 [M + H].sup.+ Trihydrochloride 289 --H ##STR00530## APCI-MS
M/Z: 490/492 [M + H].sup.+ Trihydrochloride
Example 290
Trans-3-[(4-(2-hydroxyethylamino)cyclohexyl-carbonylamino]-N-(4-chlorophen-
yl)benzofuran-2-carboxamide hydrochloride
##STR00531##
[0271]
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(4-chloro-phenyl)benzofu-
ran-2-carboxamide hydrochloride (150 mg) obtained in Example 225 is
suspended in acetonitrile/methanol (5/1, 6 ml), and thereto is
added triethylamine (93 .mu.l), and the mixture is stirred at room
temperature for several minutes. The reaction solution is cooled
with ice, and thereto is added 2-iodo-ethanol (29 .mu.l), and the
mixture is stirred at 50.degree. C. for 3 hours. 2-Iodo-ethanol (58
.mu.l) is further added thereto, and the mixture is stirred at
50.degree. C. for 3 hours. Again, 2-iodo-ethanol (58 .mu.l) is
added thereto, and the mixture is further stirred at 50.degree. C.
for 15 hours. The reaction solution is concentrated under reduced
pressure, and to the residue are poured water and a saturated
aqueous sodium hydrogen carbonate solution, and the mixture is
extracted with chloroform. The organic layer is washed with water
and a saturated brine, dried over sodium sulfate, and the solvent
is evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent: ethyl
acetate, then ethyl acetate/methanol=20/1) to give
trans-3-[4-(2-hydroxyethylamino)cyclohexylcarbonylamino]-N-(4-chloro-phen-
yl)benzofuran-2-carboxamide (104 mg). This product (104 mg) is
dissolved in chloroform/methanol (5/1, 6 ml), and thereto is added
4N hydrogen chloride in ethyl acetate (1 ml). The solvent is
evaporated under reduced pressure, and the resulting residue is
suspended in diethyl ether, and collected by filtration to give the
title compound (95 mg).
[0272] APCI-MS M/Z: 456/458 [M+H].sup.+
Examples 291-296
[0273] The corresponding starting compounds are treated in a
similar manner to Example 290 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00019 Ex. Physicochemical No. Structure properties 291
##STR00532## APCI-MS M/Z: 500/502 [M + H].sup.+ Hydrochloride
##STR00533## Ex. Physicochemical No. --R.sup.2 --AY properties 292
--H ##STR00534## APCI-MS M/Z: 469/471 [M + H].sup.+ Dihydrochloride
293 --H ##STR00535## APCI-MS M/Z: 541/543 [M + H].sup.+ 294 --H
##STR00536## APCI-MS M/Z: 499/501 [M + H].sup.+ Dihydrochloride 295
--H ##STR00537## APCI-MS M/Z: 466/468 [M + H].sup.+ 296 --H
##STR00538## APCI-MS M/Z: 484/486 [M + H].sup.+
Example 297
Trans-3-[4-(morpholin-4-yl)cyclohexylcarbonyl-amino]-3-N-(5-chloropyridin--
2-yl)benzofuran-2-carboxamide dihydrochloride
##STR00539##
[0275]
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (200 mg) obtained in
Example 219 is suspended in N,N-dimethyl acetamide (10 ml), and
thereto are added bis(2-chloroethyl)ether (73 .mu.l), sodium iodide
(185 mg), and sodium carbonate (131 mg), and the mixture is stirred
at 50.degree. C. for 5 hours, and then stirred at 80.degree. C. for
3 hours. Bis(2-chloroethyl)ether (73 .mu.l) is further added
thereto, and the mixture is stirred at 80.degree. C. for 15 hours.
The reaction solution is concentrated under reduced pressure, and
to the residue is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with chloroform.
The organic layer is washed with water and a saturated brine, dried
over sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate=5/1, then 1/1) to
give
trans-3-(4-(morpholin-4-yl)cyclohexylcarbonylamino)-N-(5-chloro-p-
yridin-2-yl)benzofuran-2-carboxamide (70 mg).
[0276] Subsequently, this product is dissolved in
chloroform/methanol (5/1, 6 ml), and thereto is added 4N hydrogen
chloride in ethyl acetate (1 ml), and the solvent is evaporated
under reduced pressure. The resulting residue is suspended in
diethyl ether, and collected by filtration to give the title
compound (65 mg).
[0277] APCI-MS M/Z: 483/485 [M+H].sup.+
Examples 298-301
[0278] The corresponding starting compounds are treated in a
similar manner to Example 297 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00020 ##STR00540## Ex. Physicochemical No. --R.sup.2 --AY
properties 298 --H ##STR00541## APCI-MS M/Z: 467 [M + H].sup.+
Dihydrochloride 299 --H ##STR00542## APCI-MS M/Z: 453/455 [M +
H].sup.+ Dihydrochloride Ex. Physicochemical No. Structure
properties 300 ##STR00543## APCI-MS M/Z: 482/484 [M + H].sup.+
Hydrochloride 301 ##STR00544## APCI-MS M/Z: 466/468 [M + H].sup.+
Hydrochloride
Example 302
Trans-3-[4-(N-carboxymethyl-N-methylamino)-cyclohexylcarbonylamino]-N-(5-c-
hloropyridin-2-yl)-benzofuran-2-carboxamide dihydrochloride
##STR00545##
[0280]
Trans-3-[4-(N-t-butoxycarbonylmethyl-N-methylamino)-cyclohexylcarbo-
nylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (820
mg) obtained in Example 293 is treated in a similar manner to
Example 15.6 to give the title compound (778 mg).
[0281] ESI-MS M/Z: 507/509 [M+Na].sup.+
Examples 303-305
[0282]
Trans-3-[4-(N-carboxymethyl-N-methylamino)cyclohexyl-carbonylamino]-
-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide dihydrochloride
obtained in Example 302 is treated in a similar manner to Example
87 to give the following compounds in a free form, or which are
further treated with hydrogen chloride to give hydrochlorides
thereof.
TABLE-US-00021 ##STR00546## Ex. Physicochemical No. --R.sup.2 --AY
properties 303 --H ##STR00547## APCI-MS M/Z: 484/486 [M + H].sup.+
Dihydrochloride 304 --H ##STR00548## APCI-MS M/Z: 498/500 [M +
H].sup.+ Dihydrochloride 305 --H ##STR00549## APCI-MS M/Z: 512/514
[M + H].sup.+ Dihydrochloride
Example 306
Trans-3-[4-(dimethylamino)cyclohexylcarbonyl-amino]-3-N-(5-chloropyridin-2-
-yl)benzofuran-2-carboxamide hydrochloride
##STR00550##
[0284]
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (9.30 g) obtained in
Example 219 is suspended in dichloromethane (430 ml), and thereto
is added triethylamine (7.99 ml) under ice-cooling, and the mixture
is stirred for several minutes. Then, 35% aqueous formaldehyde
solution (7.59 ml) and sodium triacetoxy borohydride (12.10 g) are
successively added thereto, and the reaction solution is warmed to
room temperature, and stirred for 12 hours. To the reaction
solution is poured a saturated aqueous sodium hydrogen carbonate
solution under ice-cooling, and the mixture is extracted with
chloroform. The organic layer is washed successively with water and
a saturated brine, dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The residue is purified by
NH-silica gel column chromatography (eluent: n-hexane/ethyl
acetate=3/1, then ethyl acetate) to give
trans-3-[4-(dimethylamino)-cyclohexylcarbonylamino]-N-(5-chloropyridin-2--
yl)benzo-furan-2-carboxamide (6.92 g). This product is dissolved in
chloroform/methanol (5/1, 60 ml), and thereto is added 4N hydrogen
chloride in ethyl acetate (50 ml) under ice-cooling. The reaction
solution is concentrated under reduced pressure, and the resulting
residue is suspended in diethyl ether, and collected by filtration
to give the title compound (7.83 g).
[0285] APCI-MS M/Z: 441/443 [M+H].sup.+
Example 307
Trans-3-[4-[N-[3-(t-butoxycarbonylamino)-propyl]-N-methylamino]cyclohexylc-
arbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00551##
[0287]
Trans-3-[4-(methylamino)cyclohexylcarbonylamino]-N-(5-chloropyridin-
-2-yl)benzofuran-2-carboxamide (250 mg) obtained in Example 221 is
suspended in dichloromethane (8 ml), and thereto are added
3-t-butoxycarbonylaminopropanal (198 mg) and triethylamine (160
.mu.l) under ice-cooling, and the mixture is stirred for several
minutes. Then, sodium triacetoxy borohydride (243 mg) and the
reaction solution is warmed to room temperature, and stirred for 4
hours. To the reaction solution is poured a saturated aqueous
sodium hydrogen carbonate solution under ice-cooling, and the
mixture is extracted with chloroform. The organic layer is washed
successively with water and a saturated brine, dried over sodium
sulfate, and the solvent is evaporated under reduced pressure. The
resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to
give the title compound (312 mg).
[0288] APCI-MS M/Z: 584/586 [M+H].sup.+
Examples 308-326
[0289] The corresponding starting compounds are treated in a
similar manner to Example 306 or Example 307 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00022 Ex. Physicochemical No. Structure properties 308
##STR00552## APCI-MS M/Z: 440/442 [M + H].sup.+ Hydrochloride
##STR00553## Ex. Physicochemical No. --R.sup.2 --AY properties 309
--H ##STR00554## APCI-MS M/Z: 455/457 [M + H].sup.+ Dihydrochloride
310 --H ##STR00555## APCI-MS M/Z: 455/457 [M + H].sup.+
Dihydrochloride 311 ##STR00556## ##STR00557## APCI-MS M/Z: 513/515
[M + H].sup.+ 312 --H ##STR00558## APCI-MS M/Z: 469/471 [M +
H].sup.+ Dihydrochloride 313 --H ##STR00559## APCI-MS M/Z: 481/483
[M + H].sup.+ Dihydrochloride 314 --H ##STR00560## APCI-MS M/Z:
495/497 [M + H].sup.+ Dihydrochloride 315 --H ##STR00561## APCI-MS
M/Z: 527/529 [M + H].sup.+ 316 --H ##STR00562## APCI-MS M/Z:
570/572 [M + H].sup.+ 317 --H ##STR00563## APCI-MS M/Z: 598/600 [M
+ H].sup.+ 318 --H ##STR00564## APCI-MS M/Z: 584/586 [M + H].sup.+
319 --H ##STR00565## APCI-MS M/Z: 441/443 [M + H].sup.+
Dihydrochloride 320 --H ##STR00566## APCI-MS M/Z: 415/417 [M +
H].sup.+ Hydrochloride 321 --H ##STR00567## APCI-MS M/Z: 429/432 [M
+ H].sup.+ Hydrochloride 322 --H ##STR00568## APCI-MS M/Z: 453/455
[M + H].sup.+ Dihydrochloride 323 --H ##STR00569## APCI-MS M/Z:
413/415 [M + H].sup.+ Dihydrochloride 324 --H ##STR00570## APCI-MS
M/Z: 524/526 [M + H].sup.+ Trihydrochloride 325 --H ##STR00571##
APCI-MS M/Z: 496/498 [M + H].sup.+ Trihydrochloride 326 --H
##STR00572## APCI-MS M/Z: 582/584 [M + H].sup.+
Example 327
Trans-3-[4-[N-[3-(dimethylamino)propyl]-N-methylamino]cyclohexylcarbonylam-
ino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
trihydrochloride
##STR00573##
[0290] (1) 3-Aminopropionaldehyde diethyl acetal (5.00 g) is
dissolved in dichloromethane (70 ml), and thereto are added
successively 35% aqueous formaldehyde solution (13.5 ml) and sodium
triacetoxy borohydride (18.0 g) under ice-cooling, and the reaction
solution is warmed to room temperature and stirred for 6 hours. To
the reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution under ice-cooling, and further thereto is added
potassium carbonate. The mixture is extracted with chloroform, and
the organic layer is washed with a saturated brine, dried over
sodium sulfate, and the solvent is evaporated under reduced
pressure to give crude 3-(dimethylamino)propionaldehyde diethyl
acetal (5.31 g). (2) 3-(Dimethylamino)propionaldehyde diethyl
acetal (284 mg) obtained in Example 327-(1) is dissolved in
tetrahydro-furan (3 ml), and thereto is added conc. hydrochloric
acid (3 ml), and the mixture is stirred at room temperature for 15
hours. The reaction solution is concentrated to dryness under
reduced pressure, and the resulting residue is dissolved in
dichloromethane (7 ml).
Trans-3-[4-(methyl-amino)cyclohexylcarbonylamino]-N-(5-chloropyridin-2-yl-
)benzofuran-2-carboxamide (150 mg) obtained in Example 221 and
triethylamine (226 .mu.l) are added thereto, and the mixture is
stirred for several minutes. Then, sodium triacetoxy borohydride
(137 mg) is added thereto, and the reaction solution is warmed to
room temperature, and stirred for 15 hours. To the reaction
solution is added a saturated aqueous sodium hydrogen carbonate
solution under ice-cooling, and the mixture is extracted with
chloroform. The organic layer is washed successively with water and
a saturated brine, dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent: ethyl
acetate, then ethyl acetate/methanol=20/1) to give
trans-3-[4-[N-[3-(dimethylamino)propyl]-N-methyl-amino]cyclohexylcarbonyl-
amino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (99 mg).
Subsequently, this product is dissolved in chloroform/methanol
(5/1, 6 ml), and thereto is added 4N hydrogen chloride in ethyl
acetate (1 ml), and the solvent is evaporated under reduced
pressure. The resulting residue is suspended in diethyl ether, and
collected by filtration to give the title compound (106 mg).
[0291] APCI-MS M/Z: 512/514 [M+H].sup.+
Examples 328-332
[0292] The corresponding starting compounds are treated in a
similar manner to Example 327 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00023 ##STR00574## Ex. Physicochemical No. --R.sup.2 --AY
properties 328 --H ##STR00575## APCI-MS M/Z: 498/500 [M + H].sup.+
Trihydrochloride 329 --H ##STR00576## APCI-MS M/Z: 498/500 [M +
H].sup.+ Trihydrochloride 330 --H ##STR00577## APCI-MS M/Z: 583/585
[M + H].sup.+ Tetrahydrochloride 331 --H ##STR00578## APCI-MS M/Z:
484/486 [M + H].sup.+ Trihydrochloride 332 --H ##STR00579## APCI-MS
M/Z: 555/557 [M + H].sup.+ Tetrahydrochloride
Example 333
Trans-3-[4-(piperidin-1-yl)cyclohexylcarbonyl-amino]-N-(5-chloropyridin-2--
yl)benzofuran-2-carboxamide d-hydrochloride
##STR00580##
[0294]
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (125 mg) obtained in
Example 219 is suspended in dichloromethane (10 ml), and thereto is
added triethylamine (102 .mu.l) under ice-cooling, and the mixture
is stirred for several minutes. Then, about 25% aqueous
glutaraldehyde solution (150 mg) and sodium triacetoxy borohydride
(155 mg) are added successively, and the mixture is stirred under
ice-cooling for 2 hours. To the reaction solution is poured a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture is extracted with chloroform. The organic layer is washed
successively with water and a saturated brine, dried over sodium
sulfate, and the solvent is evaporated under reduced pressure. The
resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate=3/1, then 1/1) to
give
trans-3-[4-(piperidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloro-pyridin-2-
-yl)benzofuran-2-carboxamide (106 mg). Subsequently, this product
is dissolved in chloroform/methanol (5/1, 6 ml), and 4N hydrogen
chloride in ethyl acetate (5 ml) is added thereto under
ice-cooling. The reaction solution is concentrated under reduced
pressure, and the resulting residue is suspended in diethyl ether,
and collected by filtration to give the title compound (107
mg).
[0295] APCI-MS M/Z: 481/483 [M+H].sup.+
Example 334
Trans-3-[4-(N-acetyl-N-isopropylamino)cycl)-hexylcarbonylamino]-N-(5-chlor-
opyridin-2-yl)benzofuran-2-carboxamide
##STR00581##
[0297]
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide (100 mg) obtained in Example 310
and triethylamine (61 .mu.l) is dissolved in chloroform (5 ml), and
thereto is added acetyl chloride (24 .mu.l). The mixture is stirred
at room temperature for one hour, and thereto is poured a saturated
aqueous sodium hydrogen carbonate solution, and the mixture is
extracted with chloroform. The organic layer is washed successively
with water and a saturated brine, dried over sodium sulfate, and
the solvent is evaporated under reduced pressure. The resulting
residue is purified by silica gel column chromatography (eluent:
n-hexane/ethyl acetate 1/1, then ethyl acetate). The resulting
residue is suspended in n-hexane, and collected by filtration to
give the title compound (60 mg).
[0298] APCI-MS M/Z: 497/499 [M+H].sup.+
Example 335
Trans-3-[4-(2-oxopyrrolidin-1-yl)cyclo-hexylcarbonylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide
##STR00582##
[0300]
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (150 mg) obtained in
Example 219 is suspended in dichloromethane (5 ml), and thereto is
added triethylamine (129 .mu.l) under ice-cooling, and the mixture
is stirred for several minutes. Then, 15% aqueous succinic
semialdehyde solution (290 .mu.l) and sodium triacetoxy borohydride
(131 mg) are successively added thereto, and under ice-cooling, the
mixture is stirred for 0.5 hour. Then, 1-hydroxybenzotriazole (63
mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(118 mg) and N,N-dimethylformamide (3 ml) are successively added
thereto, and the mixture is stirred at room temperature for 15
hours. The reaction solution is concentrated under reduced
pressure, and thereto is poured chloroform. The mixture is washed
successively with a saturated aqueous sodium hydrogen carbonate
solution, water, and a saturated brine, dried over sodium sulfate,
and the solvent is evaporated under reduced pressure. The resulting
residue is purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/1, then ethyl acetate), and the resulting
residue is suspended in n-hexane, and collected by filtration to
give the title compound (29 mg).
[0301] APCI-MS M/Z: 481/483 [M+H].sup.+
Example 336
Trans-3-[4-(t-butoxycarbonylamino)cyclohexyl-carbonylamino]-5-carboxy-N-(5-
-chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00583##
[0303]
Trans-3-[4-(t-butoxycarbonylamino)cyclohexylcarbonyl-amino]-5-metho-
xycarbonyl-N-(5-chloropyridine-2-yl)benzo-furan-2-carboxamide (540
mg) obtained in Example 209 is treated in a similar manner to
Example 77 to give the title compound (475 mg).
[0304] ESI-MS M/Z: 555/557 [M-H].sup.-
Example 337
Trans-3-[4-(N-t-butoxycarbonyl-N-methylamino)-cyclohexylcarbonylamino]-5-c-
arboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00584##
[0306]
Trans-3-[4-(N-t-butoxycarbonyl-N-menethylamino)cyclo-hexylcarbonyla-
mino]-5-methoxycarbonyl-N-5-chloropyridin-2-yl)benzofuran-2-carboxamide
(3.52 g) obtained in Example 202 is treated in a similar manner to
Example 77 to give the title compound (3.19 g).
[0307] ESI-MS M/Z: 569/571 [M-H].sup.-
Examples 338-340
[0308] The corresponding starting compounds are treated in a
similar manner to Example 87 to give the following compounds.
TABLE-US-00024 ##STR00585## Ex. Physicochemical No. --R.sup.2 --AY
properties 338 ##STR00586## ##STR00587## ESI-MS M/Z: 582/584 [M -
H].sup.- 339 ##STR00588## ##STR00589## APCI-MS M/Z: 601/603 [M +
NH.sub.4].sup.+ 340 ##STR00590## ##STR00591## APCI-MS M/Z: 615/617
[M + NH.sub.4].sup.+
Examples 341-344
[0309] The corresponding starting compounds are treated in a
similar manner to Example 218 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00025 ##STR00592## Ex. Physicochemical No. --R.sup.2 --AY
properties 341 ##STR00593## ##STR00594## ESI-MS M/Z: 471/473 [M +
H].sup.+ Dihydrochloride 342 ##STR00595## ##STR00596## APCI-MS M/Z:
484/486 [M + H].sup.+ Dihydrochloride 343 ##STR00597## ##STR00598##
APCI-MS M/Z: 498/500 [M + H].sup.+ Dihydrochloride 344 ##STR00599##
##STR00600## APCI-MS M/Z: 484/486 [M + H].sup.+ Hydrochloride
Example 345
Trans-5-dimethylaminocarbonyl-3-[4-(isopropyl-amino)cyclohexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
hydrochloride
##STR00601##
[0311]
Trans-3-(4-aminocyclohexylcarbonylamino)-5-dimethyl-aminocarbonyl-N-
-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride (160
mg) obtained in Example 344 is suspended in dichloromethane (8 ml),
and thereto are added successively triethylamine (129 .mu.l),
acetone (113 .mu.l), and sodium triacetoxy borohydride (130 mg)
under ice-cooling, and the reaction solution is warmed to room
temperature, and stirred for 17 hours. Under ice-cooling, to the
reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with chloroform.
