U.S. patent application number 11/093208 was filed with the patent office on 2007-02-08 for fused-ring compounds and use thereof as drugs.
This patent application is currently assigned to Japan Tobacco Inc.. Invention is credited to Hiromasa Hashimoto, Kenji Mizutani, Atsuhito Yoshida.
Application Number | 20070032497 11/093208 |
Document ID | / |
Family ID | 37075553 |
Filed Date | 2007-02-08 |
United States Patent
Application |
20070032497 |
Kind Code |
A1 |
Hashimoto; Hiromasa ; et
al. |
February 8, 2007 |
Fused-ring compounds and use thereof as drugs
Abstract
The present invention provides a fused ring compound of the
following formula [I] ##STR1## wherein each symbol is as defined in
the specification, a pharmaceutically acceptable salt thereof, and
a therapeutic agent for hepatitis C, which contains this compound.
The compound of the present invention shows an anti-hapatitis C
virus (HCV) action based on the HCV polymerase inhibitory activity,
and is useful as a therapeutic agent or prophylactic agent for
hepatitis C.
Inventors: |
Hashimoto; Hiromasa;
(Takatsuki-shi, JP) ; Mizutani; Kenji;
(Takatsuki-shi, JP) ; Yoshida; Atsuhito;
(Takatsuki-shi, JP) |
Correspondence
Address: |
LEYDIG VOIT & MAYER, LTD
TWO PRUDENTIAL PLAZA, SUITE 4900
180 NORTH STETSON AVENUE
CHICAGO
IL
60601-6780
US
|
Assignee: |
Japan Tobacco Inc.
Tokyo
JP
105-8422
|
Family ID: |
37075553 |
Appl. No.: |
11/093208 |
Filed: |
March 28, 2005 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10180558 |
Jun 26, 2002 |
|
|
|
11093208 |
Mar 28, 2005 |
|
|
|
09939374 |
Aug 24, 2001 |
6770666 |
|
|
10180558 |
Jun 26, 2002 |
|
|
|
PCT/JP00/09181 |
Dec 22, 2000 |
|
|
|
09939374 |
Aug 24, 2001 |
|
|
|
Current U.S.
Class: |
514/248 ;
514/249; 514/259.1; 514/263.1; 514/303; 514/394; 514/415;
514/443 |
Current CPC
Class: |
A61K 31/55 20130101;
A61K 31/404 20130101; C07D 495/04 20130101; A61K 31/496 20130101;
C07D 235/18 20130101; C07D 249/08 20130101; C07D 401/12 20130101;
A61K 31/4184 20130101; C07D 403/12 20130101; A61K 31/503 20130101;
C07D 417/12 20130101; C07D 405/04 20130101; C07D 401/04 20130101;
A61K 9/2018 20130101; A61P 1/16 20180101; A61P 31/20 20180101; C07D
409/14 20130101; A61K 31/519 20130101; C07D 401/14 20130101; A61K
31/7076 20130101; A61P 31/12 20180101; C07D 233/56 20130101; C07D
409/12 20130101; C07D 413/12 20130101; C07D 401/10 20130101; A61K
31/498 20130101; C07D 409/04 20130101; C07D 413/04 20130101; A61K
31/4523 20130101; C07D 403/04 20130101; A61K 31/42 20130101; A61K
31/427 20130101; A61K 31/4745 20130101; C07D 235/30 20130101; A61K
31/437 20130101; C07D 231/12 20130101; C07D 405/12 20130101; A61K
31/52 20130101; A61K 31/4439 20130101; A61K 31/522 20130101; A61K
31/53 20130101 |
Class at
Publication: |
514/248 ;
514/249; 514/263.1; 514/303; 514/259.1; 514/394; 514/443;
514/415 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 31/519 20060101 A61K031/519; A61K 31/498 20060101
A61K031/498; A61K 31/503 20060101 A61K031/503; A61K 31/4745
20060101 A61K031/4745; A61K 31/404 20060101 A61K031/404; A61K
31/4184 20060101 A61K031/4184 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 27, 1999 |
JP |
369008/1999 |
Dec 25, 2000 |
JP |
391904/2000 |
Jun 26, 2001 |
JP |
193786/2001 |
Nov 16, 2001 |
JP |
351537/2001 |
Claims
1. A therapeutic agent for hepatitis C, which comprises a fused
ring compound of the following formula [I] or a pharmaceutically
acceptable salt thereof as an active ingredient: ##STR78## wherein
a broken line is a single bond or a double bond, G.sup.1 is
C(--R.sup.1) or a nitrogen atom, G.sup.2 is C(--R.sup.2) or a
nitrogen atom, G.sup.3 is C(--R.sup.3) or a nitrogen atom, G.sup.4
is C(--R.sup.1) or a nitrogen atom, G.sup.5, G.sup.6, G.sup.8 and
G.sup.9 are each independently a carbon atom or a nitrogen atom,
G.sup.7 is C(--R.sup.7), an oxygen atom, a sulfur atom, or a
nitrogen atom optionally substituted by R.sup.8, wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are each independently, (1) hydrogen
atom, (2) C.sub.1-6 alkanoyl, (3) carboxyl, (4) cyano, (5) nitro,
(6) C.sub.1-6 alkyl optionally substituted by 1 to 3 substituent(s)
selected from the following group A, group A; halogen atom,
hydroxyl group, carboxyl, amino, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy
C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl and C.sub.1-6
alkylamino, (7) --COOR.sup.a1 wherein R.sup.a1 is optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl
C.sub.1-6 alkyl optionally substituted by 1 to 5 substituent(s)
selected from the following group B or glucuronic acid residue,
group B; halogen atom, cyano, nitro, C.sub.1-6 alkyl, halogenated
C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1,
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.b1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 wherein R.sup.b1 and
R.sup.b2 are each independently hydrogen atom or C.sub.1-6 alkyl
and r is 0 or an integer of 1 to 6, (8) --CONR.sup.a2R.sup.a3
wherein R.sup.a2 and R.sup.a3 are each independently hydrogen atom,
C.sub.1-6 alkoxy or optionally substituted C.sub.1-6 alkyl (as
defined above), (9) --C(.dbd.NR.sup.a4)NH.sub.2 wherein R.sup.a4 is
hydrogen atom or hydroxyl group, (10) --NHR.sup.a5 wherein R.sup.a5
is hydrogen atom, C.sub.1-6 alkanoyl or C.sub.1-6 alkylsulfonyl,
(11) --OR.sup.a6 wherein R.sup.a6 is hydrogen atom or optionally
substituted C.sub.1-6 alkyl(as defined above), (12)
--SO.sub.2R.sup.a7 wherein R.sup.a7 is hydroxyl group, amino,
C.sub.1-6 alkyl or C.sub.1-6 alkylamino, (13)
--P(.dbd.O)(OR.sup.a31).sub.2 wherein R.sup.a31 is hydrogen atom,
optionally substituted C.sub.1-6 alkyl (as defined above) or
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B or (14) heterocyclic
group having 1 to 4 heteroatom(s) selected from an oxygen atom, a
nitrogen atom and a sulfur atom, and R.sup.7 and R.sup.8 are each
hydrogen atom or optionally substituted C.sub.1-6 alkyl (as defined
above), ring Cy is (1) C.sub.3-8 cycloalkyl optionally substituted
by 1 to 5 substituent(s) selected from the following group C, group
C; hydroxyl group, halogen atom, C.sub.1-6 alkyl and C.sub.1-6
alkoxy, (2) C.sub.3-8 cycloalkenyl optionally substituted by 1 to 5
substituent(s) selected from the above group C, or ##STR79##
wherein u and v are each independently an integer of 1 to 3, ring A
is (1) C.sub.6-14 aryl, (2) C.sub.3-8 cycloalkyl, (3) C.sub.3-8
cycloalkenyl or (4) heterocyclic group having 1 to 4 heteroatom(s)
selected from an oxygen atom, a nitrogen atom and a sulfur atom,
R.sup.5 and R.sup.6 are each independently (1) hydrogen atom, (2)
halogen atom, (3) optionally substituted C.sub.1-6 alkyl (as
defined above) or (4) --OR.sup.a8 wherein R.sup.a8 is hydrogen
atom, C.sub.1-6 alkyl or C.sub.6-14 aryl C.sub.1-6 alkyl, and X is
(1) hydrogen atom, (2) halogen atom, (3) cyano, (4) nitro, (5)
amino, C.sub.1-6 alkanoylamino, (6) C.sub.1-6 alkylsulfonyl, (7)
optionally substituted C.sub.1-6 alkyl (as defined above), (8)
C.sub.2-6 alkenyl optionally substituted by 1 to 3 substituent(s)
selected from the above group A, (9) --COOR.sup.a9 wherein R.sup.a9
is hydrogen atom or C.sub.1-6 alkyl, (10)
--CONH--(CH.sub.2).sub.l--R.sup.a10 wherein R.sup.a10 is optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.1-6
alkoxycarbonyl or C.sub.1-6 alkanoylamino and l is 0 or an integer
of 1 to 6, (11) --OR.sup.a11 wherein R.sup.a11 is hydrogen atom or
optionally substituted C.sub.1-6 alkyl (as defined above) or
##STR80## wherein ring B is (1') C.sub.6-14 aryl, (2') C.sub.3-8
cycloalkyl or (3') heterocyclic group (as defined above), each Z is
independently (1') a group selected from the following group D,
(2') C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the following group D, (3') C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the following group D, (4') C.sub.6-14 aryl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
following group D, (5') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the following group D,
wherein the heterocyclic group has 1 to 4 hetero-atom(s) selected
from an oxygen atom, a nitrogen atom and a sulfur atom, or (6')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, wherein the
heterocycle C.sub.1-6 alkyl is C.sub.1-6 alkyl substituted by
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the group D, as defined above, group D: (a) hydrogen
atom, (b) halogen atom, (c) cyano, (d) nitro, (e) optionally
substituted C.sub.1-6 alkyl (as defined above), (f)
--(CH.sub.2).sub.t--COR.sup.a18, (hereinafter each t means
independently 0 or an integer of 1 to 6), wherein R.sup.a18 is
(1'') optionally substituted C.sub.1-6 alkyl (as defined above),
(2'') C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the above group B or (3'')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B wherein the heterocyclic group has
1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom
and a sulfur atom, (g) --(CH.sub.2).sub.t--COOR.sup.a19 wherein
R.sup.a19 is hydrogen atom, optionally substituted C.sub.1-6 alkyl
(as defined above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B (h) --(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 wherein R.sup.a27
and R.sup.a28 are each independently, (1'') hydrogen atom, (2'')
optionally substituted C.sub.1-6 alkyl (as defined above), (3'')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (4'') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5'') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, (6'')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, wherein the
heterocycle C.sub.1-6 alkyl is C.sub.1-6 alkyl substituted by
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, as defined above, (7'') C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the above group B, (8'') C.sub.3-8 cycloalkyl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, (9'') hydroxyl group or (10'') C.sub.1-6 alkoxy, (i)
--(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 wherein R.sup.a33 is
hydrogen atom, C.sub.1-6 alkyl, hydroxyl group or C.sub.1-6 alkoxy,
(j) --(CH.sub.2).sub.t--OR.sup.a20 wherein R.sup.a20 is (1'')
hydrogen atom, (2'') optionally substituted C.sub.1-6 alkyl (as
defined above), (3'') optionally substituted C.sub.2-6 alkenyl (as
defined above), (4'') C.sub.2-6 alkynyl optionally substituted by 1
to 3 substituent(s) selected from the above group A, (5'')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (6'') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (7'') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, (8'')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (9'') C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the above group B, or (10'') C.sub.3-8 cycloalkyl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (k)
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.a21' wherein
R.sup.a21 is amino, C.sub.1-6 alkylamino or heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, and p is 0 or an integer of 1 to 6, (l)
--(CH.sub.2).sub.p--NR.sup.a22R.sup.a23 wherein R.sup.a22 and
R.sup.a23 are each independently (1'') hydrogen atom, (2'')
optionally substituted C.sub.1-6 alkyl (as defined above), (3'')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (4'') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5'') heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B or (6'') heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from the above group B, (m)
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24 wherein R.sup.a29 is
hydrogen atom, C.sub.1-6 alkyl or C.sub.1-6 alkanoyl, and R.sup.a24
is (1'') amino, (2'') C.sub.1-6 alkylamino, (3'') optionally
substituted C.sub.1-6 alkyl (as defined above), (4'') C.sub.6-14
aryl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5'') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B or (6'')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (n)
--(CH.sub.2).sub.t--NR.sup.a29SO.sub.2--R.sup.a25 wherein R.sup.a29
is as defined above, and R.sup.a25 is hydrogen atom, optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B or heterocyclic group optionally substituted by 1 to
5 substituent(s) selected from the above group B, (o)
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 wherein R.sup.a25 is as
defined above, and q is 0, 1 or 2, (p)
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26 wherein R.sup.a26 is
hydrogen atom, optionally substituted C.sub.1-6 alkyl (as defined
above), C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the above group B or heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the above group B, and (q) heterocyclic group having 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, and w is an integer of 1 to 3, and Y is (1') a single
bond, (2') C.sub.1-6 alkylene, (3') C.sub.2-6 alkenylene, (4')
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--, (hereinafter m and n are
each independently 0 or an integer of 1 to 6), (5') --CO--, (6')
--CO.sub.2--(CH.sub.2).sub.n--, (7')
--CONH--(CH.sub.2).sub.n--NH--, (8') --NHCO.sub.2--, (9')
--NHCONH--, (10') --O--(CH.sub.2).sub.n--CO--, (11')
--O--(CH.sub.2).sub.n--O--, (12') --SO.sub.2--, (13')
--(CH.sub.2).sub.m--NR.sup.a12 (CH.sub.2).sub.n, wherein R.sup.a12
is (1'') hydrogen atom, (2'') optionally substituted C.sub.1-6
alkyl (as defined above), (3'') C.sub.6-14 aryl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, (4'') C.sub.6-14 aryl optionally substituted by 1 to
substituent(s) selected from the above group B, (5'') --COR.sup.b5
wherein R.sup.b5 is hydrogen atom, optionally substituted C.sub.1-6
alkyl (as defined above), C.sub.6-14 aryl optionally substituted by
1 to 5 substituent(s) selected from the above group B or C.sub.6-14
aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (6'') --COOR.sup.b5
(R.sup.b5 is as defined above) or (7'') --SO.sub.2R.sup.b5
(R.sup.b5 is as defined above), (14') --NR.sup.a12CO-- (R.sup.a12
is as defined above), (15') --CONR.sup.a13--(CH.sub.2).sub.n--
wherein R.sup.a13 is hydrogen atom, optionally substituted
C.sub.1-6 alkyl (as defined above) or C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (16') --CONH--CHR.sup.a14-- wherein R.sup.a14 is
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (17')
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
wherein R.sup.a15 and R.sup.a16 are each independently (1'')
hydrogen atom, (2'') carboxyl, (3'') C.sub.1-6 alkyl, (4'')
--OR.sup.b6 wherein R.sup.b6 is C.sub.1-6 alkyl or C.sub.6-14 aryl
C.sub.1-6 alkyl, or (5'') --NHR.sup.b7 wherein R.sup.b7 is hydrogen
atom, C.sub.1-6 alkyl, C.sub.1-6 alkanoyl or C.sub.6-14 aryl
C.sub.1-6 alkyloxycarbonyl, or R.sup.a15 is optionally ##STR81##
wherein n', ring B', Z' and w' are the same as the above-mentioned
n, ring B, Z and w, respectively, and may be the same as or
different from the respective counterparts, (18')
--(CH.sub.2).sub.n--NR.sup.a12--CHR.sup.a15-- (R.sup.a12 and
R.sup.a15 are each as defined above), (19') --NR.sup.a17SO.sub.2--
wherein R.sup.a17 is hydrogen atom or C.sub.1-6 alkyl, (20')
--S(O).sub.e--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(e is 0, 1 or 2, R.sup.a15 and R.sup.a16 are each as defined
above), or (21')
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(R.sup.a15 and R.sup.a16 are each as defined above).
2.-28. (canceled)
29. A fused ring compound of the following formula [II] ##STR82##
wherein the moiety ##STR83## is a fused ring selected from
##STR84## wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are each
independently, (1) hydrogen atom, (2) C.sub.1-6 alkanoyl, (3)
carboxyl, (4) cyano, (5) nitro, (6) C.sub.1-6 alkyl optionally
substituted by 1 to 3 substituent(s) selected from the following
group A, group A; halogen atom, hydroxyl group, carboxyl, amino,
C.sub.1-6 alkoxy, C.sub.1-6 alkoxy C.sub.1-6 alkoxy, C.sub.1-6
alkoxycarbonyl and C.sub.1-6 alkylamino, (7) --COOR.sup.a1 wherein
R.sup.a1 is optionally substituted C.sub.1-6 alkyl (as defined
above), C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1
to 5 substituent(s) selected from the following group B or
glucuronic acid residue, group B; halogen atom, cyano, nitro,
C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, C.sub.1-6 alkanoyl,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1,
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.b1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 wherein R.sup.b1 and
R.sup.b2 are each independently hydrogen atom or C.sub.1-6 alkyl
and r is 0 or an integer of 1 to 6, (8) --CONR.sup.a2R.sup.a3
wherein R.sup.a2 and R.sup.a3 are each independently hydrogen atom,
C.sub.1-6 alkoxy or optionally substituted C.sub.1-6 alkyl (as
defined above), (9) --C(.dbd.NR.sup.a4)NH.sub.2 wherein R.sup.a4 is
hydrogen atom or hydroxyl group, (10) --NHR.sup.a5 wherein R.sup.a5
is hydrogen atom, C.sub.1-6 alkanoyl or C.sub.1-6 alkylsulfonyl,
(11) --OR.sup.a6 wherein R.sup.a6 is hydrogen atom or optionally
substituted C.sub.1-6 alkyl (as defined above), (12)
--SO.sub.2R.sup.a7 wherein R.sup.a7 is hydroxyl group, amino,
C.sub.1-6 alkyl or C.sub.1-6 alkylamino, (13)
--P(.dbd.O)(OR.sup.a31).sub.2 wherein R.sup.a31 is hydrogen atom,
optionally substituted C.sub.1-6 alkyl (as defined above) or
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, or (14)
heterocyclic group having 1 to 4 heteroatom(s) selected from an
oxygen atom, a nitrogen atom and a sulfur atom, and R.sup.7 is
hydrogen atom or optionally substitute C.sub.1-6 alkyl (as defined
above), ring Cy' is (1) C.sub.3-8 cycloalkyl optionally substituted
by 1 to 5 substituent(s) selected from the following group C, group
C; hydroxyl group, halogen atom, C.sub.1-6 alkyl and C.sub.1-6
alkoxy, or ##STR85## wherein u and v are each independently an
integer of 1 to 3, ring A' is a group selected from a group
consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
cyclohexyl, cyclohexenyl, furyl and thienyl, R.sup.5' and R.sup.6'
are each independently (1) hydrogen atom, (2) halogen atom, (3)
optionally substituted C.sub.1-6 alkyl (as defined above) or (4)
hydroxyl group ring B is (1) C.sub.6-14 aryl, (2) C.sub.3-8
cycloalkyl or (3) heterocyclic group having 1 to 4 heteroatom(s)
selected from an oxygen atom, a nitrogen atom and a sulfur atom,
each Z is independently (1) a group selected from the following
group D, (2) C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the following group D, (3) C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the following group D, (4) C.sub.6-14 aryl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
following group D, (5) heterocyclic group optionally substituted by
1 to 5 substituent(s) selected from the following group D wherein
the heterocyclic group has 1 to 4 heteroatom(s) selected from an
oxygen atom, a nitrogen atom and a sulfur atom, or (6) heterocycle
C.sub.1-6 alkyl optionally substituted by 1 to 5 substituent(s)
selected from the following group D wherein the heterocycle
C.sub.1-6 alkyl is C.sub.1-6 alkyl substituted by heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the group D, as defined above, group D: (a) hydrogen atom, (b)
halogen atom, (c) cyano, (d) nitro, (e) optionally substituted
C.sub.1-6 alkyl (as defined above), (f)
--(CH.sub.2).sub.t--COR.sup.a18, (hereinafter each t means
independently 0 or an integer of 1 to 6), wherein R.sup.a18 is (1')
optionally substituted C.sub.1-6 alkyl (as defined above), (2')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B or (3') heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B wherein the heterocyclic group has 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, (g) --(CH.sub.2).sub.t--COOR.sup.a19 wherein R.sup.a19
is hydrogen atom, optionally substituted C.sub.1-6 alkyl (as
defined above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, (h) --(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 wherein R.sup.a27
and R.sup.a28 are each independently, (1') hydrogen atom, (2')
optionally substituted C.sub.1-6 alkyl (as defined above), (3')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (4') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, (6')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, wherein the
heterocycle C.sub.1-6 alkyl is C.sub.1-6 alkyl substituted by
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, as defined above, (7') C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the above group B, (8') C.sub.3-8 cycloalkyl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, (9') hydroxyl group or (10') C.sub.1-6 alkoxy, (i)
--(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 wherein R.sup.a33 is
hydrogen atom, C.sub.1-6 alkyl, hydroxyl group or C.sub.1-6 alkoxy,
(j) --(CH.sub.2).sub.t--OR.sup.a20 wherein R.sup.a20 is (1')
hydrogen atom, (2') optionally substituted C.sub.1-6 alkyl (as
defined above), (3') optionally substituted C.sub.2-6 alkenyl (as
defined above), (4') C.sub.2-6 alkynyl optionally substituted by 1
to 3 substituent(s) selected from the above group A, (5')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (6') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (7') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, (8')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (9') C.sub.3-8
cycloalkyl optionally substituted by 1 to 5 substituent(s) selected
from the above group B, or (10') C.sub.3-8 cycloalkyl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (k)
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.a21 wherein
R.sup.a21 is amino, C.sub.1-6 alkylamino or heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, and p is 0 or an integer of 1 to 6, (l)
--(CH.sub.2).sub.t--NR.sup.a22R.sup.a23 wherein R.sup.a22 and
R.sup.a23 are each independently (1') hydrogen atom, (2')
optionally substituted C.sub.1-6 alkyl (as defined above), (3')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, (4') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5') heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B or (6') heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from the above group B, (m)
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24 wherein R.sup.a29 is
hydrogen atom, C.sub.1-6 alkyl or C.sub.1-6 alkanoyl, and R.sup.a14
is (1') amino, (2') C.sub.1-6 alkylamino, (3') optionally
substituted C.sub.1-6 alkyl (as defined above), (4') C.sub.6-14
aryl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (5') heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, or (6')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (n)
--(CH.sub.2).sub.t--NR.sup.a29SO.sub.2--R.sup.a25 wherein R.sup.a29
is as defined above, and R.sup.a25 is hydrogen atom, optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B or heterocyclic group optionally substituted by 1 to
5 substituent(s) selected from the above group B, (o)
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 wherein R.sup.a25 is as
defined above, and q is 0, 1 or 2, (p)
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26 wherein R.sup.a26 is
hydrogen atom, optionally substituted C.sub.1-6 alkyl (as defined
above), C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the above group B or heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the above group B, and (q) heterocyclic group having 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, w is an integer of 1 to 3, and Y is (1) a single bond,
(2) C.sub.1-6 alkylene, (3) C.sub.2-6 alkenylene, (4)
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--, (hereinafter m and n are
each independently 0 or an integer of 1 to 6), (5) --CO--, (6)
--CO.sub.2--(CH.sub.2).sub.n--, (7) --CONH--(CH.sub.2).sub.n--NH--,
(8) --NHCO.sub.2--, (9) --NHCONH--, (10)
--O--(CH.sub.2).sub.n--CO--, (11) --O--(CH.sub.2).sub.n--O--, (12)
--SO.sub.2--, (13)
--(CH.sub.2).sub.m--NR.sup.a12--(CH.sub.2).sub.n-- wherein
R.sup.a12 is (1') hydrogen atom, (2') optionally substituted
C.sub.1-6 alkyl (as defined above), (3') C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, (4') C.sub.6-14 aryl optionally substituted by 1
to 5 substituent(s) selected from the above group B, (5')
--COR.sup.b5 wherein R.sup.b5 is hydrogen atom, optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, (6') --COOR.sup.b5 (R.sup.b5 is as defined above) or (7')
--SO.sub.2R.sup.b5 (R.sup.b5 is as defined above), (14)
--NR.sup.a12CO-- (R.sup.a12 is as defined above), (15)
--CONR.sup.a13--(CH.sub.2).sub.n-- wherein R.sup.a13 is hydrogen
atom, optionally substituted C.sub.1-6 alkyl (as defined above) or
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, (16)
--CONH--CHR.sup.a14 wherein R.sup.a14 is C.sub.6-14 aryl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, (17)
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
wherein R.sup.a15 and R.sup.a16 are each independently (1')
hydrogen atom, (2') carboxyl, (3') C.sub.1-6 alkyl, (4')
--OR.sup.b6 wherein R.sup.b6 is C.sub.1-6 alkyl or C.sub.6-14 aryl
C.sub.1-6 alkyl, or (5') --NHR.sup.b7 wherein R.sup.b7 is hydrogen
atom, C.sub.1-6 alkyl, C.sub.1-6 alkanoyl or C.sub.6-14 aryl
C.sub.1-6 alkyloxycarbonyl, or R.sup.a15 is optionally ##STR86##
wherein n', ring B', Z' and w' are the same as the above-mentioned
n, ring B, Z and w, respectively, and may be the same as or
different from the respective counterparts, (18)
--(CH.sub.2).sub.n--NR.sup.a12--CHR.sup.a15--(R.sup.a12 and
R.sup.a15 are each as defined above), (19) --NR.sup.a17SO.sub.2
wherein R.sup.a17 is hydrogen atom or C.sub.1-6 alkyl, (20)
--S(O).sub.e--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(e is 0, 1 or 2, R.sup.a15 and R.sup.a16 are each as defined
above), or (21)
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--(R.sup.a-
15 and R.sup.a16 are each as defined above), or a pharmaceutically
acceptable salt thereof.