The organic layer is washed with a saturated brine, dried over
sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: ethyl acetate, then
chloroform/methanol=30/1). The resulting residue is dissolved in
ethanol, and thereto is added 4N hydrogen chloride in ethyl
acetate. The reaction solution is concentrated and the resulting
residue is suspended in diethyl ether. The precipitates are
collected by filtration to give the title compound (94 mg).
[0312] APCI-MS M/Z: 526/528 [M+H].sup.+
Example 346
Trans-5-carboxy-3-[4-(isopropylamino)cyclo-hexylcarbonylamino]-N-(5-chloro-
pyridin-2-yl)benzofuran-2-carboxamide
##STR00602##
[0314]
Trans-3-[4-(isopropylamino)cyclohexylcarbonylamino]-5-methoxycarbon-
yl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (690 mg)
obtained in Example 311 is suspended in tetrahydrofuran/methanol
(1:1, 10 ml), and under ice-cooling, thereto is added 4N aqueous
sodium hydroxide solution (3 ml). The mixture is warmed to room
temperature, and stirred for 18 hours. The reaction solution is
concentrated under reduced pressure, and poured into ice-water. The
mixture is neutralized with 10% hydrochloric acid, and the
precipitates are collected by filtration, washed successively with
water, tetrahydrofuran, and diethyl ether, and dried to give the
title compound (702 mg).
[0315] ESI-MS M/Z: 497/499 [M-H].sup.-
Examples 347-349
[0316] Trans-5-carboxy-3-[(4-(isopropylamino)cyclohexyl-carbonyl
amino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in
Example 346 is treated in a similar manner to Example 87 to give
the following compounds in a free form, or which are further
treated with hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00026 ##STR00603## Ex. Physicochemical No. -R.sup.2 -AY
properties 347 ##STR00604## ##STR00605## APCI-MS M/Z: 568/570 [M +
H].sup.+ Hydrochloride 348 ##STR00606## ##STR00607## APCI-MS M/Z:
552/554 [M + H].sup.+ Hydrochloride 349 ##STR00608## ##STR00609##
APCI-MS M/Z: 596/598 [M + H].sup.+ Hydrochloride
Examples 350-354
[0317] The corresponding starting compounds are treated in a
similar manner to Example 218 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00027 ##STR00610## Ex. Physicochemical No. -R.sup.2 -AY
properties 350 --H ##STR00611## APCI-MS M/Z: 484/486 [M + H].sup.+
Trihydrochloride 351 --H ##STR00612## APCI-MS M/Z: 498/500 [M +
H].sup.+ Trihydrochloride 352 --H ##STR00613## APCI-MS M/Z: 470/472
[M + H].sup.+ Trihydrochloride 353 --H ##STR00614## APCI-MS M/Z:
484/486 [M + H].sup.+ Trihydrochloride 354 --H ##STR00615## APCI-MS
M/Z: 482/484 [M + H].sup.+ Trihydrochloride
Examples 355-362
[0318] The corresponding starting compounds are treated in a
similar manner to Example 239 or Example 246 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00028 ##STR00616## Ex. Physicochemical No. -R.sup.2 -AY
properties 355 --H ##STR00617## APCI-MS M/Z: 526/528 [M + H].sup.+
Dihydrochloride 356 --H ##STR00618## APCI-MS M/Z: 540/542 [M +
H].sup.+ Dihydrochloride 357 --H ##STR00619## APCI-MS M/Z: 512-514
[M + H].sup.+ Dihydrochloride 358 --H ##STR00620## APCI-MS M/Z:
526/528 [M + H].sup.+ Dihydrochloride 359 --H ##STR00621## APCI-MS
M/Z: 569/571 [M + H].sup.+ Trihydrochloride 360 --H ##STR00622##
APCI-MS M/Z: 583/585 [M + H].sup.+ Trihydrochloride 361 --H
##STR00623## APCI-MS M/Z: 555/557 [M + H].sup.+ Trihydrochloride
362 --H ##STR00624## APCI-MS M/Z: 569/571 [M + H].sup.+
Trihydrochloride
Examples 363-364
[0319] The corresponding starting compounds are treated in a
similar manner to Example 306 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00029 ##STR00625## Ex. Physicochemical No. -R.sup.2 -AY
properties 363 --H ##STR00626## APCI-MS M/Z: 495/497 [M + H].sup.+
Dihydrochloride 364 --H ##STR00627## APCI-MS M/Z: 541/543 [M +
H].sup.+
Examples 365-366
[0320] The corresponding starting compounds are treated in a
similar manner to Example 201 to give the following compounds in a
free form, or which are further treated with hydrogen chloride to
give hydrochlorides thereof.
TABLE-US-00030 ##STR00628## Ex. Physicochemical No. -R.sup.2 -AY
properties 365 --H ##STR00629## APCI-MS M/Z: 487/489 [M + H].sup.+
Dihydrochloride 366 --H ##STR00630## APCI-MS M/Z: 501/503 [M +
H].sup.+ Dihydrochloride
Example 367
[4-[2-(4-Chlorophenylcarbamoyl)benzofuran-3-ylcarbamoyl]cyclohexyl]trimeth-
ylammonium iodide
##STR00631##
[0322]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(4-chloropheny-
l)benzofuran-2-carboxamide (106 mg) obtained in Example 308 is
dissolved in dichloromethane (5 ml), and thereto is added methyl
iodide (30 .mu.l), and the mixture is stirred at room temperature
for 5 hours. To the reaction solution is poured dichloromethane
diethyl ether (1/5, 25 ml), and the precipitates are collected by
filtration to give the title compound (126 mg)
[0323] ESI-MS M/Z: 454/456 [M-I].sup.+
Example 368
[4-[2-(5-Chloropyridin-2-ylcarbamoyl)benzo-furan-3-ylcarbamoyl]cyclohexyl]-
trimethylammonium iodide
##STR00632##
[0325]
Trans-3-[4-(dimethylamino)cyclohexylcarbonylamino]-N-(5-chloropyrid-
in-2-yl)benzofuran-2-carboxamide (150 mg) obtained in Example 306
and methyl iodide (21 .mu.l) are treated in a similar manner to
Example 367 to give the title compound (137 mg).
[0326] ESI-MS M/Z: 455/457 [M+I].sup.+
Example 369
3-[2-[1-(4,5-Dihydroxazol-2-yl)piperidin-4-yl]acetylamino]-N-(5-chloropyri-
din-2-yl)benzofuran-2-carboxamide
##STR00633##
[0328]
3-[2-(Piperidin-4-yl)acetylamino]-N-(5-chloropyridin-2-yl)benzofura-
n-2-carboxamide (103 mg) obtained in Example 220 is suspended in
tetrahydrofuran (5 ml), and thereto is added 2-bromoethyl
isocyanate (27 .mu.l), and the mixture is stirred at room
temperature for one hour. Triethylamine (280 .mu.l) is added
thereto, and the mixture is further stirred at room temperature for
6 hours. To the reaction solution are poured water and ethyl
acetate, and the precipitates are collected by filtration, washed
with ethyl acetate, and dried to give the title compound (50
mg).
[0329] APCI-MS M/Z: 482/484 [M+H].sup.+
Examples 370-372
[0330] The corresponding starting compounds are treated in a
similar manner to Example 369 to give the following compounds.
TABLE-US-00031 ##STR00634## Ex. Physicochemical No. -R.sup.2 -AY
properties 370 --H ##STR00635## APCI-MS M/Z: 496/498 [M + H].sup.+
371 --H ##STR00636## APCI-MS M/Z: 468/470 [M + H].sup.+ 372 --H
##STR00637## APCI-MS M/Z: 496/498 [M + H].sup.+
Example 373
3-[[1-(2-Thiazolyl)piperidin-4-yl]carbonyl-amino]-N-(5-chloropyridin-2-yl)-
benzofuran-2-carboxamide hydrochloride
##STR00638##
[0332]
3-[(Piperidin-4-yl)carbonylamino]-N-(5-chloropyridin-2-yl)benzofura-
n-2-carboxamide (100 mg) obtained in Example 228 is suspended in
2-butanol (5 ml), and thereto are added 2-bromothiazole (113 .mu.l)
and N,N-diisopropylethylamine (131 .mu.l), and the mixture is
heated under reflux for 24 hours. To the reaction solution are
added 2-bromothiazole (57 .mu.l) and N,N-dimethylacetamide (2 ml),
and the mixture is further heated under reflux for 24 hours. To the
reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with chloroform.
The organic layer is washed with water and a saturated brine, and
dried over sodium sulfate. The solvent is evaporated under reduced
pressure, and the resulting residue is purified by silica gel
column chromatography (eluent: n-hexane/ethyl acetate=3/1, then
ethyl acetate) to give
3-[[1-(2-thiazolyl)piperidin-4-yl]-carbonylamino]-N-(5-chloropyridin-2-yl-
)benzofuran-2-carboxamide (38 mg). This product is further treated
with hydrogen chloride in dioxane to give the title compound (25
mg).
[0333] APCI-MS M/Z: 482/484 [M+H].sup.+
Example 374
Trans-3-[4-((pyrimidin-2-yl)amino)cyclo-hexylcarbonylamino]-N-(5-chloropyr-
idin-2-yl)benzofuran-2-carboxamide dihydrochloride
##STR00639##
[0335]
Trans-3-[4-aminocyclohexylcarbonylamino]-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (350 mg) obtained in
Example 219 and 2-chloropyrimidine (99 mg) are treated in a similar
manner to Example 373 to give the title compound (65 mg).
[0336] APCI-MS M/Z: 491/493 [M+H].sup.+
Example 375
Trans-3-[4-(pyrrol-1-yl)cyclohexylcarbonyl-amino]-N-(5-chloropyridin-2-yl)-
benzofuran-2-carboxamide
##STR00640##
[0338]
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloro-pyridin-2-yl)b-
enzofuran-2-carboxamide dihydrochloride (200 mg) obtained in
Example 219, tetrahydro-2,5-dimethoxyfuran (53 .mu.l), sodium
acetate (68 mg) are stirred at 80.degree. C. for 2 hours in acetic
acid (3 ml). To the mixture is added tetrahydro-2,5-dimethoxyfuran
(26 .mu.l), and the mixture is further stirred at 80.degree. C. for
2 hours. After cooling, the reaction solution is poured into
ice-water, and the mixture is extracted with chloroform. The
organic layer is washed with a saturated aqueous sodium hydrogen
carbonate solution, a saturated brine, and dried over sodium
sulfate, and the solvent is evaporated under reduced pressure. The
resulting residue is purified by NH-silica gel column
chromatography (eluent: ethyl acetate/hexane=1/5.fwdarw.ethyl
acetate/hexane=1/3) to give the title compound (96 mg).
[0339] APCI-MS M/Z: 463/465 [M+H].sup.+
Example 376
3-[(1-t-Butoxycarbonylpiperidin-4-yl)oxy-carbonylamino]-N-(5-chloropyridin-
-2-yl)benzofuran-2-carboxamide
##STR00641##
[0341] t-Butyl 4-hydroxy-1-piperidinecarboxylate (175 mg) and
triphosgene (90 mg) are dissolved in dichloromethane (5 ml), and
thereto is added pyridine (77 .mu.l) with stirring under
ice-cooling. The reaction solution is stirred at room temperature
for 3 hours, and then cooled again with ice. To the mixture is
added 3-amino-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
(250 mg) obtained in Reference Example 74, and the mixture is
stirred for several minutes. Pyridine (105 .mu.l) is added to the
mixture, and the mixture is stirred at room temperature for 3
hours. The reaction solution is poured into water, and the mixture
is extracted with chloroform. The organic layer is washed
successively with 5% aqueous citric acid solution, water, a
saturated aqueous sodium hydrogen carbonate solution and a
saturated brine, dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=10/1, then 5/1) to give the title compound
(406 mg).
[0342] APCI-MS M/Z: 515/517 [M+H].sup.+
Example 377
Trans-3-[4-(t-butoxycarbonylamino)cyclohexyl-oxycarbonylamino]-N-(5-chloro-
pyridin-2-yl)benzofuran-2-carboxamide
##STR00642##
[0344] 3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(500 mg) obtained in Reference Example 74 and t-butyl
trans-(4-hydroxycyclohexyl)carbamate (375 mg) is treated in a
similar manner to Example 376 to give the title compound (680
mg).
[0345] APCI-MS M/Z: 529/531 [M+H].sup.+
Examples 378-379
[0346] The compound obtained in Example 376 or Example 377 is
treated in a similar manner to Example 220 to give the following
compounds.
TABLE-US-00032 ##STR00643## Ex. Physicochemical No. -R.sup.2 -AY
properties 378 --H ##STR00644## APCI-MS M/Z: 415/417 [M + H].sup.+
Dihydrochloride 379 --H ##STR00645## APCI-MS M/Z: 429/431 [M +
H].sup.+ Dihydrochloride
Examples 380-381
[0347] The compound obtained in Example 378 or Example 379 is
treated in a similar manner to Example 345 to give the following
compounds in a free form, or which are further treated with
hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00033 ##STR00646## Ex. Physicochemical No. -R.sup.2 -AY
properties 380 --H ##STR00647## APCI-MS M/Z: 457/459 [M + H].sup.+
Dihydrochloride 381 --H ##STR00648## APCI-MS M/Z: 457/459 [M +
H].sup.+ Dihydrochloride
Example 382
3-[3-(1-Isopropylpiperidin-4-yl)ureido]-N-(5-chloropyridin-2-yl)benzofuran-
-2-carboxamide dihydrochloride
##STR00649##
[0348] (1) 1-Isopropylpiperidine-4-carboxylic acid hydrochloride
(3.00 g) obtained in Reference Example 130 is suspended in toluene
(180 ml), and thereto are added triethylamine (5.0 ml) and
diphenylphosphoryl azide (4.0 ml), and the mixture is heated at
100.degree. C. for 2 hours. After cooling, to the reaction solution
is added benzyl alcohol (4.5 ml) at room temperature, and the
mixture is heated under reflux for 4 hours. The reaction solution
is concentrated under reduced pressure, and the resulting residue
is diluted with ethyl acetate, and washed successively with a
saturated aqueous sodium hydrogen carbonate solution, water and a
saturated brine. The resultant is dried over sodium sulfate, and
the solvent is evaporated under reduced pressure. The residue is
purified by NH-silica gel column chromatography (eluent:
n-hexane/diethyl ether=2/1, then n-hexane/ethyl acetate=2/1) to
give a crude product (6.32 g) containing benzyl
(1-isopropylpiperidin-4-yl)carbamate.
[0349] APCI-MS M/Z: 277 r[M+H].sup.+
(2) The crude product (6.32 g) containing benzyl
(1-isopropylpiperidin-4-yl)carbamate obtained in Example 382-(1) is
dissolved in ethanol (100 ml), and thereto is added 10% palladium
on carbon (600 mg), and the mixture is stirred at ambient
temperature under hydrogen atmosphere overnight. The insoluble
materials are removed by filtration, and the filtrate is
concentrated under reduced pressure, and subjected to azeotropic
distillation with toluene. The resulting residue is purified by
NH-silica gel column chromatography (eluent: n-hexane/ethyl acetate
1/1, then chloroform/methanol=20/1, and further 10/1) to give
4-amino-1-isopropylpiperidine (1.90 g). The resulting
4-amino-1-isopropylpiperidine is treated with 4N hydrogen chloride
in dioxane to give 4-amino-1-isopropylpiperidine
dihydrochloride.
[0350] APCI-MS M/Z: 143 [M+H].sup.+
(3) 4-amino-1-isopropylpiperidine dihydrochloride (112 mg) obtained
in Example 382-(2) and triphosgene (54 mg) are suspended in
dichloromethane (3 ml), and thereto is added pyridine (253 .mu.l)
with stirring under ice-cooling. The reaction solution is stirred
at room temperature for 3 hours, and
3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (150 mg)
obtained in Reference Example 74 is added thereto, and the mixture
is stirred at room temperature for 12 hours, then further heated
under reflux for 15 hours. To the reaction solution are poured
water and a saturated aqueous sodium hydrogen carbonate solution,
and the mixture is extracted with chloroform. The organic layer is
washed with a saturated brine, dried over sodium sulfate, and the
solvent is evaporated under reduced pressure. The resulting residue
is purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=4/1, then 2/1) to give
3-[3-(1-isopropylpiperidin-4-yl)-ureido]-N-(5-chloropyridin-2-yl)ben-
zofuran-2-carboxamide (112 mg). Subsequently, this product is
treated with 4N hydrogen chloride in ethyl acetate (2 ml) to give
the title compound (114 mg).
[0351] APCI-MS M/Z: 456/458 [M+H].sup.+
Example 383
Trans-3-(4-methylhomopiperazin-1-ylcarbonyl-amino)-N-(5-chloropyridin-2-yl-
)benzofuran-2-carboxamide dihydrochloride
##STR00650##
[0353] 3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(200 mg) obtained in Reference Example 74 and
1-methylhomopiperazine (86 .mu.l) are treated in a similar manner
to Example 382-(3) to give the title compound (110 mg).
[0354] APCI-MS M/Z: 428/430 [M+H].sup.+
Example 384
Trans-3-[4-(2-oxopiperidin-1-yl)cyclohexyl-carbonylamino]-N-(5-chloropyrid-
in-2-yl)benzofuran-2-carboxamide
##STR00651##
[0355] (1)
Trans-3-(4-aminocyclohexylcarbonylamino)-N-(5-chloro-pyridin-2--
yl)benzofuran-2-carboxamide dihydrochloride (300 mg) obtained in
Example 219 is suspended in N,N-dimethyl-acetamide (5 ml), and
thereto are added methyl 5-bromo-valerate (106 .mu.l),
N,N-diisopropylethylamine (537 .mu.l), and potassium iodide (111
mg), and the mixture is stirred at 100.degree. C. for 24 hours.
Methyl 5-bromovalerate (106 .mu.l), N,N-diisopropylethylamine (537
.mu.l) and potassium iodide (111 mg) are further added thereto, and
the mixture is stirred at 100.degree. C. for 12 hours. The reaction
solution is diluted with ethyl acetate, and washed successively
with a saturated aqueous sodium hydrogen carbonate solution, water,
a saturated brine, and dried over sodium sulfate. The solvent is
evaporated under reduced pressure, and the resulting residue is
purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/1, then ethyl acetate) to give
trans-3-[4-(4-methoxycarbonylbutyl-amino)cyclohexylcarbonylamino]-N-(5-ch-
loropyridin-2-yl)-benzofuran-2-carboxamide (101 mg).
[0356] APCI-MS M/Z: 527/529 [M+H].sup.+
(2)
Trans-3-[4-(4-methoxycarbonylbutylamino)cyclohexyl-carbonylamino]-N-(-
5-chloropyridin-2-yl)benzofuran-2-carboxamide (95 mg) obtained in
the above (1) is dissolved in tetrahydrofuran (3 ml), and thereto
is added 1N aqueous sodium hydroxide solution (216 .mu.l), and the
mixture is stirred at room temperature for 4 hours. To the mixture
is added 1N aqueous sodium hydroxide solution (684 .mu.l), and the
mixture is further stirred for 2 days. The reaction solution is
concentrated to dryness under reduced pressure, and to the
resulting residue are added N,N-dimethyl-formamide (3 ml),
1-hydroxybenzotriazole (73 mg) and
i-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104
mg). The mixture is stirred at room temperature for one day, and
further thereto are added 1-hydroxybenzotriazole (73 mg) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (104
mg), and the mixture is further stirred for one day. To the
reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with ethyl
acetate. The organic layer is washed with water and a saturated
brine, and dried over sodium sulfate, and the solvent is evaporated
under reduced pressure. The resulting residue is purified by silica
gel column chromatography (eluent: ethyl acetate) to give the title
compound (40 mg).
[0357] APCI-MS M/Z: 495/497 [M+H].sup.+
Example 385
Trans-5-(N.sup.2-hydroxy)amidino-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcar-
bonylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00652##
[0359]
Trans-5-cyano-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (107 mg) obtained
in Example 6 is suspended in dimethyl sulfoxide (2 ml), and thereto
are added hydroxy-ammonium chloride (36 mg) and a 28% sodium
methoxide in methanol (100 .mu.l). The mixture is heated at
50.degree. C. for 2 hours, and further at 80.degree. C. for 2
hours. The reaction solution is poured into ice-water, and the
precipitates are collected by filtration, and purified by recycle
HPLC to give the title compound (25 mg; APCI-MS M/Z: 539/541
[M+H].sup.+) and
trans-5-aminocarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]-
-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (18 mg; APCI-MS
M/Z: 52:4/526 [M+H].sup.+).
Example 386
Trans-5-[2-(guanidinoxy)ethoxy]-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbo-
nylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
dihydrochloride
##STR00653##
[0360] (1)
Trans-5-(2-aminoxyethoxy)-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-
carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
dihydrochloride (90 mg) obtained in Example 183 is dissolved in
N,N-dimethyl formamide (3 ml), and thereto are added
N,N-diisopropyl-ethylamine (38 .mu.l) and
N,N'-bis(t-butoxycarbonyl)-1H-pyrazole-1-carboxamidine (57 mg), and
the mixture is stirred at room temperature for one day. The
reaction solution is concentrated under reduced pressure, and the
residue is poured into water, and extracted with chloroform. The
organic layer is dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/1, then ethyl acetate) to give
trans-5-{2-[N,N'-bis(t-butoxycarbonyl)-guanidinoxy]ethoxy}-3-[4-(2-oxopyr-
rolidin-1-yl)cyclo-hexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran--
2-carboxamide (82 mg).
[0361] ESI-MS M/Z: 820/822 [M+Na].sup.+, 798/800 [M+H].sup.+
(2) To
trans-5-{2-[N,N'-bis(t-butoxycarbonyl)guadinoxy]-ethoxy}-3-[4-(2-o-
xopyrrolidin-1-yl)cyclohexylcarbonyl-amino]-N-(5-chloropyridin-2-yl)benzof-
uran-2-carboxamide (73 mg) obtained in the above (1) is added
trifluoroacetic acid (2 ml), and the mixture is stirred at room
temperature for 12 hours. The reaction solution is concentrated
under reduced pressure, and the residue is neutralized with a
saturated aqueous potassium carbonate solution, and extracted with
chloroform. The organic layer is dried over sodium sulfate, and the
solvent is evaporated under reduced pressure. The residue is
purified by NH-silica gel column chromatography (eluent:
chloroform, then chloroform/methanol=97/3) to give
trans-5-[2-(guanidinoxy)ethoxy]-3-[4-(2-oxopyrrolidin-1-yl)cyclohexy-
lcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(15 mg)-Subsequently, this product (15 mg) is suspended in methanol
(0.5 ml), and thereto is added 4N hydrogen chloride in dioxane (25
.mu.l). To the mixture is poured diethyl ether, and the
precipitates are washed with diethyl ether, and dried to give the
title compound (17 mg).
[0362] ESI-MS M/Z: 598/600 [M+H].sup.+
Examples 387-391
##STR00654##
[0364]
Trans-5-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino-
]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in
Example 77 and the corresponding starting compounds are treated in
a similar manner to Example 87 to give the following compounds.
TABLE-US-00034 ##STR00655## Physico- Ex. chemical No. -R.sup.2 -AY
properties 387 ##STR00656## ##STR00657## APCI-MS M/Z: 610/612 [M +
H].sup.+ 388 ##STR00658## ##STR00659## APCI-MS M/Z: 614/616 [M +
H].sup.+ 389 ##STR00660## ##STR00661## APCI-MS M/Z: 628/630 [M +
H].sup.+ 390 ##STR00662## ##STR00663## APCI-MS M/Z: 615/617 [M +
H].sup.+ 391 ##STR00664## ##STR00665## APCI-MS M/Z: 615/617 [M +
H].sup.+
Examples 392-393
##STR00666##
[0366]
Trans-5-carboxy-3-[4-(N-formyl-N-methylamino)cyclo-hexylcarbonylami-
no]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide obtained in
Example 258 and amino compounds are treated in a similar manner to
Example 261 to give the following compounds in a free form, or
which are further treated with hydrogen chloride to give
hydrochlorides thereof.
TABLE-US-00035 ##STR00667## Physico- Ex. chemical No. -R.sup.2 -AY
properties 392 ##STR00668## ##STR00669## APCI-MS M/Z: 581/583 [M +
H].sup.+ Hydrochloride 393 ##STR00670## ##STR00671## APCI-MS M/Z:
583/585 [M + H].sup.+ Hydrochloride
Examples 394-399
##STR00672##
[0368] Trans-5-dimethylaminocarbonyl-3-[4-(methylamino)
cyclo-hexylcarbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamid-
e dihydrochloride obtained in Example 343 and acid chloride
compounds are treated in a similar manner to Example 239 to give
the following compounds.
TABLE-US-00036 ##STR00673## Ex. Physicochemical No. -R.sup.2 -AY
properties 394 ##STR00674## ##STR00675## APCI-MS M/Z: 576/578 [M +
H].sup.+ 395 ##STR00676## ##STR00677## APCI-MS M/Z: 556/558 [M +
H].sup.+ 396 ##STR00678## ##STR00679## APCI-MS M/Z: 569/571 [M +
H].sup.+ 397 ##STR00680## ##STR00681## APCI-MS M/Z: 570/572 [M +
H].sup.+ 398 ##STR00682## ##STR00683## APCI-MS M/Z: 598/600 [M +
H].sup.+ 399 ##STR00684## ##STR00685## APCI-MS M/Z: 602/604 [M +
H].sup.+
Example 400
Trans-5-dimethylaminocarbonyl-3-[4-(N-hydroxy-acetyl-N-methylamino)cyclohe-
xylcarbonylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00686##
[0370]
Trans-3-[4-(N-acetoxyacetyl-N-methylamino)cyclohexyl-carbonylamino]-
-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
(91 mg) obtained in Example 398 is dissolved in
tetrahydrofuran/methanol (2:3, 5 ml), and thereto is added at room
temperature 2N aqueous sodium hydroxide solution (300 .mu.l), and
the mixture is stirred for 4 hours. The reaction solution is
acidified with diluted hydrochloric acid, and the mixture is
diluted with chloroform. The mixture is dried over sodium sulfate,
and the solvent is evaporated under reduced pressure. The resulting
residue is purified by recycle HPLC to give the title compound (44
mg).
[0371] APCI-MS M/Z: 556/558 [M+H].sup.+
Examples 401-403
##STR00687##
[0373] The compound obtained in Example 345, 347 or 348 and acetyl
chloride are treated in a similar manner to Example 334 to give the
following compounds.
TABLE-US-00037 ##STR00688## Ex. Physicochemical No. -R.sup.2 -AY
properties 401 ##STR00689## ##STR00690## APCI-MS M/Z: 568/570 [M +
H].sup.+ 402 ##STR00691## ##STR00692## APCI-MS M/Z: 610/612 [M +
H].sup.+ 403 ##STR00693## ##STR00694## APCI-MS M/Z: 594/596 [M +
H].sup.+
Examples 404-405
3-Amino-5-nitro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
obtained in Reference Example 86 and a carboxylic acid are treated
in a similar manner to Example 1 or Example 2 to give the following
compounds.
TABLE-US-00038 ##STR00695## [0374] Ex. Physicochemical No. -R.sup.2
-AY properties 404 ##STR00696## ##STR00697## APCI-MS M/Z: 526/528
[M + H].sup.+ 405 ##STR00698## ##STR00699## APCI-MS M/Z: 514/516 [M
+ H].sup.+
Example 406
Trans-5-amino-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbonylamino]-N-(5-ch-
loropyridin-2-yl)-benzofuran-2-carboxamide hydrochloride
##STR00700##
[0376]
Trans-5-nitro-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.50 g) obtained
in Example 404 is suspended in ethanol/tetrahydrofuran (1:1, 400
ml), and thereto is added Raney nickel, and the mixture is stirred
at room temperature under atmospheric hydrogen pressure for 12
hours. To the resulting yellow suspension is poured chloroform (200
ml), and the mixture is stirred at room temperature for 0.5 hour.
The insoluble materials are removed by filtration, and the filtrate
is concentrated under reduced pressure. The residue is purified by
silica gel column chromatography (eluent: chloroform to
chloroform/methanol=4/1), suspended in ethyl acetate/diethyl ether.
The precipitates are collected by filtration, washed with diethyl
ether, and dried to give
trans-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]-N-(5-c-
hloropyridin-2-yl)benzofuran-2-carboxamide (1.94 g). This product
(150 mg) is suspended in methanol, and the mixture is treated with
4N hydrogen chloride in dioxane to give the title compound (158
mg).
[0377] APCI-MS M/Z: 496/498 [M+H].sup.+
Example 407
Trans-3-[4-(N-acetyl-N-methylamino)cyclo-hexylcarbonylamino]-5-amino-N-(5--
chloropyridin-2-yl)benzo-furan-2-carboxamide hydrochloride
##STR00701##
[0379]
Trans-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonyl-amino]-5-nitr-
o-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (2.27 g)
obtained in Example 405 is treated in a similar manner to Example
406 to give
trans-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonylamino]-5-amino-N-(5--
chloropyridin-2-yl)benzofuran-2-carboxamide (1.62 g). The resulting
free compound (150 mg) is suspended in methanol, and treated with
4N hydrogen chloride in dioxane to give the title compound (158
mg).
[0380] APCI-MS M/Z: 484/486 [M+H].sup.+
Examples 408-409
[0381]
Trans-5-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride
obtained in Example 406 or
trans-3-[4-(N-acetyl-N-methylamino)cyclohexylcarbonylamino]-5-amino-N-(5--
chloropyridin-2-yl)benzofuran-2-carboxamide hydrochloride obtained
in Example 407 is treated in a similar manner to Example 198 to
give the following compounds in a free form, or which are further
treated with hydrogen chloride to give hydrochlorides thereof.
TABLE-US-00039 ##STR00702## Ex. Physicochemical No. -R.sup.2 -AY
properties 408 ##STR00703## ##STR00704## APCI-MS M/Z: 524/526 [M +
H].sup.+ Dihydrochloride 409 ##STR00705## ##STR00706## APCI-MS M/Z:
512/514 [M + H].sup.+ Dihydrochloride
Example 410
Trans-5-dimethylaminocarbonyl-3-[4-(3-oxo-morpholin-4-yl)cyclohexylcarbony-
lamino]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00707##
[0383] Trans-4-(3-oxomorpholin-4-yl)cyclohexanecarboxylic acid (85
mg) obtained in Reference Example 141 is dissolved in chloroform (3
ml), and thereto are added thionyl chloride (30 .mu.l) and a drop
of N,N-dimethylformamide, and the mixture is stirred at room
temperature for 15 hours. To the resulting reaction solution is
added
3-amino-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carb-
oxamide (96 mg) obtained in Reference Example 156 and pyridine (2
ml), and the mixture is stirred at room temperature for 2 hours. To
the reaction solution is poured a saturated aqueous sodium hydrogen
carbonate solution, and the mixture is extracted with chloroform.
The organic layer is dried over sodium sulfate, and the solvent is
evaporated under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=2/1, then ethyl acetate), and further
purified by recycle HPLC to give the title compound (28 mg).
[0384] APCI-MS M/Z: 568/570 [M+H].sup.+
Examples 411-417
[0385] The amino compounds obtained in Reference Example 156-158
and corresponding carboxylic acids are treated in a similar manner
to Example 410 to give the following compounds.
TABLE-US-00040 ##STR00708## Ex. Physicochemical No. -R.sup.2 -AY
properties 411 ##STR00709## ##STR00710## APCI-MS M/Z: 554/556 [M +
H].sup.+ 412 ##STR00711## ##STR00712## APCI-MS M/Z: 566/568 [M +
H].sup.+ 413 ##STR00713## ##STR00714## APCI-MS M/Z: 554/556 [M +
H].sup.+ 414 ##STR00715## ##STR00716## APCI-MS M/Z: 526/528 [M +
H].sup.+ Ex. Physicochemical No. Structure properties 415
##STR00717## APCI-MS M/Z: 552/554 [M + H].sup.+ 416 ##STR00718##
APCI-MS M/Z: 552/554 [M + H].sup.+ 417 ##STR00719## ESI-MS M/Z:
568/570 [M + H].sup.+
Example 418
Trans-4-methoxycarbonyl-3-[4-(2-oxo-oxazolidin-3-yl)cyclohexylcarbonylamin-
o]-3-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00720##
[0387]
3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)-benzofuran-2-car-
boxamide (351 mg) obtained in Reference Example 152 and
trans-4-(2-oxo-oxazolidin-3-yl)cyclohexane-carboxylic acid (432 mg)
obtained in Reference Example 142 are treated in a similar manner
to Example 1 to give the title compound (129 mg).
[0388] APCI-MS M/Z: 541/543 [M+H].sup.+
Example 419
Trans-4-carboxy-3-[4-(2-oxo-oxazolidin-3-yl)-cyclohexylcarbonylamino]-N-(5-
-chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00721##
[0390]
Trans-4-methoxycarbonyl-3-[4-(2-oxo-oxazolidin-3-yl)cyclohexylcarbo-
nylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (107
mg) obtained in Example 418 is treated in a similar manner to
Example 77 to give the title compound (80.4 mg).
[0391] ESI-MS M/Z: 525/527 [M-H].sup.-
Example 420
Trans-4-dimethylaminocarbonyl-3-[4-(2-oxo-oxazolidin-3-yl)cyclohexylcarbon-
ylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00722##
[0393]
Trans-4-carboxy-3-[4-(2-oxo-oxazolidin-3-yl)cyclo-hexylcarbonylamin-
o]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (50 mg)
obtained in Example 419 is treated in a similar manner to Example
87 to give the title compound (36.4 mg).
[0394] APCI-MS M/Z: 554/556 [M+H].sup.+
Example 421
Trans-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino-
]-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
##STR00723##
[0396]
3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)-benzofuran-2-car-
boxamide (2.33 g) obtained in Reference Example 152 and
trans-4-(2-oxopyrrolidin-1-yl)cyclohexane-carboxylic acid (2.06 g)
obtained in Reference Example 142 are treated in a similar manner
to Example 1 to give the title compound (1.90 g).
[0397] APCI-MS M/Z: 539/541 [F+H].sup.+
Example 422
Trans-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbonylamino]-N-(5--
chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00724##
[0399]
Trans-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbon-
ylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (880 mg)
obtained in Example 421 is treated in a similar manner to Example
77 to give the title compound (623 mg).
[0400] ESI-MS M/Z: 523/525 [M-H].sup.-
Example 423
Trans-4-hydroxymethyl-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00725##
[0402]
Trans-4-methoxycarbonyl-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbo-
nylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide (350
mg) obtained in Example 421 is treated in a similar manner to
Example 145 to give the title compound (40.9 mg).
[0403] ESI-MS M/Z: 511/513 [M+H].sup.+
Example 424
Trans-4-[N-(2-dimethylaminoethyl)-N-methyl]-aminocarbonyl-3-[4-(2-oxopyrro-
lidin-1-yl)cyclohexyl-carbonylamino]-N-(5-chloropyridin-2-yl)benzofuran-2--
carboxamide dihydrochloride
##STR00726##
[0405]
Trans-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino-
]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (70 mg) obtained
in Example 422 is treated in a similar manner to Example 87 to give
trans-4-[N-(2-dimethylaminoethyl)-N-methyl]aminocarbonyl-3-[4-(2-oxo-pyrr-
olidin-1-yl)cyclohexylcarbonylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-
-carboxamide (40.7 mg). This product is dissolved in methanol, and
treated with 4N hydrogen chloride in dioxane (50 .mu.l) to give the
title compound (35.7 mg).
[0406] APCI-MS M/Z: 609/611 [M+H].sup.+
Example 425
Trans-4-t-butoxycarbonylamino-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbon-
ylamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00727##
[0408]
Trans-4-carboxy-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino-
]-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (325 mg)
obtained in Example 422 is dissolved in t-butanol (8 ml), and
thereto are added at room temperature triethylamine (91 .mu.l) and
diphenylphosphoryl azide (140 .mu.l), and the mixture is stirred at
60.degree. C. for 1.5 hour, and then heated under reflux for 5.5
hours. The reaction solution is diluted with a saturated aqueous
sodium hydrogen carbonate solution, and extracted with chloroform.
The organic layer is washed with a saturated brine, dried over
sodium sulfate, and the solvent is evaporated under reduced
pressure. The resulting residue is purified by silica gel column
chromatography (eluent: chloroform/methanol=100/1, then 10/1) to
give the title compound (141.7 mg).
[0409] ESI-MS M/Z: 596/598 [M+H].sup.+
Example 426
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)-cyclohexylcarbonylamino]-N-(5-ch-
loropyridin-2-yl)benzo-furan-2-carboxamide
##STR00728##
[0411]
Trans-4-t-butoxycarbonylamino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-
carbonylamino]-N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide
(108 mg) obtained in Example 425 is dissolved in trifluoroacetic
acid (2 ml), and the mixture is stirred at room temperature for 2
hours. The reaction solution is concentrated under reduced
pressure, and the resulting residue is neutralized with a saturated
aqueous sodium hydrogen carbonate solution, and extracted with
chloroform. The organic layer is dried over sodium sulfate, and the
solvent is evaporated under reduced pressure. The resulting residue
is purified by NH-silica gel column chromatography (eluent:
n-hexane/ethyl acetate=1/1, then ethyl acetate) to give the title
compound (85.4 mg).
[0412] ESI-MS M/Z: 496/498 [M+H].sup.+
Example 427
Trans-4-dimethylamino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexylcarbonylamino]--
N-(5-chloropyridin-2-yl)benzo-furan-2-carboxamide
##STR00729##
[0414]
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (41.7 mg) obtained
in Example 426 is treated in a similar manner to Example 198 to
give the title compound (8.0 mg).
[0415] APCI-MS M/Z: 524/526 [M+H].sup.+
Example 428
Trans-4-methanesulfonylamino-3-[4-(2-oxo-pyrrolidin-1-yl)cyclohexylcarbony-
lamino]-N-(5-chloro-pyridin-2-yl)benzofuran-2-carboxamide
##STR00730##
[0417]
Trans-4-amino-3-[4-(2-oxopyrrolidin-1-yl)cyclohexyl-carbonylamino]--
N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (27 mg) obtained
in Example 426 is dissolved in pyridine (2 ml), and thereto is
added methanesulfonyl chloride (7 .mu.l) under ice-cooling. The
mixture is stirred at room temperature overnight, and thereto are
further added pyridine (3 ml) and methanesulfonyl chloride (500
.mu.l) under ice-cooling. The mixture is stirred at room
temperature for 6 hours. Water is added to the reaction solution,
and the mixture is extracted with chloroform. The solvent is
evaporated under reduced pressure, and the resulting residue is
purified by silica gel column chromatography (eluent: chloroform,
then chloroform/methanol=9/1) to give the title compound (21.2
mg).
[0418] APCI-MS M/Z: 574/576 [M+H].sup.+
Example 429
Trans-3-[(4-(3-oxo-morpholin-4-yl)cyclohexyl-carbonylamino]-N-(5-chloropyr-
idin-2-yl)benzofuran-2-carboxamide
##STR00731##
[0420] 3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (66
mg) obtained in Reference Example 74 and
trans-4-(3-oxo-morpholin-4-yl)cyclohexanecarboxylic acid (68 mg)
obtained in Reference Example 141 are treated in a similar manner
to Example 410 to give the title compound (74 mg).