30.-63. (canceled)
64. A hepatitis C virus polymerase inhibitor comprising a fused
ring compound of claim 1, or a pharmaceutically acceptable salt
thereof, and a pharmaceutically acceptable carrier.
65. An anti-hepatitis C virus agent comprising a fused ring
compound of claim 1, or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable carrier.
66. (canceled)
67. An anti-hepatitis C virus agent comprising (a) the
anti-hepatitis C virus agent of claim 65 and (b) at least one agent
selected from the group consisting of a different antiviral agent,
an antiinflammatory agent and an immunostimulant.
68. An anti-hepatitis C virus agent comprising (a) the
anti-hepatitis C virus agent of claim 65 and (b) interferon.
69. A therapeutic agent for hepatitis C comprising (a) the
hepatitis C virus polymerase inhibitor of claim 64 and (b) at least
one agent selected from the group consisting of a different
antiviral agent, an antiinflammatory agent and an
immunostimulant.
70. A therapeutic agent for hepatitis C comprising (a) the
hepatitis C virus polymerase inhibitor of claim 64 and (b)
interferon.
71. A benzimidazole compound of the folllowing formula [III]
##STR87## wherein R.sup.a36 is hydrogen atom or carboxyl-protecting
group, R.sup.a37 is cyclopentyl or cyclohexyl, and R.sup.a38 is
hydrogen atom or fluorine atom, or a salt thereof.
72. A thiazole compound selected from the group consisting of
4-(4-fluorophenyl)-5-hydroxymethyl-2-methylthiazole and
4-(4-fluorophenyl)-5-chloromethyl-2-methylthiazole, or a
pharmaceutically acceptable salt thereof.
73. A biphenyl compound selected from the group consisting of
1-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)-2-pyrrolidinone and
1-(4'-chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone, or a
pharmaceutically acceptable salt thereof.
74. A pharmaceutical composition comprising (a) a fused ring
compound of the formula [I] of claim 1 or a pharmaceutically
acceptable salt thereof and (b) at least one agent selected from
the group consisting of an antiviral agent other than the compound
of claim 1, an antiinflammatory agent and an immunostimulant.
75. A pharmaceutical composition comprising (a) a fused ring
compound of the formula [I] of claim 1 or a pharmaceutically
acceptable salt thereof and (b) interferon.
76. A method for treating hepatitis C, which comprises
administering an effective amount of a fused ring compound of the
formula [I] of claim 1 or a pharmaceutically acceptable salt
thereof.
77. The method of claim 76, further comprising administering an
effective amount of at least one agent selected from the group
consisting of an antiviral agent other than the compound of claim
1, an antiinflammatory agent and an immunostimulant.
78. The method of claim 76, further comprising administering an
effective amount of interferon.
79. A method for inhibiting hepatitis C virus polymerase, which
comprises administering an effective amount of a fused ring
compound of the formula [I] of claim 1 or a pharmaceutically
acceptable salt thereof.
80. The method of claim 79, further comprising administering an
effective amount of at least one agent selected from the group
consisting of an antiviral agent other than the compound of claim
1, an antiinflammatory agent and an immunostimulant.
81. The method of claim 79, further comprising administering an
effective amount of interferon.
82. 1-Cyclohexyl-2-(3-furanyl)-1H-benzimidazole-5-carboxylic acid.
Description
[0001] This is a continuation in part of U.S. patent application
Ser. No. 09/939,374 filed on Aug. 24, 2001, which is a continuation
in part of PCT/JP00/09181 filed on Dec. 22, 2000.
TECHNICAL FIELD
[0002] The present invention relates to a novel fused ring compound
and a pharmaceutically acceptable salt thereof useful as a
therapeutic agent for hepatitis C, and to an intermediate compound
for the synthesis thereof. The present invention also relates to a
novel use of a certain fused ring compound or a pharmaceutically
acceptable salt thereof as a therapeutic agent for hepatitis C.
More particularly, the present invention relates to a therapeutic
agent for hepatitis C, which contains a novel fused ring compound
or a pharmaceutically acceptable salt thereof, which is effective
for the prophylaxis or treatment of hepatitis C and which shows
anti-hepatitis C virus (HCV) activity, particularly anti-HCV
activity based on an RNA-dependent RNA polymerase inhibitory
activity.
BACKGROUND ART
[0003] In 1989, a main causative virus of non-A non-B
posttransfusion hepatitis was found and named hepatitis C virus
(HCV). Since then, several types of hepatitis viruses have been
found besides type A, type B and type C, wherein hepatitis caused
by HCV is called hepatitis C.
[0004] The patients infected with HCV are considered to involve
several percent of the world population, and the infection with HCV
characteristically becomes chronic.
[0005] HCV is an envelope RNA virus, wherein the genome is a single
strand plus-strand RNA, and belongs to the genus Hepacivirus of
Flavivirus (from The International Committee on Taxonomy of
Viruses, International Union of Microbiological Societies). Of the
same hepatitis viruses, for example, hepatitis B virus (HBV), which
is a DNA virus, is eliminated by the immune system and the
infection with this virus ends in an acute infection except for
neonates and infants having yet immature immunological competence.
In contrast, HCV somehow avoids the immune system of the host due
to an unknown mechanism. Once infected with this virus, even an
adult having a mature immune system frequently develops persistent
infection.
[0006] When chronic hepatitis is associated with the persistent
infection with HCV, it advances to cirrhosis or hepatic cancer in a
high rate. Enucleation of tumor by operation does not help much,
because the patient often develops recurrent hepatic cancer due to
the sequela inflammation in non-cancerous parts. In addition, there
is a report on the involvement of HCV infection in dermatosis such
as chronic urticaria, lichen planus, cryoglobulinemic purpura and
the like (The Japanese Journal of Dermatology, 111(7), 1075-81,
2001).
[0007] Thus, an effective therapeutic method of hepatitis C is
desired. Apart from the symptomatic therapy to suppress
inflammation with an anti-inflammatory agent, the development of a
therapeutic agent that reduces HCV to a low level free from
inflammation and that eradicates HCV has been strongly
demanded.
[0008] At present, a treatment with interferon is the only
effective method known for the eradication of HCV. However,
interferon can eradicate the virus only in about one-third of the
patient population. For the rest of the patients, it has no effect
or provides only a temporary effect. Therefore, an anti-HCV drug to
be used in the place of or concurrently with interferon is awaited
in great expectation.
[0009] In recent years, Ribavirin
(1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) has
become commercially available as a therapeutic agent for hepatitis
C, which is to be used concurrently with interferon. It enhances
the efficacy of interferon but only to a low efficacy rate, and a
different novel therapeutic agent for hepatitis C is desired.
[0010] Also, an attempt has been made to potentiate the
immunocompetence of the patient with an interferon agonist, an
interleukin-12 agonist and the like, thereby to eradicate the
virus, but an effective pharmaceutical agent has not been found
yet.
[0011] In addition, the inhibition of HCV growth, wherein
HCV-specific protein is targeted, has been drawing attention these
days.
[0012] The gene of HCV encodes a protein such as serine protease,
RNA helicase, RNA-dependent RNA polymerase and the like. These
proteins function as a specific protein essential for the growth of
HCV.
[0013] One of the specific proteins, RNA-dependent RNA polymerase
(hereinafter to be also briefly referred to as an HCV polymerase),
is an enzyme essential for the growth of the virus. The gene
replication of HCV having a plus-strand RNA gene is considered to
involve synthesis of a complementary minus-strand RNA by the use of
the plus-strand RNA as a template, and, using the obtained
minus-strand RNA as a template, amplifying the plus-strand RNA. The
portion called NS5B of a protein precursor, that HCV codes for, has
been found to show an RNA-dependent RNA polymerase activity (EMBO
J., 15, 12-22, 1996), and is considered to play a central role in
the HCV gene replication.
[0014] Therefore, an HCV polymerase inhibitor can be a target in
the development of an anti-HCV drug, and the development thereof is
eagerly awaited. However, an effective HCV polymerase inhibitor has
not been developed yet, like in other attempts to develop an
anti-HCV drug based on other action mechanisms. As the situation
stands, no pharmaceutical agent can treat hepatitis C
satisfactorily.
[0015] The following discloses known compounds relatively similar
to the compound of the present invention.
[0016] The therapeutic agents for hepatitis C, which have a
benzimidazole skeleton, are known from JP-A-2001-247550
(WO01/47883, EP1162196A1) and WO02/04425.
[0017] These publications disclose the following .beta.-ketoamide
compounds J etc. and K etc., respectively, as anti-HIV agents
having an integrase inhibitory activity: ##STR2##
[0018] Note that the earliest publication dates of these
publications are Jul. 5, 2001 (WO01/47883) and Jan. 17, 2002
(WO02/04425), and the priority date of the present application is
Jun. 26, 2001, antedating these publication dates.
[0019] In addition, a known therapeutic agent for hepatitis C
having a benzimidazole skeleton is also disclosed in WO97/36866,
Japanese Patent Application under PCT laid-open under kohyo No.
2000-511899 (EP906097) and WO99/51619.
[0020] WO97/36866 discloses the following compound D and the like,
and HCV helicase inhibitory activity of the compounds.
[0021] Japanese Patent Application under PCT laid-open under kohyo
No. 2000-511899 (EP906097) discloses the following compound E and
the like, and WO99/51619 discloses the following compound F and the
like, in both of which a possibility of these compounds being
effective as an HCV inhibitor is mentioned.
[0022] However, these publications do not include the compound
disclosed in the present specification, or a disclosure suggestive
thereof. ##STR3##
[0023] A known anti-hepatitis virus agent having a benzimidazole
skeleton is disclosed in Japanese Patent Application under PCT
laid-open under kohyo No. 2000-503017 (WO97/25316) and Japanese
Patent Application under PCT laid-open under kohyo No. 10-505092
(WO96/7646).
[0024] WO97/25316 discloses the following compound A and the like,
wherein the use thereof is for a treatment of viral infection. The
target virus is a DNA virus such as hepatitis B virus and the like.
However, this publication does not include the compound disclosed
in the present specification or a description regarding or
suggestive of HCV.
[0025] Japanese Patent Application under PCT laid-open under kohyo
No. 10-505092 discloses the following compound B and the like,
wherein the use thereof is for a treatment of viral infection. The
target virus is a DNA virus such as herpesvirus and hepatitis B
virus. However, this publication does not include the compound
disclosed in the present specification or a description regarding
or suggestive of HCV. ##STR4##
[0026] The benzimidazole derivatives having an antiviral activity
have been disclosed in JP-A-3-31264, U.S. Pat. No. 3,644,382 and
U.S. Pat. No. 3,778,504. In addition, WO98/37072 discloses, as a
production inhibitor of tumor necrosis factor (TNF) and cyclic AMP,
a benzimidazole derivative for the use as an anti-human
immunodeficiency virus (HIV) agent and an anti-inflammation agent.
WO98/05327 discloses, as a reverse transcriptase inhibitor, a
benzimidazole derivative for the use as an anti-HIV agent. J. Med.
Chem. (13(4), 697-704, 1970) discloses, as a neuraminidase
inhibitor, a benzimidazole derivative for the use as an
anti-influenza virus agent.
[0027] However, none of these publications includes the compound of
the present invention or a description regarding or suggestive of
an anti-HCV effect.
[0028] Known benzimidazole derivatives having a pharmaceutical use
other than as an antiviral agent are disclosed in JP-A-8-501318
(U.S. Pat. No. 5,814,651) and JP-A-8-134073 (U.S. Pat. No.
5,563,143). These publications disclose the following compound C
and the like as a catechol diether compound, and the use thereof as
an anti-inflammation agent. However, neither of the publications
includes the compound of the present invention, and as the action
mechanism, the former discloses phosphodiesterase IV and the latter
discloses TNF. These publications do not include a description
regarding or suggestive of an anti-HCV effect.
[0029] Japanese Patent Application under PCT laid-open under kohyo
No. 2000-159749 (EP882718) discloses the following compound G and
the like, and the use thereof for the treatment of bronchitis,
glomerulonephritis and the like. However, this publication does not
include the compound of the present invention, but discloses only a
phosphodiesterase IV inhibitory and hypoglycemic action. This
publication does not include a description regarding or suggestive
of an anti-HCV effect.
[0030] U.S. Pat. No. 6,211,177 discloses the following compound H
and the like with their use as antitumor agents. However, this
publication does not encompass the compound of the present
invention, and does not disclose or suggest an anti-HCV effect.
##STR5##
[0031] WO98/50029, WO98/50030 and WO98/50031 disclose benzimidazole
derivatives as an antitumor agent having a protein isoprenyl
transferase action. While this publication discloses a wide scope
of the claims, at least it does not include a compound analogous to
the compound of the present invention or a description regarding or
suggestive of an anti-HCV effect.
[0032] JP-A-8-109169 (EP694535) discloses the application of a
tachykinin receptor antagonist to treat an inflammatory disease,
and WO96/35713 discloses the application thereof as a growth
hormone release promoter to treat a growth hormone-related disease
such as osteoporosis and the like. However, none of these
publications includes a description regarding or suggestive of an
anti-HCV effect.
[0033] WO2001/21634 discloses the following compound I in a
chemical library. However, this publication does not encompass the
compound of the present invention. While it discloses an
antimicrobial activity of certain compounds, this publication does
not teach or suggest an anti-HCV effect. ##STR6##
[0034] JP-A-53-14735 discloses a benzimidazole derivative as a
brightener besides its pharmaceutical use, but this publication
does not include the compound of the present invention.
SUMMARY OF THE INVENTION
[0035] Based on the findings from the preceding studies, it has
been elucidated that a pharmaceutical agent having an anti-HCV
activity is effective for the prophylaxis and treatment of
hepatitis C, and particularly an anti-HCV agent having an
inhibitory activity on RNA-dependent RNA polymerase of HCV can be a
prophylactic and therapeutic agent effective against hepatitis C
and a prophylactic and therapeutic agent for the disease caused by
hepatitis C.
[0036] Accordingly, the present invention provides a pharmaceutical
agent having an anti-HCV activity, particularly a pharmaceutical
agent having an RNA-dependent RNA polymerase inhibitory
activity.
[0037] The present inventors have made an in-depth study of
compounds having an anti-HCV activity, particularly RNA-dependent
RNA polymerase inhibitory activity, and completed the present
invention.
[0038] Thus, the present invention provides the following (1) to
(88). [0039] (1) A therapeutic agent for hepatitis C, which
comprises a fused ring compound of the following formula [I] or a
pharmaceutically acceptable salt thereof as an active ingredient:
##STR7## wherein [0040] a broken line is a single bond or a double
bond, [0041] G.sup.1 is C(--R.sup.1) or a nitrogen atom, [0042]
G.sup.2 is C(--R.sup.2) or a nitrogen atom, [0043] G.sup.3 is
C(--R.sup.3) or a nitrogen atom, [0044] G.sup.4 is C(--R.sup.4) or
a nitrogen atom, [0045] G.sup.5, G.sup.6, G.sup.8 and G.sup.9 are
each independently a carbon atom or a nitrogen atom, [0046] G.sup.7
is C(--R.sup.7), an oxygen atom, a sulfur atom, or a nitrogen atom
optionally substituted by R.sup.8, [0047] wherein R.sup.1, R.sup.2,
R.sup.3 and R.sup.4 are each independently, [0048] (1) hydrogen
atom, [0049] (2) C.sub.1-6 alkanoyl, [0050] (3) carboxyl, [0051]
(4) cyano, [0052] (5) nitro, [0053] (6) C.sub.1-6 alkyl optionally
substituted by 1 to 3 substituent(s) selected from the following
group A, [0054] group A; halogen atom, hydroxyl group, carboxyl,
amino, C.sub.1-6 alkoxy, C.sub.1-6 alkoxy C.sub.1-6 alkoxy,
C.sub.1-6 alkoxycarbonyl and C.sub.1-6 alkylamino, [0055] (7)
--COOR.sup.a1 [0056] wherein R.sup.a1 is optionally substituted
C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
following group B or glucuronic acid residue, [0057] group B;
halogen atom, cyano, nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6
alkyl, C.sub.1-6 alkanoyl, --(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1,
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.b1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2, [0058] wherein
R.sup.b1 and R.sup.b2 are each independently hydrogen atom or
C.sub.1-6 alkyl and r is 0 or an integer of 1 to 6, [0059] (8)
--CONR.sup.a2R.sup.a3 [0060] wherein R.sup.a2 and R.sup.a3 are each
independently hydrogen atom, C.sub.1-6 alkoxy or optionally
substituted C.sub.1-6 alkyl (as defined above), [0061] (9)
--C(.dbd.NR.sup.a4)NH.sub.2 [0062] wherein R.sup.a4 is hydrogen
atom or hydroxyl group, [0063] (10) --NHR.sup.a5 [0064] wherein
R.sup.a5 is hydrogen atom, C.sub.1-6 alkanoyl or C.sub.1-6
alkylsulfonyl, [0065] (11) --OR.sup.86 [0066] wherein R.sup.a6 is
hydrogen atom or optionally substituted C.sub.1-6 alkyl (as defined
above), [0067] (12) --SO.sub.2R.sup.a7 [0068] wherein R.sup.a7 is
hydroxyl group, amino, C.sub.1-6 alkyl or C.sub.1-6 alkylamino,
[0069] (13) --P(.dbd.O)(OR.sup.a31).sub.2 [0070] wherein R.sup.a31
is hydrogen atom, optionally substituted C.sub.1-6 alkyl (as
defined above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B [0071] or [0072] (14) heterocyclic group having 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, and [0073] R.sup.7 and R.sup.8 are each hydrogen atom
or optionally substituted C.sub.1-6 alkyl (as defined above),
[0074] ring Cy is [0075] (1) C.sub.3-8 cycloalkyl optionally
substituted by 1 to 5 substituent(s) selected from the following
group C, [0076] group C; hydroxyl group, halogen atom, C.sub.1-6
alkyl and C.sub.1-6 alkoxy, [0077] (2) C.sub.3-8 cycloalkenyl
optionally substituted by 1 to 5 substituent(s) selected from the
above group C, or ##STR8## [0078] wherein u and v are each
independently an integer of 1 to 3, [0079] ring A is [0080] (1)
C.sub.6-14 aryl, [0081] (2) C.sub.3-8 cycloalkyl, [0082] (3)
C.sub.3-8 cycloalkenyl or [0083] (4) heterocyclic group having 1 to
4 heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, [0084] R.sup.5 and R.sup.6 are each independently
[0085] (1) hydrogen atom, [0086] (2) halogen atom, [0087] (3)
optionally substituted C.sub.1-6 alkyl (as defined above) or [0088]
(4) --OR.sup.a8 [0089] wherein R.sup.a8 is hydrogen atom, C.sub.1-6
alkyl or C.sub.6-14 aryl C.sub.1-6 alkyl, and [0090] X is [0091]
(1) hydrogen atom, [0092] (2) halogen atom, [0093] (3) cyano,
[0094] (4) nitro, [0095] (5) amino, C.sub.1-6 alkanoylamino, [0096]
(6) C.sub.1-6 alkylsulfonyl, [0097] (7) optionally substituted
C.sub.1-6 alkyl (as defined above), [0098] (8) C.sub.2-6 alkenyl
optionally substituted by 1 to 3 substituent(s) selected from the
above group A, [0099] (9) --COOR.sup.a9 [0100] wherein R.sup.a9 is
hydrogen atom or C.sub.1-6 alkyl, [0101] (10) --CONH--
(CH.sub.2).sub.l--R.sup.a10 [0102] wherein R.sup.a10 is optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.1-6
alkoxycarbonyl or C.sub.1-6 alkanoylamino and l is 0 or an integer
of 1 to 6, [0103] (11) --OR.sup.a11 [0104] wherein R.sup.a11 is
hydrogen atom or optionally substituted C.sub.1-6 alkyl (as defined
above) [0105] or ##STR9## [0106] wherein [0107] ring B is [0108]
(1') C.sub.6-14 aryl, [0109] (2') C.sub.3-8 cycloalkyl or [0110]
(3') heterocyclic group (as defined above), [0111] each Z is
independently [0112] (1') a group selected from the following group
D, [0113] (2') C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0114] (3')
C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0115] (4')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0116] (5')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the following group D, [0117] wherein the
heterocyclic group has 1 to 4 hetero-atom(s) selected from an
oxygen atom, a nitrogen atom and a sulfur atom, or [0118] (6')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0119] wherein
the heterocycle C.sub.1-6 alkyl is C.sub.1-6 alkyl substituted by
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the group D, as defined above, [0120] group D: [0121]
(a) hydrogen atom, [0122] (b) halogen atom, [0123] (c) cyano,
[0124] (d) nitro, [0125] (e) optionally substituted C.sub.1-6 alkyl
(as defined above), [0126] (f) --(CH.sub.2).sub.t--COR.sup.a18,
[0127] (hereinafter each t means independently 0 or an integer of 1
to 6), [0128] wherein R.sup.a18 is [0129] (1'') optionally
substituted C.sub.1-6 alkyl (as defined above), [0130] (2'')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B or [0131] (3'') heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B [0132] wherein the heterocyclic group has 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, [0133] (g) --(CH.sub.2).sub.t--COOR.sup.a19 [0134]
wherein R.sup.a19 is hydrogen atom, optionally substituted
C.sub.1-6 alkyl (as defined above) or C.sub.6-14 aryl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0135] (h)
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 [0136] wherein R.sup.a27
and R.sup.a28 are each independently, [0137] (1'') hydrogen atom,
[0138] (2'') optionally substituted C.sub.1-6 alkyl (as defined
above), [0139] (3'') C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B, [0140] (4'')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0141] (5'')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0142] (6'') heterocycle C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0143] wherein the heterocycle C.sub.1-6 alkyl
is C.sub.1-6 alkyl substituted by heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, as defined above, [0144] (7'') C.sub.3-8 cycloalkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0145] (8'') C.sub.3-8 cycloalkyl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0146] (9'') hydroxyl group or [0147] (10'') C.sub.1-6 alkoxy,
[0148] (i) --(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 [0149]
wherein R.sup.a33 is hydrogen atom, C.sub.1-6 alkyl, hydroxyl group
or C.sub.1-6 alkoxy, [0150] (j) --(CH.sub.2)--OR.sup.a20 [0151]
wherein R.sup.a20 is [0152] (1'') hydrogen atom, [0153] (2'')
optionally substituted C.sub.1-6 alkyl (as defined above), [0154]
(3'') optionally substituted C.sub.2-6 alkenyl (as defined above),
[0155] (4'') C.sub.2-6 alkynyl optionally substituted by 1 to 3
substituent(s) selected from the above group A, [0156] (5'')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0157] (6'') C.sub.6-14 aryl
C.sub.1-6 alkyl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0158] (7'') heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, [0159] (8'') heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0160] (9'') C.sub.3-8 cycloalkyl optionally substituted by 1 to
5 substituent(s) selected from the above group B, or [0161] (10'')
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl optionally substituted by 1 to
5 substituent(s) selected from the above group B, [0162] (k)
--(CH.sub.2).sub.t--O-- (CH.sub.2).sub.p--COR.sup.a21 [0163]
wherein R.sup.a21 is amino, C.sub.1-6 alkylamino or heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the above group B, and p is 0 or an integer of 1 to 6, [0164] (1)
--(CH.sub.2).sub.t--NR.sup.a22R.sup.a23 [0165] wherein R.sup.a22
and R.sup.a23 are each independently [0166] (1'') hydrogen atom,
[0167] (2'') optionally substituted C.sub.1-6 alkyl (as defined
above), [0168] (3'') C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B, [0169] (4'')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0170] (5'')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B or [0171] (6'')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0172] (m)
--(CH.sub.2).sub.t--NR.sup.a29 CO--R.sup.a24 [0173] wherein
R.sup.a29 is hydrogen atom, C.sub.1-6 alkyl or C.sub.1-6 alkanoyl,
and R.sup.a24 is [0174] (1'') amino, [0175] (2'') C.sub.1-6
alkylamino, [0176] (3'') optionally substituted C.sub.1-6 alkyl (as
defined above), [0177] (4'') C.sub.6-14 aryl optionally substituted
by 1 to 5 substituent(s) selected from the above group B, [0178]
(5'') heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from the above group B or [0179] (6'')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0180] (n)
--(CH.sub.2).sub.t--NR.sup.a29SO.sub.2--R.sup.a25 [0181] wherein
R.sup.a29 is as defined above, and [0182] R.sup.a25 is hydrogen
atom, optionally substituted C.sub.1-6 alkyl (as defined above),
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B or heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0183] (o) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 [0184]
wherein R.sup.a25 is as defined above, and q is 0, 1 or 2, [0185]
(p) --(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26 [0186] wherein
R.sup.a26 is hydrogen atom, optionally substituted C.sub.1-6 alkyl
(as defined above), C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B or heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0187] and [0188] (q) heterocyclic group having
1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom
and a sulfur atom, and [0189] w is an integer of 1 to 3, and [0190]
Y is [0191] (1') a single bond, [0192] (2') C.sub.1-6 alkylene,
[0193] (3') C.sub.2-6 alkenylene, [0194] (4')
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--, [0195] (hereinafter m
and n are each independently 0 or an integer of 1 to 6), [0196]
(5') --CO--, [0197] (6') --CO.sub.2-- (CH.sub.2).sub.n--, [0198]
(7') --CONH-- (CH.sub.2).sub.n--NH--, [0199] (8') --NHCO.sub.2--,
[0200] (9') --NHCONH--, [0201] (10') --O--(CH.sub.2).sub.n--CO--,
[0202] (11') --O--(CH.sub.2).sub.n--O--, [0203] (12') --SO.sub.2--,
[0204] (13') --(CH.sub.2).sub.m--NR.sup.a12--(CH.sub.2).sub.n--
[0205] wherein R.sup.a12 is [0206] (1'') hydrogen atom, [0207]
(2'') optionally substituted C.sub.1-6 alkyl (as defined above),
[0208] (3'') C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted
by 1 to 5 substituent(s) selected from the above group B, [0209]
(4'') C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0210] (5'')
COR.sup.b5 [0211] wherein R.sup.b5 is hydrogen atom, optionally
substituted C.sub.1-6 alkyl (as defined above), C.sub.6-14 aryl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0212] (6'') --COOR.sup.b5 (R.sup.b5 is as defined above) or
[0213] (7'') --SO.sub.2R.sup.b5 (R.sup.b5 is as defined above),
[0214] (14') --NR.sup.a12CO-- (R.sup.a12 is as defined above),
[0215] (15') --CONR.sup.a13--(CH.sub.2).sub.n-- [0216] wherein
R.sup.a13 is hydrogen atom, optionally substituted C.sub.1-6 alkyl
(as defined above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0217] (16) --CONH--CHR.sup.a14-- [0218] wherein R.sup.a14 is
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0219] (17) O--
(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n-- [0220]
wherein R.sup.a15 and R.sup.a16 are each independently [0221] (1'')
hydrogen atom, [0222] (2'') carboxyl, [0223] (3'') C.sub.1-6 alkyl,
[0224] (4'') --OR.sup.b6 [0225] wherein R.sup.b6 is C.sub.1-6 alkyl
or C.sub.6-14 aryl C.sub.1-6 alkyl, [0226] or [0227] (5'')
--NHR.sup.b7 [0228] wherein R.sup.b7 is hydrogen atom, C.sub.1-6
alkyl, C
.sub.1-6 alkanoyl or C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl, or
R.sup.a15 is optionally ##STR10## [0229] wherein n', ring B', Z'
and w' are the same as the above-mentioned n, ring B, Z and w,
respectively, and may be the same as or different from the
respective counterparts, [0230] (18')
--(CH.sub.2).sub.n--NR.sup.a12--CHR.sup.a15--(R.sup.a12 and
R.sup.a15 are each as defined above), [0231] (19')
--NR.sup.a17SO.sub.2 [0232] wherein R.sup.a17 is hydrogen atom or
C.sub.1-6 alkyl, [0233] (20')
--S(O).sub.e--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(e is 0, 1 or 2, R.sup.a15 and R.sup.a16 are each as defined
above), [0234] or [0235] (21)
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(R.sup.a15 and R.sup.a16 are each as defined above). [0236] (2) The
therapeutic agent of (1) above, wherein 1 to 4 of the G.sup.1,
G.sup.2, G.sup.3, G.sup.4, G.sup.5, G.sup.6, G.sup.7, G.sup.8 and
G.sup.9 is (are) a nitrogen atom. [0237] (3) The therapeutic agent
of (2) above, wherein G.sup.2 is C(--R.sup.2) and G.sup.6 is a
carbon atom. [0238] (4) The therapeutic agent of (2) or (3) above,
wherein G.sup.5 is a nitrogen atom. [0239] (5) The therapeutic
agent of (1) above, wherein, in formula [I], the moiety ##STR11##
is a fused ring selected from ##STR12## ##STR13## [0240] (6) The
therapeutic agent of (5) above, wherein, in formula [I], the moiety
##STR14## is a fused ring selected from ##STR15## [0241] (7) The
therapeutic agent of (6) above, which comprises a fused ring
compound of the following formula [I-1] ##STR16## wherein each
symbol is as defined in (1), or a pharmaceutically acceptable salt
thereof as an active ingredient. [0242] (8) The therapeutic agent
of (6) above, which comprises a fused ring compound of the
following formula [I-2] ##STR17## wherein each symbol is as defined
in (1), or a pharmaceutically acceptable salt thereof as an active
ingredient. [0243] (9) The therapeutic agent of (6) above, which
comprises a fused ring compound of the following formula [I-3]
##STR18## wherein each symbol is as defined in (1), or a
pharmaceutically acceptable salt thereof as an active ingredient.
[0244] (10) The therapeutic agent of (6) above, which comprises a
fused ring compound of the following formula [I-4] ##STR19##
wherein each symbol is as defined in (1), or a pharmaceutically
acceptable salt thereof as an active ingredient. [0245] (11) The
therapeutic agent of any of (1) to (10) above, wherein at least one
of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is carboxyl,
--COOR.sup.a1, --CONR.sup.a2R.sup.a3, --SO.sub.2R.sup.a7 (wherein
R.sup.a1, R.sup.a2, R.sup.a3 and R.sup.a7 are as defined in (1)),
##STR20## [0246] (12) The therapeutic agent of (11) above, wherein
at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is carboxyl,
--COOR.sup.a1, --CONR.sup.a2R.sup.a3 or --SO.sub.2R.sup.a7 wherein
R.sup.a1, R.sup.a2, R.sup.a3 and R.sup.a7 are as defined in (1).
[0247] (13) The therapeutic agent of any of (1) to (10) above,
wherein at least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is
--COOR.sup.a1 wherein R.sup.a1 is glucuronic acid residue. [0248]
(14) The therapeutic agent of any of (1) to (10) above, wherein at
least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is heterocyclic
group having 1 to 4 heteroatom(s) selected from an oxygen atom, a
nitrogen atom and a sulfur atom. [0249] (15) The therapeutic agent
of any of (1) to (14) above, wherein the ring Cy is cyclopentyl,
cyclohexyl, cycloheptyl, tetrahydrothiopyranyl or piperidino.
[0250] (16) The therapeutic agent of any of (1) to (14) above,
wherein the ring Cy is ##STR21## wherein each symbol is as defined
in (1). [0251] (17) The therapeutic agent of any of (1) to (16)
above, wherein the ring A is C.sub.6-14 aryl. [0252] (18) The
therapeutic agent of any of (1) to (17) above, wherein at least one
substituent optionally substituted by group A is a substituent
substituted by C.sub.1-6 alkoxy C.sub.1-6 alkoxy. [0253] (19) The
therapeutic agent of any of (1) to (18) above, wherein the Y is
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n-- wherein
each symbol is as defined in (1). [0254] (20) The therapeutic agent
of any of (1) to (19) above, wherein at least one group represented
by Z is heterocycle C.sub.1-6 alkyl optionally substituted by 1 to
5 substituent(s) selected from the group D. [0255] (21) The
therapeutic agent of any of (1) to (19) above, wherein at least one
group represented by Z is a heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the group D,
wherein said heterocyclic group is selected from the following
groups: ##STR22## wherein E.sup.1 is an oxygen atom, a sulfur atom
or N(--R.sup.a35), E.sup.2 is an oxygen atom, CH.sub.2 or
N(--R.sup.a35), E.sup.3 is an oxygen atom or a sulfur atom, wherein
each R.sup.a35 is independently hydrogen atom or C.sub.1-6 alkyl, f
is an integer of 1 to 3, and h and h' are the same or different and
each is an integer of 1 to 3. [0256] (22) The therapeutic agent of
(21) above, wherein at least one group represented by Z is
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the group D wherein said heterocyclic group is
selected from the following groups: ##STR23## wherein each symbol
is as defined in (21). [0257] (23) The therapeutic agent of any of
(1) to (19) above, wherein at least one group represented by group
D is --(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 wherein each symbol
is as defined in (1), and at least one of R.sup.a27 and R.sup.a28
is C.sub.1-6 alkoxy. [0258] (24) The therapeutic agent of any of
(1) to (19) above, wherein at least one group represented by group
D is --(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 wherein each
symbol is as defined in (1), and R.sup.a33 is hydroxyl group or
C.sub.1-6 alkoxy. [0259] (25) The therapeutic agent of any of (1)
to (19) above, wherein at least one group represented by group D is
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.a21, wherein each
symbol is as defined in (1), and R.sup.a21 is amino. [0260] (26)
The therapeutic agent of any of (1) to (19) above, wherein at least
one group represented by group D is
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24 wherein each symbol is
as defined in (1), and R.sup.a24 is amino or C.sub.1-6 alkylamino.
[0261] (27) The therapeutic agent of any of (1) to (19) above,
wherein at least one group represented by group D is
--(CH.sub.2).sub.t--NR.sup.a22R.sup.a23 wherein each symbol is as
defined in (1), and at lease one of R.sup.a22 and R.sup.a23 is
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the group B. [0262] (28) The therapeutic agent of any
of (1) to (19) above, wherein at least one group represented by
group D is heterocyclic group having 1 to 4 heteroatom(s) selected
from an oxygen atom, a nitrogen atom and a sulfur atom. [0263] (29)
A fused ring compound of the following formula [II] ##STR24##
wherein the moiety ##STR25## is a fused ring selected from
##STR26## [0264] wherein R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are
each independently, [0265] (1) hydrogen atom, [0266] (2) C.sub.1-6
alkanoyl, [0267] (3) carboxyl, [0268] (4) cyano, [0269] (5) nitro,
[0270] (6) C.sub.1-6 alkyl optionally substituted by 1 to 3
substituent(s) selected from the following group A, [0271] group A;
halogen atom, hydroxyl group, carboxyl, amino, C.sub.1-6 alkoxy,
C.sub.1-6 alkoxy C.sub.1-6 alkoxy, C.sub.1-6 alkoxycarbonyl and
C.sub.1-6 alkylamino, [0272] (7) --COOR.sup.a1 [0273] wherein
R.sup.a1 is optionally substituted C.sub.1-6 alkyl (as defined
above), C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1
to 5 substituent(s) selected from the following group B or
glucuronic acid residue, [0274] group B; halogen atom, cyano,
nitro, C.sub.1-6 alkyl, halogenated C.sub.1-6 alkyl, C.sub.1-6
alkanoyl, --(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1 COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1,
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.b1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 [0275] wherein
R.sup.b1 and R.sup.b2 are each independently hydrogen atom or
C.sub.1-6 alkyl and r is 0 or an integer of 1 to 6, [0276] (8)
--CONR.sup.a2R.sup.a3 [0277] wherein R.sup.a2 and R.sup.a3 are each
independently hydrogen atom, C.sub.1-6 alkoxy or optionally
substituted C.sub.1-6 alkyl (as defined above), [0278] (9)
--C(.dbd.NR.sup.a4)NH.sub.2 [0279] wherein R.sup.a4 is hydrogen
atom or hydroxyl group, [0280] (10) --NHR.sup.a5 [0281] wherein
R.sup.a5 is hydrogen atom, C.sub.1-6 alkanoyl or C.sub.1-6
alkylsulfonyl, [0282] (11) --OR.sup.a6 [0283] wherein R.sup.a6 is
hydrogen atom or optionally substituted C.sub.1-6 alkyl (as defined
above), [0284] (12) --SO.sub.2R.sup.a7 [0285] wherein R.sup.a7 is
hydroxyl group, amino, C.sub.1-6 alkyl or C.sub.1-6 alkylamino,
[0286] (13) --P(.dbd.O)(OR.sup.a31).sub.2 [0287] wherein R.sup.a31
is hydrogen atom, optionally substituted C.sub.1-6 alkyl (as
defined above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0288] or [0289] (14) heterocyclic group having 1 to 4
heteroatom(s) selected from an oxygen atom, a nitrogen atom and a
sulfur atom, and [0290] R.sup.7 is hydrogen atom or optionally
substitute C.sub.1-6 alkyl (as defined above), [0291] ring Cy' is
[0292] (1) C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from the following group C, [0293] group C;
hydroxyl group, halogen atom, C.sub.1-6 alkyl and C.sub.1-6 alkoxy,
or ##STR27## [0294] wherein u and v are each independently an
integer of 1 to 3, [0295] ring A' is a group selected from a group
consisting of phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
cyclohexyl, cyclohexenyl, furyl and thienyl, [0296] R.sup.5' and
R.sup.6' are each independently [0297] (1) hydrogen atom, [0298]
(2) halogen atom, [0299] (3) optionally substituted C.sub.1-6 alkyl
(as defined above) or [0300] (4) hydroxyl group [0301] ring B is
[0302] (1) C.sub.6-14 aryl, [0303] (2) C.sub.3-8 cycloalkyl or
[0304] (3) heterocyclic group having 1 to 4 heteroatom(s) selected
from an oxygen atom, a nitrogen atom and a sulfur atom, [0305] each
Z is independently [0306] (1) a group selected from the following
group D, [0307] (2) C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the following group D, [0308] (3)
C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0309] (4)
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the following group D, [0310] (5)
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the following group D wherein the heterocyclic group
has 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen
atom and a sulfur atom, or [0311] (6) heterocycle C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
following group D wherein the heterocycle C.sub.1-6 alkyl is
C.sub.1-6 alkyl substituted by heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the group D, as
defined above, [0312] group D: [0313] (a) hydrogen atom, [0314] (b)
halogen atom, [0315] (c) cyano, [0316] (d) nitro, [0317] (e)
optionally substituted C.sub.1-6 alkyl (as defined above), [0318]
(f) --(CH.sub.2).sub.t--COR.sup.a18, [0319] (hereinafter each t
means independently 0 or an integer of 1 to 6), [0320] wherein
R.sup.a18 is [0321] (1') optionally substituted C.sub.1-6 alkyl (as
defined above), [0322] (2') C.sub.6-14 aryl optionally substituted
by 1 to 5 substituent(s) selected from the above group B or [0323]
(3') heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from the above group B [0324] wherein the
heterocyclic group has 1 to 4 heteroatom(s) selected from an oxygen
atom, a nitrogen atom and a sulfur atom, [0325] (g)
--(CH.sub.2).sub.t--COOR.sup.a19 [0326] wherein R.sup.a19 is
hydrogen atom, optionally substituted C.sub.1-6 alkyl (as defined
above) or C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by
1 to 5 substituent(s) selected from the above group B, [0327] (h)
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 [0328] wherein R.sup.a27
and R.sup.a28 are each independently, [0329] (1') hydrogen atom,
[0330] (2') optionally substituted C.sub.1-6 alkyl (as defined
above), [0331] (3') C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B, [0332] (4')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0333] (5')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0334] (6') heterocycle C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0335] wherein the heterocycle C.sub.1-6 alkyl
is C.sub.1-6 alkyl substituted by heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, as defined above, [0336] (7') C.sub.3-8 cycloalkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0337] (8') C.sub.3-8 cycloalkyl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0338] (9') hydroxyl group or [0339] (10') C.sub.1-6 alkoxy,
[0340] (i) --(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 [0341]
wherein R.sup.a33 is hydrogen atom, C.sub.1-6 alkyl, hydroxyl group
or C.sub.1-6 alkoxy, [0342] (j) --(CH.sub.2).sub.t--OR.sup.a20
[0343] wherein R.sup.a20 is [0344] (1') hydrogen atom, [0345] (2')
optionally substituted C.sub.1-6 alkyl (as defined above), [0346]
(3') optionally substituted C.sub.2-6 alkenyl (as defined above),
[0347] (4') C.sub.2-6 alkynyl optionally substituted by 1 to 3
substituent(s) selected from the above group A, [0348] (5')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0349] (6') C.sub.6-14 aryl
C.sub.1-6 alkyl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0350] (7') heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, [0351] (8') heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0352] (9') C.sub.3-8 cycloalkyl optionally substituted by 1 to
5 substituent(s) selected from the above group B, or [0353] (10')
C.sub.3-8 cycloalkyl C.sub.1-6
alkyl optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0354] (k) --(CH.sub.2).sub.t--O--
(CH.sub.2).sub.p--COR.sup.a21 [0355] wherein R.sup.a21 is amino,
C.sub.1-6 alkylamino or heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from the above group B, [0356]
and p is 0 or an integer of 1 to 6, [0357] (l)
--(CH.sub.2).sub.t--NR.sup.a22R.sup.a23 [0358] wherein R.sup.a22
and R.sup.a23 are each independently [0359] (1') hydrogen atom,
[0360] (2') optionally substituted C.sub.1-6 alkyl (as defined
above), [0361] (3') C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B, [0362] (4')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0363] (5')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B or [0364] (6')
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0365] (m)
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24 [0366] wherein
R.sup.a29 is hydrogen atom, C.sub.1-6 alkyl or C.sub.1-6 alkanoyl,
and [0367] R.sup.a24 is [0368] (1') amino, [0369] (2') C.sub.1-6
alkylamino, [0370] (3') optionally substituted C.sub.1-6 alkyl (as
defined above), [0371] (4') C.sub.6-14 aryl optionally substituted
by 1 to 5 substituent(s) selected from the above group B, [0372]
(5') heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from the above group B, or [0373] (6')
heterocycle C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0374] (n)
--(CH.sub.2).sub.t--NR.sup.a29SO.sub.2--R.sup.a25 [0375] wherein
R.sup.a29 is as defined above, and [0376] R.sup.a25 is hydrogen
atom, optionally substituted C.sub.1-6 alkyl (as defined above),
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B or heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the above group
B, [0377] (o) --(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 [0378]
wherein R.sup.a25 is as defined above, and q is 0, 1 or 2, [0379]
(p) --(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26 [0380] wherein
R.sup.a26 is hydrogen atom, optionally substituted C.sub.1-6 alkyl
(as defined above), C.sub.6-14 aryl optionally substituted by 1 to
5 substituent(s) selected from the above group B or heterocyclic
group optionally substituted by 1 to 5 substituent(s) selected from
the above group B, [0381] and [0382] (q) heterocyclic group having
1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen atom
and a sulfur atom, [0383] w is an integer of 1 to 3, and [0384] Y
is [0385] (1) a single bond, [0386] (2) C.sub.1-6 alkylene, [0387]
(3) C.sub.2-6 alkenylene, [0388] (4) --(CH.sub.2).sub.m--O--
(CH.sub.2).sub.n--, [0389] (hereinafter m and n are each
independently 0 or an integer of 1 to 6), [0390] (5) --CO--, [0391]
(6) --CO.sub.2-- (CH.sub.2).sub.n--, [0392] (7) --CONH-- (CH.sub.2)
n-NH--, [0393] (8) --NHCO.sub.2--, [0394] (9) --NHCONH--, [0395]
(10) --O--(CH.sub.2).sub.n--CO--, [0396] (11) --O--
(CH.sub.2)--O--, [0397] (12) --SO.sub.2--, [0398] (13)
--(CH.sub.2).sub.m--NR.sup.a12--(CH.sub.2).sub.n-- [0399] wherein
R.sup.a12 is [0400] (1') hydrogen atom, [0401] (2') optionally
substituted C.sub.1-6 alkyl (as defined above), [0402] (3')
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0403] (4')
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from the above group B, [0404] (5') --COR.sup.b5 [0405]
wherein R.sup.b5 is hydrogen atom, optionally substituted C.sub.1-6
alkyl (as defined above), C.sub.6-14 aryl optionally substituted by
1 to 5 substituent(s) selected from the above group B or C.sub.6-14
aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0406] (6')
--COOR.sup.5 (R.sup.b5 is as defined above) or [0407] (7')
--SO.sub.2R.sup.b5 (R.sup.b5 is as defined above), [0408] (14)
--NR.sup.a12CO-- (R.sup.a12 is as defined above), [0409] (15)
--CONR.sup.a13--(CH.sub.2) n [0410] wherein R.sup.a13 is hydrogen
atom, optionally substituted C.sub.1-6 alkyl (as defined above) or
C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B, [0411] (16)
--CONH--CHR.sup.a14-- [0412] wherein R.sup.a14 is C.sub.6-14 aryl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, [0413] (17) --O--
(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n-- [0414]
wherein R.sup.a15 and R.sup.a16 are each independently [0415] (1')
hydrogen atom, [0416] (2') carboxyl, [0417] (3') C.sub.1-6 alkyl,
[0418] (4') --OR.sup.b6 [0419] wherein R.sup.b6 is C.sub.1-6 alkyl
or C.sub.6-14 aryl C.sub.1-6 alkyl, [0420] or [0421] (5')
--NHR.sup.b7 [0422] wherein R.sup.b7 is hydrogen atom, C.sub.1-6
alkyl, C.sub.1-6 alkanoyl or C.sub.6-14 aryl C.sub.1-6
alkyloxycarbonyl, or R.sup.a15 is optionally ##STR28## [0423]
wherein n', ring B', Z' and w' are the same as the above-mentioned
n, ring B, Z and w, respectively, and may be the same as or
different from the respective counterparts, [0424] (18)
--(CH.sub.2)--NR.sup.a12--CHR.sup.a15--(R.sup.a12 and R.sup.a15 are
each as defined above), [0425] (19) --NR.sup.a17SO.sub.2-- [0426]
wherein R.sup.a17 is hydrogen atom or C.sub.1-6 alkyl, [0427] (20)
--S(O).sub.e--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(e is 0, 1 or 2, R.sup.a15 and R.sup.a16 are each as defined
above), [0428] or [0429] (21)
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(R.sup.a15 and R.sup.a16 are each as defined above), or a
pharmaceutically acceptable salt thereof. [0430] (30) The fused
ring compound of (29) above, which is represented by the following
formula [II-1] ##STR29## wherein each symbol is as defined in (29),
or a pharmaceutically acceptable salt thereof. [0431] (31) The
fused ring compound of (29) above, which is represented by the
following formula [II-2] ##STR30## wherein each symbol is as
defined in (29), or a pharmaceutically acceptable salt thereof.