[0421] APCI-MS M/Z: 497/499 [M+H].sup.+
Reference Example 1
Methyl 3-formyl-4-hydroxybenzoate
##STR00732##
[0423] Methyl 4-hydroxybenzoate (1.52 g) is dissolved in
trifluoroacetic acid (20 ml), thereto is added
hexamethylenetetramine (700 mg) and the mixture is heated under
reflux for 2 hours. The reaction solution is concentrated under
reduced pressure, thereto is poured ice-water, and then the mixture
is extracted with ethyl acetate The organic layer is washed with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, dried over sodium sulfate and the solvent is evaporated
under reduced pressure. The resulting residue is dissolved in
chloroform, and then filtered to remove the insoluble materials.
The filtrate is concentrated under reduced pressure, and then
purified by silica gel column chromatography (eluent:
n-hexane/ethyl acetate=4/1) to give the title compound (540
mg).
[0424] ESI-MS M/Z: 179 [M-H].sup.-.
Reference Example 2
Methyl (3-formyl-4-hydroxyphenyl)-acetate
##STR00733##
[0426] Methyl (4-hydroxyphenyl)acetate (1.66 g) is dissolved in
trifluoroacetic acid (20 ml), thereto is added
hexamethylenetetramine (700 mg) and the mixture is heated under
reflux for 2 hours. The reaction solution is concentrated under
reduced pressure, thereto is poured ice-water, and then the mixture
is extracted with ethyl acetate. The organic layer is washed with
saturated aqueous sodium hydrogen carbonate solution and saturated
brine, dried over sodium sulfate and evaporated to remove the
solvent under reduced pressure. The resulting residue is purified
by silica gel column chromatography (eluent: n-hexane/ethyl
acetate=9/1 followed by 4/1) to give the title compound (1.08
g).
[0427] ESI-MS M/Z: 193 [M-H].sup.-.
Reference Examples 3-4
[0428] The corresponding compounds are treated in a similar manner
to Reference Example 1 or Reference Example 2 to give the following
compounds.
TABLE-US-00041 Ref. Ex. Physicochemical No. Structure Properties 3
##STR00734## APCI-MS M/Z: 225 [M + H + MeOH--H.sub.2O].sup.+ 4
##STR00735## EI-MS M/Z: 265 [M ].sup.+
Reference Example 5
Methyl 3-cyano-4-hydroxybenzoate
##STR00736##
[0430] Methyl 3-formyl-4-hydroxybenzoate (28.60 g) obtained in
Reference Example 1 is dissolved in formic acid (120 ml), thereto
is added hydroxylammonium chloride (14.30 g) and the mixture is
heated under reflux for 15 hours. The reaction solution is
concentrated under reduced pressure, diluted with ethyl acetate,
washed successively with water and saturated brine, dried over
sodium sulfate and the solvent is evaporated under reduced pressure
to give the title compound (24.25 g).
[0431] ESI-MS M/Z: 176 [M-H].sup.-.
Reference Example 6
Methyl (3-cyano-4-hydroxyphenyl)-acetate
##STR00737##
[0433] Methyl (3-formyl-4-hydroxyphenyl)acetate (1.05 g) obtained
in Reference Example 2 is dissolved in formic acid (15 ml), and
thereto are added hydroxylammonium chloride (0.49 g) and sodium
formate (0.81 g) and the mixture is heated under reflux for 8
hours. The reaction solution is concentrated under reduced
pressure, diluted with ethyl acetate, washed successively with
water and saturated brine, dried over sodium sulfate and the
solvent is evaporated under reduced pressure to give the title
compound (520 mg).
[0434] ESI-MS M/Z: 190 [M-H].sup.-.
Reference Examples 7-19
[0435] The corresponding compounds are treated in a similar manner
to Reference Example 5 or Reference Example 6 to give the following
compounds.
TABLE-US-00042 Ref. Ex. Physicochem- No. Structure ical Properties
7 ##STR00738## ESI-MS M/Z: 192 [M - H].sup.- 8 ##STR00739## APCI-MS
M/Z: 263 [M + H].sup.+ 9 ##STR00740## ESI-MS M/Z: 152/154 [M -
H].sup.- 10 ##STR00741## ESI-MS M/Z: 196/198 [M - H].sup.- 11
##STR00742## ESI-MS M/Z: 132 [M - H].sup.- 12 ##STR00743## ESI-MS
M/Z: 163 [M - H].sup.- 13 ##STR00744## ESI-MS M/Z: 148 [M -
H].sup.- 14 ##STR00745## ESI-MS M/Z: 148 [M - H].sup.- 15
##STR00746## ESI-MS M/Z: 196/198 [M - H].sup.- 16 ##STR00747##
ESI-MS M/Z: 132 [M - H].sup.- 17 ##STR00748## This compound is used
at the next step without purification. 18 ##STR00749## ESI-MS M/Z:
148 [M - H].sup.- 19 ##STR00750## This compound is used at the next
step without purification.
Reference Example 20
2-(4-Methoxycarbonyl-2-cyano-phenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00751##
[0437] (1) Chloroacetyl chloride (95.5 ml) is dissolved in
dichloromethane (500 ml), and thereto is added dropwise a
suspension of 2-amino-5-chloropyridine (128.6 g) and triethylamine
(169 ml) in dichloromethane (1000 ml) under ice-cooling, and the
reaction solution is warmed to room temperature, and stirred for
0.5 hours. The reaction solution is concentrated under reduced
pressure, thereto is poured ice-water, and then the reaction
mixture is extracted with ethyl acetate. The organic layer is
washed with saturated brine, dried over sodium sulfate and treated
with activated charcoal. After filtration to remove insoluble
materials, the filtrate is concentrated under reduced pressure and
the resulting residue is suspended in diisopropyl ether. The
precipitates are collected by filtration, washed with diisopropyl
ether and dried to give 2-chloro-N-(5-chloropyridin-2-yl)acetamide
(153.4 g).
[0438] APCI-MS M/Z: 205/207 [M+H].sup.4.
[0439] (2) Methyl 3-cyano-4-hydroxybenzoate (500 mg) obtained in
Reference Example 5 is dissolved in acetone (25 ml), thereto are
added 2-chloro-N-(5-chloropyridin-2-yl)acetamide (695 mg) obtained
in Reference Example 20(1), potassium carbonate (546 mg) and sodium
iodide (550 mg) and the mixture is heated under reflux for 2 hours.
After allowing to cool, insoluble materials are removed by
filtration and the insolubles are washed with acetone several
times. The filtrate and the washing are combined and concentrated
under reduced pressure, and then purified by silica gel column
chromatography (eluent: chloroform followed by chloroform/ethyl
acetate=4/1). The resulting residue is suspended in diethyl ether,
and then the precipitates are collected by filtration to give the
title compound (660 mg).
[0440] APCI-MS M/Z: 346/348 [M+H].sup.+.
Reference Example 21
2-[2-Cyano-4-(methoxycarbonyl-methyl)phenoxy]-N-(5-chloropyridin-2-yl)acet-
amide
##STR00752##
[0442] Methyl (3-cyano-4-hydroxyphenyl)acetate (500 mg) obtained in
Reference Example 6 is dissolved in acetone (25 ml), thereto are
added 2-chloro-N-(5-chloropyridin-2-yl)acetamide (640 mg) obtained
in Reference Example 20(1), cesium carbonate (1.20 g) and sodium
iodide (510 mg) and the mixture is heated under reflux for 5 hours.
After allowing to cool, the insoluble materials are removed by
filtration and the insoluble materials are washed with acetone
several times. The filtrate and the washing are combined,
concentrated under reduced pressure, to the residue is poured water
and extracted with ethyl acetate. The organic layer is washed with
saturated brine, dried over sodium sulfate and evaporated to remove
solvent under reduced pressure. The resulting residue is purified
by silica gel column chromatography (eluent: n-hexane/ethyl
acetate/chloroform=3/1/1). The resulting residue is suspended in
diethyl ether-n-hexane, and then the precipitates are collected by
filtration to give the title compound (570 mg).
[0443] APCI-MS M/Z: 360/362 [M+H].sup.+.
Reference Examples 22-23
[0444] The corresponding compounds are treated in a similar manner
to Reference Example 20 or Reference Example 21 to give the
following compounds.
TABLE-US-00043 Ref. Ex. Physicochemical No. Structure Properties 22
##STR00753## APCI-MS M/Z: 376/378 [M + H].sup.+ 23 ##STR00754##
APCI-MS M/Z: 431/433 [M + H].sup.+
Reference Example 24
t-Butyl (2-cyanophenoxy)acetate
##STR00755##
[0446] 2-Cyanophenol (107.1 g) is dissolved in acetone (1000 ml)
and is added t-butyl bromoacetate (200.0 g). Furthermore, potassium
carbonate (141.6 g) is added, and then the reaction solution is
heated under reflux for 2 hours. After allowing to cool, the
insoluble materials are removed by filtration, and then the
insoluble materials are washed with acetone several times. The
filtrate and the washing are combined, concentrated under reduced
pressure and treated with diisopropyl ether azeotropically The
resulting residue is crystallized from n-hexane-diisopropyl ether
(5/1) (600 ml), and then stirred under ice-cooling. The
precipitates are collected by filtration, washed with cold
n-hexane-diisopropyl ether (10/1) (600 ml) several times and dried
to give the title compounds (194.5 g).
[0447] APCI-MS M/Z: 251 [M+NH.sub.4].sup.+.
Reference Examples 25-36
[0448] The corresponding compounds are treated in a similar manner
to Reference Example 24 to give the following compounds.
TABLE-US-00044 Ref. Ex. Physicochemical No. Structure Properties 25
##STR00756## APCI-MS M/Z: 309 [M + NH.sub.4].sup.+ 26 ##STR00757##
APCI-MS M/Z: 285/287 [M + NH.sub.4].sup.+ 27 ##STR00758## APCI-MS
M/Z: 329/331 [M + NH.sub.4].sup.+ 28 ##STR00759## APCI-MS M/Z: 265
[M + NH.sub.4].sup.+ 29 ##STR00760## APCI-MS M/Z: 296 [M +
NH.sub.4].sup.+ 30 ##STR00761## APCI-MS M/Z: 281 [M +
NH.sub.4].sup.+ 31 ##STR00762## APCI-MS M/Z: 281 [M +
NH.sub.4].sup.+ 32 ##STR00763## APCI-MS M/Z: 329/331 [M +
NH.sub.4].sup.+ 33 ##STR00764## APCI-MS M/Z: 265 [M +
NH.sub.4].sup.+ 34 ##STR00765## APCI-MS M/Z: 305 [M + H].sup.+ 35
##STR00766## APCI-MS M/Z: 281 [M + NH.sub.4].sup.+ 36 ##STR00767##
APCI-MS M/Z: 265 [M + NH.sub.4].sup.+
Reference Example 37
(2-Cyanophenoxy)acetic acid
##STR00768##
[0450] t-Butyl (2-cyanophenoxy)acetate (300.0 g) obtained in
Reference Example 24 is dissolved in dichloromethane (400 ml), and
thereto is added trifluoroacetic acid (990 ml) and the mixture is
stirred at room temperature for 4 hours. The reaction solution is
concentrated under reduced pressure, the resulting residue is
suspended in diethyl ether (100 ml) and diisopropyl ether (500 ml)
is poured thereto. The precipitates are collected by filtration,
washed with diisopropyl ether several times and dried to give the
title compound (198.4 g).
[0451] ESI-MS M/Z: 76 [M-H].sup.-.
Reference Examples 38-49
[0452] The corresponding compounds are treated in a similar manner
to Reference Example 37 to give the following compounds.
TABLE-US-00045 Ref. Ex. Physicochemical No. Structure Properties 38
##STR00769## ESI-MS M/Z: 234 [M - H].sup.- 39 ##STR00770## ESI-MS
M/Z: 210/212 [M - H].sup.- 40 ##STR00771## ESI-MS M/Z: 254/256 [M -
H].sup.- 41 ##STR00772## ESI-MS M/Z: 190 [M - H].sup.- 42
##STR00773## ESI-MS M/Z: 221 [M - H].sup.- 43 ##STR00774## ESI-MS
M/Z: 206 [M - H].sup.- 44 ##STR00775## ESI-MS M/Z: 206 [M -
H].sup.- 45 ##STR00776## ESI-MS M/Z: 254/256 [M - H].sup.- 46
##STR00777## ESI-MS M/Z: 190 [M - H].sup.- 47 ##STR00778## ESI-MS
M/Z: 247 [M - H].sup.- 48 ##STR00779## ESI-MS M/Z: 206 [M -
H].sup.- 49 ##STR00780## ESI-MS M/Z: 190 [M - H].sup.-
Reference Example 50
[4-(N-Benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetic
acid
##STR00781##
[0454] (1) t-Butyl 2-(4-nitro-2-cyanophenoxy)acetate (500 mg)
obtained in Reference Example 29 is dissolved in tetrahydrofuran
(20 ml), thereto is added 10% palladium-carbon (100 mg) and the
mixture is stirred for 2 hours under atmospheric hydrogen pressure.
The insolubles are removed by filtration, and then the filtrate is
concentrated under reduced pressure to give t-butyl
(4-amino-2-cyanophenoxy)acetate (440 mg).
[0455] APCI-MS M/Z: 249 [M+H].sup.+.
[0456] (2) t-Butyl (4-amino-2-cyanophenoxy)acetate (430 mg)
obtained in Reference Example 50(1) is dissolved in tetrahydrofuran
(10 ml), is added saturated sodium hydrogen carbonate solution (10
ml), and then is added benzyl chloroformate (355 mg) under
ice-cooling. Under ice-cooling, the reaction solution is stirred
for 1 hour and extracted with ethyl acetate. The organic layer is
washed with saturated brine, dried over sodium sulfate, evaporated
to remove the solvent under reduced pressure. The resulting residue
is purified by silica gel column chromatography (eluent:
n-hexane/ethyl acetate=9/1 followed by 3/1) to give t-butyl
(4-benzyloxycarbonylamino-2-cyanophenoxy)acetate (540 mg).
[0457] APCI-MS M/Z: 383 [M+H].sup.-.
[0458] (3) t-Butyl (4-benzyloxycarbonylamino-2-cyanophenoxy)acetate
(100 mg) obtained in Reference Example 50(2) is dissolved in
N,N-dimethylformamide (3 ml) and thereto is added 60% oleaginous
sodium hydride (12.5 mg). After the mixture is stirred for 20
minutes at room temperature, methyl iodide (2.4.4 .mu.l) is added
thereto dropwise and the mixture is further stirred for one hour.
To the reaction solution is poured saturated aqueous ammonium
chloride solution and extracted with ethyl acetate. The organic
layer is washed successively with water and saturated brine, dried
over sodium sulfate and evaporated to remove the solvent. The
resulting residue is purified by silica gel column chromatography
(eluent: n-hexane/ethyl acetate=9/1 followed by 3/1) to give
t-butyl
[4-(N-benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetate (91
mg).
[0459] APCI-MS M/Z: 414 [M+NH.sub.4].sup.+.
[0460] (4) t-Butyl
[4-(N-benzyloxycarbonyl-N-methylamino)-2-cyanophenoxy]acetate (2.42
g) obtained in Reference Example 50(3) is treated in a similar
manner to Reference Example 37 to give the title compound (2.06
g).
[0461] ESI-MS M/Z: 339 [M-H].sup.-.
Reference Example 51
(2-Cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00782##
[0463] (2-Cyanophenoxy)acetic acid (48.63 g) obtained n Reference
Example 37 is dissolved in dichloromethane (1000 ml), thereto are
added oxalyl chloride (26.34 ml) and N,N-dimethylformamide
(.about.10 drops) and the mixture is stirred at room temperature
for 3.5 hours. The reaction solution is cooled on ice-bath, thereto
is added 2-amino-5-chloropyridine (32.08 g), and then pyridine
(60.54 ml) is added. After 5 minutes, the reaction solution is
warmed to room temperature and stirred overnight. To the reaction
solution is added ice-water, and the solution is adjusted to about
pH 4 with 10% hydrochloric acid, and then is extracted with
chloroform. The organic layer is washed successively with water,
saturated aqueous sodium hydrogen carbonate and saturated brine,
dried over sodium sulfate and evaporated to remove the solvent. The
resulting residue is suspended in chloroform-ethyl acetate and
collected by filtration to give
(2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (51.58 g).
Furthermore, the filtrate is concentrated under reduced pressure,
and then purified by silica gel column chromatography (eluent:
chloroform) to give the title compound (11.50 g).
[0464] APCI-MS M/Z: 28.8/290 [M+H].sup.+.
Reference Example 52-66
[0465] The corresponding compounds are treated in a similar manner
to Reference Example 51 to give the following compounds.
TABLE-US-00046 Ref. Ex. Physicochemical No. Structure Properties 52
##STR00783## APCI-MS M/Z: 332/334 [M + H].sup.+ 53 ##STR00784##
APCI-MS M/Z: 268 [M + H].sup.+ 54 ##STR00785## APCI-MS M/Z: 326 [M
+ H].sup.+ 55 ##STR00786## APCI-MS M/Z: 332/334 [M + H].sup.+ 56
##STR00787## APCI-MS M/Z: 366/368 [M + H].sup.+ 57 ##STR00788##
APCI-MS M/Z: 302/304 [M + H].sup.+ 58 ##STR00789## APCI-MS M/Z:
329/331 [M + H].sup.+ 59 ##STR00790## APCI-MS M/Z: 318/320 [M +
H].sup.+ 60 ##STR00791## APCI-MS M/Z: 451/453 [M + H].sup.+ 61
##STR00792## APCI-MS M/Z: 318/320 [M + H].sup.+ 62 ##STR00793##
APCI-MS M/Z: 366/368 [M + H].sup.+ 63 ##STR00794## APCI-MS M/Z:
302/304 [M + H].sup.+ 64 ##STR00795## APCI-MS M/Z: 359/361 [M +
H].sup.+ 65 ##STR00796## APCI-MS M/Z: 318/320 [M + H].sup.+ 66
##STR00797## APCI-MS M/Z: 302/304 [M + H].sup.+
Reference Example 67
(2-Cyanophenoxy)-N-(4-chlorophenyl)-acetamide
##STR00798##
[0467] (2-Cyanophenoxy)acetic acid (30.00 g) obtained in Reference
Example 37 is dissolved in N,N-dimethylformamide (300 ml), thereto
are added 4-chloroaniline (25.9 g), 4-dimethylaminopyridine (22.7
g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(35.6 g) successively and the mixture is stirred for 3 hours at
room temperature. The reaction solution is concentrated under
reduced pressure and the resulting residue is diluted with ethyl
acetate-tetrahydrofuran, washed successively with water, 5%
hydrochloric acid, water and saturated brine, dried over sodium
sulfate and evaporated to remove the solvent. The resulting residue
is suspended in diisopropyl ether, and then the precipitates are
collected by filtration to give the title compound (44.00 g).
[0468] APCI-MS M/Z: 287/289[M+H].sup.+.
Reference Examples 68-71
[0469] The corresponding compounds are treated in a similar manner
to Reference Example 67 to give the following compounds.
TABLE-US-00047 Ref. Ex. Physicochem- No. Structure ical Properties
68 ##STR00799## APCI-MS M/Z: 331/333 [M + H].sup.+ 69 ##STR00800##
APCI-MS M/Z: 267 [M + H].sup.+ 70 ##STR00801## APCI-MS M/Z: 271 [M
+ H].sup.+ 71 ##STR00802## APCI-MS M/Z: 283 [M + H].sup.+
Reference Example 72
3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00803##
[0471]
2-(4-Methoxycarbonyl-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetam-
ide (1.73 g) obtained in Reference Example 20 is dissolved in
N,N-dimethylacetamide (15 ml), thereto is added sodium carbonate
(160 mg) and the mixture is stirred at 100.degree. C. for 2 hours.
After allowing to cool, to the reaction solution is poured
ice-water, and the resulting precipitates are collected by
filtration, washed successively with water, tetrahydrofuran and
diethyl ether and dried to give the title compound (1.20 g).