[0432] (32) The fused ring compound of (29) above, which is
represented by the following formula [II-3] ##STR31## wherein each
symbol is as defined in (29), or a pharmaceutically acceptable salt
thereof. [0433] (33) The fused ring compound of (29) above, which
is represented by the following formula [II-4] ##STR32## wherein
each symbol is as defined in (29), or a pharmaceutically acceptable
salt thereof. [0434] (34) The fused ring compound of any of (29) to
(33) above, wherein at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is carboxyl, --COOR.sup.a1,
--CONR.sup.a2R.sup.a3--SO.sub.2R.sup.a7 (wherein R.sup.a1,
R.sup.a2, R.sup.a3 and R.sup.a7 are as defined in (29)), ##STR33##
or a pharmaceutically acceptable salt thereof. [0435] (35) The
fused ring compound of (34) above, wherein at least one of R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 is carboxyl, --COOR.sup.a1 or
--SO.sub.2R.sup.a7 wherein R.sup.a1 and R.sup.a7 are as defined in
(29), or a pharmaceutically acceptable salt thereof. [0436] (36)
The fused ring compound of (35) above, wherein at least one of
R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is carboxyl or --COOR.sup.a1
wherein R.sup.a1 is as defined in (29), or a pharmaceutically
acceptable salt thereof. [0437] (37) The fused ring compound of
(36) above, wherein R.sup.2 is carboxyl and R.sup.1, R.sup.3 and
R.sup.4 are hydrogen atoms, or a pharmaceutically acceptable salt
thereof. [0438] (38) The fused ring compound of any of (29) to (33)
above, wherein at least one of R.sup.1, R.sup.2, R.sup.3 and
R.sup.4 is --COOR.sup.a1 wherein R.sup.a1 is glucuronic acid
residue, or a pharmaceutically acceptable salt thereof. [0439] (39)
The fused ring compound of any of (29) to (33) above, wherein at
least one of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 is heterocyclic
group having 1 to 4 heteroatom(s) selected from an oxygen atom, a
nitrogen atom and a sulfur atom, or a pharmaceutically acceptable
salt thereof. [0440] (40) The fused ring compound of any of (29) to
(33) above, wherein the ring Cy' is cyclopentyl, cyclohexyl,
cycloheptyl or tetrahydrothiopyranyl, or a pharmaceutically
acceptable salt thereof. [0441] (41) The fused ring compound of
(40) above, wherein the ring Cy' is cyclopentyl, cyclohexyl or
cycloheptyl, or a pharmaceutically acceptable salt thereof. [0442]
(42) The fused ring compound of any of (29) to (39) above, wherein
the ring Cy' is ##STR34## wherein each symbol is as defined in
(29), or a pharmaceutically acceptable salt thereof. [0443] (43)
The fused ring compound of any of (29) to (42) above, wherein the
ring A' is phenyl, pyridyl, pyrazinyl, pyrimidinyl or pyridazinyl,
or a pharmaceutically acceptable salt thereof. [0444] (44) The
fused ring compound of (43) above, wherein the ring A' is phenyl or
pyridyl, or a pharmaceutically acceptable salt thereof. [0445] (45)
The fused ring compound of (44) above, wherein the ring A' is
phenyl, or a pharmaceutically acceptable salt thereof. [0446] (46)
The fused ring compound of any of (29) to (45) above, wherein at
least one substituent optionaly substituted by group A is a
substituent substituted by C.sub.1-6 alkoxy C.sub.1-6 alkoxy, or a
pharmaceutically acceptable salt thereof. [0447] (47) The fused
ring compound of any of (29) to (46) above, wherein the Y is
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--, --NHCO.sub.2--,
--CONH--CHR.sup.a14--,
--(CH.sub.2).sub.m--NR.sup.a12--(CH.sub.2).sub.n--,
--CONR.sup.a13--(CH.sub.2).sub.n--, --O--
(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n-- or
--(CH.sub.2).sub.n--NR.sup.a12--CHR.sup.a15-- (wherein each symbol
is as defined in (29)), or a pharmaceutically acceptable salt
thereof. [0448] (48) The fused ring compound of (47) above, wherein
the Y is --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- or
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(wherein each symbol is as defined in (29)), or a pharmaceutically
acceptable salt thereof. [0449] (49) The fused ring compound of
(48) above, wherein the Y is
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- wherein each symbol is as
defined in (29), or a pharmaceutically acceptable salt thereof.
[0450] (50) The fused ring compound of any of (29) to (46) above,
wherein the Y is
--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--
(wherein each symbol is as defined in (29)), or a pharmaceutically
acceptable salt thereof. [0451] (51) The fused ring compound of any
of (29) to (50) above, wherein the R.sup.2 is carboxyl, R.sup.1,
R.sup.3 and R.sup.4 are hydrogen atoms, the ring Cy' is
cyclopentyl, cyclohexyl or cycloheptyl, and the ring A' is phenyl,
or a pharmaceutically acceptable salt thereof. [0452] (52) The
fused ring compound of any of (29) to (51) above, wherein at least
one group represented by Z is heterocycle C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from the
group D, or a pharmaceutically acceptable salt thereof. [0453] (53)
The fused ring compound of any of (29) to (51) above, wherein at
least one group represented by Z is heterocyclic group optionally
substituted by 1 to 5 substituent(s) selected from the group D,
wherein said heterocyclic group is selected from the following
groups: ##STR35## wherein E.sup.1 is an oxygen atom, a sulfur atom
or N(--R.sup.a35), E.sup.2 is an oxygen atom, CH.sub.2 or
N(--R.sup.a35), E.sup.3 is an oxygen atom or a sulfur atom, wherein
each R.sup.a35 is independently hydrogen atom or C.sub.1-6 alkyl, f
is an integer of 1 to 3, and h and h' are the same or different and
each is an integer of 1 to 3, or a pharmaceutically acceptable salt
thereof. [0454] (54) The fused ring compound of (53) above, wherein
at least one group represented by Z is heterocyclic group
optionally substituted by 1 to 5 substituent(s) selected from the
group D, wherein said heterocyclic group is selected from the
following groups: ##STR36## [0455] wherein each symbol is as
defined in (53), or a pharmaceutically acceptable salt thereof.
[0456] (55) The fused ring compound of any of (29) to (51) above,
wherein at least one group represented by group D is
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28 wherein each symbol is as
defined in (29), and at least one of R.sup.a27 and R.sup.a28 is
C.sub.1-6 alkoxy, or a pharmaceutically acceptable salt thereof.
[0457] (56) The fused ring compound of any of (29) to (51) above,
wherein at least one group represented by group D is
--(CH.sub.2).sub.t--C(.dbd.NR.sup.a33)NH.sub.2 wherein each symbol
is as defined in (29), and R.sup.a33 is hydroxyl group or C.sub.1-6
alkoxy, or a pharmaceutically acceptable salt thereof. [0458] (57)
The fused ring compound of any of (29) to (51) above, wherein at
least one group represented by group D is
--(CH.sub.2).sub.t--O--(CH.sub.2).sub.p--COR.sup.a21 wherein each
symbol is as defined in (29), and R.sup.a21 is amino, or a
pharmaceutically acceptable salt thereof. [0459] (58) The fused
ring compound of any of (29) to (51) above, wherein at least one
group represented by group D is
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24 wherein each symbol is
as defined in (29), and R.sup.a24 is amino or C.sub.1-6 alkylamino,
or a pharmaceutically acceptable salt thereof. [0460] (59) The
fused ring compound of any of (29) to (51) above, wherein at least
one group represented by group D is
--(CH.sub.2).sub.t--NR.sup.a22R.sup.a23 wherein each symbol is as
defined in (29), and at least one of R.sup.a22 and R.sup.a23 is
heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from the group B, or a pharmaceutically acceptable salt
thereof. [0461] (60) The fused ring compound of any of (29) to (51)
above, wherein at least one group represented by group D is
heterocyclic group having 1 to 4 heteroatom(s) selected from an
oxygen atom, a nitrogen atom and a sulfur atom, or a
pharmaceutically acceptable salt thereof. [0462] (61) The fused
ring compound of the formula [I] or a pharmaceutically acceptable
salt thereof, which is selected from the group consisting of [0463]
ethyl
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
(Example 1), [0464]
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 2), [0465] ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate
(Example 3), [0466] ethyl
2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylate (Example 4), [0467] ethyl
2-{4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylate (Example 5), [0468]
2-{4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 6),
[0469] ethyl
2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carb-
oxylate (Example 7), [0470] ethyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate (Example 8), [0471]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 9), [0472] ethyl
1-cyclohexyl-2-{4-[(E)-2-phenylvinyl]phenyl}benzimidazole-5-carboxylate
(Example 10), [0473]
1-cyclohexyl-2-{4-[(E)-2-phenylvinyl]phenyl}benzimidazole-5-carboxylic
acid (Example 11), [0474]
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxylic acid
(Example 12), [0475]
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxamide
(Example 13), [0476]
2-(4-benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole (Example
14), [0477]
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxamide
oxime (Example 15), [0478] ethyl
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-methyl-5-thiazolyl}methoxy]pheny-
l}benzimidazole-5-carboxylate (Example 16), [0479]
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-methyl-5-thiazolyl}-methoxy]phen-
yl}benzimidazole-5-carboxylic acid (Example 17), [0480] ethyl
1-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)benzimidazole-5-carboxylate
(Example 18), [0481] ethyl
2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylate (Example 19), [0482]
2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 20), [0483] ethyl
1-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5-carboxylate (Example
21), [0484] ethyl
2-(4-aminophenyl)-1-cyclopentylbenzimidazole-5-carboxylate (Example
22), [0485] ethyl
2-(4-benzoylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylate
(Example 23), [0486]
2-(4-benzoylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 24), [0487] ethyl
2-{4-[3-(3-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylate (Example 25), [0488]
2-{4-[3-(3-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 26), [0489] ethyl
2-[4-(3-acetoxyphenyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
(Example 27), [0490] ethyl
1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)phenyl]-benzimidazole-5-carboxylate
(Example 28), [0491] ethyl
1-cyclohexyl-2-{4-[3-(4-pyridylmethoxy)phenyloxy]phenyl}-benzimidazole-5--
carboxylate (Example 29), [0492]
1-cyclohexyl-2-{4-[3-(4-pyridylmethoxy)phenyloxy]phenyl}-benzimidazole-5--
carboxylic acid (Example 30), [0493]
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole (Example 31),
[0494] ethyl
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxylate
(Example 32), [0495]
2-(4-benzyloxyphenyl)-1-cyclopentyl-N,N-dimethylbenzimidazole-5-carboxami-
de (Example 33), [0496]
2-(4-benzyloxyphenyl)-1-cyclopentyl-N-methoxy-N-methylbenzimidazole-5-car-
boxamide (Example 34), [0497]
2-(4-benzyloxyphenyl)-1-cyclopentyl-5-(1-hydroxy-1-methylethyl)benzimidaz-
ole (Example 35), [0498]
5-acetyl-2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole (Example
36), [0499]
2-(4-benzyloxyphenyl)-1-cyclopentyl-N-(2-dimethylaminoethyl)-benz-
imidazole-5-carboxamide dihydrochloride (Example 37), [0500]
2-(4-benzyloxyphenyl)-1-cyclopentyl-5-nitrobenzimidazole (Example
38), [0501]
5-amino-2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole
hydrochloride (Example 39), [0502]
5-acetylamino-2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole
(Example 40), [0503]
2-(4-benzyloxyphenyl)-1-cyclopentyl-5-methanesulfonyl-aminobenzimidazole
(Example 41), [0504]
5-sulfamoyl-2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole
(Example 42), [0505]
2-[4-(4-tert-butylbenzyloxy)phenyl]-1-cyclopentylbenzimidazole-5-carboxyl-
ic acid (Example 43), [0506]
2-[4-(4-carboxybenzyloxy)phenyl]-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 44), [0507]
2-[4-(4-chlorobenzyloxy)phenyl]-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 45), [0508]
2-{4-[(2-chloro-5-thienyl)methoxy]phenyl}-1-cyclopentylbenzimidazole-5-ca-
rboxylic acid (Example 46), [0509]
1-cyclopentyl-2-[4-(4-trifluoromethylbenzyloxy)phenyl]-benzimidazole-5-ca-
rboxylic acid (Example 47), [0510]
1-cyclopentyl-2-[4-(4-methoxybenzyloxy)phenyl]benzimidazole-5-carboxylic
acid (Example 48), [0511]
1-cyclopentyl-2-[4-(4-pyridylmethoxy)phenyl]benzimidazole-5-carboxylic
acid hydrochloride (Example 49), [0512]
1-cyclopentyl-2-[4-(4-methylbenzyloxy)phenyl]benzimidazole-5-carboxylic
acid (Example 50), [0513]
1-cyclopentyl-2-{4-[(3,5-dimethyl-4-isoxazolyl)methoxy]phenyl}-benzimidaz-
ole-5-carboxylic acid (Example 51), [0514]
1-cyclopentyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylic acid
(Example 52), [0515]
[2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazol-5-yl]-carbonylaminoaceti-
c acid (Example 53), [0516]
2-[4-(2-chlorobenzyloxy)phenyl]-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 54), [0517]
2-[4-(3-chlorobenzyloxy)phenyl]-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 55), [0518]
2-(4-benzyloxyphenyl)-3-cyclopentylbenzimidazole-5-carboxylic acid
(Example 56), [0519]
2-[4-(benzenesulfonylamino)phenyl]-1-cyclopentylbenzimidazole-5-carboxyli-
c acid (Example 57), [0520]
1-cyclopentyl-2-[4-(3,5-dichlorophenylcarbonylamino)phenyl]-benzimidazole-
-5-carboxylic acid (Example 58), [0521]
2-{4-[(4-chlorophenyl)carbonylamino]phenyl}-1-cyclopentylbenzimidazole-5--
carboxylic acid (Example 59), [0522]
2-{4-[(4-tert-butylphenyl)carbonylamino]phenyl}-1-cyclopentylbenzimidazol-
e-5-carboxylic acid (Example 60), [0523]
2-{4-[(4-benzyloxyphenyl)carbonylamino]phenyl}-1-cyclopentylbenzimidazole-
-5-carboxylic acid (Example 61), [0524]
trans-4-[2-(4-benzyloxyphenyl)-5-carboxybenzimidazol-1-yl]cyclohexan-1-ol
(Example 62), [0525]
trans-1-[2-(4-benzyloxyphenyl)-5-carboxybenzimidazol-1-yl]-4-methoxycyclo-
hexane (Example 63), [0526]
2-(4-benzyloxyphenyl)-5-carboxymethyl-1-cyclopentylbenzimidazole
(Example 64), [0527]
2-[1-benzyloxycarbonyl-4-piperidyl]-1-cyclopentylbenzimidazole-5-carboxyl-
ic acid (Example 65), [0528]
2-[(4-cyclohexylphenyl)carbonylamino]-1-cyclopentylbenzimidazole-5-carbox-
ylic acid (Example 66), [0529]
1-cyclopentyl-2-[4-(3,5-dichlorobenzyloxy)phenyl]benzimidazole-5-carboxyl-
ic acid (Example 67), [0530]
1-cyclopentyl-2-[4-(3,4-dichlorobenzyloxy)phenyl]benzimidazole-5-carboxyl-
ic acid (Example 68), [0531]
1-cyclopentyl-2-[4-(phenylcarbamoylamino)phenyl]benzimidazole-5-carboxyli-
c acid (Example 69), [0532]
1-cyclopentyl-2-[4-(diphenylmethoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 70), [0533]
1-cyclopentyl-2-(4-phenethyloxyphenyl)benzimidazole-5-carboxylic
acid (Example 71), [0534]
trans-1-[2-(4-benzyloxyphenyl)-5-carboxybenzimidazol-1-yl]-4-tert-butylcy-
clohexane (Example 72), [0535]
2-(4-benzyloxyphenyl)-5-carboxymethoxy-1-cyclopentylbenzimidazole
(Example 73), [0536]
2-(4-benzylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 74), [0537]
2-[4-(N-benzenesulfonyl-N-methylamino)phenyl]-1-cyclopentylbenzimidazole--
5-carboxylic acid (Example 75), [0538]
2-[4-(N-benzyl-N-methylamino)phenyl]-1-cyclopentylbenzimidazole-5-carboxy-
lic acid (Example 76), [0539]
1-cyclohexyl-2-(4-phenethylphenyl)benzimidazole-5-carboxylic acid
(Example 77), [0540]
2-(1-benzyl-4-piperidyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 78), [0541]
2-(1-benzoyl-4-piperidyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid (Example 79), [0542]
1-cyclopentyl-2-[1-(p-toluenesulfonyl)-4-piperidyl]-benzimidazole-5-carbo-
xylic acid (Example 80), [0543]
1-cyclohexyl-2-[4-(3,5-dichlorobenzyloxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 81), [0544]
1-cyclohexyl-2-[4-(diphenylmethoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 82), [0545]
1-cyclohexyl-2-[4-(3,5-di-tert-butylbenzyloxy)phenyl]-benzimidazole-5-car-
boxylic acid (Example 83), [0546]
2-(4-benzyloxyphenyl)-1-(4-methylcyclohexyl)benzimidazole-5-carboxylic
acid (Example 84), [0547]
1-cyclohexyl-2-{4-[2-(2-naphthyl)ethoxy]phenyl}benzimidazole-5-carboxylic
acid (Example 85), [0548]
1-cyclohexyl-2-[4-(1-naphthyl)methoxyphenyl]benzimidazole-5-carboxylic
acid (Example 86), [0549]
1-cyclohexyl-2-[4-(dibenzylamino)phenyl]benzimidazole-5-carboxylic
acid (Example 87), [0550]
2-[4-(2-biphenylylmethoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 88), [0551]
2-(4-benzyloxyphenyl)-1-cyclohexylbenzimidazole-5-carboxylic acid
(Example 89), [0552]
1-cyclohexyl-2-[4-(dibenzylmethoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 90), [0553]
2-(4-benzoylmethoxyphenyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 91), [0554]
2-(4-benzyl-1-piperazinyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid dihydrochloride (Example 92), [0555]
1-cyclohexyl-2-[4-(3,3-diphenylpropyloxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 93), [0556]
2-[4-(3-chloro-6-phenylbenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 94), [0557]
2-(4-benzyloxypiperidino)-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 95), [0558]
1-cyclohexyl-2-{4-[2-(phenoxy)ethoxy]phenyl}benzimidazole-5-carboxylic
acid (Example 96), [0559]
1-cyclohexyl-2-[4-(3-phenylpropyloxy)phenyl]benzimidazole-5-carboxylic
acid (Example 97), [0560]
1-cyclohexyl-2-[4-(5-phenylpentyloxy)phenyl]benzimidazole-5-carboxylic
acid (Example 98), [0561]
2-(3-benzyloxy-5-isoxazolyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 99), [0562]
2-(2-benzyloxy-5-pyridyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 100), [0563]
1-cyclohexyl-2-{4-[2-(3,4,5-trimethoxyphenyl)ethoxy]phenyl}-benzimidazole-
-5-carboxylic acid (Example 101), [0564]
2-(4-benzyloxyphenyl)-1-(4,4-dimethylcyclohexyl)benzimidazole-5-carboxyli-
c acid (Example 102), [0565]
1-cyclohexyl-2-{4-[2-(1-naphthyl)ethoxy]phenyl}benzimidazole-5-carboxylic
acid (Example 103), [0566]
2-[4-(2-benzyloxyphenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 104), [0567]
2-[4-(3-benzyloxyphenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 105), [0568]
1-cyclohexyl-2-[4-(2-hydroxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 106), [0569]
1-cyclohexyl-2-[4-(3-hydroxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 107), [0570]
1-cyclohexyl-2-[4-(2-methoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 108), [0571]
1-cyclohexyl-2-[4-(3-methoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 109), [0572]
1-cyclohexyl-2-[4-(2-propoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 110), [0573]
1-cyclohexyl-2-[4-(3-propoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 111), [0574]
1-cyclohexyl-2-{4-[2-(3-methyl-2-butenyloxy)phenoxy]phenyl}-benzimidazole-
-5-carboxylic acid (Example 112), [0575]
1-cyclohexyl-2-{4-[3-(3-methyl-2-butenyloxy)phenoxy]phenyl}-benzimidazole-
-5-carboxylic acid (Example 113), [0576]
1-cyclohexyl-2-[4-(2-isopentyloxyphenoxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 114), [0577]
1-cyclohexyl-2-[4-(3-isopentyloxyphenoxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 115), [0578]
1-cyclohexyl-2-{4-[2-(10,11-dihydro-5H-dibenzo[b,f]azepin-5-yl)ethoxy]phe-
nyl}benzimidazole-5-carboxylic acid (Example 116), [0579]
1-cyclohexyl-2-{4-[2-(4-trifluoromethylphenyl)benzyloxy]-phenyl}benzimida-
zole-5-carboxylic acid (Example 117), [0580]
2-{4-[bis(4-chlorophenyl)methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 118), [0581]
1-cyclohexyl-2-{4-[2-(4-methoxyphenyl)ethoxy]phenyl}-benzimidazole-5-carb-
oxylic acid (Example 119), [0582]
1-cyclohexyl-2-{4-[2-(2-methoxyphenyl)ethoxy]phenyl}-benzimidazole-5-carb-
oxylic acid (Example 120), [0583]
1-cyclohexyl-2-{4-[2-(3-methoxyphenyl)ethoxy]phenyl}-benzimidazole-5-carb-
oxylic acid (Example 121), [0584]
2-(4-benzyloxyphenyl)-1-cycloheptylbenzimidazole-5-carboxylic acid
(Example 122), [0585]
1-cyclohexyl-2-[4-(2-phenethyloxyphenoxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 123), [0586]
1-cyclohexyl-2-[4-(3-phenethyloxyphenoxy)phenyl]benzimidazole-5-carboxyli-
c acid (Example 124), [0587]
1-cyclohexyl-2-[4-(2,2-diphenylethoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 125), [0588]
2-(4-benzyloxyphenyl)-1-(3-cyclohexenyl)benzimidazole-5-carboxylic
acid (Example 126), [0589]
cis-1-[2-(4-benzyloxyphenyl)-5-carboxybenzimidazol-1-yl]-4-fluorocyclohex-
ane (Example 127), [0590]
1-cyclohexyl-2-[4-(2-phenoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 128), [0591]
1-cyclohexyl-2-[4-(3-phenoxyphenoxy)phenyl]benzimidazole-5-carboxylic
acid (Example 129), [0592]
2-{4-[(2R)-2-benzyloxycarbonylamino-2-phenylethoxy]phenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 130), [0593]
1-cyclohexyl-2-{2-fluoro-4-[2-(4-trifluoromethylphenyl)-benzyloxy]phenyl}-
benzimidazole-5-carboxylic acid (Example 131), [0594]
2-[4-(4-benzyloxyphenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 132), [0595]
2-{4-[bis(4-methylphenyl)methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 133), [0596]
2-{4-[bis(4-fluorophenyl)methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 134), [0597]
1-cyclohexyl-6-methoxy-2-[4-(3-phenylpropoxy)phenyl]-benzimidazole-5-carb-
oxylic acid (Example 135), [0598]
1-cyclohexyl-6-hydroxy-2-[4-(3-phenylpropoxy)phenyl]-benzimidazole-5-carb-
oxylic acid (Example 136), [0599]
1-cyclohexyl-6-methyl-2-[4-(3-phenylpropoxy)phenyl]-benzimidazole-5-carbo-
xylic acid (Example 137), [0600]
2-{4-[2-(2-benzyloxyphenyl)ethoxy]phenyl}-1-cyclohexylbenzimidazole-5-car-
boxylic acid (Example 138), [0601]
2-{4-[2-(3-benzyloxyphenyl)ethoxy]phenyl}-1-cyclohexylbenzimidazole-5-car-
boxylic acid (Example 139), [0602]
2-[4-(2-carboxymethyloxyphenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 140), [0603]
2-[4-(3-carboxymethyloxyphenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 141), [0604]
2-{4-[3-chloro-6-(4-methylphenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 142), [0605]
2-{4-[3-chloro-6-(4-methoxyphenyl)benzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 143), [0606]
1-cyclohexyl-2-{2-methyl-4-[2-(4-trifluoromethylphenyl)-benzyloxy]phenyl}-
benzimidazole-5-carboxylic acid (Example 144), [0607]
2-{4-[2-(4-tert-butylphenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 145), [0608]
2-{4-(3-chloro-6-phenylbenzyloxy)-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 146), [0609]
2-{4-[3-chloro-6-(3,5-dichlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 147), [0610]
2-{4-[bis(4-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 148), [0611]
2-{4-(4-benzyloxyphenoxy)-2-chlorophenyl}-1-cyclohexylbenzimidazole-5-car-
boxylic acid (Example 149), [0612]
2-{4-(4-benzyloxyphenoxy)-2-trifluoromethylphenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 150), [0613]
2-{4-[3-chloro-6-(2-trifluoromethylphenyl)benzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid (Example 151),
[0614]
2-{4-[(2R)-2-amino-2-phenylethoxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 152), [0615]
2-[4-(2-biphenylyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 153), [0616]
2-[4-(3-biphenylyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 154), [0617] 2-{4-[2-{1
(1-tert-butoxycarbonyl-4-piperidyl)methoxy}phenoxy]-phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid (Example 155), [0618]
2-{4-[3-{(1-tert-butoxycarbonyl-4-piperidyl)methoxy}phenoxy]-phenyl}-1-cy-
clohexylbenzimidazole-5-carboxylic acid (Example 156), [0619]
2-{4-[3-chloro-6-(3,4,5-trimethoxyphenyl)benzyloxy]phenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 157), [0620]
2-{4-[2-(2-biphenylyl)ethoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxyl-
ic acid (Example 158), [0621]
2-[4-(2-biphenylylmethoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 159), [0622]
1-cyclohexyl-2-{4-[2-(4-piperidylmethoxy)phenoxy]phenyl}-benzimidazole-5--
carboxylic acid hydrochloride (Example 160), [0623]
1-cyclohexyl-2-{4-[3-(4-piperidylmethoxy)phenoxy]phenyl}-benzimidazole-5--
carboxylic acid hydrochloride (Example 161), [0624]
2-{4-[(2R)-2-acetylamino-2-phenylethoxy]phenyl}-1-cyclohexylbenzimidazole-
-5-carboxylic acid (Example 162), [0625]
1-cyclohexyl-2-{4-[3-(4-methyl-3-pentenyloxy)phenoxy]phenyl}-benzimidazol-
e-5-carboxylic acid (Example 163), [0626]
1-cyclohexyl-2-{4-[3-(3-methyl-3-butenyloxy)phenoxy]phenyl}-benzimidazole-
-5-carboxylic acid (Example 164), [0627]
2-{4-[{(2S)-1-benzyl-2-pyrrolidinyl}methoxy]phenyl}-1-cyclohexyl-benzimid-
azole-5-carboxylic acid hydrochloride (Example 165), [0628]
2-{4-[3-chloro-6-(4-methylthiophenyl)benzyloxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 166), [0629]
2-{4-[3-chloro-6-(4-methanesulfonylphenyl)benzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid (Example 167), [0630]
2-{4-[3-chloro-6-(2-thienyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-
-carboxylic acid (Example 168), [0631]
2-{4-[3-chloro-6-(3-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 169), [0632]
2-{4-[3-chloro-6-(3-pyridyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-
-carboxylic acid (Example 170), [0633]
2-{4-[3-chloro-6-(4-fluorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 171), [0634]
2-[4-(4-benzyloxyphenoxy)-3-fluorophenyl]-1-cyclohexylbenzimidazole-5-car-
boxylic acid (Example 172), [0635]
2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 173), [0636]
2-{4-[3-chloro-6-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid (Example 174), [0637]
2-{4-[2-{(1-acetyl-4-piperidyl)methoxy}phenoxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 175), [0638]
2-{4-[3-{(1-acetyl-4-piperidyl)methoxy}phenoxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 176), [0639]
1-cyclohexyl-2-{4-[3-(2-propynyloxy)phenoxy]phenyl}-benzimidazole-5-carbo-
xylic acid (Example 177), [0640]
1-cyclohexyl-2-{4-[3-(3-pyridylmethoxy)phenoxy]phenyl}-benzimidazole-5-ca-
rboxylic acid (Example 178), [0641]
2-(4-benzyloxy-2-methoxyphenyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid (Example 179), [0642]
2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 180), [0643]
2-[4-(carboxydiphenylmethoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxyl-
ic acid (Example 181), [0644]
2-{4-[2-(4-chlorophenyl)-5-nitrobenzyloxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 182), [0645]
2-{4-[3-acetylamino-6-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzi-
midazole-5-carboxylic acid (Example 183), [0646]
2-{4-[2-(4-carboxyphenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 184), [0647]
2-{4-[{(2S)-1-benzyloxycarbonyl-2-pyrrolidinyl}methoxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid (Example 185), [0648]
2-{2-chloro-4-[2-(4-trifluoromethylphenyl)benzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid (Example 186), [0649]
1-cyclohexyl-2-{4-[3-(2-pyridylmethoxy)phenoxy]phenyl}-benzimidazole-5-ca-
rboxylic acid (Example 187), [0650]
2-{4-[2-(4-chlorophenyl)-5-fluorobenzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 188), [0651]
2-{4-[3-carboxy-6-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 189), [0652]
2-{4-[3-carbamoyl-6-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimi-
dazole-5-carboxylic acid (Example 190), [0653]
1-cyclohexyl-2-{4-[2-(dimethylcarbamoylmethoxy)phenoxy]-phenyl}benzimidaz-
ole-5-carboxylic acid (Example 191), [0654]
1-cyclohexyl-2-{4-[2-(piperidinocarbonylmethoxy)phenoxy]-phenyl}benzimida-
zole-5-carboxylic acid (Example 192), [0655]
2-{4-[{(2S)-1-benzenesulfonyl-2-pyrrolidinyl}methoxy]phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 193), [0656]
2-{4-[{(2S)-1-benzoyl-2-pyrrolidinyl}methoxy]phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylic acid (Example 194), [0657]
2-{4-[2-(4-carbamoylphenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimi-
dazole-5-carboxylic acid (Example 195), [0658]
1-cyclohexyl-2-{4-[3-(dimethylcarbamoylmethoxy)phenoxy]-phenyl}benzimidaz-
ole-5-carboxylic acid (Example 196), [0659]
1-cyclohexyl-2-{4-[3-(piperidinocarbonylmethoxy)phenoxy]-phenyl}benzimida-
zole-5-carboxylic acid (Example 197), [0660]
1-cyclohexyl-2-{4-[3-{(1-methanesulfonyl-4-piperidyl)methoxy}-phenoxy]phe-
nyl}benzimidazole-5-carboxylic acid (Example 198), [0661]
1-cyclohexyl-2-{4-[{2-methyl-5-(4-chlorophenyl)-4-oxazolyl}-methoxy]pheny-
l}benzimidazole-5-carboxylic acid (Example 199), [0662]
2-{4-[3-(3-chlorobenzyloxy)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-ca-
rboxylic acid (Example 200), [0663]
2-{4-[3-(4-chlorobenzyloxy)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-ca-
rboxylic acid (Example 201), [0664]
1-cyclohexyl-2-{4-[3-(4-fluorobenzyloxy)phenoxy]phenyl}-benzimidazole-5-c-
arboxylic acid (Example 202), [0665]
1-cyclohexyl-2-{4-[{(2S)-1-(4-nitrophenyl)-2-pyrrolidinyl}-methoxy]phenyl-
}benzimidazole-5-carboxylic acid (Example 203), [0666]
1-cyclohexyl-2-{4-[{(2S)-1-phenyl-2-pyrrolidinyl}methoxy]-phenyl}benzimid-
azole-5-carboxylic acid hydrochloride (Example 204), [0667]
2-{4-[{(2S)-1-(4-acetylaminophenyl)-2-pyrrolidinyl}methoxy]-phenyl}-1-cyc-
lohexylbenzimidazole-5-carboxylic acid (Example 205), [0668]
2-{4-[{5-(4-chlorophenyl)-2-methyl-4-thiazolyl}methoxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid (Example 206), [0669]
2-{4-[bis(3-fluorophenyl)methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carb-
oxylic acid (Example 207), [0670]
1-cyclohexyl-2-{4-[2-(4-chlorophenyl)-3-nitrobenzyloxy]phenyl}-benzimidaz-
ole-5-carboxylic acid (Example 208), [0671]
1-cyclohexyl-2-{4-[3-(4-tetrahydropyranyloxy)phenoxy]phenyl}-benzimidazol-
e-5-carboxylic acid (Example 209), [0672]
1-cyclohexyl-2-{4-[3-(4-trifluoromethylbenzyloxy)phenoxy]phenyl}-benzimid-
azole-5-carboxylic acid (Example 210), [0673]
1-cyclohexyl-2-{4-[3-{(1-methyl-4-piperidyl)methoxy}phenoxy]-phenyl}benzi-
midazole-5-carboxylic acid (Example 211), [0674]
2-{4-[3-(4-tert-butylbenzyloxy)phenoxy]phenyl}-1-cyclohexylbenzimidazole--
5-carboxylic acid (Example 212), [0675]
2-{4-[3-(2-chlorobenzyloxy)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-ca-
rboxylic acid (Example 213), [0676]
1-cyclohexyl-2-{4-[3-(3-pyridyl)phenoxy]phenyl}benzimidazole-5-carboxylic
acid (Example 214), [0677]
2-{4-[3-(4-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 215), [0678]
1-cyclohexyl-2-{4-[3-(4-methoxyphenyl)phenoxy]phenyl}-benzimidazole-5-car-
boxylic acid (Example 216), [0679]
1-cyclohexyl-2-{4-[{4-(4-methanesulfonylphenyl)-2-methyl-5-thiazolyl}meth-
oxy]phenyl}benzimidazole-5-carboxylic acid (Example 217), [0680]
2-{4-[{4-(4-chlorophenyl)-2-methyl-5-thiazolyl}methoxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid (Example 218), [0681]
2-{4-[1-(4-chlorobenzyl)-3-piperidyloxy]phenyl}-1-cyclohexylbenzimidazole-
-5-carboxylic acid (Example 219), [0682]
1-cyclohexyl-2-{4-[3-{(2-methyl-4-thiazolyl)methoxy}phenoxy]-phenyl}benzi-
midazole-5-carboxylic acid (Example 220), [0683]
1-cyclohexyl-2-{4-[3-{(2,4-dimethyl-5-thiazolyl)methoxy}phenoxy]-phenyl}b-
enzimidazole-5-carboxylic acid (Example 221), [0684]
1-cyclohexyl-2-{4-[3-(3,5-dichlorophenyl)phenoxy]phenyl}-benzimidazole-5--
carboxylic acid (Example 222), [0685]
2-{4-[1-(4-chlorobenzyl)-4-piperidyloxy]phenyl}-1-cyclohexylbenzimidazole-
-5-carboxylic acid (Example 223), [0686]
2-{4-[3-(4-chlorobenzyloxy)piperidino]phenyl}-1-cyclohexylbenzimidazole-5-
-carboxylic acid (Example 224), [0687]
2-{4-[4-carbamoyl-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimi-
dazole-5-carboxylic acid (Example 225), [0688]
2-{4-[4-(4-chlorobenzyloxy)piperidino]phenyl}-1-cyclohexylbenzimidazole-5-
-carboxylic acid (Example 226), [0689]
2-{4-[3-{(2-chloro-4-pyridyl)methoxy}phenoxy]phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylic acid (Example 227), [0690]
2-{4-[{(2S)-1-(4-dimethylcarbamoylphenyl)-2-pyrrolidinyl}-methoxy]phenyl}-
-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 228), [0691]
2-{4-[2-(4-chlorophenyl)-5-ethoxycarbonylbenzyloxy]phenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 229), [0692]
1-cyclohexyl-2-[4-(3-trifluoromethylphenoxy)phenyl]-benzimidazole-5-carbo-
xylic acid (Example 230), [0693]
1-cyclohexyl-2-{4-[{4-(4-dimethylcarbamoylphenyl)-2-methyl-5-thiazolyl}me-
thoxy]phenyl}benzimidazole-5-carboxylic acid (Example 231), [0694]
2-{4-[2-(4-chlorophenyl)-5-dimethylcarbamoylbenzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid (Example 232), [0695]
2-{4-[{4-(4-chlorophenyl)-2-methyl-5-pyrimidinyl}methoxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 233),
[0696]
2-{4-[{2-(4-chlorophenyl)-3-pyridyl}methoxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid dihydrochloride (Example 234), [0697]
2-{4-[{3-(4-chlorophenyl)-2-pyridyl}methoxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 235), [0698]
2-{4-[2-(3-chlorophenyl)-4-methylamino-1,3,5-triazin-6-yloxy]phenyl}-1-cy-
clohexylbenzimidazole-5-carboxylic acid trifluoroacetate (Example
236), [0699]
2-{4-[2-(4-chlorophenyl)-4-(5-tetrazolyl)benzyloxy]phenyl}-1-cycl-
ohexylbenzimidazole-5-carboxylic acid (Example 237), [0700]
2-[4-(4-benzyloxy-6-pyrimidinyloxy)phenyl]-1-cyclohexylbenzimidazole-5-ca-
rboxylic acid (Example 238), [0701]
1-cyclohexyl-2-{4-[4-(4-pyridylmethoxy)-6-pyrimidinyloxy]phenyl}-benzimid-
azole-5-carboxylic acid (Example 239), [0702]
2-{4-[4-(3-chlorophenyl)-6-pyrimidinyloxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 240), [0703] methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate (Example 241), [0704]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-benzimid-
azole-5-carboxylic acid hydrochloride (Example 242), [0705] ethyl
2-{4-[3-(4-chlorophenyl)pyridin-2-ylmethoxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate (Example 243), [0706] methyl
2-[4-(2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl]-1-cyclohexylbenzimid-
azole-5-carboxylate (Example 244), [0707] methyl
2-{4-[5-tert-butoxycarbonyl-2-(4-chlorophenyl)benzyloxy]-phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylate (Example 245), [0708] methyl
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate hydrochloride (Example 246), [0709] methyl
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]-phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylate (Example 247), [0710]
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 248), [0711]
2-{4-[3-(tert-butylsulfamoyl)-6-(4-chlorophenyl)benzyloxy]-phenyl}-1-cycl-
ohexylbenzimidazole-5-carboxylic acid (Example 249), [0712]
2-{4-[2-(4-chlorophenyl)-5-sulfamoylbenzyloxy]phenyl}-1-cyclohexylbenzimi-
dazole-5-carboxylic acid trifluoroacetate (Example 250), [0713]
2-(4-benzyloxycyclohexyl)-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 251), [0714]
2-[2-(2-biphenylyloxymethyl)-5-thienyl]-1-cyclohexylbenzimidazole-5-carbo-
xylic acid (Example 252), [0715]
2-[2-(2-biphenylyloxymethyl)-5-furyl]-1-cyclohexylbenzimidazole-5-carboxy-
lic acid (Example 253), [0716]
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-hydroxymethyl-5-thiazolyl}methox-
y]phenyl}benzimidazole-5-carboxylic acid (Example 254), [0717]
1-cyclohexyl-2-{4-[{4-(4-carboxyphenyl)-2-methyl-5-thiazolyl}-methoxy]phe-
nyl}benzimidazole-5-carboxylic acid hydrochloride (Example 255),
[0718]
1-cyclohexyl-2-{2-fluoro-4-[4-fluoro-2-(3-fluorobenzoyl)-benzyloxy]phenyl-
}benzimidazole-5-carboxylic acid (Example 256), [0719]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-sulfonic acid (Example 257), [0720]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-3-cyclohexylbenzimida-
zole-4-carboxylic acid (Example 258), [0721]
1-cyclohexyl-2-{4-[3-dimethylcarbamoyl-5-(4-pyridylmethoxy)-phenoxy]pheny-
l}benzimidazole-5-carboxylic acid dihydrochloride (Example 259),
[0722]
1-cyclohexyl-2-{4-[3-carboxy-5-(4-pyridylmethoxy)phenoxy]-phenyl}benzimid-
azole-5-carboxylic acid dihydrochloride (Example 260), [0723]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-4-carboxylic acid (Example 261), [0724]
2-{4-[3-carbamoyl-6-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimi-
dazole-5-carboxylic acid hydrochloride (Example 262), [0725]
2-{4-[{2-(4-carboxyphenyl)-3-pyridyl
methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
(Example 263), [0726]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-(4-tetrahydrothiopy-
ranyl)benzimidazole-5-carboxylic acid (Example 264), [0727]
2-{4-[2-(4-chlorophenyl)-5-dimethylcarbamoylbenzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 265),
[0728]
1-cyclohexyl-2-{4-[3-dimethylcarbamoyl-6-(4-trifluoromethylphenyl)benzylo-
xy]phenyl}benzimidazole-5-carboxylic acid hydrochloride (Example
266), [0729]
1-cyclohexyl-2-{4-[3-dimethylcarbamoyl-6-(4-methylthiophenyl)-ben-
zyloxy]phenyl}benzimidazole-5-carboxylic acid hydrochloride
(Example 267), [0730]
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 268), [0731]
2-{4-[2-(4-chlorophenyl)-5-dimethylcarbamoylbenzyloxy]-2-fluorophenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
269), [0732]
2-{4-[3-carbamoyl-6-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
270), [0733]
2-{4-[3-dimethylcarbamoyl-6-(4-methanesulfonylphenyl)benzyloxy]-p-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 271), [0734]
2-{4-[3-dimethylcarbamoyl-6-(3-pyridyl)benzyloxy]phenyl}-1-cyclohexylbenz-
imidazole-5-carboxylic acid dihydrochloride (Example 272),
[0735]
2-{4-[3-dimethylcarbamoyl-6-(4-dimethylcarbamoylphenyl)-benzyloxy-
]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 273),
[0736]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-(1-oxo-4-te-
trahydrothiopyranyl)benzimidazole-5-carboxylic acid (Example 274),
[0737]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-(1,1-dioxo-4-tetra-
hydrothiopyranyl)benzimidazole-5-carboxylic acid (Example 275),
[0738]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy)-2-fluorophenyl}-1-(4-tetrahy-
drothiopyranyl)benzimidazole-5-carboxylic acid (Example 276),
[0739]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]-2-fluorophenyl}-1-(1-oxo-4-t-
etrahydrothiopyranyl)benzimidazole-5-carboxylic acid (Example 277),
[0740]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]-2-fluorophenyl}-1-(1-
,1-dioxo-4-tetrahydrothiopyranyl)benzimidazole-5-carboxylic acid
(Example 278), [0741]
2-{4-[2-(4-chlorophenyl)-5-dimethylsulfamoylbenzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 279),
[0742]
2-{4-[2-(4-chlorophenyl)-5-methanesulfonylbenzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 280), [0743]
methyl
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1-cyc-
lohexylbenzimidazole-5-carboxylate hydrochloride (Example 281),
[0744]
2-{4-[2-(4-chlorophenyl)-5-dimethylaminobenzyloxy]phenyl}-1-cyclohexylben-
zimidazole-5-carboxylic acid dihydrochloride (Example 282), [0745]
2-{4-[2-(4-chlorophenyl)-5-methanesulfonylaminobenzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 283),
[0746]
2-{4-[2-(4-chlorophenyl)-5-diethylcarbamoylbenzyloxy]-2-fluorophenyl}-1-c-
yclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
284), [0747]
2-{4-[2-(4-chlorophenyl)-5-isopropylcarbamoylbenzyloxy]-2-fluorop-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 285), [0748]
2-{4-[2-(4-chlorophenyl)-5-piperidinocarbonylbenzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
286), [0749]
2-{4-[2-(4-chlorophenyl)-5-(1-pyrrolidinyl)carbonylbenzyloxy]-2-f-
luorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 287), [0750]
2-{4-[2-(4-chlorophenyl)-5-(2-hydroxyethyl)carbamoylbenzyloxy]-2-fluoroph-
enyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 288), [0751]
2-{4-(2-(4-chlorophenyl)-5-(4-hydroxypiperidino)-carbonylbenzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 289), [0752]
2-{4-[2-(4-chlorophenyl)-5-morpholinocarbonylbenzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
290), [0753]
2-{4-[2-(4-chlorophenyl)-5-thiomorpholinocarbonylbenzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 291), [0754]
2-{4-[3-(carboxymethylcarbamoyl)-6-(4-chlorophenyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 292), [0755]
2-{4-[2-{4-(2-carboxyethyl)phenyl}-5-chlorobenzyloxy]phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 293), [0756]
2-{4-[3-chloro-6-(4-hydroxymethylphenyl)benzyloxy]phenyl}-1-cyclohexylben-
zimidazole-5-carboxylic acid hydrochloride (Example 294), [0757]
2-{4-[3-chloro-6-(4-methoxymethylphenyl)benzyloxy]phenyl}-1-cyclohexylben-
zimidazole-5-carboxylic acid hydrochloride (Example 295), [0758]
2-{4-[2-(3-carboxyphenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid (Example 296), [0759]
2-{4-[2-(4-chlorophenyl)-5-methylthiobenzyloxy]phenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid (Example 297), [0760]
2-{4-[2-(4-chlorophenyl)-5-methylsulfinylbenzyloxy]phenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 298), [0761]
2-{4-[2-(4-chlorophenyl)-5-cyanobenzyloxy]phenyl}-1-cyclohexyl-benzimidaz-
ole-5-carboxylic acid hydrochloride (Example 299), [0762]
2-{4-[bis(3-pyridyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5--
carboxylic acid (Example 300), [0763]
2-{4-[bis(4-dimethylcarbamoylphenyl)methoxy]-2-fluorophenyl}-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 301), [0764] sodium
2-{4-[2-thienyl-3-thienylmethoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylate (Example 302), [0765] methyl
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexylbenzimidazole-5-carboxylate (Example 303), [0766]
sodium
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexylbenzimidazole-5-carboxylate (Example 304), [0767]
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 305), [0768]
2-{4-[2-(4-carboxyphenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylic acid (Example 306), [0769]
2-{4-[2-(4-carbamoylphenyl)-5-(dimethylcarbamoyl)benzyloxy]-phenyl}-1-cyc-
lohexylbenzimidazole-5-carboxylic acid (Example 307), [0770]
2-{4-[5-amino-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid (Example 308), [0771]
2-{4-[5-(4-chlorophenyl)-2-methoxybenzylsulfinyl]phenyl}-1-cyclohexylbenz-
imidazole-5-carboxylic acid hydrochloride (Example 309), [0772]
2-{4-[5-(4-chlorophenyl)-2-methoxybenzylsulfonyl]phenyl}-1-cyclohexylbenz-
imidazole-5-carboxylic acid hydrochloride (Example 310), [0773]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzylthio]phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylic acid hydrochloride (Example 311), [0774]
2-{4-[bis(4-carboxyphenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid (Example 312), [0775]
2-[4-(phenyl}-3-pyridylmethoxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-
-5-carboxylic acid (Example 313), [0776] methyl
2-{4-[2-(4-chlorophenyl)-5-(methylcarbamoyl)benzyloxy]-2-fluorophenyl}-1--
cyclohexylbenzimidazole-5-carboxylate (Example 314), [0777]
2-{4-[5-chloro-2-(4-pyridyl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenzim-
idazole-5-carboxylic acid hydrochloride (Example 315), [0778]
2-{4-[2-(4-chlorophenyl)-5-(benzylcarbamoyl)benzyloxy]-2-fluorophenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
316), [0779]
2-{4-[2-(4-chlorophenyl)-5-(cyclohexylmethylcarbamoyl)benzyloxy]--
2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 317), [0780]
2-{4-[2-(4-chlorophenyl)-5-(4-pyridylmethylcarbamoyl)benzyloxy]-2-fluorop-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 318), [0781]
2-{4-[2-(4-chlorophenyl)-5-(N-benzyl-N-methylcarbamoyl)-benzyloxy]-2-fluo-
rophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 319), [0782]
2-{4-[5-dimethylaminocarbonyl-2-(4-pyridyl)benzyloxy]phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylic acid dihydrochloride (Example 320),
[0783]
2-{4-[2-(4-chlorophenyl)-5-(4-methylpiperazin-1-ylcarbonyl)benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 321), [0784]
2-{4-[2-(4-chlorophenyl)-5-[{N-(3-pyridylmethyl)carbamoyl}-benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 322), [0785]
2-{4-[2-(4-chlorophenyl)-5-[{N-(2-pyridylmethyl)carbamoyl}-benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 323), [0786]
2-{4-[2-(4-chlorophenyl)-5-(cyclohexylcarbamoyl)benzyloxy]-phenyl}-1-cycl-
ohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 324),
[0787]
2-{4-[2-(4-chlorophenyl)-5-(2-pyridin-4-ylethylcarbamoyl)-benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 325), [0788]
2-{4-[(4-fluorophenyl){4-(dimethylaminocarbonyl)phenyl}methoxy]-2-fluorop-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 326),
[0789]
2-{4-[(4-fluorophenyl)(4-carboxyphenyl)methoxy]-2-fluorophenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylic acid (Example 327), [0790]
2-{4-[2-(4-chlorophenyl)-5-(4-oxopiperidinocarbonyl)-benzyloxy]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
328), [0791]
2-{4-[2-(4-chlorophenyl)-5-hydroxybenzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 329), [0792]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 330),
[0793]
2-{4-[2-(4-chlorophenyl)-5-(N-isopropyl-N-methylcarbamoyl)-benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 331), [0794]
2-{4-[2-(4-chlorophenyl)-5-(phenylcarbamoyl)benzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 332),
[0795]
2-{4-[2-(4-chlorophenyl)-5-(4-methoxypiperidinocarbonyl)-benzyloxy]phenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 333), [0796]
2-{4-[2-(4-chlorophenyl)-5-(3-hydroxypropyloxy)benzyloxy]phenyl}-
-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 334), [0797]
2-{4-[2-(4-chlorophenyl)-5-(2-hydroxyethoxy)benzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 335),
[0798] methyl
2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzim-
idazole-5-carboxylate (Example 336), [0799] methyl
2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate (Example 337), [0800] methyl
2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy-2-fluorophenyl]-1-cyclohexylben-
zimidazole-5-carboxylate (Example 338), [0801] methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate (Example 339), [0802]
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 340), [0803]
2-{4-[2-(4-chlorophenyl)-5-(4-methylpiperidin-1-ylcarbonyl)benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 341), [0804]
2-{4-[5-acetyl-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid hydrochloride (Example 342), [0805]
2-{4-[2-(4-chlorophenyl)-5-{(4-hydroxypiperidin-1-ylcarbonyl)-methoxy
benzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
(Example 343), [0806]
2-{4-[2-(4-chlorophenyl)-5-(2-methoxyethoxy)benzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 344),
[0807]
2-{4-[2-(4-chlorophenyl)-5-{2-(2-methoxyethoxy)ethoxy}-benzyloxy]phenyl}--
1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
345), [0808]
2-{4-[2-(4-chlorophenyl)-5-(isobutylcarbonyl)benzyloxy]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid (Example 346), [0809]