[0472] APCI-MS M/Z: 346/348 [M+H].
Reference Example 73
3-Amino-5-methoxycarbonylmethyl-N-(5-chloropyridin-2-yl)benzofuran-2-carbo-
xamide
##STR00804##
[0474]
2-[2-Cyano-4-(methoxycarbonylmethyl)phenoxy]-N-(5-chloropyridin-2-y-
l)acetamide (500 mg) obtained in Reference Example 21 is dissolved
in N,N-dimethylacetamide (15 ml), thereto is added sodium carbonate
(74 mg) and the mixture is stirred at 100.degree. C. for 16 hours.
After allowing to cool, to the reaction solution is poured
ice-water and extracted with ethyl acetate. The organic layer is
washed successively with water and saturated brine, dried over
sodium sulfate and evaporated to remove the solvent. The resulting
residue is purified by silica gel column chromatography (eluent:
n-hexane/ethyl acetate/chloroform=3/1/1), suspended in diethyl
ether-n-hexane, and then the precipitates are collected by
filtration to give title compound (180 mg).
[0475] APCI-MS M/Z: 360/362 [M+H].sup.+.
Reference Example 74
3-Amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00805##
[0477] (2-Cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (150.00
g) obtained in Reference Example 51 is dissolved in
N,N-dimethylacetamide (1500 ml), thereto is added sodium carbonate
(60.8 g) and the mixture is stirred at 70.degree. C. for 7 hours.
After allowing to cool, the reaction solution is poured to
ice-water, and the resulting precipitates are collected by
filtration and washed with water several times. The precipitates
are dissolved in ethyl acetate, washed with water and saturated
brine, dried over sodium sulfate and the organic layer is treated
with activated charcoal. The insoluble materials are filtered, and
then the filtrate is concentrated under reduced pressure and the
resulting residue is suspended in diethyl ether-ethyl acetate. The
precipitates are collected by filtration, washed with diethyl
ether, and dried to give the title compound (119.33 g).
[0478] APCI-MS M/Z: 288/290 [M+H].sup.+.
Reference Examples 75-96
[0479] The corresponding compounds are treated in a similar manner
to Reference Example 72, 73 or 74 to give the following
compounds.
TABLE-US-00048 Ref. Ex. Physicochemical No. Structure Properties 75
##STR00806## APCI-MS M/Z: 332/334 [M + H].sup.+ 76 ##STR00807##
APCI-MS M/Z: 268 [M + H].sup.+ 77 ##STR00808## APCI-MS M/Z: 287/289
[M + H].sup.+ 78 ##STR00809## APCI-MS M/Z: 331/333 [M + H].sup.+ 79
##STR00810## APCI-MS M/Z: 267 [M + H].sup.+ 80 ##STR00811## APCI-MS
M/Z: 271 [M + H].sup.+ 81 ##STR00812## APCI-MS M/Z: 283 [M +
H].sup.+ 82 ##STR00813## APCI-MS M/Z: 826 [M + H].sup.+ 83
##STR00814## APCI-MS M/Z: 322/324 [M + H].sup.+ 84 ##STR00815##
APCI-MS M/Z: 366/368 [M + H].sup.+ 85 ##STR00816## APCI-MS M/Z:
302/304 [M + H].sup.+ 86 ##STR00817## APCI-MS M/Z: 333/335 [M +
H].sup.+ 87 ##STR00818## APCI-MS M/Z: 318/320 [M + H].sup.+ 88
##STR00819## APCI-MS M/Z: 376/378 [M + H].sup.+ 89 ##STR00820##
APCI-MS M/Z: 431/433 [M + H].sup.+ 90 ##STR00821## APCI-MS M/Z:
451/453 [M + H].sup.+ 91 ##STR00822## APCI-MS M/Z: 318/320 [M +
H].sup.+ 92 ##STR00823## APCI-MS M/Z: 366/368 [M + H].sup.+ 93
##STR00824## APCI-MS M/Z: 302/304 [M + H].sup.+ 94 ##STR00825##
APCI-MS M/Z: 359/361 [M + H].sup.+ 95 ##STR00826## APCI-MS M/Z:
318/320 [M + H].sup.+ 96 ##STR00827## APCI-MS M/Z: 302/304 [M +
H].sup.+
Reference Example 97
(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00828##
[0481] To the suspension of
(2-cyano-4-methoxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (40.0
g) obtained in Reference Example 59 in dichloromethane (2000 ml),
boron tribromide (173 g) is added at -58.degree. C. dropwise over
40 minutes. The reaction solution is stirred for 26 hours with
keeping the internal temperature between -20.degree. C. and
0.degree. C., and then poured to an ice-water. The precipitated
solid is collected by filtration, washed with water, and then dried
under reduced pressure. A part of the resulting solid (37.2 g),
i.e. 24.3 g thereof is purified by silica gel column chromatography
(eluent: chloroform/methanol=50/1-10/1) to give the title compound
(17.0 g).
[0482] APCI-MS M/Z: 304/306 [M+H].sup.+.
Reference Example 98
3-Amino-5-hydroxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00829##
[0484] (2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide
(321 mg) obtained in Reference Example 97 is treated in a similar
manner to Reference Example 73 to give the title compound (274
mg).
[0485] APCI-MS M/Z: 304/306 [M+H].sup.+.
Reference Example 99
(4-t-Buthoxycarbonylmethoxy-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetam-
ide
##STR00830##
[0487] (2-cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide
(5.75 g) obtained in Reference Example 97 is dissolved in acetone
(160 ml) and to the solution, are added cesium carbonate (8.08 g),
t-butyl bromoacetate (4.58 g) and sodium iodide (3.64 g). The
reaction solution is heated under reflux for 8 hour, thereto are
added additional cesium carbonate (1.89 g), t-butyl bromoacetate
(840 .mu.l) and sodium iodide (875 mg) and the mixture is heated
under reflux for additional 14 hours. After allowing to cool, the
reaction solution is poured to an ice-water, adjusted pH 1-2 with
10% hydrochloric acid and extracted with ethyl acetate. The organic
layer is dried over sodium sulfate and evaporated to remove the
solvent. The resulting residue is purified by silica gel column
chromatography (eluent: hexane/ethyl acetate=3/1, 2/1 followed by
1/1) and furthermore, purified by NH-silica gel column
chromatography (eluent: hexane/ethyl acetate=2/1 followed by 1/1)
to give the title compound (4.02 g).
[0488] APCI-MS M/Z: 418/420 [M+H].sup.+.
Reference Example 100
3-Amino-5-t-butoxycarbonylmethoxy-N-(5-chloropyridin-2-yl)benzofuran-2-car-
boxamide
##STR00831##
[0490]
(4-t-Buthoxycarbonylmethoxy-2-cyanophenoxy)-N-(5-chloropyridin-2-yl-
)acetamide (8.18 g) obtained in Reference Example 99 is treated in
a similar manner to Reference Example 73 to give the title compound
(5.72 g).
[0491] APCI-MS M/Z: 418/420 [M+H].sup.+.
Reference Example 101
3-Amino-5-(2-methoxyethoxy)-N-(5-chloropyridin-2-yl)benzofuran-2-carboxami-
de
##STR00832##
[0493] (1)
(2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide (100
mg) obtained in Reference Example 97 is dissolved in
tetrahydrofuran, and thereto are added 2-methoxyethanol (9.30 ml)
and triphenylphosphine (31.0 g), and further diethyl
azodicarboxylate (22.2 ml) is added dropwise under ice-cooling. The
reaction solution is warmed to room temperature and stirred for 17
hours and concentrated under reduced pressure. To the resulting
residue is poured diisopropyl ether, and the insoluble materials
are removed by filtration, and then the filtrate is concentrated
under reduced pressure. The resulting residue is purified by silica
gel column chromatography (eluent: chloroform/ethyl acetate=10/1)
to give
[4-(2-methoxyethoxy)-2-cyanophenoxy]-N-(5-chloropyridin-2-yl)acetamide
(71.48 g) as a crude material, which is used for next step without
further purification.
[0494] APCI-MS M/Z: 362/364 [M+H].sup.+.
[0495] (2) The crude material containing
[4-(2-methoxyethoxy)-2-cyanophenoxy]-N-(5-chloropyridin-2-yl)acetamide
(71.48 g) obtained in Reference Example 101(1) is treated in a
similar manner to Reference Example 72 to give the title compound
(24.40 g).
[0496] APCI-MS M/Z: 362/364 [M+H].sup.4.
Reference Examples 102-106
[0497] (2-Cyano-4-hydroxyphenoxy)-N-(5-chloropyridin-2-yl)acetamide
obtained in Reference Example 97 and the corresponding alcohol are
treated in a similar manner to Reference Example 101 to give the
following compounds.
TABLE-US-00049 Ref. Physicochemical Ex. No. Structure Properties
102 ##STR00833## APCI-MS M/Z: 375/377 [M + H].sup.+ 103
##STR00834## APCI-MS M/Z: 406/408 [M + H].sup.+ 104 ##STR00835##
APCI-MS M/Z: 466/468 [M + H].sup.+ 105 ##STR00836## APCI-MS M/Z:
461/463 [M + H].sup.+ 106 ##STR00837## APCI-MS M/Z: 463/465 [M +
H].sup.+
Reference Example 107
(2,4-Dicyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00838##
[0499] 4-Nitrobenzonitrile (3.02 g) and potassium cyanide (2.02 g)
are dissolved in dimethyl sulfoxide (100 ml) and stirred at
100.degree. C. for an hour. The reaction solution is allowed to
cool until room temperature and, thereto are added potassium
carbonate (1.49 g), 2-chloro-N-(5-chloropyridin-2-yl)acetamide
(10.42 g) obtained in Reference Example 20(1) and sodium iodide
(8.76 g), and the mixture is stirred at 60.degree. C. for 4.5
hours. The reaction solution is poured to water, and the
precipitated solids are collected by filtration, washed with water
and dried in air. The resulting solid is dissolved in ethyl
acetate, dried over sodium sulfate, evaporated to remove the
solvent under reduced pressure. The resulting residue is purified
by silica gel column chromatography (eluent: hexane/ethyl
acetate=5/1 to 1/1), and then the resulting residue is suspended in
ethyl acetate-diisopropyl ether. The precipitates are collected by
filtration and dried to give the title compound (2.81 g).
[0500] APCI-MS M/Z: 313/315 [M+H].sup.+.
Reference Example 108
3-Amino-5-cyano-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00839##
[0502] (2,4-Dicyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide (1.02
g) obtained in Reference Example 107 is treated in a similar manner
to Reference Example 73 to give the title compound (0.96 g).
[0503] APCI-MS M/z: 313/315 [M+H].sup.-.
Reference Example 109
(3-Chloro-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00840##
[0505] (1) 2-Cloro-N-(5-chloropyridin-2-yl)acetamide (30.68 g)
obtained in Reference Example 20(1) is dissolved in
N,N-dimethylformamide (500 ml), thereto is added sodium acetate
(24.55 g) and the mixture is stirred at 60.degree. C. for 5 hours
the reaction solution is diluted with ethyl acetate, washed
successively with water and saturated brine. The solution is dried
over magnesium sulfate, treated with activated charcoal, and the
filtrate is concentrated under reduced pressure. The resulting
residue is suspended in n-hexane and the resulting crystals are
collected by filtration, washed with n-hexane, and dried to give
N-(5-chloropyridin-2-yl)-2-acetoxyacetamide (30.58 g).
[0506] APCI-MS M/Z: 229/231 [M+H].sup.+.
[0507] (2) 2-Acetoxy-N-(5-chloropyridin-2-yl)acetamide (30.36 g)
obtained in Reference Example 109(1) is suspended in methanol (1200
ml) and thereto is added potassium carbonate (22.0 g) under
ice-cooling. The reaction solution is warmed to room temperature,
stirred for 0.5 hours and concentrated under reduced pressure. To
the resulting residue are poured ethyl acetate (1.500 ml) and
ice-water (1000 ml), and then the mixture is extracted with ethyl
acetate. The organic layer is washed with saturated brine, dried
over sodium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is suspended in a small
amount of ethyl acetate, thereto is added diisopropyl ether and the
precipitated crystals are collected by filtration, washed with
diisopropyl ether and dried to give
2-hydroxy-N-1(5-chloropyridin-2-yl)acetamide (22.85 g).
[0508] APCI-MS M/Z: 187/189 [M+H].sup.+.
[0509] (3) 2-Chloro-6-nitrobenzonitrile (187 mg) and
2-hydroxy-N-(5-chloropyridin-2-yl)acetamide (183 mg) obtained in
Reference Example 109(2) are dissolved in N,N-dimethylformamide (2
ml) and thereto is added 60% oleaginous sodium hydride (80 mg)
under ice-cooling. After stirring for 6 hours with cooling, to the
reaction solution is poured saturated aqueous ammonium chloride
solution and extracted with ethyl acetate. The organic layer is
washed with water and saturated brine, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended in n-hexane-diisopropyl ether, the
resulting product is collected by filtration and dried to give the
title compound (286 mg).
[0510] APCI-MS M/Z: 322/324 [M+H].sup.+.
Reference Example 110
3-Amino-4-chloro-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00841##
[0512] (3-Cloro-2-cyanophenoxy)-N-(5-chloropyridin-2-yl)acetamide
(274 mg) obtained in Reference Example 109 is dissolved in
N,N-dimethylacetamide (10 ml), thereto is added cesium carbonate
(333 mg) and the mixture is stirred at 100.degree. C. for 8 hours.
After allowing to cool, to the reaction solution is added
ice-water, the precipitates are collected by filtration and washed
with water. The precipitates are dissolved in hot ethyl acetate,
washed with saturated brine and dried over sodium sulfate. To the
organic layer are added activated charcoal and NH-silica gel (5 g)
and the mixture is filtered to remove the insoluble materials. The
filtrate is concentrated under reduced pressure, the resulting
residue is suspended in ethyl acetate-diethyl ether and the
resulting product is collected by filtration to give the title
compound (112 mg).
[0513] APCI-MS M/Z: 322/324 [M+H].sup.+.
Reference Example 111
3-Amino-4-methoxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00842##
[0515] 2-Methoxy-6-nitrobenzonitrile (589 mg) and
2-hydroxy-N-(5-chloropyridin-2-yl)acetamide (560 mg) obtained in
Reference Example 109(2) are dissolved in N N-dimethylacetamide (10
ml) and thereto is added potassium carbonate (810 mg). The reaction
solution is stirred at 60.degree. C. overnight, thereto is added
additional potassium carbonate (810 mg) and the mixture is stirred
at 100.degree. C. for 4 hours. After allowing to cool, to the
reaction solution is poured ice-water and extracted with ethyl
acetate. The organic layer is washed with water and saturated
brine, dried over sodium sulfate and treated with activated
charcoal. The insoluble materials are removed by filtration, washed
with chloroform-methanol, and the filtrate and the washing are
combined and concentrated under reduced pressure. The resulting
residue is suspended in diisopropyl ether, and then the resulting
product is collected by filtration to give the title compound (104
mg).
[0516] APCI-MS M/Z: 317/319 [M+H].sup.+.
Reference Example 112
Methyl trans-4-(t-butoxycarbonyl-amino)cyclohexanecarboxylate
##STR00843##
[0518] (1) Thionyl chloride (254 ml) is added dropwise to methanol
(1500 ml) under cooling to -30.degree. C. over a period of about
one hour. After the addition, the reaction mixture is stirred at
room temperature for 0.5 hours, thereto is added
trans-cyclohexane-1,4-dicarboxylic acid (500.0 g) and the mixture
is stirred at room temperature for 17 hours. The reaction solution
is concentrated under reduced pressure, the residue is diluted with
chloroform, and then washed with saturated aqueous sodium hydrogen
carbonate solution and saturated brine. The organic layer is dried
over sodium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is crystallized from
n-hexane, the resulting product is collected by filtration, dried
to give dimethyl trans-cyclohexane-1,4-dicarboxylate (545.0 g).
[0519] APCI-MS M/Z: 201 [M+H].sup.+.
(2) Dimethyl trans-cyclohexane-1,4-dicarboxylate (150.0 g) obtained
in Reference Example 112(1) is dissolved in tetrahydrofuran (1500
ml) and to the solution is added dropwise a mixture of 28% sodium
methoxide--in methanol (149 g) and water (13.2 g) under
ice-cooling. The reaction solution warmed to room temperature,
stirred for 3.5 hours, thereto is added n-hexane (1500 ml) and the
mixture is filtrated to collect the precipitates. The resulting
solid is added to a mixture of conc. hydrochloric acid (50 ml),
water (450 ml) and chloroform (1000 ml) under ice-cooling, and
stirred at room temperature for 20 minutes. The chloroform layer is
separated and the aqueous layer is extracted with chloroform. The
organic layers are combined, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is crystallized from n-hexane, the resulting
product is collected by filtration and dried to give monomethyl
trans-cyclohexane-1,4-dicarboxylate (106.0 g).
[0520] ESI-MS M/z: 185 [M-H].sup.-.
[0521] (3) Monomethyl trans-cyclohexane-1,4-dicarboxylate (100.0 g)
obtained in Reference Example 112(2) is dissolved in t-buthanol
(1000 ml), thereto are added diphenylphosphoryl azide (155 g) and
triethylamine (78.6 ml). The mixture is heated at about 60.degree.
C. for one hour and further heated under reflux for additional 17
hours. After allowing to cool, to the reaction solution is added
ice-water, and the mixture is extracted with ethyl acetate. The
organic layer is washed with saturated aqueous sodium hydrogen
carbonate solution and saturated brine, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is dissolved in methanol (250 ml), thereto is
added water (750 ml) and the mixture is stirred under ice-cooling.
After 0.5 hours, the precipitates are collected by filtration,
washed with water-methanol (3:1, 1000 ml) and n-hexane successively
and dried to give the title compound (117.0 g).
[0522] APCI-MS M/Z: 275 [M+H].sup.+.
Reference Example 113
Trans-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylic acid
##STR00844##
[0524] (1) Methyl
trans-4-(t-butoxycarbonylamino)-cyclohexanecarboxylate (234.0 g)
obtained in Reference Example 112 is dissolved in dioxane (500 ml),
and thereto is added 4 N hydrogen chloride-dioxane (500 ml), and
the mixture is stirred at room temperature for 19 hours. The
reaction solution is concentrated under reduced pressure, and the
resulting residue is suspended in diethyl ether, and then the
precipitates are collected by filtration to give methyl
trans-4-aminocyclohexanecarboxylate hydrochloride (121.9 g).
[0525] APCI-MS M/Z: 158 [M+H].sup.+.
[0526] (2) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride
(45.31 g) is suspended in dichloromethane (1000 ml), thereto is
added 4-chlorobutyryl chloride (31.5 ml) under ice-cooling and to
the mixture is added dropwise a solution of triethylamine (81.5 ml)
in dichloromethane (80 ml). The reaction solution is warmed to room
temperature, stirred for 3 hours and the reaction solution is
concentrated under reduced pressure. To the resulting residue are
poured ethyl acetate and 5% hydrochloric acid, and the organic
layer is separated, washed with saturated aqueous sodium hydrogen
carbonate solution and saturated brine. The organic layer is dried
over sodium sulfate and treated with activated carbon, and the
filtrate is concentrated under reduced pressure. The resulting
residue is suspended in diisopropyl ether, filtered to collect the
precipitates, dried to give methyl
trans-4-(4-chloro-butyrylamino)cyclohexanecarboxylate (38.81
g).
[0527] APCI-MS M/Z: 262/264 [M+H].sup.+.
[0528] (3) Sixty % sodium hydride in oil (9.60 g) is suspended in
N,N-dimethyacetamide (500 ml), to this mixture is added methyl
trans-4-(4-chlorobutyrylamino)-cyclohexanecarboxylate (52.32 g)
obtained in Reference Example 113(2) gradually under ice-cooling.
The reaction solution is warmed to room temperature, stirred for 24
hours, and thereto are poured saturated aqueous ammonium chloride
solution and ice-water, and the mixture is extracted with
chloroform. The organic layer is washed with saturated brine, dried
over magnesium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is purified by silica gel
column chromatography (eluent: ethyl acetate) and the obtained
solid is suspended in n-hexane-diisopropyl ether. The resulting
crystals are collected by filtration and dried to give methyl
trans-4-(2-oxo-pyrrolidin-1-yl)cyclohexane-carboxylate (39.20
g).