2-{4-[2-(4-chlorophenyl)-5-(2-methylthiazol-4-yl)benzyloxy]-phenyl}-1-cyc-
lohexylbenzimidazole-5-carboxylic acid (Example 347), [0810]
2-{4-[2-(4-chlorophenyl)-5-(3,4-dihydroxypiperidin-1-ylcarbonyl)benzyloxy-
]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 348), [0811]
2-{4-[2-(4-chlorophenyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)benzyloxy]pheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 349), [0812]
2-{4-[2-(4-chlorophenyl)-4-(isopropylcarbamoyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 350),
[0813]
2-{4-[2-(4-chlorophenyl)-4-(piperidinocarbonyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 351),
[0814]
2-{4-[2-(4-chlorophenyl)-5-{(1-hydroxy-2-methylpropan-2-yl)carbamoyl}benz-
yloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 352), [0815]
2-{4-[2-(4-chlorophenyl)-5-(4,4-dimethyl-2-oxazolin-2-yl)}benzyloxy]pheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 353), [0816]
2-{4-[2-(4-chlorophenyl)-4-(4-hydroxypiperidin-1-ylcarbonyl)benzyloxy]phe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 354), [0817]
2-{4-[2-(4-chlorophenyl)-4-{(2-hydroxyethyl)carbamoyl}-benzyloxy]phenyl}--
1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
355), [0818]
2-{4-[2-(4-chlorophenyl)-4-{(4-pyridylmethyl)carbamoyl}-benzyloxy-
]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 356),
[0819]
2-{4-[2-(4-chlorophenyl)-4-(dimethylcarbamoyl)benzyloxy]phenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
357), [0820]
2-{4-[5-(2-aminothiazol-4-yl)-2-(4-chlorophenyl)benzyloxy]-phenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 358), [0821]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylsulfonyl)benzyloxy]phe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 359), [0822]
2-{4-[5-(dimethylcarbamoyl)-2-(4-fluorophenyl)benzyloxy]phenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylic acid hydrochloride (Example 360),
[0823]
2-{4-[5-(dimethylcarbamoyl)-2-(3-fluorophenyl)benzyloxy]phenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylic acid hydrochloride (Example 361),
[0824]
2-{4-[2-(5-chlorothiophen-2-yl)-5-(dimethylcarbamoyl)benzyloxy]-phenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
362), [0825]
2-{4-[2-bromo-5-(5-methyloxazol-2-yl)benzyloxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid hydrochloride (Example 363),
[0826]
2-{4-[2-bromo-5-(5-methylthiazol-2-yl)benzyloxy]phenyl}-1-cyclohexylbenzi-
midazole-5-carboxylic acid hydrochloride (Example 364), [0827]
2-{4-[2-(4-chlorophenyl)-5-(5-methyloxazol-2-yl)benzyloxy]-phenyl}-1-cycl-
ohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 365),
[0828]
2-{4-[2-(4-chlorophenyl)-5-(5-methylthiazol-2-yl)benzyloxy]-phenyl}-1-cy-
clohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
366), [0829]
2-{4-[2-(4-chlorophenyl)-5-tetrazol-5-ylbenzyloxy]phenyl}-1-cyclo-
hexylbenzimidazole-5-carboxylic acid hydrochloride (Example 367),
[0830]
2-{4-[5-chloro-2-(4-cyanophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid hydrochloride (Example 368), [0831]
2-{4-[5-chloro-2-(4-tetrazol-5-ylphenyl)benzyloxy]phenyl}-1-cyclohexylben-
zimidazole-5-carboxylic acid hydrochloride (Example 369), [0832]
2-{4-[2-(4-chlorophenyl)-5-{2-(4-hydroxypiperidin-1-yl)ethoxy}benzyloxy]p-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 370), [0833]
2-{4-[2-(4-chlorophenyl)-5-(2-oxopiperidin-1-yl)benzyloxy]-2-fluorophenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 371), [0834]
2-{4-[3-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluor-
ophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 372), [0835]
2-{4-[2-(4-chlorophenyl)-5-(N-hydroxyamidino)benzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example
373), [0836]
2-{4-[2-(4-chlorophenyl)-5-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol--
3-yl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 374), [0837]
2-{4-[2-(4-chlorophenyl)-5-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)benzyloxy-
]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 375),
[0838]
2-{4-[2-(4-chlorophenyl)-5-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-
-3-yl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 376), [0839]
2-{4-[2-(4-chlorophenyl)-5-(cyclopropylcarbamoyl)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 377), [0840]
2-{4-[2-(4-chlorophenyl)-5-(cyclobutylcarbamoyl)benzyloxy]-2-fluorophenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 378), [0841]
2-{4-[2-(4-chlorophenyl)-5-(tert-butylcarbamoyl)benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 379), [0842]
2-{4-[2-(4-chlorophenyl)-5-(isobutylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
380), [0843]
2-{4-[2-(4-chlorophenyl)-5-{(1-hydroxypropan-2-yl)carbamoyl}-benz-
yloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 381), [0844]
2-{4-[2-(4-chlorophenyl)-5-(methoxycarbamoyl)benzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
382), [0845]
2-{4-[2-(4-chlorophenyl)-5-{(2,3-dihydroxypropyl)carbamoyl}-benzy-
loxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 383), [0846]
2-{4-[2-(4-chlorophenyl)-5-(N-ethyl-N-methylcarbamoyl)benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 384), [0847]
2-{4-[2-(4-chlorophenyl)-5-(N-methyl-N-propylcarbamoyl)-benzyloxy]-2-fluo-
rophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 385), [0848]
2-{4-[2-(4-chlorophenyl)-5-(N-isopropyl-N-methylcarbamoyl)-benzyloxy]-2-f-
luorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 386), [0849]
2-{4-[2-(4-chlorophenyl)-5-(2,6-dimethylpiperidin-1-ylcarbonyl)-benzyloxy-
]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 387), [0850]
2-{4-[5-(butylcarbamoyl)-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1-c-
yclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
388), [0851]
2-{4-[2-(4-chlorophenyl)-5-(propylcarbamoyl)benzyloxy]-2-fluoroph-
enyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 389), [0852]
2-{4-[2-(4-chlorophenyl)-5-(ethylcarbamoyl)benzyloxy]-2-fluorophenyl}-1-c-
yclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
390), [0853]
2-{4-[2-(4-chlorophenyl)-5-{(dimethylcarbamoyl)amino}benzyloxy]-2-
-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 391), [0854]
2-{4-[2-(4-chlorophenyl)-5-{(morpholinocarbonyl)amino}benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 392), [0855]
2-{4-[2-(4-chlorophenyl)-5-ureidobenzyloxy]-2-fluorophenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 393), [0856]
2-{4-[2-(4-chlorophenyl)-5-{(ethylcarbamoyl)amino}benzyloxy]-2-fluorophen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 394), [0857]
2-{4-[2-(4-chlorophenyl)-5-{(isopropylcarbamoyl)amino}benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 395), [0858]
2-{4-[2-(3,4-difluorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 396),
[0859]
2-{4-[2-(2,4-difluorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 397), [0860]
2-{4-[2-(3,5-dichlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 398), [0861]
2-{4-[2-(3-chloro-4-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 399), [0862]
2-{4-[2-(3,4-dichlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 400), [0863]
2-{4-[2-(4-chloro-2-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 401), [0864]
2-{4-[2-(4-chloro-2-fluorophenyl)-5-(pyrrolidin-1-ylcarbonyl)-benzyloxy]--
2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 402), [0865]
2-{4-[2-(4-chloro-3-fluorophenyl)-5-(pyrrolidin-1-ylcarbonyl)-benzyloxy]--
2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 403), [0866]
2-{4-[2-(4-chloro-3-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 404), [0867] 2-{4-[2-{4-(methylthio)
phenyl}-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid hydrochloride (Example 405), [0868]
2-{4-[2-{4-(methylthio)
phenyl}-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenz-
imidazole-5-carboxylic acid hydrochloride (Example 406), [0869]
2-{4-[4-chloro-2-(4-chlorophenyl)-5-(1,1-dioxoisothiazolidin-2-yl)benzylo-
xy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 407), [0870]
2-{4-[4-chloro-2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fl-
uorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 408), [0871]
2-{4-[2-(4-chlorophenyl)-5-(isopropylaminosulfonyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 409), [0872]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example
410), [0873]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)-benz-
yloxy]-2-fluorophenyl}-1-cyclopentylbenzimidazole-5-carboxylic acid
hydrochloride (Example 411), [0874]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride
(Example 412), [0875]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-
-1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride
(Example 413), [0876]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]phenyl}--
1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example
414), [0877]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)benzy-
loxy]phenyl}-1-cyclopentylbenzimidazole-5-carboxylic acid
hydrochloride (Example 415), [0878]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-1-(tetra-
hydrothiopyran-4-yl)benzimidazole-5-carboxylic acid hydrochloride
(Example 416), [0879]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-phenyl}-1--
(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 417), [0880]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 418), [0881]
2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluoropheny-
l}-1-(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 419), [0882]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-piperidinobenzimidazole-5-carboxylic acid hydrochloride (Example
420), [0883]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-2--
fluorophenyl}-1-piperidinobenzimidazole-5-carboxylic acid (Example
421), [0884]
2-{4-[2-(4-chlorophenyl)-5-(2-imidazolin-2-yl)benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 422), [0885]
2-{4-[2-(4-chlorophenyl)-5-(2-oxooxazolidin-3-yl)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 423), [0886]
2-{4-[2-(4-chlorophenyl)-5-(2-oxoimidazolidin-1-yl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 424), [0887]
2-{4-[2-(4-chlorophenyl)-5-(2-oxazolin-2-ylamino)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 425), [0888]
2-{4-[{2-[{(dimethylcarbamoyl)methoxy}methyl]-4-(4-fluorophenyl)thiazol-5-
-yl}methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 426), [0889]
2-{4-[{4-(4-fluorophenyl)-2-(4-hydroxypiperidin-1-ylmethyl)thiazol-5-yl}m-
ethoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
dihydrochloride (Example 427), [0890]
2-{4-[{4-(4-fluorophenyl)-2-[(carbamoylmethoxy)methyl]thiazol-5-yl
methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 428), [0891]
2-{4-[{4-(4-fluorophenyl)-2-(methylcarbamoyl)thiazol-5-yl}methoxy]-2-fluo-
rophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 429), [0892]
2-{4-[{4-(4-fluorophenyl)-2-{(2-hydroxyethyl)carbamoyl}thiazol-5-yl}metho-
xy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 430), [0893]
2-{4-[{2-(4-fluorophenyl)-5-(dimethylcarbamoyl)thiophen-3-yl}methoxy]-2-f-
luorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 431), [0894]
2-{4-[{2-(4-fluorophenyl)-5-(isopropylcarbamoyl)thiophen-3-yl}methoxy]-2--
fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 432), [0895]
2-{4-[{2-(4-fluorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)thiophen-3-y-
l methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 433), [0896]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexyl-5-tetrazol-5-ylbenzimidazole (Example 434), [0897]
2-{4-[2-(4-carboxyphenyl)-5-chlorobenzyloxy]-2-fluorophenyl}-1-cyclohexyl-
-5-tetrazol-5-ylbenzimidazole hydrochloride (Example 435), [0898]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-cyclohexyl-5-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)benzimidazole
hydrochloride (Example 436), [0899]
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-5-cyano-1-cy-
clohexylbenzimidazole (Example 437), [0900]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
5-cyano-1-cyclohexylbenzimidazole (Example 438), [0901]
2-{4-[{N-(4-dimethylcarbamoyl)-N-(4-fluorophenyl)amino}-methyl]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid (Example 439), [0902]
2-{5-[bis(3-fluorophenyl)methyl]-2-fluoro-4-hydroxyphenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 440), [0903]
2-{3-[bis(3-fluorophenyl)methyl]-2-fluoro-4-hydroxyphenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 441), [0904]
2-{4-[(3-dimethylcarbamoylphenyl)(4-fluorophenyl)methoxy]-2-fluorophenyl}-
-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
442), [0905]
2-{4-[{3-(4-hydroxypiperidyl-1-ylcarbonyl)phenyl}(4-fluorophenyl)-
methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 443), [0906]
1-{[2-{4-([4-(4-fluorophenyl)-2-methylthiazol-5-yl]methoxy)phenyl}-1-cycl-
ohexylbenzimidazol-5-yl]carbonyl}-.beta.-D-glucuronic acid (Example
444), [0907]
{[2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylb-
enzimidazol-5-yl]carbonyl}-.beta.-D-glucuronic acid (Example 445),
[0908]
2-{4-[2-(4-chlorophenyl)-5-(1,1-dioxoisothiazolidin-2-yl)benzyloxy]-2-fl-
uorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 446), [0909]
3-{[4-(5-aminosulfonyl-1-cyclohexylbenzimidazol-2-yl)-3-fluorophenoxy]met-
hyl}-4-(4-chlorophenyl)-N-isopropylbenzamide (Example 447), [0910]
2-[4-{2-(4-chlorophenyl)-6-(isopropylaminocarbonyl)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 448), [0911]
2-[4-{2-(4-chlorophenyl)-4-fluoro-5-(1,1-dioxoisothiazolidin-2-yl)benzylo-
xy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 449), [0912]
2-[4-{2-(4-chlorophenyl)-5-(isopropylaminocarbonyl)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexyl-4-methoxybenzimidazole-5-carboxylic acid
hydrochloride (Example 450), [0913]
2-[4-{2-(4-chlorophenyl)-5-(N-isopropylcarbonyl-N-methylamino)benzyloxy}--
2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 451), [0914]
2-[4-{2-(4-chlorophenyl)-5-(isopropylcarbonylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 452), [0915]
2-[3-{[4-(4-fluorophenyl)-2-methylthiazol-5-yl]methyl}-4-hydroxyphenyl]-1-
-cyclohexylbenzimidazole-5-carboxylic acid (Example 453), [0916]
2-[4-{2-(4-chlorophenyl)-4-fluoro-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fl-
uorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 454), [0917]
2-[4-{2-(4-chlorophenyl)-5-(methylsulfonylamino)benzyloxy}-2-fluorophenyl-
]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 455), [0918]
2-[4-{2-(4-chlorophenyl)-5-[N-methyl-N-(methylsulfonyl)amino]ben-
zyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 456), [0919]
2-[4-{[3-(4-chlorophenyl)-6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]methyloxy}-
-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 457), [0920]
2-[4-{2-(4-chlorophenyl)-5-(acetylamino)benzyloxy}-2-fluorophenyl]-1-cycl-
ohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 458),
[0921]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-ethylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 459), [0922]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-propylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 460), [0923]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(methylsulfonyl)amino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 461), [0924]
2-[4-{2-(4-chlorophenyl)-5-[N-(methylsulfonyl)-N-propylamino]benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 462), [0925]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-methylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 463), [0926]
2-[4-{2-(4-chlorophenyl)-5-[N-(ethylsulfonyl)-N-methylamino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 464), [0927]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(ethylsulfonyl)amino]-benzyloxy}-2--
fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 465), [0928]
2-[4-{2-(4-chlorophenyl)-5-[N-(ethylcarbonyl)-N-methylamino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 466), [0929]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(ethylcarbonyl)amino]-benzyloxy}-2--
fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 467), [0930]
2-[4-{2-(4-chlorophenyl)-5-methoxybenzyloxy}-2-fluorophenyl]-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 468), [0931]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-isopropylamino)-benzyloxy}-2-fluor-
ophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 469),
[0932]
{[2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-f-
luorophenyl}-1-cyclohexylbenzoimidazol-5-yl]carbonyl-.beta.-D-glucuronic
acid (Example 470), [0933] methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylate (Example 501), [0934]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylic acid (Example 502), [0935]
2-(4-benzyloxyphenyl)-1-cyclopentyl-1H-indole-5-carboxylic acid
(Example 503), [0936] ethyl
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2-a]pyridine-7-carboxylate
(Example 601), [0937]
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2-a]pyridine-7-carboxylic
acid (Example 602), [0938]
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-3-cyclohexyl-3H-imida-
zo[4,5-b]pyridine-6-carboxylic acid (Example 701), [0939]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-3-cycloh-
exyl-3H-dimidazo[4,5-b]pyridine-6-carboxylic acid hydrochloride
(Example 702), and [0940]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-phenyl}-3--
cyclohexyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid
hydrochloride (Example 703). [0941] (62) The fused ring compound of
the formula [I] or a pharmaceutically acceptable salt thereof,
which is selected from the group consisting of [0942]
2-{4-[2-(4-chlorophenyl)-5-(4-oxopiperidinocarbonyl)-benzyloxy]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
328), [0943]
2-{4-[2-(4-chlorophenyl)-5-hydroxybenzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 329), [0944]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 330),
[0945]
2-{4-[2-(4-chlorophenyl)-5-(N-isopropyl-N-methylcarbamoyl)-benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 331), [0946]
2-{4-[2-(4-chlorophenyl)-5-(phenylcarbamoyl)benzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 332),
[0947]
2-{4-[2-(4-chlorophenyl)-5-(4-methoxypiperidinocarbonyl)-benzyloxy]phenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 333), [0948]
2-{4-[2-(4-chlorophenyl)-5-(3-hydroxypropyloxy)benzyloxy]phenyl}-
-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 334), [0949]
2-{4-[2-(4-chlorophenyl)-5-(2-hydroxyethoxy)benzyloxy]phenyl}-1-cyclohexy-
lbenzimidazole-5-carboxylic acid hydrochloride (Example 335),
[0950] methyl
2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzim-
idazole-5-carboxylate (Example 336), [0951] methyl
2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate (Example 337), [0952] methyl
2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate (Example 338), [0953] methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate (Example 339), [0954]
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 340), [0955]
2-{4-[2-(4-chlorophenyl)-5-(4-methylpiperidin-1-ylcarbonyl)benzyloxy]phen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 341), [0956]
2-{4-[5-acetyl-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid hydrochloride (Example 342), [0957]
2-{4-[2-(4-chlorophenyl)-5-[{(4-hydroxypiperidin-1-ylcarbonyl)-methoxy}be-
nzyloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
(Example 343), [0958]
2-{4-[2-(4-chlorophenyl)-5-(2-methoxyethoxy)benzyloxy]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
344), [0959]
2-{4-[2-(4-chlorophenyl)-5-{2-(2-methoxyethoxy)ethoxy}-benzyloxy]-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 345), [0960]
2-{4-[2-(4-chlorophenyl)-5-(isobutylcarbonyl)benzyloxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid (Example 346), [0961]
2-{4-[2-(4-chlorophenyl)-5-(2-methylthiazol-4-yl)benzyloxy]-phenyl}-1-cyc-
lohexylbenzimidazole-5-carboxylic acid (Example 347), [0962]
2-{4-[2-(4-chlorophenyl)-5-(3,4-dihydroxypiperidin-1-ylcarbonyl)benzyloxy-
]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 348), [0963]
2-{4-[2-(4-chlorophenyl)-5-(3-methyl-1,2,4-oxadiazol-5-yl)benzyloxy]pheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 349), [0964]
2-{4-[2-(4-chlorophenyl)-4-(isopropylcarbamoyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 350),
[0965]
2-{4-[2-(4-chlorophenyl)-4-(piperidinocarbonyl)benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylic acid hydrochloride (Example 351),
[0966]
2-{4-[2-(4-chlorophenyl)-5-{(1-hydroxy-2-methylpropan-2-yl)carbamoyl}benz-
yloxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 352), [0967]
2-{4-[2-(4-chlorophenyl)-5-(4,4-dimethyl-2-oxazolin-2-yl)benzyloxy]phenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 353), [0968]
2-{4-[2-(4-chlorophenyl)-4-(4-hydroxypiperidin-1-ylcarbonyl)benzyloxy]phe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 354), [0969]
2-{4-[2-(4-chlorophenyl)-4-{(2-hydroxyethyl)carbamoyl}-benzyloxy]phenyl}--
1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
355), [0970]
2-{4-[2-(4-chlorophenyl)-4-{(4-pyridylmethyl)carbamoyl}-benzyloxy-
]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 356),
[0971]
2-{4-[2-(4-chlorophenyl)-4-(dimethylcarbamoyl)benzyloxy]phenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
357), [0972]
2-{4-[5-(2-aminothiazol-4-yl)-2-(4-chlorophenyl)benzyloxy]-phenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 358), [0973]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylsulfonyl)benzyloxy]phe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 359), [0974]
2-{4-[5-(dimethylcarbamoyl)-2-(4-fluorophenyl)benzyloxy]phenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylic acid hydrochloride (Example 360),
[0975]
2-{4-[5-(dimethylcarbamoyl)-2-(3-fluorophenyl)benzyloxy]phenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylic acid hydrochloride (Example 361),
[0976]
2-{4-[2-(5-chlorothiophen-2-yl)-5-(dimethylcarbamoyl)benzyloxy]-phenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
362), [0977]
2-{4-[2-bromo-5-(5-methyloxazol-2-yl)benzyloxy]phenyl}-1-cyclohex-
ylbenzimidazole-5-carboxylic acid hydrochloride (Example 363),
[0978]
2-{4-[2-bromo-5-(5-methylthiazol-2-yl)benzyloxy]phenyl}-1-cyclohexylbenzi-
midazole-5-carboxylic acid hydrochloride (Example 364), [0979]
2-{4-[2-(4-chlorophenyl)-5-(5-methyloxazol-2-yl)benzyloxy]-phenyl}-1-cycl-
ohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 365),
[0980]
2-{4-[2-(4-chlorophenyl)-5-(5-methylthiazol-2-yl)benzyloxy]-phenyl}-1-cy-
clohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
366), [0981]
2-{4-[2-(4-chlorophenyl)-5-tetrazol-5-ylbenzyloxy]phenyl}-1-cyclo-
hexylbenzimidazole-5-carboxylic acid hydrochloride (Example 367),
[0982]
2-{4-[5-chloro-2-(4-cyanophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid hydrochloride (Example 368), [0983]
2-{4-[5-chloro-2-(4-tetrazol-5-ylphenyl)benzyloxy]phenyl}-1-cyclohexylben-
zimidazole-5-carboxylic acid hydrochloride (Example 369), [0984]
2-{4-[2-(4-chlorophenyl)-5-{2-(4-hydroxypiperidin-1-yl)ethoxy}benzyloxy]p-
henyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 370), [0985]
2-{4-[2-(4-chlorophenyl)-5-(2-oxopiperidin-1-yl)benzyloxy]-2-fluorophenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 371), [0986]