[0529] APCI-MS M/Z: 226[M+H].sup.+.
[0530] (4) Methyl
trans-4-(2-oxo-pyrrolidin-1-yl)cyclohexanecarboxylate (39.15 g)
obtained in Reference Example 113(3) dissolved in methanol (400
ml), and thereto is added 2 N aqueous sodium hydroxide solution (60
ml) and the mixture is stirred at room temperature for 3 hours. The
reaction solution is adjusted to pH 1-2 by pouring 10% hydrochloric
acid under ice-cooling, saturated with sodium chloride, and then
extracted with chloroform. The organic layer is dried over sodium
sulfate, and then evaporated to remove the solvent under reduced
pressure. The resulting residue is suspended in a small amount of
ethyl acetate, and diisopropyl ether is poured thereto, and the
resulting crystals are collected by filtration. The crystals are
washed with diisopropyl ether several times and dried to give the
title compound (35.94 g).
[0531] ESI-MS M/Z: 210 [M-H].sup.-.
Reference Example 114
Trans-4-(N-acetyl-N-methylamino)-cyclohexanecarboxylic acid
##STR00845##
[0533] (1) Methyl
trans-4-(t-butoxycarbonylamino)-cyclohexanecarboxylate (30.00 g) is
dissolved in N,N-dimethylformamide (150 ml) and thereto is added
60% sodium hydride in oil (5.60 g) under ice-cooling. After
stirring for 0.5 hours under cooling, to the reaction solution are
added methyl iodide (14.5 ml) and methanol (0.15 ml) successively,
and the reaction solution is warmed to room temperature and stirred
for 4 hours. Under ice-cooling, to the reaction solution are poured
saturated ammonium chloride and ice-water, and the mixture is
extracted with ethyl acetate. The organic layer is washed with
water and saturated brine successively, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by silica gel column chromatography
(eluent: n-hexane/ethyl acetate=10/1, followed by 7/1) to give
methyl
trans-4-(N-t-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate
(26.33 g).
[0534] APCI-MS M/Z: 272 [M+H].sup.+.
[0535] (2) Methyl
trans-4-(N-t-butoxycarbonyl-N-methylamino)cyclohexanecarboxylate
(26.32 g) obtained in Reference Example 114(1) is dissolved in
dioxane (100 ml) and thereto is added 4 N hydrogen chloride-dioxane
solution (100 ml). The reaction solution is stirred at room
temperature for 4 hours and to the solution is poured diisopropyl
ether (500 ml). The precipitates are collected by filtration,
washed with diisopropyl ether and dried to give methyl
trans-4-(methylamino)cyclohexanecarboxylate hydrochloride (19.01
g).
[0536] APCI-MS M/Z: 172 [M+H].sup.+.
[0537] (3) Methyl trans-4-(methylamino)cyclohexane-carboxylate
hydrochloride (18.93 g) obtained in Reference Example 114(2) is
suspended in dichloromethane (400 ml), to the solution is added
acetyl chloride (8.42 ml) under ice-cooling, and then a solution of
triethylamine (38.1 ml) in dichloromethane (40 ml) is added
dropwise. The reaction solution is warmed to room temperature,
stirred for 2 hours, thereto is added 5% hydrochloric acid and the
mixture is extracted with dichloromethane. The organic layer is
washed with saturated brine, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by NH-silica gel column
chromatography (eluent: ethyl acetate) to give methyl
trans-4-(N-acetyl-N-methylamino)cyclohexanecarboxylate (19.05
g).
[0538] APCI-MS M/Z: 214 [M+H].sup.+.
[0539] (4) Methyl
trans-4-(N-acetyl-N-methylamino)-cyclohexanecarboxylate (19.00 g)
obtained in Reference Example 114(3) is dissolved in methanol (200
ml), thereto is added aqueous 2 N sodium hydroxide solution (60 ml)
and the mixture is stirred at room temperature for 3 hours. Under
ice-cooling, the reaction solution is adjusted to pH 1-2 with 10%
hydrochloric acid, saturated with sodium chloride, and then
extracted with chloroform. The organic layer is dried over sodium
sulfate, and then evaporated to remove the solvent under reduced
pressure. The resulting residue is suspended in a small amount of
ethyl acetate, to the mixture is poured diisopropyl ether and the
crystals are collected by filtration. The crystals are washed with
diisopropyl ether several times and dried to give the title
compound (16.31 g).
[0540] ESI-MS M/Z: 198 [M-H].sup.-.
Reference Example 115
Trans-4-(N-t-butoxycarbonyl-N-methylamino)cyclohexanecarboxylic
acid
##STR00846##
[0542] Methyl
trans-4-(N-t-butoxycarbonyl-N-methylamino)-cyclohexanecarboxylate
(44.78 g) obtained in Reference Example 114(1) is dissolved in
methanol (300 ml), thereto is added aqueous 2 N sodium hydroxide
solution (100 ml) and the mixture is stirred at room temperature
for 6 hours. The reaction solution is concentrated under reduced
pressure, to the residue are added ice-water, ethyl acetate and 10%
hydrochloric acid under ice-cooling and then the mixture is
extracted with ethyl acetate. The organic layer is washed with
water and saturated brine successively, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended in a small amount of ethyl acetate,
to the mixture is poured n-hexane and the crystals are collected by
filtration. The crystals are washed with n-hexane-diisopropyl ether
several times and dried to give the title compound (39.20 g).
[0543] ESI-MS M/z: 256 [M-H].sup.-
Reference Example 116
Trans-4-(t-butoxycarbonyl-amino)cyclohexanecarboxylic acid
##STR00847##
[0545] Methyl
trans-4-(t-butoxycarbonylamino)cyclohexane-carboxylate (44.78 g)
obtained in Reference Example 112 is treated in a similar manner to
Reference Example 115 to give the title compound (24.04 g).
[0546] ESI-MS M/Z: 242 [M-H].sup.-.
Reference Example 117
Trans-4-dimethylaminocyclohexane-carboxylic acid hydrochloride
##STR00848##
[0548] (1) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride
(93.0 g) obtained in Reference Example 113(1) is dissolved in
methanol (1000 ml), thereto are added aqueous 35% formaldehyde
solution (95.4 ml), sodium acetate (39.4 g), and 10%
palladium-carbon (10 g), and the mixture is stirred for 3.5 hours
under atmospheric hydrogen pressure. The insoluble materials are
removed by filtration, the filtrate is concentrated under reduced
pressure, to the resulting residue is added aqueous 20% potassium
carbonate solution (500 ml), and the reaction mixture is extracted
with chloroform. The organic layer is dried over sodium sulfate and
potassium carbonate and evaporated to remove the solvent under
reduced pressure. suspended in a mixture of tetrahydrofuran (300
ml) and N,N-dimethyl acetamide (60 ml), and the mixture is stirred
at 70.degree. C. for 20 hours. The reaction solution is
concentrated under reduced pressure, the residue is dissolved in
ethyl acetate-water and the organic layer is separated. The organic
layer is washed with water and saturated brine, dried over sodium
sulfate and evaporated to remove the solvent under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: ethyl acetate/hexane 1/5) to give methyl
trans-4-(pyrrolidin-1-yl)cyclohexanecarboxylate (10.9 g).
[0549] APCI-MS M/Z: 212 [M+H].sup.+.
[0550] (2) To a solution of methyl
trans-4-(pyrrolidin-1-yl)cyclohexanecarboxylate (10.9 g) obtained
in Reference Example 118(1) in dioxane (150 ml) is added 2 N
hydrochloric acid (80 ml), and the mixture is stirred at
110.degree. C. for 3 hours while evaporating to remove methanol.
The reaction solution is concentrated under reduced pressure, the
resulting residue is suspended in diethyl ether, and then collected
by filtration to give the title compound (11.1 g).
[0551] APCI-MS M/z: 198 [M+H].sup.+.
Reference Example 119
Trans-4-(morpholin-4-yl)cyclohexane-carboxylic acid
hydrochloride
##STR00849##
[0553] (1) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride
(47.5 g) obtained in Reference Example 113(1),
bis(2-chloroethyl)ether (34.5 ml), sodium carbonate (77.9 g) and
sodium iodide (88 g) are suspended in a mixture of tetrahydrofuran
(1400 ml) and N,N-dimethylacetamide (280 ml), and the mixture is
heated-under reflux for 18 hours. Bis(2-chloroethyl)ether (23 ml)
and sodium iodide (22 g) are added to the reaction solution and the
mixture is refluxed for additional 6 hours. The reaction solution
is concentrated under reduced pressure, and the residue is
dissolved in ethyl acetate-water and the organic layer is
separated. The organic layer is washed with water and saturated
brine, dried over sodium sulfate and evaporated to remove the
solvent under reduced pressure. The resulting residue is purified
by NH-silica gel column chromatography (eluent: ethyl
acetate/hexane=1/30, followed by ethyl acetate/hexane=1/5, and then
1/3) to give methyl trans-4-(morpholin-4-yl)cyclohexanecarboxylate
(53.9 g).
[0554] APCI-MS M/z: 228 [M+H].sup.+.
[0555] (2) To a solution of methyl
trans-4-(morpholin-4-yl)cyclohexanecarboxylate (53.8 g) obtained in
Reference Example 119(1) in dioxane (750 ml) is added 2 N
hydrochloric acid (400 ml), and the mixture is stirred at
110.degree. C. for 4 hours while evaporating to remove methanol.
The reaction solution is concentrated, and the resulting residue is
suspended in diethyl ether, and then the resulting product is
collected by filtration to give the title compound (54.8 g).
[0556] APCI-MS M/Z: 214 [M+H].sup.+.
Reference Example 120
Trans-[4-(dimethylamino)cyclohexyl]-acetic acid hydrochloride
##STR00850##
[0558] (1) Potassium hydroxide (12.8 g) is dissolved in water (30
ml) and thereto is added diethyl ether (45 ml). Under ice-cooling,
to the resulting mixture is added N-nitroso-N-methylurea (5.07 g).
The reaction solution is stirred for 10 minutes under cooling, and
the organic layer is separated and dried over potassium hydroxide
to give a solution of diazomethane in diethyl ether.
[0559] (2) Under argon atmosphere,
trans-4-(t-butoxycarbonylamino)cyclohexanecarboxylic acid (3.0 g)
obtained in Reference Example 116 is suspended in diethyl ether (40
ml), thereto is added triethylamine (1.89 ml) at -10.degree. C.,
and then isobutyl chloroformate (1.75 ml) is added dropwise to the
mixture. The reaction solution is stirred at -0.degree. C. for 30
minutes, and a solution of diazomethane in diethyl ether obtained
in Reference Example 120(1) is added dropwise to the reaction
solution at -10.degree. C., and the mixture is warmed to room
temperature and stirred for 15 hours. Under ice-cooling, 10%
aqueous citric acid solution is poured to the solution, and the
organic layer is separated. The organic layer is washed with
saturated aqueous sodium hydrogen carbonate solution, water and
saturated brine, dried over sodium sulfate and evaporated to remove
the solvent under reduced pressure. The resulting residue is
purified by silica gel column chromatography (eluent: ethyl
acetate/hexane=1/3, followed by ethyl acetate/hexane 1/2) to give
t-butyl trans-[4-(2-diazoacetyl)cyclohexyl]-carbamate (1.86 g).
[0560] APCI-MS M/Z: 285[M+NH.sub.4].sup.+.
[0561] (3) t-Butyl trans-[4-(2-diazoacetyl)cyclohexyl]-carbamate
(1.62 g) obtained in Reference Example 120(2) is dissolved in
methanol (30 ml) in a light shielding reaction vessel under argon
atmosphere, and the mixture is cooled to -25.degree. C. To the
reaction solution is added a solution of silver benzoate (153 mg)
in triethylamine (2.4 ml), and the mixture is warmed to room
temperature and stirred for 3 hours. The reaction solution is
concentrated under reduced pressure, the resulting residue is
dissolved in ethyl acetate, washed with saturated aqueous sodium
hydrogen carbonate solution, saturated aqueous ammonium chloride
solution and saturated brine successively, dried over sodium
sulfate and evaporated to remove the solvent, which provides methyl
trans-4-(t-butoxycarbonylamino)-cyclohexyl]acetate (1.25 g).
[0562] APCI-MS M/Z: 289 [M+NH.sub.4].sup.+.
[0563] (4) To a solution of methyl
trans-[4-(t-butoxycarbonyl-amino)cyclohexyl]acetate (1.23 g)
obtained in Reference Example 120(3) in 1,4-dioxane (8 ml), is
added 4 N hydrogen chloride-dioxane solution (8 ml) and the mixture
is stirred at room temperature for 5 hours. The reaction solution
is concentrated to dryness under reduced pressure to give methyl
trans-(4-aminocyclohexyl)acetate hydrochloride (898 mg).
[0564] APCI-MS M/z: 172 [M+H].sup.+.
[0565] (5) Under ice-cooling, to a suspension of methyl
trans-(4-aminocyclohexyl)acetate hydrochloride (895 mg) obtained in
Reference Example 120(4) in dichloromethane (30 ml), triethylamine
(1.2 ml) is added and the mixture is stirred. Aqueous 35%
formaldehyde solution (1.71 ml) and sodium triacetoxy borohydride
(2.74 g) are added thereto successively under ice-cooling. The
reaction solution is warmed to room temperature and stirred for 6
hours. Saturated aqueous sodium hydrogen carbonate solution is
poured into the mixture under ice-cooling and the mixture is
extracted with chloroform. The organic layer is washed with
saturated brine, dried over sodium sulfate, and then the solvent is
removed under reduced pressure to give methyl
trans-[4-(dimethylamino)cyclohexyl]acetate (771 mg).
[0566] APCI-MS M/Z: 200 [M+H].sup.+.
[0567] (6) To a solution of methyl
trans-[4-(dimethylamino)cyclohex-yl]acetate (760 mg) obtained in
Reference Example 120(5) in dioxane (25 ml), 1 N hydrochloric acid
(15 ml) is added and the mixture is heated under reflux for 3
hours. The reaction solution is concentrated under reduced
pressure, and the resulting residue is suspended in diethyl ether.
The precipitates are collected by filtration and dried to give the
title compound (795 mg).
[0568] APCI-MS M/Z: 186 [M+H].sup.+.
Reference Example 121
Trans-4-(dimethylaminomethyl)-cyclohexanecarboxylic acid
hydrochloride
##STR00851##
[0570] (1) Trans-4-(aminomethyl)cyclohexanecarboxylic acid (6.29 g)
is suspended in methanol (32 ml) and to the suspension is added
dropwise thionyl chloride (6 ml) under ice-cooling. The reaction
solution is warmed to room temperature, stirred overnight and
concentrated under reduced pressure to dryness, which provides
methyl trans-4-(aminomethyl)cyclohexanecarboxylate hydrochloride
(8.69 g).
[0571] APCI-MS M/Z: 172 [M+H].sup.+.
[0572] (2) Methyl trans-4-(aminomethyl)cyclohexane-carboxylate
hydrochloride (8.69 g) obtained in Reference Example 121(1) is
suspended in dichloromethane (400 ml), thereto is added
triethylamine (11.2 ml), and the mixture is stirred at room
temperature for several minutes and thereto are added 35% aqueous
formaldehyde solution (15.9 ml) and sodium triacetoxyborohydride
(25.43 g) under ice-cooling. The reaction solution is warmed to
room temperature, stirred for 2 hours, to the solution is poured a
saturated aqueous sodium hydrogen carbonate solution and the
solution is extracted with chloroform. The organic layer is washed
with water and saturated brine successively, dried over sodium
sulfate and evaporated to remove the solvent to give methyl
trans-4-(dimethylamino-methyl)cyclohexanecarboxylate (7.42 g).
[0573] APCI-MS M/Z: 200 [M+H].sup.+.
[0574] (3) Methyl
trans-4-(dimethylaminomethyl)-cyclohexanecarboxylate (7.41 g)
obtained in Reference Example 121(2) is dissolved in dioxane (140
ml), thereto is added 2 N hydrochloric acid (70 ml), and the
mixture is heated under reflux for 3 hours. After allowing to cool,
the reaction solution is concentrated under reduced pressure, the
resulting residue is subjected to azeotropic distillation with
toluene, and then the resulting product is dried to give the title
compound (8.45 g).
[0575] APCI-MS M/Z: 186 [M+H].sup.+.
Reference Example 122
Trans-4-(t-butoxycarbonylamino-methyl)cyclohexanecarboxylic
acid
##STR00852##
[0577] Trans-4-(aminomethyl)cyclohexanecarboxylic acid (8.35 g) is
suspended in dioxane (100 ml), thereto are added water (50 ml) and
1 N aqueous sodium hydroxide solution (50 ml), and then di-t-butyl
dicarbonate (12.7 g) is added dropwise under ice-cooling. The
reaction solution is warmed to room temperature, stirred for 4
hours and the reaction solution is concentrated under reduced
pressure. The resulting residue is diluted with ethyl acetate,
adjusted to about pH 3-4 by addition of aqueous citric acid
solution and extracted with ethyl acetate. The organic layer is
washed with water and saturated brine, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended in n-hexane, and the resulting
product is collected by filtration and dried to give the title
compound (13.30 g).
[0578] ESI-MS M/Z: 256 [M-H].sup.-.
Reference Example 123
Ethyl 3-(piperidin-4-yl)propionate hydrochloride
##STR00853##
[0580] (1) Sixty % sodium hydride in oil (33.6 g) is suspended in
tetrahydrofuran (600 ml) and a solution of triethyl
phosphonoacetate (188.4 g) in tetrahydrofuran (100 ml) is added
dropwise thereto under ice-cooling. The mixture is stirred for 0.5
hours under ice-cooling, and a solution of pyridine-4-carbaldehyde
(75.00 g) in tetrahydrofuran (100 ml) is added thereto dropwise and
the mixture is stirred or one hour. To the reaction solution is
poured ice-water (1000 ml) under ice-cooling and the mixture is
extracted with ethyl acetate. The organic layer is washed with
water, saturated aqueous sodium hydrogen carbonate solution and
saturated brine successively, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended in a small amount of diisopropyl
ether under ice-cooling and the precipitates are collected by
filtration. The precipitates are washed with a small amount of
diisopropyl ether and n-hexane successively and dried to give ethyl
3-(pyridin-4-yl)acrylate (77.53 g).
[0581] APCI-MS M/Z: 178 [M+H].sup.+.
[0582] (2) Ethyl 3-(pyridin-4-yl)acrylate (28.00 g) obtained in
Reference Example 123(1) is dissolved in acetic acid (280 ml),
thereto is added platinum oxide (1.80 g) and the mixture is shaken
under 55 psi hydrogen atmosphere at room temperature for 24 hours.
The insoluble materials are removed by filtration and the filtrate
is concentrated under reduced pressure. The resulting residue is
dissolved in dioxane (200 ml), thereto are added 4 N hydrogen
chloride-dioxane (200 ml) and the mixture is evaporated to remove
the solvent under reduced pressure. The resulting residue is
suspended in diethyl ether-diisopropyl ether, the precipitates are
collected by filtration, washed with diisopropyl ether, and dried
to give the title compound (33.50 g).
[0583] APCI-MS M/Z: 186 [M+H].sup.+.
Reference Example 124
Ethyl (piperidin-4-yl)acetate hydrochloride
##STR00854##
[0585] Ethyl (pyridin-4-yl)acetate (50.00 g) is dissolved in acetic
acid (500 ml), thereto is added platinum oxide (3.44 g) and the
mixture is shaken under 55 psi hydrogen atmosphere at room
temperature for 20 hours. The insoluble materials are removed by
filtration and the filtrate is concentrated under reduced pressure.
The resulting residue is dissolved in dioxane (200 ml), thereto is
added 4 N hydrogen chloride-dioxane (400 ml), and then the mixture
is evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended in diethyl ether-diisopropyl ether,
and the precipitates are collected by filtration, washed with
diisopropyl ether, and then dried to give the title compound (61.80
g).
[0586] APCI-MS M/Z: 172 [M+H].sup.+.
Reference Example 125
Ethyl 3-(1-isopropylpiperidin-4-yl)propionate
##STR00855##
[0588] Ethyl 3-(piperidin-4-yl)propionate hydrochloride (70.83 g)
obtained in Reference Example 123 is dissolved in ethanol (700 ml),
thereto are added 2-iodopropane (38.2 ml) and potassium carbonate
(132.3 g) and the mixture is heated under reflux for 6 hours. The
insoluble materials are removed by filtration and the filtrate is
concentrated under reduced pressure. The resulting residue is
diluted with ethyl acetate (800 ml), washed with water and
saturated brine successively, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate=20/1 followed by
9/1) to give the title compound (57.13 g).
[0589] APCI-MS M/Z: 228 [M+H].sup.+.
Reference Examples 126-127
[0590] The corresponding compounds are treated in a similar manner
to Reference Example 125 to give the following compounds
TABLE-US-00050 Ref. Ex. Physicochemical No. Structure Properties
126 ##STR00856## APCI-MS M/Z: 214 [M + H].sup.+ 127 ##STR00857##
APCI-MS M/Z: 200 [M + H].sup.+
Reference Example 128
3-(1-Isopropylpiperidin-4-yl)propionic acid hydrochloride
##STR00858##
[0592] Ethyl 3-(1-isopropylpiperidin-4-yl)propionate (57.12 g)
obtained in Reference Example 125 is dissolved in dioxane (1200
ml), thereto is added 2 N hydrochloric acid (600 ml) and the
mixture heated under reflux for 3 hours. The reaction solution is
concentrated under reduced pressure, subjected to azeotropic
distillation with dioxane, and the resulting residue is suspended
in diethyl ether-diisopropyl ether (1:1, 500 ml). The precipitates
are collected by filtration, washed with diisopropyl ether and
dried to give the title compound (55.36 g).
[0593] APCI-MS M/Z: 200 [M+H].sup.+.
Reference Examples 129-130
[0594] The corresponding compounds are treated in a similar manner
to Reference Example 128 to give the following compounds.
TABLE-US-00051 Ref. Ex. Physicochemical No. Structure Properties
129 ##STR00859## APCI-MS M/Z: 186 [M + H].sup.+ hydrochloride 130
##STR00860## APCI-MS M/Z: 172 [M + H].sup.+ hydrochloride
Reference Example 131
1-(Pyridin-4-yl)piperidin-4-carboxylic acid
##STR00861##
[0596] 4-Chloropyridine hydrochloride (9.55 g) and triethylamine
(26.0 ml) are dissolved in ethanol (10 ml) and water (30 ml),
thereto is added ethyl isonicotinate (10.00 g), and then the
reaction solution is heated at 150.degree. C. for 96 hours in a
sealed tube. After allowing to cool, ethanol is added to the
reaction solution and the insoluble materials are removed by
filtration. The filtrate is concentrated under reduced pressure,
the residue is suspended in chloroform, the precipitates are
collected by filtration and recrystallized from
water-N,N-dimethylformamide to give the title compound (10.34
g).
[0597] APCI-MS M/Z: 207 [M+H].sup.+.
Reference Example 132
[1-(Pyridin-4-yl)piperidin-4-yl]acetic acid hydrochloride
##STR00862##
[0598] (1) Ethyl (piperidin-4-yl)acetate hydrochloride (5.00 g)
obtained in Reference Example 124, 4-chloro-pyridine hydrochloride
(3.62 g) and triethylamine (10.1 ml) are suspended in xylene (130
ml) and heated under reflux for 20 hours. The reaction solution is
cooled with water and the insoluble materials are removed by
filtration. The filtrate is concentrated under reduced pressure,
the resulting residue is diluted with chloroform, washed with
water, dried over magnesium sulfate, and then evaporated to remove
the solvent under reduced pressure. The resulting residue is
purified by NH-silica gel column chromatography (eluent:
chloroform/ethyl acetate=4/1) to give ethyl
[1-(pyridin-4-yl)piperidin-4-yl]acetate (4.15 g).
[0599] APCI-MS M/Z: 249 [M+H].sup.+.
[0600] (2) Ethyl [1-(pyridin-4-yl)piperidin-4-yl]acetate (4.15 g)
obtained in Reference Example 132(1) is dissolved in dioxane (200
ml), thereto is added 1 N hydrochloric acid (70 ml) and the mixture
is heated under reflux for 4 hours. The reaction solution is
concentrated under reduced pressure and the resulting residue is
lyophilized to give the title compound (3.90 g).
[0601] APCI-MS M/Z: 221 [M+H].sup.+.
Reference Example 133
3-[1-(Pyrimidin-4-yl)piperidin-4-yl]propionic acid
hydrochloride
##STR00863##
[0603] (1) Ethyl 3-(piperidin-4-yl)propionate hydrochloride (5.00
g) obtained in Reference Example 123 is suspended in
tetrahydrofuran (50 ml) and thereto are added
4,6-dichloropyrimidine (2.80 g) and diisopropylethylamine (13.1 ml)
at room temperature. The reaction solution is stirred for 3 hours
at room temperature, thereto is added water, and the mixture is
extracted with ethyl acetate. The organic layer is washed with
water and saturated brine successively, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by silica gel column chromatography
(eluent: n-hexane/ethyl acetate=5/1, followed by 3/1) to give ethyl
3-[1-(6-chloropyrimidin-4-yl)piperidin-4-yl]propionate (5.58
g).
[0604] APCI-MS M/Z: 298/300 [M+H].sup.+.
[0605] (2) Ethyl
3-[1-(6-chloropyrimidin-4-yl)piperidin-4-yl]propionate (5.54 g)
obtained in Reference Example 133(1) is dissolved in ethanol (100
ml), thereto is added 10% palladium-carbon (0.55 g) and the mixture
is stirred for 4 hours under hydrogen atmosphere under normal
pressure. The insoluble materials are removed by filtration and the
filtrate is concentrated under reduced pressure. Ethyl acetate and
saturated aqueous sodium hydrogen carbonate solution are poured to
the resulting residue, the organic layer is separated, washed with
water and saturated brine successively, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure to give
ethyl 3-[1-(pyrimidin-4-yl)piperidin-4-yl]propionate (3.57 g).
[0606] APCI-MS M/Z: 264 [M+H].sup.+.
[0607] (3) Ethyl 3-[1-(pyrimidin-4-yl)piperidin-4-yl]-propionate
(3.54 g) obtained in Reference Example 133(2) is dissolved in
dioxane (140 ml), thereto is added 1 N hydrochloric acid (70 ml)
and the mixture is heated under reflux for 3 hours. After allowing
to cool, the reaction solution is concentrated under reduced
pressure and subjected to diazetropic distillation with dioxane.
The resulting residue is suspended in diethyl ether, and the
resulting product is collected by filtration, washed with diethyl
ether, and then dried to give the title compound (3.63 g).
[0608] ESI-MS M/Z: 234 [M-H].sup.-.
Reference Example 134
3-(1-Isopropylpiperidin-4-yl)acrylic acid hydrochloride
##STR00864##
[0610] (1) Lithium aluminum hydride (1.10 g) is suspended in
tetrahydrofuran (80 ml), and thereto is added a solution of ethyl
1-isopropylpiperidine-4-carboxylate (5.00 g) obtained in Reference
Example 127 in tetrahydrofuran (30 ml) dropwise under ice-cooling.
The reaction solution is stirred for 2 hours under the ice-cooling,
and water (1.1 ml), 15% aqueous sodium hydroxide solution (1.1 ml)
and water (3.3 ml) are added dropwise successively and stirred for
additional 10 minutes. To the resulting reaction solution is added
potassium carbonate, and the mixture is stirred for 20 minutes, and
then the insoluble materials are removed by filtration. The
filtrate is concentrated under reduced pressure, and then the
resulting residue is purified by NH-silica gel column
chromatography (eluent: chloroform/ethyl acetate=1/1) to give
(1-isopropylpiperidin-4-yl)methanol (4.29 g).
[0611] APCI-MS M/Z: 158 [M+H].sup.+.
[0612] (2) Oxalyl chloride (2.0 ml) is dissolved in dichloromethane
(120 ml) and thereto is added dropwise a solution of
dimethylsulfoxide (3.3 ml) in dichloromethane (15 ml) under dry
ice-acetone cooling. After stirring for 10 minutes under
ice-cooling, a solution of (1-isopropylpiperidin-4-yl)methanol
(3.00 g) obtained in Reference Example 134(1) in dichloromethane
(30 ml) is added dropwise over a period of 15 minutes. After
addition, the reaction solution is stirred for 2 hours under
ice-cooling, and thereto is added dropwise triethylamine (13.3 ml)
over a period of 10 minutes. The reaction solution is stirred for
one hour while it is warmed to room temperature, and then the
solution is poured to saturated aqueous sodium hydrogen carbonate
solution. The mixture is extracted with dichloromethane and
evaporated to remove the solvent under reduced pressure. The
aqueous layer is extracted with ethyl acetate, and the extract is
combined with the residue obtained by removing solvent from the
above dichloromethane-extract, washed with water and saturated
brine and dried over sodium sulfate. The solvent is evaporated
under reduced pressure to give the crude material,
1-isopropylpiperidine-4-carbaldehyde (1.96 g).
[0613] APCI-MS M/Z: 156 [M+H].sup.+.
[0614] (3) Triethyl phosphonoacetate (7.96 g) is dissolved in
tetrahydrofuran (50 ml) and thereto is added gradually 60% sodium
hydride in oil (1.45 g) under ice-cooling. After stirring for 20
minutes under ice-cooling, to the mixture is added
1-isopropylpiperidine-4-carbaldehyde (5.03 g) obtained in Reference
Example 134 (2) in tetrahydrofuran (25 ml). The reaction solution
is stirred for 3 hours, diluted with diethyl ether, thereto is
added water and the mixture is extracted with ethyl acetate. The
organic layer is washed with water and saturated brine, dried over
sodium sulfate and evaporated to remove the solvent under reduced
pressure. The resulting residue is purified by NH-silica gel column
chromatography (eluent: n-hexane/ethyl acetate 9/1) to give ethyl
3-(1-isopropylpiperidin-4-yl)acrylate (6.87 g).
[0615] APCI-MS M/Z: 226 [M+H].sup.3.
[0616] (4) Ethyl 3-(1-isopropylpiperidin-4-yl)acrylate (1.01 g)
obtained in Reference Example 134(3) is dissolved in ethanol (20
ml), thereto is added 2 N aqueous sodium hydroxide solution (4.5
ml) and the mixture is stirred at room temperature for 24 hours. To
the reaction solution is added 2 N hydrochloric acid (9 ml), and
the mixture is concentrated under reduced pressure, and then the
resulting residue is lyophilized to give the title compound (1.43
g).
[0617] APCI-MS M/Z: 198 [M+H].sup.+.
Reference Example 135
(1-t-Butoxycarbonylpiperidin-4-yl)acetic acid
##STR00865##
[0619] (1) Ethyl (piperidin-4-yl)acetate hydrochloride obtained in
Reference Example 124 (10.00 g) is suspended in tetrahydrofuran (95
ml), and thereto are added sodium hydrogen carbonate (12.14 g) and
water (150 ml), and then thereto is added a solution of di-t-butyl
dicarbonate (11.60 g) in tetrahydrofuran (55 ml) dropwise under
ice-cooling. The reaction solution is stirred at room temperature
for 20 hours, aqueous potassium carbonate solutions is poured to
the solution and the mixture is extracted with ethyl acetate. The
organic layer is washed with saturated brine, dried over magnesium
sulfate and evaporated to remove the solvent under reduced
pressure. The resulting residue is purified by silica gel column
chromatography (eluent: n-hexane/ethyl acetate=5/1) to give ethyl
(1-t-butoxycarbonylpiperidin-4-yl)acetate (13.06 g).
[0620] APCI-MS M/Z: 272 [M+H].sup.+.
[0621] (2) Ethyl (1-t-butoxycarbonylpiperidin-4-yl)acetate (13.00
g) obtained in Reference Example 135(1) is dissolved in
tetrahydrofuran-ethanol (2:1, 180 ml) and thereto is added a
solution of sodium hydroxide (4.80 g) in water (60 ml). The
reaction solution is stirred at room temperature overnight,
concentrated under reduced pressure and the resulting aqueous layer
is washed with diethyl ether. The aqueous layer is acidified with 1
N hydrochloric acid under ice-cooling, and then extracted with
ethyl acetate. The organic layer is washed with water and saturated
brine, and then dried with magnesium sulfate. The solvent is
evaporated under reduced pressure to give the title compound (11.10
g).
[0622] ESI-MS M/Z: 242 [M-H].sup.-.
Reference Examples 136-137
[0623] The corresponding compounds are treated in a similar manner
to Reference Example 135 to give the Following compounds.
TABLE-US-00052 Ref. Ex. Physicochemical No. Structure Properties
136 ##STR00866## ESI-MS M/Z: 256 [M - H].sup.- 137 ##STR00867##
ESI-MS M/Z: 228 [M - H].sup.-
Reference Example 138
t-Butyl 4-carboxymethylene-1-piperidinecarboxylate
##STR00868##
[0625] (1) t-Butoxy potassium (4.49 g) is suspended in
N,N-dimethylformamide under argon atmosphere, and to the mixture is
added dropwise triethyl phosphonoacetate (5.83 g) under
ice-cooling. After stirring for 0.5 hours under the ice-cooling,
t-butyl 4-oxo-1-piperidinecarboxylate (4.07 g) is added dropwise to
the reaction solution, and the mixture is warmed to room
temperature and stirred for 1.5 hours. To the reaction solution is
added ice-water under ice-cooling, and the precipitates are
collected by filtration and dried to give t-butyl
4-ethoxycarbonylmethylene-1-piperidinecarboxylate (3.02 g).
[0626] APCI-MS M/Z: 287 [M+NH.sub.4].sup.+.
[0627] (2) t-Butyl
4-ethoxycarbonylmethylene-1-piperidinecarboxylate (1.08 g) obtained
in Reference Example 138(1) is dissolved in dioxane (12 ml),
thereto is added 1 N aqueous sodium hydroxide solution (8 ml) and
the mixture is stirred at room temperature overnight. The reaction
solution is acidified with 1 N hydrochloric acid, and then
extracted with ethyl acetate. The organic layer is washed with
water and saturated brine successively, dried over sodium sulfate
and evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by silica gel column chromatography
(eluent: chloroform/methanol=50/1) to give the title compound (0.72
g).
[0628] ESI-MS M/Z: 240 [M-H].sup.-.
Reference Example 139
(4-Isopropylpiperazin-1-yl)acetic acid
##STR00869##
[0630] (1) 1-Isopropylpiperazine (1.21 g) is dissolved in
acetonitrile (12 ml), thereto is added potassium carbonate (3.15
g), and then a solution of benzyl bromoacetate (2.08 g) in
acetonitrile (2 ml) is added dropwise. The reaction solution is
heated under reflux for one hour, after allowing to cool, the
insoluble materials are removed by filtration and the filtrate is
concentrated under reduced pressure. The resulting residue is
purified by silica gel column chromatography (eluent:
chloroform/methanol=50/1 followed by 9/1) to give benzyl
(4-isopropylpiperazin-1-yl)acetate (2.84 g).
[0631] APCI-MS M/Z: 277 [M+H].sup.+.
[0632] (2) Benzyl (4-isopropylpiperazin-1-yl)acetate (2.83 g)
obtained in Reference Example 139(1) is dissolved in methanol (40
ml), thereto is added 10% palladium-carbon (0.31 g), and then the
mixture is stirred for 7 hours under hydrogen atmosphere under
normal pressure. The insoluble materials are removed by filtration,
the filtrate is concentrated under reduced pressure to give the
title compound (1.82 g).
[0633] APCI-MS M/Z: 187 [M+H].sup.+.
Reference Example 140
3-(4-Isopropylpiperazin-1-yl)propionic acid dihydrochloride
##STR00870##
[0635] (1) 1-Isopropylpiperazine (650 mg) is dissolved in
acetonitrile (7 ml) and thereto is added t-butyl acrylate (743
.mu.l) under ice-cooling. The reaction solution is warmed to room
temperature and stirred for 4 hours, and thereto is added
additional t-butyl acrylate (148 .mu.l), and then the mixture is
stirred at room temperature for another 10 hours. Additional
t-butyl acrylate (222 .mu.l) is added to the reaction solution, and
the mixture is stirred for 6 hours, thereto is poured water and the
solution is extracted with ethyl acetate. The organic layer is
washed with saturated brine, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is purified by silica gel column chromatography
(eluent: chloroform/methanol=20/1 followed by 10/1) to give t-butyl
3-(4-isopropylpiperazin-1-yl)propionate (1.18 g).
[0636] APCI-MS M/Z: 257 [M+H].sup.+.
[0637] (2) t-Butyl 3-(4-isopropylpiperazin-1-yl)propionate (1.15 g)
obtained in Reference Example 140(1) is dissolved in dioxane (10
ml), and thereto is added 4 N hydrogen chloride-dioxane (25 ml) and
the reaction solution is stirred at room temperature for 48 hours.
The reaction solution is concentrated under reduced pressure and
the resulting residue is suspended in diethyl ether. The
precipitates are collected and dried to give the title compound
(1.06 g).
[0638] APCI-MS M/Z: 201 [M+H].sup.+.
Reference Example 141
Trans-4-(3-oxo-morpholin-4-yl)cyclohexanecarboxylic acid
##STR00871##
[0640] Sixty % sodium hydride in oil (6.80 g) is suspended in
N,N-dimethylacetamide (80 ml) and a solution of 2-benzyloxyethanol
(12.9 g) in N,N-dimethylacetamide (50 ml) is added dropwise to the
mixture over a period of 10 minutes under ice-cooling. After
stirring at room temperature for 15 minutes, the reaction solution
is cooled with ice, thereto is added chloroacetic acid (8.13 g)
gradually and the mixture is stirred at room temperature for 11
hours. The reaction solution is concentrated under reduced
pressure, to the resulting residue is added aqueous sodium hydrogen
carbonate solution and the mixture is washed with diethyl ether.
The aqueous layer is acidified with conc. hydrochloric acid, and
then extracted with ethyl acetate. The organic layer is washed with
saturated brine, dried over sodium sulfate and evaporated to remove
solvent under reduced pressure to give (2-benzyloxyethoxy)acetic
acid (18.24 g).
[0641] ESI-MS M/Z: 209 [M-H].sup.-.
##STR00872##
[0642] (2-Benzyloxyethoxy)acetic acid (6.51 g) obtained in (1),
methyl trans-4-aminocyclohexanecarboxylate hydrochloride (5.27 g)
obtained in Reference Example 113(1) and 1-hydroxybenzotriazole
(5.06 g) are dissolved in N,N-dimethylformamide (100 ml). To the
mixture are added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (7.10 g) and triethylamine (4.50 ml) successively
under ice-cooling, and the mixture is stirred at room temperature
for 3 drays. The reaction solution is concentrated under reduced
pressure, to the resulting residue is added an aqueous sodium
hydrogen carbonate solution and the mixture is extracted with ethyl
acetate. The organic layer is washed with a saturated brine, dried
over sodium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is purified by silica gel
column chromatography (eluent: hexane/ethyl acetate=1:1 followed by
ethyl acetate) to give methyl trans-4-[2-(2
benzyloxyethoxy)acetylamino]cyclohexanecarboxylate (8.24 g).
[0643] APCI-MS M/Z: 350 [M+H].sup.-.
##STR00873##
[0644] Methyl
trans-4-[2-(2-benzyloxyethoxy)acetylamino]-cyclohexanecarboxylate
(5.09 g) obtained in (2) is dissolved in acetic acid (150 ml), and
thereto is added 5% palladium carbon (1.01 g) and the mixture is
stirred for 2.4 hours under hydrogen atmosphere under normal
pressure. The reaction solution is filtrated to remove the
catalyst, and then the filtrate is concentrated under reduced
pressure. The resulting residue is dissolved in chloroform, washed
with a saturated sodium hydrogen carbonate solution, dried over
sodium sulfate and evaporated to remove the solvent to give methyl
trans-4-[2-(2-hydroxyethoxy)acetylamino]cyclohexanecarboxylate
(3.32 g).