2-{4-[3-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluor-
ophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 372), [0987]
2-{4-[2-(4-chlorophenyl)-5-(N-hydroxyamidino)benzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride (Example
373), [0988]
2-{4-[2-(4-chlorophenyl)-5-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol--
3-yl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 374), [0989]
2-{4-[2-(4-chlorophenyl)-5-(2-oxo-3H-1,2,3,5-oxathiadiazol-4-yl)benzyloxy-
]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 375), [0990]
2-{4-[2-(4-chlorophenyl)-5-(2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl)be-
nzyloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 376), [0991]
2-{4-[2-(4-chlorophenyl)-5-(cyclopropylcarbamoyl)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 377), [0992]
2-{4-[2-(4-chlorophenyl)-5-(cyclobutylcarbamoyl)benzyloxy]-2-fluorophenyl-
}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 378), [0993]
2-{4-[2-(4-chlorophenyl)-5-(tert-butylcarbamoyl)benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 379), [0994]
2-{4-[2-(4-chlorophenyl)-5-(isobutylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
380), [0995]
2-{4-[2-(4-chlorophenyl)-5-{(1-hydroxypropan-2-yl)carbamoyl}-benz-
yloxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 381), [0996]
2-{4-[2-(4-chlorophenyl)-5-(methoxycarbamoyl)benzyloxy]-2-fluorophenyl}-1-
-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
382), [0997]
2-{4-[2-(4-chlorophenyl)-5-{(2,3-dihydroxypropyl)carbamoyl}-benzy-
loxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 383), [0998]
2-{4-[2-(4-chlorophenyl)-5-(N-ethyl-N-methylcarbamoyl)benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 384), [0999]
2-{4-[2-(4-chlorophenyl)-5-(N-methyl-N-propylcarbamoyl)-benzyloxy]-2-fluo-
rophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 385), [1000]
2-{4-[2-(4-chlorophenyl)-5-(N-isopropyl-N-methylcarbamoyl)-benzyloxy]-2-f-
luorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 386), [1001]
2-{4-[2-(4-chlorophenyl)-5-(2,6-dimethylpiperidin-1-ylcarbonyl)-benzyloxy-
]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 387), [1002]
2-{4-[5-(butylcarbamoyl)-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-1-c-
yclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
388), [1003]
2-{4-[2-(4-chlorophenyl)-5-(propylcarbamoyl)benzyloxy]-2-fluoroph-
enyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 389), [1004]
2-{4-[2-(4-chlorophenyl)-5-(ethylcarbamoyl)benzyloxy]-2-fluorophenyl}-1-c-
yclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
390), [1005]
2-{4-[2-(4-chlorophenyl)-5-{(dimethylcarbamoyl)amino}benzyloxy]-2-
-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 391), [1006]
2-{4-[2-(4-chlorophenyl)-5-{(morpholinocarbonyl)amino}benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 392), [1007]
2-{4-[2-(4-chlorophenyl)-5-ureidobenzyloxy]-2-fluorophenyl}-1-cyclohexylb-
enzimidazole-5-carboxylic acid hydrochloride (Example 393), [1008]
2-{4-[2-(4-chlorophenyl)-5-{(ethylcarbamoyl)amino}benzyloxy]-2-fluorophen-
yl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 394), [1009]
2-{4-[2-(4-chlorophenyl)-5-[(isopropylcarbamoyl)amino}benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 395), [1010]
2-{4-[2-(3,4-difluorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid (Example 396),
[1011]
2-{4-[2-(2,4-difluorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 397), [1012]
2-{4-[2-(3,5-dichlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 398), [1013]
2-{4-[2-(3-chloro-4-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 399), [1014]
2-{4-[2-(3,4-dichlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 400), [1015]
2-{4-[2-(4-chloro-2-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 401), [1016]
2-{4-[2-(4-chloro-2-fluorophenyl)-5-(pyrrolidin-1-ylcarbonyl)-benzyloxy]--
2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 402), [1017]
2-{4-[2-(4-chloro-3-fluorophenyl)-5-(pyrrolidin-1-ylcarbonyl)-benzyloxy]--
2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 403), [1018]
2-{4-[2-(4-chloro-3-fluorophenyl)-5-(isopropylcarbamoyl)-benzyloxy]-2-flu-
orophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 404), [1019] 2-{4-[2-{4-(methylthio)
phenyl}-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid hydrochloride (Example 405), [1020]
2-{4-[2-{4-(methylthio)
phenyl}-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-1-cyclohexylbenz-
imidazole-5-carboxylic acid hydrochloride (Example 406), [1021]
2-{4-[4-chloro-2-(4-chlorophenyl)-5-(1,1-dioxoisothiazolidin-2-yl)benzylo-
xy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 407), [1022]
2-{4-[4-chloro-2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fl-
uorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 408), [1023]
2-{4-[2-(4-chlorophenyl)-5-(isopropylaminosulfonyl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 409), [1024]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example
410), [1025]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)-benz-
yloxy]-2-fluorophenyl}-1-cyclopentylbenzimidazole-5-carboxylic acid
hydrochloride (Example 411), [1026]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride
(Example 412), [1027]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-
-1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride
(Example 413), [1028]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]phenyl}--
1-cyclopentylbenzimidazole-5-carboxylic acid hydrochloride (Example
414), [1029]
2-{4-[2-(4-chlorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)benzy-
loxy]phenyl}-1-cyclopentylbenzimidazole-5-carboxylic acid
hydrochloride (Example 415), [1030]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-1-(tetra-
hydrothiopyran-4-yl)benzimidazole-5-carboxylic acid hydrochloride
(Example 416),
[1031]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-ph-
enyl}-1-(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 417), [1032]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 418), [1033]
2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluoropheny-
l}-1-(tetrahydrothiopyran-4-yl)benzimidazole-5-carboxylic acid
hydrochloride (Example 419), [1034]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-piperidinobenzimidazole-5-carboxylic acid hydrochloride (Example
420), [1035]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-2--
fluorophenyl}-1-piperidinobenzimidazole-5-carboxylic acid (Example
421), [1036]
2-{4-[2-(4-chlorophenyl)-5-(2-imidazolin-2-yl)benzyloxy]-2-fluoro-
phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 422), [1037]
2-{4-[2-(4-chlorophenyl)-5-(2-oxooxazolidin-3-yl)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 423), [1038]
2-{4-[2-(4-chlorophenyl)-5-(2-oxoimidazolidin-1-yl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 424), [1039]
2-{4-[2-(4-chlorophenyl)-5-(2-oxazolin-2-ylamino)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid dihydrochloride
(Example 425), [1040]
2-{4-[{2-[{(dimethylcarbamoyl)methoxy}methyl]-4-(4-fluorophenyl)thiazol-5-
-yl}methoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 426), [1041]
2-{4-[{4-(4-fluorophenyl)-2-(4-hydroxypiperidin-1-ylmethyl)thiazol-5-yl}m-
ethoxy]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
dihydrochloride (Example 427), [1042]
2-{4-[{4-(4-fluorophenyl)-2-[(carbamoylmethoxy)methyl]thiazol-5-yl}methox-
y]phenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 428), [1043]
2-{4-[{4-(4-fluorophenyl)-2-(methylcarbamoyl)thiazol-5-yl}methoxy]-2-fluo-
rophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 429), [1044]
2-{4-[{4-(4-fluorophenyl)-2-{(2-hydroxyethyl)carbamoyl}thiazol-5-yl}metho-
xy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 430), [1045]
2-{4-[{2-(4-fluorophenyl)-5-(dimethylcarbamoyl)thiophen-3-yl}methoxy]-2-f-
luorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 431), [1046]
2-{4-[{2-(4-fluorophenyl)-5-(isopropylcarbamoyl)thiophen-3-yl}methoxy]-2--
fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 432), [1047]
2-{4-[{2-(4-fluorophenyl)-5-(4-hydroxypiperidin-1-ylcarbonyl)thiophen-3-y-
l}methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 433), [1048]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
1-cyclohexyl-5-tetrazol-5-ylbenzimidazole (Example 434), [1049]
2-{4-[2-(4-carboxyphenyl)-5-chlorobenzyloxy]-2-fluorophenyl}-1-cyclohexyl-
-5-tetrazol-5-ylbenzimidazole hydrochloride (Example 435), [1050]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]-2-fluorophenyl}-
-1-cyclohexyl-5-(2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)benzimidazole
hydrochloride (Example 436), [1051]
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]-2-fluorophenyl}-5-cyano-1-cy-
clohexylbenzimidazole (Example 437), [1052]
2-{4-[2-(4-chlorophenyl)-5-(dimethylcarbamoyl)benzyloxy]-2-fluorophenyl}--
5-cyano-1-cyclohexylbenzimidazole (Example 438), [1053]
2-{4-[{N-(4-dimethylcarbamoyl)-N-(4-fluorophenyl)amino}-methyl]phenyl}-1--
cyclohexylbenzimidazole-5-carboxylic acid (Example 439), [1054]
2-{5-[bis(3-fluorophenyl)methyl]-2-fluoro-4-hydroxyphenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 440), [1055]
2-{3-[bis(3-fluorophenyl)methyl]-2-fluoro-4-hydroxyphenyl}-1-cyclohexylbe-
nzimidazole-5-carboxylic acid (Example 441), [1056]
2-{4-[(3-dimethylcarbamoylphenyl)(4-fluorophenyl)methoxy]-2-fluorophenyl}-
-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride (Example
442), [1057]
2-{4-[{3-(4-hydroxypiperidyl-1-ylcarbonyl)phenyl}(4-fluorophenyl)-
methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic
acid hydrochloride (Example 443), [1058]
1-{[2-{4-([4-(4-fluorophenyl)-2-methylthiazol-5-yl]methoxy)phenyl}-1-cycl-
ohexylbenzimidazol-5-yl]carbonyl}-.beta.-D-glucuronic acid (Example
444), [1059]
{[2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylb-
enzimidazol-5-yl]carbonyl}-.beta.-D-glucuronic acid (Example 445),
[1060]
2-{4-[2-(4-chlorophenyl)-5-(1,1-dioxoisothiazolidin-2-yl)benzyloxy]-2-fl-
uorophenyl}-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 446), [1061]
3-{[4-(5-aminosulfonyl-1-cyclohexylbenzimidazol-2-yl)-3-fluorophenoxy]met-
hyl}-4-(4-chlorophenyl)-N-isopropylbenzamide (Example 447), [1062]
2-[4-{2-(4-chlorophenyl)-6-(isopropylaminocarbonyl)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 448), [1063]
2-[4-{2-(4-chlorophenyl)-4-fluoro-5-(1,1-dioxoisothiazolidin-2-yl)benzylo-
xy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 449), [1064]
2-[4-{2-(4-chlorophenyl)-5-(isopropylaminocarbonyl)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexyl-4-methoxybenzimidazole-5-carboxylic acid
hydrochloride (Example 450), [1065]
2-[4-{2-(4-chlorophenyl)-5-(N-isopropylcarbonyl-N-methylamino)benzyloxy}--
2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 451), [1066]
2-[4-{2-(4-chlorophenyl)-5-(isopropylcarbonylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 452), [1067]
2-[3-{[4-(4-fluorophenyl)-2-methylthiazol-5-yl]methyl}-4-hydroxyphenyl]-1-
-cyclohexylbenzimidazole-5-carboxylic acid (Example 453), [1068]
2-[4-{2-(4-chlorophenyl)-4-fluoro-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fl-
uorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 454), [1069]
2-[4-{2-(4-chlorophenyl)-5-(methylsulfonylamino)benzyloxy}-2-fluorophenyl-
]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 455), [1070]
2-[4-{2-(4-chlorophenyl)-5-[N-methyl-N-(methylsulfonyl)amino]ben-
zyloxy}-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 456), [1071]
2-[4-{[3-(4-chlorophenyl)-6-(2-oxopyrrolidin-1-yl)pyridin-2-yl]methyloxy}-
-2-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 457), [1072]
2-[4-{2-(4-chlorophenyl)-5-(acetylamino)benzyloxy}-2-fluorophenyl]-1-cycl-
ohexylbenzimidazole-5-carboxylic acid hydrochloride (Example 458),
[1073]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-ethylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 459), [1074]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-propylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 460), [1075]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(methylsulfonyl)amino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 461), [1076]
2-[4-{2-(4-chlorophenyl)-5-[N-(methylsulfonyl)-N-propylamino]benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 462), [1077]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-methylamino)benzyloxy}-2-fluorophe-
nyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 463), [1078]
2-[4-{2-(4-chlorophenyl)-5-[N-(ethylsulfonyl)-N-methylamino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 464), [1079]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(ethylsulfonyl)amino]-benzyloxy}-2--
fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 465), [1080]
2-[4-{2-(4-chlorophenyl)-5-[N-(ethylcarbonyl)-N-methylamino]-benzyloxy}-2-
-fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 466), [1081]
2-[4-{2-(4-chlorophenyl)-5-[N-ethyl-N-(ethylcarbonyl)amino]-benzyloxy}-2--
fluorophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid
hydrochloride (Example 467), [1082]
2-[4-{2-(4-chlorophenyl)-5-methoxybenzyloxy}-2-fluorophenyl]-1-cyclohexyl-
benzimidazole-5-carboxylic acid (Example 468), [1083]
2-[4-{2-(4-chlorophenyl)-5-(N-acetyl-N-isopropylamino)-benzyloxy}-2-fluor-
ophenyl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
(Example 469), [1084]
{[2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluorophe-
nyl}-1-cyclohexylbenzoimidazol-5-yl]carbonyl-.beta.-D-glucuronic
acid (Example 470), [1085]
2-{4-[2-(4-chlorophenyl)-5-(isopropylcarbamoyl)benzyloxy]phenyl}-3-cycloh-
exyl-3H-dimidazo[4,5-b]pyridine-6-carboxylic acid hydrochloride
(Example 702), and [1086]
2-{4-[2-(4-chlorophenyl)-5-(pyrrolidin-1-ylcarbonyl)benzyloxy]-phenyl}-3--
cyclohexyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid
hydrochloride (Example 703). [1087] (63) A pharmaceutical
composition comprising a fused ring compound of any of (29) to (62)
above, or a pharmaceutically acceptable salt thereof, and a
pharmaceutically acceptable carrier. [1088] (64) A hepatitis C
virus polymerase inhibitor comprising a fused ring compound of any
of (1) to (28) and (29) to (62) above, or a pharmaceutically
acceptable salt thereof, and a pharmaceutically acceptable carrier.
[1089] (65) An anti-hepatitis C virus agent comprising a fused ring
compound of any of (1) to (28) and (29) to (62) above, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. [1090] (66) A therapeutic agent for hepatitis C
comprising a fused ring compound of any of (29) to (62) above, or a
pharmaceutically acceptable salt thereof, and a pharmaceutically
acceptable carrier. [1091] (67) An anti-hepatitis C virus agent
comprising (a) the anti-hepatitis C virus agent of (65) above and
(b) at least one agent selected from the group consisting of a
different antiviral agent, an antiinflammatory agent and an
immunostimulant. [1092] (68) An anti-hepatitis C virus agent
comprising (a) the anti-hepatitis C virus agent of (65) above and
(b) interferon. [1093] (69) A therapeutic agent for hepatitis C
comprising (a) the hepatitis C virus polymerase inhibitor of (64)
above and (b) at least one agent selected from the group consisting
of a different antiviral agent, an antiinflammatory agent and an
immunostimulant. [1094] (70) A therapeutic agent for hepatitis C
comprising (a) the hepatitis C virus polymerase inhibitor of (64)
above and (b) interferon. [1095] (71) A benzimidazole compound of
the folllowing formula [III] ##STR37## wherein R.sup.a36 is
hydrogen atom or carboxyl-protecting group, R.sup.a37 is
cyclopentyl or cyclohexyl, and R.sup.a38 is hydrogen atom or
fluorine atom, or a salt thereof. [1096] (72) A thiazole compound
selected from the group consisting of
4-(4-fluorophenyl)-5-hydroxymethyl-2-methylthiazole and
4-(4-fluorophenyl)-5-chloromethyl-2-methylthiazole, or a
pharmaceutically acceptable salt thereof. [1097] (73) A biphenyl
compound selected from the group consisting of
1-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)-2-pyrrolidinone and
1-(4'-chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone, or a
pharmaceutically acceptable salt thereof. [1098] (74) A
pharmaceutical composition comprising (a) a fused ring compound of
the formula [I] of (1) above or a pharmaceutically acceptable salt
thereof and (b) at least one agent selected from the group
consisting of an antiviral agent other than the compound of (1)
above, an antiinflammatory agent and an immunostimulant. [1099]
(75) A pharmaceutical composition comprising (a) a fused ring
compound of the formula [I] of (1) above or a pharmaceutically
acceptable salt thereof and (b) interferon. [1100] (76) A method
for treating hepatitis C, which comprises administering an
effective amount of a fused ring compound of the formula [I] of (1)
above or a pharmaceutically acceptable salt thereof. [1101] (77)
The method of (76) above, further comprising administering an
effective amount of at least one agent selected from the group
consisting of an antiviral agent other than the compound of claim
1, an antiinflammatory agent and an immunostimulant. [1102] (78)
The method of (76) above, further comprising administering an
effective amount of interferon. [1103] (79) A method for inhibiting
hepatitis C virus polymerase, which comprises administering an
effective amount of a fused ring compound of the formula [I] of (1)
above or a pharmaceutically acceptable salt thereof. [1104] (80)
The method of (79) above, further comprising administering an
effective amount of at least one agent selected from the group
consisting of an antiviral agent other than the compound of (1)
above, an antiinflammatory agent and an immunostimulant. [1105]
(81) The method of (79) above, further comprising administering an
effective amount of interferon. [1106] (82) Use of a fused ring
compound of the formula [I] of (1) above or a pharmaceutically
acceptable salt thereof for the production of a pharmaceutical
agent for treating hepatitis C. [1107] (83) Use of a fused ring
compound of the formula [I] of (1) above or a pharmaceutically
acceptable salt thereof for the production of a hepatitis C virus
polymerase inhibitor. [1108] (84) A pharmaceutical composition for
the treatment of hepatitis C, which comprises a fused ring compound
of the formula [I] of (1) above or a pharmaceutically acceptable
salt thereof, and a pharmaceutically acceptable carrier. [1109]
(85) A pharmaceutical composition for inhibiting hepatitis C virus
polymerase, which comprises a fused ring compound of the formula
[I] of (1) above or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable carrier. [1110] (86) A commercial
package comprising a pharmaceutical composition of (84) above and a
written matter associated therewith, the written matter stating
that the pharmaceutical composition can or should be used for
treating hepatitis C. [1111] (87) A commercial package comprising a
pharmaceutical composition of (85) above and a written matter
associated therewith, the written matter stating that the
pharmaceutical composition can or should be used for inhibiting
hepatitis C virus polymerase. [1112] (88)
1-Cyclohexyl-2-(3-furanyl)-1H-benzimidazole-5-carboxylic acid
(Example 471).
DETAILED DESCRIPTION OF THE INVENTION
[1113] The definitions of respective substituents and moieties used
in the present specification are as follows.
[1114] The halogen atom is a fluorine atom, chlorine atom, bromine
atom or iodine atom, preferably fluorine atom, chlorine atom or
bromine atom.
[1115] Particularly preferably, the halogen atom is fluorine atom
at R.sup.5, R.sup.5', R.sup.6, R.sup.6', group A and group C, and
fluorine atom or chlorine atom at X, Z, Z', group B and group
D.
[1116] The C.sub.1-6 alkyl is straight chain or branched chain
alkyl having 1 to 6 carbon atoms, and is exemplified by methyl,
ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,
pentyl, isopentyl, tert-pentyl, hexyl and the like.
[1117] Preferably, it is straight chain or branched chain alkyl
having 1 to 4 carbon atoms, and is particularly preferably methyl
at R.sup.a7, R.sup.a8, R.sup.a9, R.sup.a15, R.sup.a16, R.sup.a17,
R.sup.a33, R.sup.a35, R.sup.b6 and R.sup.b7 and methyl or
tert-butyl at R.sup.b1, R.sup.b2, group B and group C, and methyl,
ethyl, propyl or isopropyl at R.sup.a29.
[1118] The halogenated C.sub.1-6 alkyl is the above-defined
C.sub.1-6 alkyl except that it is substituted by the above-defined
halogen atom. Preferably, it is halogenated alkyl wherein the alkyl
moiety thereof is straight chain or branched chain alkyl having 1
to 4 carbon atoms. Examples thereof include fluoromethyl,
difluoromethyl, trifluoromethyl, bromomethyl, chloromethyl,
1,2-dichloromethyl, 2,2-dichloromethyl, 2,2,2-trifluoroethyl and
the like.
[1119] The halogenated C.sub.1-6 alkyl is particularly preferably
trifluoromethyl at group B.
[1120] The C.sub.1-6 alkylene is straight chain alkylene having 1
to 6 carbon atoms, and is exemplified by methylene, ethylene,
trimethylene, tetramethylene, pentamethylene or hexamethylene.
[1121] The C.sub.1-6 alkylene is preferably methylene or ethylene
at Y.
[1122] The C.sub.2-6 alkenylene is straight chain alkenylene having
2 to 6 carbon atoms, and is exemplified by vinylene, propenylene,
1-butenylene, 1,3-butadienylene and the like.
[1123] The C.sub.2-6 alkenylene is preferably vinylene at Y.
[1124] The C.sub.1-6 alkoxy is alkyloxy wherein the alkyl moiety
thereof is the above-defined C.sub.1-6 alkyl. Preferably, it is
alkoxy wherein the alkyl moiety thereof is straight chain or
branched chain alkyl having 1 to 4 carbon atoms. Examples thereof
include methoxy, ethoxy, propoxy, isopropyloxy, butoxy,
isobutyloxy, tert-butyloxy, pentyloxy, hexyloxy and the like.
[1125] The C.sub.1-6 alkoxy is particularly preferably methoxy at
R.sup.a2, R.sup.a3, R.sup.a27, R.sup.a28, R.sup.a33, group A and
group C.
[1126] The C.sub.1-6 alkoxy C.sub.1-6 alkoxy is that wherein
C.sub.1-6 alkoxy in the above definition is substituted by
C.sub.1-6 alkoxy defined above and is preferably that wherein the
alkyl moiety thereof is straight chain or branched chain alkyl
having 1 to 4 carbon atoms. Specific examples include
methoxymethyl, ethoxymethyl, methoxyethoxy, methoxypropoxy,
isopropyloxyethoxy and the like.
[1127] The group A is particularly preferably methoxyethoxy.
[1128] The C.sub.1-6 alkanoyl is alkylcarbonyl wherein the alkyl
moiety thereof is the above-defined C.sub.1-6 alkyl. Preferably, it
is alkanoyl wherein the alkyl moiety thereof is straight chain or
branched chain alkyl having 1 to 4 carbon atoms. Examples thereof
include acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the
like.
[1129] The C.sub.1-6 alkanoyl is particularly preferably acetyl at
R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.a5, R.sup.a29, R.sup.b7
and group B.
[1130] The C.sub.1-6 alkoxycarbonyl is alkyloxycarbonyl wherein the
alkoxy moiety thereof is the above-defined C.sub.1-6 alkoxy.
Preferably, it is alkoxycarbonyl wherein the alkyl moiety thereof
is straight chain or branched chain alkyl having 1 to 4 carbon
atoms. Examples thereof include methoxycarbonyl, ethoxycarbonyl,
propoxycarbonyl, isopropyloxycarbonyl, butoxycarbonyl,
isobutyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl,
hexyloxycarbonyl and the like.