[0645] APCI-MS M/Z: 260 [M+H].sup.+.
##STR00874##
[0646] Methyl
trans-4-[2-(2-hydroxyethoxy)acetylamino]-cyclohexanecarboxylate
(1.37 g) obtained in (3) is dissolved in chloroform (15 ml) and
thereto is added triethylamine (890 .mu.l) under ice-cooling. Then,
methanesulfonyl chloride (450 .mu.l) is added dropwise at the same
temperature. The reaction solution is stirred for 3 hours under
ice-cooling, diluted with water and extracted with chloroform. The
organic layer is washed with saturated brine, dried over sodium
sulfate and removed the solvent by evaporation under reduced
pressure to give methyl
trans-4-[2-(2-methanesulfonyloxyethoxy)acetylamino]-cyclohexanecarboxylat-
e (1.83 g).
[0647] APCI-MS M/Z: 338 [M+H].sup.+.
##STR00875##
[0648] Methyl
trans-4-[2-(2-methanesulfonyloxyethoxy)-acetylamino]cyclohexanecarboxylat-
e (1.08 g) obtained in (4) is dissolved in N,N-dimethylacetamide
(15 ml), thereto is added 60% sodium hydride in oil (135 mg) under
ice-cooling and the mixture is stirred for 16 hours at room
temperature. To the residue obtained by concentrating the reaction
solution under reduced pressure are added water and excess sodium
chloride, and the mixture is extracted with chloroform. The organic
layer is dried over sodium sulfate and evaporated to remove the
solvent under reduced pressure. The resulting residue is purified
by silica gel column chromatography (eluent: hexane/ethyl
acetate=1:1 followed by ethyl acetate) to give methyl
trans-4-(3-oxo-morpholin-4-yl)cyclohexanecarboxylate (715 mg).
[0649] APCI-MS M/Z: 242 [M+H].sup.+.
##STR00876##
[0650] Methyl trans-4-(3-oxo-morpholin-4-yl)cyclohexane-carboxylate
(500 mg) obtained in (5) is treated in a similar manner to
Reference Example 113(4) to give the title compound (322 mg).
[0651] ESI-MS M/Z: 226 [M-H].sup.-.
Reference Example 142
Trans-4-(2-oxo-oxazolidin-3-yl)cyclohexanecarboxylic acid
##STR00877##
[0653] (1) Methyl trans-4-aminocyclohexanecarboxylate hydrochloride
(5.00 g) obtained in Reference Example 113(1) is dissolved in
chloroform (60 ml), thereto is added triethylamine (11 ml) under
ice-cooling, and then a solution of 2-chloroethyl chloroformate
(3.3 ml) in chloroform (10 ml) is added dropwise. After stirring at
room temperature for 2.5 hours, to the reaction solution is added
5% hydrochloric acid, and then the mixture is extracted with
chloroform. The organic layer is washed with saturated brine, dried
over sodium sulfate, and then evaporated to remove the solvent
under reduced pressure. The resulting residue is suspended in
chloroform-diisopropyl ether, the precipitates are collected by
filtration and dried to give methyl
trans-4-(2-chloro-ethyloxycarbonylamino)cyclohexanecarboxylate
(5.11 g).
[0654] APCI-MS M/Z: 264/266 [M+H].sup.+.
[0655] (2) Methyl
trans-4-(2-chloroethyloxycarbonylamino)-cyclohexanecarboxylate
(3.70 g) obtained in (1) is dissolved in N,N-dimethylacetamide (50
ml), thereto is added 60% sodium hydride in oil (630 mg) under
ice-cooling and the mixture is stirred at room temperature for 16.5
hours. To the reaction solution is added water, the mixture is
extracted with ethyl acetate, the organic layer is washed with
water and saturated brine, and then dried over sodium sulfate. The
solvent is removed by evaporation under reduced pressure and the
resulting residue is purified by silica gel column chromatography
(eluent: hexane/ethyl acetate=1/1 followed by ethyl acetate) to
give methyl trans-4-(2-oxo-oxazolidin-3-yl)cyclohexanecarboxylate
(1.83 g).
[0656] APCI-MS M/Z: 228 [M+H].sup.+.
[0657] (3) Methyl
trans-4-(2-oxo-oxazolidin-3-yl)-cyclohexanecarboxylate (1.84 g)
obtained in (2) is treated in a similar manner to Reference Example
113(4) to give the title compound (1.75 g).
[0658] ESI-MS M/Z: 212 [M-H].sup.-.
Reference Example 143
Trans-4-(2-oxo-pyrrolidin-1-ylmethyl)cyclohexanecarboxylic acid
##STR00878##
[0660] (1) Methyl trans-4-(aminomethyl)cyclohexane-carboxylate
hydrochloride (4.57 g) obtained in Reference Example 121(1) is
treated in a similar manner to Reference Example 113(2) to give
methyl trans-4-(4-chlorobutyrylaminomethyl)cyclohexanecarboxylate
(5.35 g).
[0661] APCI-MS M/Z: 276/278 [M+H].sup.+.
[0662] (2) Methyl
trans-4-(4-chlorobutyrylaminomethyl)-cyclohexanecarboxylate (3.75
g) obtained in (1) is treated in a similar manner to Reference
Example 113(3) to give methyl
trans-4-(2-oxo-pyrrolidin-1-ylmethyl)cyclohexanecarboxylate (2.07
g).
[0663] APCI-MS M/Z: 240 [M+H].sup.+.
[0664] (3) Methyl
trans-4-(2-oxo-pyrrolidin-1-ylmethyl)-cyclohexanecarboxylate (2.04
g) obtained in (2) is treated in a similar manner to Reference
Example 113(4) to give
trans-4-(2-oxo-pyrrolidin-1-ylmethyl)cyclohexanecarboxylic acid
(2.41 g).
[0665] ESI-MS M/Z: 224[M-H].sup.-.
Reference Example 144
Trans-4-[(N-acetyl-N-methylamino)-methyl]cyclohexanecarboxylic
acid
##STR00879##
[0667] (1) methyl trans-4-(aminomethyl)cyclohexane-carboxylate
hydrochloride (5.86 g) obtained in Reference Example 121(1) is
dissolved in chloroform (100 ml), thereto is added triethylamine
(12 ml) under ice-cooling, and then acetyl chloride (2.69 g) is
added thereto. The mixture is stirred at room temperature for one
hour and 40 minutes, and water is added to the reaction solution
and the mixture is extracted with chloroform. The organic layer is
washed with 10% hydrochloric acid, saturated brine, a saturated
aqueous sodium hydrogen carbonate solution and saturated brine
successively, dried over magnesium sulfate and evaporated to remove
the solvent under reduced pressure. The resulting residue is
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate=1/1 followed by ethyl acetate) to give methyl
trans-4-(acetylaminomethyl)cyclohexanecarboxylate (5.92 g).
[0668] APCI-MS M/Z: 214 [M+H].sup.+.
[0669] (2) Methyl
trans-4-(acetylaminomethyl)cyclohexane-carboxylate (4.32 g)
obtained in (1) is dissolved in N,N-dimethylformamide (50 ml) and
thereto are added 60% sodium hydride in oil (1.00 g), methyl iodide
(5.91 g) and methanol (5 drops) successively under ice-cooling.
After stirring for 8 hours at room temperature, thereto are added
additional sodium hydride (430 mg), methyl iodide (1.5 ml) and
methanol (2 drops), and the mixture is stirred for 2 hours. To the
reaction solution is added water, and the mixture is extracted with
ethyl acetate. The organic layer is washed with water and dried
over sodium sulfate. The solvent is removed by evaporation and the
resulting residue is purified by silica gel column chromatography
(eluent: hexane/ethyl acetate=1/2 followed by ethyl acetate) to
give methyl
trans-4-[(N-acetyl-N-methylamino)methyl]cyclohexanecarboxylate
(3.04 g).
[0670] APCI-MS M/Z: 228 [M+H].sup.+.
[0671] (3) Methyl
trans-4-[(N-acetyl-N-methylamino)-methyl]cyclohexanecarboxylate
(3.03 g) obtained in (2) is treated in a similar manner to
Reference Example 113(4) to give the title compound (2.67 g).
[0672] ESI-MS M/Z: 212 [M-H].sup.-.
Reference Example 145
5-(2-Oxo-pyrrolidin-1-yl)pentanoic acid
##STR00880##
[0674] (1) 5-Aminovaleric acid (7.35 g) is dissolved in methanol
(50 ml), thereto is added dropwise thionyl chloride (4.9 ml) under
ice-cooling, and the reaction solution is warmed to room
temperature and stirred for 17 hours. The reaction solution is
concentrated under reduced pressure, and the resulting residue is
suspended in diethyl ether and the precipitates are collected by
filtration to give methyl 5-aminovalerate hydrochloride (9.93 g).
APCI-MS M/Z: 132 [M+H].sup.+.
[0675] (2) Methyl 5-aminovalerate hydrochloride (1.68 g) obtained
in (1) is suspended in chloroform (20 ml). To the suspension,
triethylamine (2.54 g) is added under ice-cooling, and then
4-chlorobutyryl chloride (1.55 g) is added dropwise. The reaction
solution is warmed to room temperature, stirred for 2 hours,
ice-water is poured to the reaction solution and the mixture is
extracted with chloroform. The organic layer is washed with 10%
hydrochloric acid, a saturated aqueous sodium hydrogen carbonate
solution and saturated brine, and then dried over sodium sulfate.
The resultant is evaporated to remove the solvent under reduced
pressure to give methyl 5-(4-chlorobutyrylamino)pentanoate (2.34
g).
[0676] APCI-MS M/Z: 236/238 [M+H].sup.+.
[0677] (3) Methyl 5-(4-chlorobutyrylamino)pentanoate (2.33 g)
obtained in (2) is dissolved in N,N-dimethylacetamide (20 ml) and
60% sodium hydride in oil (0.47 g) is added thereto gradually under
ice-cooling. The reaction solution is warmed to room temperature,
stirred for 20 hours and evaporated to remove the solvent under
reduced pressure. The resulting residue is purified by silica gel
column chromatography (eluent: chloroform followed by
chloroform/ethyl acetate=20/1) to give methyl
5-(2-oxo-pyrrolidin-1-yl)pentanoate (2.15 g).
[0678] APCI-MS M/Z: 200 [M+H].sup.+.
[0679] (4) Methyl 5-(2-oxo-pyrrolidin-1-yl)pentanoate (1.00 g)
obtained in (3) is dissolved in methanol (20 ml), thereto is added
4 N aqueous sodium hydroxide solution (2.5 ml), the reaction
solution is warmed to room temperature and stirred for 18 hours.
The reaction solution is washed with diethyl ether, thereto is
added 2 N hydrochloric acid (5.0 ml), and then concentrated under
reduced pressure. The resulting residue is extracted with
chloroform and dried over sodium sulfate. The resultant is
evaporated to remove solvent under reduced pressure to give the
title compound (0.90 g).
[0680] ESI-MS M/Z: 184 [M-H].sup.-.
Reference Example 146
Methyl 2-formyl-3-hydroxybenzoate and methyl
4-formyl-3-hydroxybenzoate
##STR00881##
[0682] Methyl 3-hydroxybenzoate (75.5 g) is dissolved in
trifluoroacetic acid (2 L), thereto is added hexamethylenetetramine
(141.4 g) at room temperature and the mixture is heated under
reflux for 3 hours. The reaction solution is concentrated under
reduced pressure, to the resulting residue is added water, the
mixture is adjusted to pH 8 with potassium carbonate and sodium
hydrogen carbonate, diluted with water and extracted with ethyl
acetate. The organic layer is washed with saturated brine, dried
over sodium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is purified by silica gel
column chromatography (eluent: hexane/ethyl acetate=8/1, 5/1
followed by 2/1) to give methyl 2-formyl-3-hydroxybenzoate (54.6 g)
(ESI-MS m/z: 179 [M-H].sup.-) and methyl 4-formyl-3-hydroxybenzoate
(4.4 g) (ESI-MS m/z: 179 [M-H].sup.-).
Reference Example 147
Methyl 4-cyano-3-hydroxybenzoate
##STR00882##
[0684] Methyl 4-formyl-3-hydroxybenzoate (1.96 g) obtained in
Reference Example 146 is dissolved in formic acid (50 ml), thereto
are added hydroxylammonium chloride (0.85 g) and sodium formate
(0.85 g) and the mixture is heated under reflux for 14 hours. The
reaction solution is concentrated under reduced pressure, diluted
with water and extracted with ethyl acetate. The organic layer is
washed with saturated brine, dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure. The
resulting residue is suspended chloroform/diisopropyl ether, and
then the precipitates are collected by filtration to give the title
compound (0.66 g). Furthermore, the filtrate is concentrated under
reduced pressure and the resulting residue is purified by silica
gel column chromatography (eluent: hexane/ethyl acetate=3/2) to
give the title compound (1.08 g).
[0685] ESI-MS M/Z: 176 [M-H].sup.-.
Reference Example 148
2-(2-Cyano-5-methoxycarbonyl-phenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00883##
[0687] Methyl 4-cyano-3-hydroxybenzoate (655 mg) obtained in
Reference Example 147 is dissolved in acetone (20 ml), thereto are
added 2-chloro-N-(5-chloropyridin-2-yl)acetamide (897 mg) obtained
in Reference Example 20(1), potassium carbonate (773 mg) and sodium
iodide (657 mg) and the mixture is heated under reflux for 40
minutes. The reaction solution is concentrated under reduced
pressure, thereto is added water and the mixture is extracted with
ethyl acetate-tetrahydrofuran. The organic layer is washed with
saturated brine, dried over sodium sulfate and evaporated to remove
the solvent under reduced pressure. The resulting residue is
suspended in chloroform-diisopropyl ether and the precipitates are
collected by filtration to give the title compound (1.16 g).
[0688] APCI-MS M/Z: 346/348 [M+H].sup.+.
Reference Example 149
3-Amino-6-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00884##
[0690]
2-(2-Cyano-5-methoxycarbonylphenoxy)-N-(5-chloropyridin-2-yl)acetam-
ide (1.03 g) obtained in Reference Example 148 is dissolved in
N,N-dimethylacetamide (10 ml), thereto is added sodium carbonate
(97 mg) and the mixture is stirred at 100.degree. C. for 4 hours.
The reaction solution is poured to water (50 ml), the precipitates
are collected by filtration, washed with water and ethanol and
dried to give the title compound (839 mg).
[0691] APCI-MS M/Z: 346/348 [M+H].sup.+.
Reference Example 150
Methyl 2-cyano-3-hydroxybenzoate
##STR00885##
[0693] (1) Methyl 2-formyl-3-hydroxybenzoate (9.23 g) obtained in
Reference Example 146 is suspended in methanol (150 ml), and an
aqueous solution (15 ml) of hydroxylammonium chloride (3.56 g) and
an aqueous solution (15 ml) of sodium acetate (4.36 g) are added to
the suspension under ice-cooling. The mixture is warmed to room
temperature, stirred for 2 hours, and then evaporated to remove
methanol. The resulting residue is diluted with water and extracted
with chloroform. The organic layer is dried over sodium sulfate and
evaporated to remove the solvent under reduced pressure to give
methyl 2-hydroxy-iminomethyl-3-hydroxybenzoate (9.89 g).
[0694] APCI-MS M/Z: 196 [M+H].sup.+.
[0695] (2) Methyl 2-hydroxyiminomethyl-3-hydroxybenzoate (10.57 g)
obtained in (1) is suspended in, chloroform (100 ml) and thereto is
added triethylamine (19.35 g) under ice-cooling. At the same
temperature, to the resulting solution is added dropwise
trifluoroacetic anhydride (25.40 g) over a period of 30 minutes.
The reaction solution is stirred at room temperature for 3 days,
thereto is added an aqueous saturated sodium hydrogen carbonate
solution and extracted with chloroform. The organic layer is dried
over magnesium sulfate and evaporated to remove the solvent under
reduced pressure. The resulting residue is dissolved in methanol
(150 ml), thereto is added potassium carbonate (15.6 g), and the
mixture is stirred at room temperature for 50 minutes. The reaction
solution is diluted with water, acidified with conc. hydrochloric
acid, and then extracted with chloroform. The organic layer is
dried over magnesium sulfate, the solvent thereof is removed by
evaporation and the resulting residue is suspended in ethyl
acetate-diisopropyl ether. The precipitates are collected by
filtration to give the title compound (8.71 g).
[0696] ESI-MS M/Z: 176 [M-H].sup.-.
Reference Example 151
2-(2-Cyano-3-methoxycarbonyl-phenoxy)-N-(5-chloropyridin-2-yl)acetamide
##STR00886##
[0698] Methyl 2-cyano-3-hydroxybenzoate (1.70 g) obtained in
Reference Example 150 is treated in a similar manner to Reference
Example 148 to give the title compound (2.69 g).
[0699] APCI-MS M/Z: 346/348 [M+H].sup.+.
Reference Example 152
3-Amino-4-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00887##
[0701]
2-(2-Cyano-3-methoxycarbonylphenoxy)-N-(5-chloropyridin-2-yl)acetam-
ide (1.51 g) obtained in Reference Example 151 is treated in a
similar manner to Reference Example 149 to give the title compound
(335 mg).
[0702] APCI-MS M/Z: 346/348 [M+H].sup.+.
Reference Example 153
3-Amino-5-carboxy-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide
##STR00888##
[0704]
3-Amino-5-methoxycarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carb-
oxamide (2.01 g) is suspended in tetrahydrofuran (20 ml)-methanol,
thereto is added 4. N aqueous sodium hydroxide solution (5 ml)
under ice-cooling and the reaction solution is stirred at room
temperature for 13 hours. The reaction solution is concentrated
under reduced pressure, the resulting residue is diluted with
water, and the mixture is adjusted to around pH 3 by pouring 10%
hydrochloric acid. The precipitates are collected by filtration,
washed with water and ethanol successively and dried to give the
title compound (1.87 g).
[0705] ESI-MS M/Z: 330 [M-H].sup.-.
Reference Examples 154-155
[0706] The ester obtained in Reference Example 149 or Reference
Example 152 is treated in a similar manner to Reference Example 153
to give the following compounds.
TABLE-US-00053 Ref. Ex. Physicochemical No. Structure Properties
154 ##STR00889## ESI-MS M/Z: 330/332 [M - H].sup.- 155 ##STR00890##
ESI-MS M/Z: 330/332 [M - H].sup.-
Reference Example 156
3-Amino-5-dimethylaminocarbonyl-N-(5-chloropyridin-2-yl)benzofuran-2-carbo-
xamide
##STR00891##
[0708]
3-Amino-5-carboxy-N-(5-chloropyridin-2-yl)-benzofuran-2-carboxamide
(1.51 g) obtained in Reference Example 153 is suspended in pyridine
(15 ml), thereto are added dimethylamine hydrochloride (0.77 g),
1-hydroxy-benzotriazole (1.37 g) and
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.79
g) successively under ice-cooling and the mixture is stirred at
room temperature for 14 hours. The reaction solution is diluted
with water (100 ml) and thereto is added saturated aqueous sodium
hydrogen carbonate solution to adjust to pH 8-9. The precipitates
are collected by filtration, washed with water and ethanol
successively, and then dried to give the title compound (1.50
g).
[0709] APCI-MS M/Z: 359/361 [M+H].sup.+.
Reference Examples 157-158
[0710] The carboxylic acid obtained in Reference. Example 154 or
Reference Example 155 is treated in a similar manner to Reference
Example 156 to give the following compounds.
TABLE-US-00054 Ref. Ex. Physicochemical No. Structure Properties
157 ##STR00892## APCI-MS M/Z: 359/361 [M + H].sup.+ 158
##STR00893## APCI-MS M/Z: 359/361 [M + H].sup.+
INDUSTRIAL APPLICABILITY
[0711] The compound of the formula [1] or a pharmaceutically
acceptable salt thereof is less toxic and safe, and has an
excellent inhibitory effect on activated blood coagulation factor
X. Accordingly, the said compound [1] is useful as a medicament for
prevention and treatment of diseases caused by thrombus or
embolus.
* * * * *