[1131] The C.sub.1-6 alkoxycarbonyl is particularly preferably
methoxycarbonyl or ethoxycarbonyl at R.sup.a10 and group A.
[1132] The C.sub.1-6 alkylamino is alkylamino or dialkylamino
wherein the alkyl moiety thereof is the above-defined C.sub.1-6
alkyl. Preferably, it is alkylamino or dialkylamino wherein the
alkyl moiety thereof is straight chain or branched chain alkyl
having 1 to 4 carbon atoms. Examples thereof include methylamino,
ethylamino, propylamino, isopropylamino, butylamino, isobutylamino,
tert-butylamino, pentylamino, hexylamino, dimethylamino,
diethylamino, methylethylamino, N-isopropyl-N-isobutylamino and the
like.
[1133] The C.sub.1-6 alkylamino is particularly preferably
methylamino at R.sup.a7, and particularly preferably dimethylamino
at R.sup.a21 and group A, and particularly preferably
dimethylamino, ethylamino or isopropylamino at R.sup.a24.
[1134] The C.sub.1-6 alkanoylamino is alkylcarbonylamino wherein
the alkanoyl moiety thereof is the above-defined C.sub.1-6
alkanoyl. Preferably, it is alkylcarbonylamino wherein the alkyl
moiety thereof is straight chain or branched chain alkyl having 1
to 4 carbon atoms. Examples thereof include acetylamino,
propionylamino, butyrylamino, isobutyrylamino, pivaloylamino and
the like.
[1135] The C.sub.1-6 alkanoylamino is particularly preferably
acetylamino at X and R.sup.a10.
[1136] The C.sub.1-6 alkylsulfonyl is alkylsulfonyl wherein the
alkyl moiety thereof is the above-defined C.sub.1-6 alkyl.
Preferably, it is alkylsulfonyl wherein the alkyl moiety thereof is
straight chain or branched chain alkyl having 1 to 4 carbon atoms.
Examples thereof include methylsulfonyl, ethylsulfonyl,
propylsulfonyl, isopropylsulfonyl, butylsulfonyl, isobutylsulfonyl,
tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl and the like.
[1137] The C.sub.1-6 alkylsulfonyl is particularly preferably
methylsulfonyl at X and R.sup.a5.
[1138] The C.sub.6-14 aryl is aromatic hydrocarbon having 6 to 14
carbon atoms. Examples thereof include phenyl, naphthyl, anthryl,
indenyl, azulenyl, fluorenyl, phenanthryl and the like.
[1139] The C.sub.6-14 aryl is preferably phenyl or naphthyl,
particularly preferably phenyl at the ring A, ring A', ring B and
ring B'.
[1140] The C.sub.3-8 cycloalkyl is saturated cycloalkyl having 3 to
8, preferably 5 to 7, carbon atoms. Examples thereof include
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and
cyclooctyl.
[1141] The C.sub.3-8 cycloalkyl is particularly preferably
cyclohexyl at the ring A, ring A', ring B and ring B'.
[1142] The C.sub.3-8 cycloalkenyl is cycloalkenyl having 3 to 8,
preferably 5 to 7, carbon atoms and has at least 1, preferably 1 or
2, double bond(s). Examples thereof include cyclopropenyl,
cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl,
2,4-cyclohexadien-1-yl, 2,5-cyclohexadien-1-yl, cycloheptenyl and
cyclooctenyl and the like, but do not include aryl (e.g., phenyl)
or completely saturated cycloalkyl.
[1143] The C.sub.3-8 cycloalkenyl is preferably cyclohexenyl at the
ring A and ring A'.
[1144] The heterocyclic group has, as an atom constituting the
ring, 1 to 4 heteroatom(s) selected from an oxygen atom, a nitrogen
atom and a sulfur atom, besides a carbon atom, and includes
saturated ring and unsaturated ring, monocyclic ring and fused ring
having the number of ring atom constituting the ring of 3 to
14.
[1145] The heterocyclic group as a monocyclic ring includes, for
example, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,
tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyrrolinyl, pyrrolidinyl,
imidazolidinyl, piperidyl, piperazinyl, morpholinyl,
thiomorpholinyl, tetrahydropyranyl and the like.
[1146] The heterocyclic group includes the groups of the following
formulas. ##STR38## wherein E.sup.1 is an oxygen atom, a sulfur
atom or N(--R.sup.a35), E.sup.2 is an oxygen atom, CH.sub.2 or
N(--R.sup.a35), E.sup.3 is an oxygen atom or a sulfur atom, wherein
R.sup.a35 is independently hydrogen atom or C.sub.1-6 alkyl, f is
an integer of 1 to 3, and h and h' are the same or different and
each is an integer of 1 to 3.
[1147] Specific examples of the heterocyclic group include
##STR39## ##STR40## and the like.
[1148] Examples of the heterocyclic group as a fused ring include
quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, phthalazinyl,
cinnolinyl, naphthyridinyl, 5,6,7,8-tetrahydroquinolyl, indolyl,
benzimidazolyl, 2,3-dihydrobenzimidazolyl,
2,3-dihydro-2-oxobenzimidazolyl, indolinyl, benzofuranyl,
benzothienyl, benzoxazolyl, benzothiazolyl and the like.
[1149] Preferably, it is a heterocyclic group which is a 5-membered
or a 6-membered monocyclic group. Examples thereof include pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiadiazolyl,
pyrrolidinyl, piperidyl, piperazinyl ##STR41## ##STR42## and the
like.
[1150] At R.sup.1, R.sup.2, R.sup.3, R.sup.4, Z and group D,
tetrazolyl and 5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl are
particularly preferable.
[1151] The heterocyclic group is preferably pyridyl, pyrazinyl,
pyrimidinyl or pyridazinyl which is an aromatic group, and
particularly preferably pyridyl at the ring A and ring A'.
[1152] The heterocyclic group is particularly preferably pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thiadiazolyl,
which is an aromatic group, at the ring B and ring B'. More
preferably it is pyridyl or thiazolyl, most preferably
thiazolyl.
[1153] The C.sub.6-14 aryl C.sub.1-6 alkyl is arylalkyl wherein the
alkyl moiety thereof is the above-defined C.sub.1-6 alkyl and the
aryl moiety is the above-defined C.sub.6-14 aryl. Preferably, it is
arylalkyl wherein the alkyl moiety thereof is straight chain alkyl
having 1 to 4 carbon atoms and the aryl moiety is phenyl. Examples
thereof include benzyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl,
4-phenylbutyl and the like.
[1154] The C.sub.6-14 aryl C.sub.1-6 alkyl is particularly
preferably benzyl at R.sup.a8 and R.sup.b6.
[1155] The glucuronic acid residue is glucuronic acid less any
hydroxyl group, preferably .beta.-D-glucuronic acid substituted at
1-position.
[1156] The C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl is
arylalkyloxycarbonyl wherein the C.sub.6-14 aryl C.sub.1-6 alkyl
moiety thereof is the above-defined C.sub.6-14 aryl C.sub.1-6
alkyl. Preferably, it is arylalkyloxycarbonyl wherein the alkyl
moiety thereof is straight chain alkyl having 1 to 4 carbon atoms
and the aryl moiety is phenyl. Examples thereof include
benzyloxycarbonyl, phenethyloxycarbonyl, 3-phenylpropyloxycarbonyl,
2-phenylpropyloxycarbonyl, 4-phenylbutyloxycarbonyl and the
like.
[1157] The C.sub.6-14 aryl C.sub.1-6 alkyloxycarbonyl is
particularly preferably benzyloxycarbonyl at R.sup.b7.
[1158] The optionally substituted C.sub.1-6 alkyl is the
above-defined C.sub.1-6 alkyl, preferably that wherein straight
chain or branched chain alkyl having 1 to 4 carbon atoms is
optionally substituted with 1 to 3 substituent(s), and includes
unsubstituted alkyl. The substituent(s) is(are) selected from the
above-defined halogen atom, hydroxyl group, carboxyl, amino, the
above-defined C.sub.1-6 alkoxy, the above-defined C.sub.1-6 alkoxy
C.sub.1-6 alkoxy, the above-defined C.sub.1-6 alkoxycarbonyl and
the above-defined C.sub.1-6 alkylamino. Examples of optionally
substituted C.sub.1-6 alkyl include methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
isopentyl, tert-pentyl, neopentyl, 1-ethylpropyl, hexyl,
trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl,
4-hydroxybutyl, 1-hydroxy-1-methylethyl, 1-hydroxypropan-2-yl,
1,3-dihydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl,
carboxylmethyl, 2-carboxylethyl, methoxymethyl, methoxyethyl,
methoxyethoxyethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl,
2-dimethylaminoethyl and the like.
[1159] Preferably, the optionally substituted C.sub.1-6 alkyl is
methyl, 1-hydroxy-1-methylethyl, carboxylmethyl or
2-dimethylaminoethyl at R.sup.1, R.sup.2, R.sup.2 and R.sup.3,
methyl or trifluoromethyl at R.sup.5, R.sup.5', R.sup.6 and
R.sup.6', methyl at R.sup.7, R.sup.8, R.sup.a31 and R.sup.b5,
methyl, ethyl or isopropyl at R.sup.a24, methyl or isopropyl at
R.sup.a18, methyl or ethyl at R.sup.a1, R.sup.a19 and R.sup.a25,
methyl, carboxylmethyl or 2-dimethylaminoethyl at R.sup.a2 and
R.sup.a3, methyl or carboxylmethyl at R.sup.a6, methyl, ethyl,
isopropyl, butyl or trifluoromethyl at X, methyl, ethyl, isopropyl,
butyl, isobutyl, tert-butyl, isopentyl, neopentyl, 1-ethylpropyl or
carboxylmethyl at R.sup.a10, methyl, ethyl, propyl, isopropyl,
butyl, isobutyl, trifluoromethyl, 2-hydroxyethyl or carboxylmethyl
at R.sup.a11, methyl or 4-hydroxybutyl at R.sup.a12, methyl, ethyl,
isopropyl, butyl, 2-hydroxyethyl, 4-hydroxybutyl,
ethoxycarbonylmethyl, 2-(ethoxycarbonyl)ethyl or
2-dimethylaminoethyl at R.sup.a13, methyl, propyl, butyl,
isopentyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl,
3-hydroxypropyl, methoxyethyl, methoxyethoxyethyl or carboxymethyl
at R.sup.a20, methyl or ethyl at R.sup.a22 and R.sup.a23, methyl
isopropyl or tert-butyl at R.sup.a26, methyl, ethyl, propyl,
isopropyl, butyl, tert-butyl, isobutyl, 2-hydroxyethyl,
1-hydroxypropan-2-yl, 1-hydroxy-2-methylpropan-2-yl or
carboxylmethyl at R.sup.a27 and R.sup.a28, and methyl, ethyl,
propyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl,
2-hydroxyethyl, 2-carboxylethyl, methoxymethyl or
ethoxycarbonylmethyl at Z, Z' and group D.
[1160] It is particularly preferably, trifluoromethyl at R.sup.5,
R.sup.5', R.sup.6 and R.sup.6', methyl or tert-butyl at R.sup.a26,
methyl, tert-butyl, trifluoromethyl or hydroxymethyl at Z, Z' and
group D, and methyl at other substituents.
[1161] The optionally substituted C.sub.2-6 alkenyl is that wherein
straight chain or branched chain alkenyl having 2 to 6 carbon atoms
is optionally substituted by 1 to 3 substituent(s), and includes
unsubstituted alkenyl. The substituent (s) is (are) selected from
the above-defined halogen atom, hydroxyl group, carboxyl, amino,
the above-defined C.sub.1-6 alkoxy, the above-defined C.sub.1-6
alkoxy C.sub.1-6 alkoxy, the above-defined C.sub.1-6 alkoxycarbonyl
and the above-defined C.sub.1-6 alkylamino. Examples of optionally
substituted C.sub.2-6 alkenyl include vinyl, allyl, 1-propenyl,
isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 2-isopentenyl,
3-isohexenyl, 4-methyl-3-pentenyl, 2-carboxylethenyl and the
like.
[1162] The optionally substituted C.sub.2-6 alkenyl is preferably
2-carboxylethenyl at X, and preferably 2-isopentenyl, 3-isohexenyl
or 4-methyl-3-pentenyl at R.sup.a20.
[1163] The optionally substituted C.sub.2-6 alkynyl is that wherein
straight chain or branched chain alkynyl having 2 to 6 carbon atoms
is optionally substituted by 1 to 3 substituent(s), and includes
unsubstituted alkynyl. The substituent(s) is(are) selected from the
above-defined halogen atom, hydroxyl group, carboxyl, amino, the
above-defined C.sub.1-6 alkoxy, the above-defined C.sub.1-6
alkoxycarbonyl and the above-defined C.sub.1-6 alkylamino. Examples
thereof include ethynyl, 1-propynyl, 2-propynyl, 3-butynyl and the
like.
[1164] The optionally substituted C.sub.2-6 alkynyl is preferably
2-propynyl at R.sup.a20.
[1165] The C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group B is that wherein the
above-defined C.sub.6-14 aryl is optionally substituted by 1 to 5
substituent(s), and includes unsubstituted aryl. The substituent(s)
is(are) selected from the above-defined halogen atom, cyano, nitro,
the above-defined C.sub.1-6 alkyl, the above-defined halogenated
C.sub.1-6 alkyl, the above-defined C.sub.1-6 alkanoyl,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1R.sup.b2,
--(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 (wherein R.sup.b1 and
R.sup.b2 are each independently hydrogen atom or the above-defined
C.sub.1-6 alkyl and r is 0 or an integer of 1 to 6).
[1166] Examples thereof include phenyl, naphthyl, anthryl, indenyl,
azulenyl, fluorenyl, phenanthryl, 3-fluorophenyl, 4-fluorophenyl,
3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,
3,5-dichlorophenyl, pentafluorophenyl, 4-methylphenyl,
4-tert-butylphenyl, 2-trifluoromethylphenyl,
4-trifluoromethylphenyl, 4-nitrophenyl, 4-cyanophenyl,
4-acetylphenyl, 4-carboxylphenyl, 4-carbamoylphenyl, 4-aminophenyl,
4-dimethylaminophenyl, 4-acetylaminophenyl,
4-(methylsulfonylamino)phenyl, 4-methoxyphenyl,
3,4,5-trimethoxyphenyl, 4-methylthiophenyl, 4-methylsulfonylphenyl,
4-aminosulfonylphenyl, 3-nitro-4-methoxyphenyl and
4-nitro-3-methoxyphenyl.
[1167] The aryl moiety is preferably phenyl, the group B here is
preferably the above-defined halogen atom, nitro, the above-defined
C.sub.1-6 alkyl, the above-defined halogenated C.sub.1-6 alkyl or
--(CH.sub.2).sub.r--OR.sup.b1. Examples of group B include fluorine
atom, chlorine atom, nitro, methyl, tert-butyl, trifluoromethyl and
methoxy. Particularly preferably, it is fluorine atom or chlorine
atom.
[1168] With regard to "C.sub.6-14 aryl optionally substituted by 1
to 5 substituent(s) selected from group B", it is preferably
phenyl, 4-tert-butylphenyl, 4-fluorophenyl, 3-chlorophenyl,
4-chlorophenyl, 4-methoxyphenyl or 4-trifluoromethylphenyl at
R.sup.a12, R.sup.a27 and R.sup.a28, phenyl at R.sup.a14, R.sup.a22,
R.sup.a23, R.sup.a26 and R.sup.b5, phenyl or 3 fluorophenyl at
R.sup.a18, phenyl or 2,4-dichlorophenyl at R.sup.a20, phenyl,
4-chlorophenyl, 4-trifluoromethylphenyl, 3,5-dichlorophenyl,
3-nitro-4-methoxyphenyl or 4-nitro-3-methoxyphenyl at R.sup.a24,
and phenyl or 4-methylphenyl at R.sup.a25.
[1169] It is particularly preferably phenyl at other
substituents.
[1170] The C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D is that wherein the
above-defined C.sub.6-14 aryl is optionally substituted by 1 to 5
substituent(s), and includes unsubstituted aryl. The substituent(s)
is(are) selected from the above-mentioned group D (substituents
shown under (a) to (q)).
[1171] Examples of group D here include fluorine atom, chlorine
atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl,
tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl,
methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl,
ethoxycarbonyl, carbamoyl, methylaminocarbonyl,
isopropylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl, (2-hydroxyethyl)aminocarbonyl,
(carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy,
propyloxy, isopropyloxy, isopentyloxy, 2-isopentenyloxy,
3-isohexenyloxy, 4-methyl-3-pentenyloxy, 2-propynyloxy,
hydroxymethyloxy, carboxylmethyloxy,
(dimethylaminocarbonyl)methyloxy, amino, methylamino,
dimethylamino, diethylamino, acetylamino, methylsulfonylamino,
methylthio, methylsulfonyl, methylsulfinyl, aminosulfonyl,
methylaminosulfonyl, dimethylaminosulfonyl and tetrazolyl.
[1172] Examples of C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D include phenyl, naphthyl,
anthryl, indenyl, azulenyl, fluorenyl, phenanthryl, 3-fluorophenyl,
4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl,
3,5-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl,
pentafluorophenyl, 4-methylphenyl, 4-tert-butylphenyl,
2-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-(hydroxymethyl)phenyl, 4-(methoxymethyl)phenyl,
4-(2-carboxylethyl)phenyl, 3-carboxylphenyl, 4-carboxylphenyl,
4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-carbamoylphenyl,
4-methylthiophenyl, 4-(dimethylaminocarbonyl)phenyl,
4-methylsulfonylphenyl, 4-acetylaminophenyl, 4-cyanophenyl,
4-acetylphenyl, 4-aminophenyl, 4-dimethylaminophenyl,
4-(methylsulfonylamino)phenyl, 4-methylsulfinylphenyl,
4-aminosulfonylphenyl and 3-nitro-4-methoxyphenyl,
4-nitro-3-methoxyphenyl and 4-tetrazol-5-ylphenyl.
[1173] At Z and Z', the aryl moiety is preferably phenyl.
[1174] The group D here is preferably the above-defined halogen
atom, nitro, the above-defined optionally substituted C.sub.1-6
alkyl, (CH.sub.2).sub.t--COOR.sup.a19,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.a20,
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 or
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26.
[1175] Particularly preferably, it is the above-defined halogen
atom, the above-defined optionally substituted C.sub.1-6 alkyl,
--(CH.sub.2).sub.t--COOR.sup.a19--,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.a20 or
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25, which is specifically
fluorine atom, chlorine atom, bromine atom, nitro, methyl,
tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl,
methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio,
dimethylaminocarbonyl, methylsulfonyl or acetylamino. More
preferably, it is fluorine atom, chlorine atom, methyl, tert-butyl,
carboxyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl,
methylsulfonyl or acetylamino, most preferably fluorine atom or
chlorine atom.
[1176] Examples of C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D preferably include phenyl,
3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3,5-dichlorophenyl, 4-bromophenyl, 4-nitrophenyl, 4-methylphenyl,
4-tert-butylphenyl, 2-trifluoromethylphenyl,
4-trifluoromethylphenyl, 4-(hydroxymethyl)phenyl,
4-(methoxymethyl)phenyl, 4-(2-carboxylethyl)phenyl,
3-carboxylphenyl, 4-carboxylphenyl, 4-methoxyphenyl,
3,4,5-trimethoxyphenyl, 4-carbamoylphenyl, 4-methylthiophenyl,
4-(dimethylaminocarbonyl)phenyl, 4-methylsulfonylphenyl,
4-acetylaminophenyl, 4-methylsulfinylphenyl, 4-aminosulfonylphenyl,
4-cyanophenyl and 4-tetrazolylphenyl, particularly preferably
4-chlorophenyl.
[1177] The heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from group B is that wherein the
above-defined heterocyclic group is optionally substituted by 1 to
5 substituent(s), and includes unsubstituted heterocyclic group.
The substituent(s) is(are) selected from the above-defined halogen
atom, cyano, nitro, the above-defined C.sub.1-6 alkyl, the
above-defined halogenated C.sub.1-6 alkyl, the above-defined
C.sub.1-6 alkanoyl, --(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2, --(CH.sub.2).sub.r
NR.sup.b1R.sup.b2, --(CH.sub.2).sub.r--NR.sup.b1--COR.sup.b2,
--(CH.sub.2).sub.r--NHSO.sub.2R.sup.b1,
--(CH.sub.2).sub.r--OR.sup.b1, --(CH.sub.2).sub.r--SR.sup.b1,
--(CH.sub.2).sub.r--SO.sub.2R.sup.b1 and
--(CH.sub.2).sub.r--SO.sub.2NR.sup.b1R.sup.b2 wherein R.sup.b1 and
R.sup.b2 are each independently hydrogen atom or the above-defined
C.sub.1-6 alkyl and r is 0 or an integer of 1 to 6.
[1178] Examples thereof include 2-pyridyl, 3-pyridyl, 4-pyridyl,
3-fluoropyridin-4-yl, 3-chloropyridin-4-yl, 4-chloropyridin-3-yl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, 2-thienyl,
3-thienyl, furyl, oxazolyl, 2-methyloxazol-4-yl, isoxazolyl,
thiazolyl, 2-methylthiazol-4-yl, 2,5-dimethylthiazol-4-yl,
2,4-dimethylthiazol-5-yl, isothiazolyl, thiadiazolyl, pyrrolinyl,
pyrrolidinyl, 3-hydroxypyrrolidinyl, imidazolidinyl, azetidinyl,
piperidyl, 3-hydroxypiperidino, 4-hydroxypiperidino,
3,4-dihydroxypiperidino, 4-methoxypiperidino, 4-carboxypiperidino,
4-(hydroxymethyl)piperidino, 2-oxopiperidino, 4-oxopiperidino,
2,2,6,6-tetramethylpiperidino,
2,2,6,6-tetramethyl-4-hydroxypiperidino, N-methylpiperidin-4-yl,
N-(tert-butoxycarbonyl)piperidin-4-yl, N-acetylpiperidin-4-yl,
N-methylsulfonylpiperidin-4-yl, piperazinyl, 4-methylpiperazinyl,
4-methylsulfonylpiperazinyl, morpholinyl, thiomorpholinyl,
1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl,
tetrahydropyranyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalyl,
phthalazinyl, cinnolinyl, naphthyridinyl,
5,6,7,8-tetrahydroquinolyl, indolyl, benzimidazolyl, indolinyl,
benzofuranyl, benzothienyl, benzoxazolyl, benzothiazolyl, ##STR43##
##STR44## and the like.
[1179] The heterocyclic moiety is preferably a heterocyclic group
which is a 5-membered or a 6-membered monocyclic group. Examples
thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,
tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl,
morpholinyl, thiomorpholinyl and tetrahydropyranyl, and the group B
here is preferably the above-defined halogen atom, the
above-defined C.sub.1-6 alkyl, the above-defined halogenated
C.sub.1-6 alkyl, the above-defined C.sub.1-6 alkanoyl,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2 or
--(CH.sub.2).sub.r--OR.sup.b1.
[1180] Examples of heterocyclic group optionally substituted by 1
to 5 substituent(s) selected from group B preferably include
piperidino, 4-methylpiperidino, 2,6-dimethylpiperidino,
4-hydroxypiperidino, 1-piperazinyl,
1-(methylsulfonyl)piperidin-4-yl, 1-pyrrolidinyl, morpholino,
4-thiomorpholinyl, tetrahydropyranyl, pyridyl, thiazolyl,
##STR45##
[1181] Particularly preferably, it is piperidino,
4-methylpiperidino, 2,6-dimethylpiperidino, 4-hydroxypiperidino,
1-piperazinyl, 1-pyrrolidinyl, morpholino or 4-thiomorpholinyl at
R.sup.a18, tetrahydropyranyl or 4-hydroxypiperidino at R.sup.a20,
piperidino, 4-hydroxypiperidino or 3,4-dihydroxypiperidino at
R.sup.a21, pyridyl or morpholino at R.sup.a24, pyridyl or
4-hydroxypiperidino at R.sup.a25, pyridyl or thiazolyl at R.sup.a26
and at R.sup.a27 and R.sup.a28, it is
1-(methylsulfonyl)piperidin-4-yl, 3-hydroxypyrrolidinyl,
3-hydroxypiperidino, 4-hydroxypiperidino, 3,4-dihydroxypiperidino,
4-methoxypiperidino, 4-carboxypiperidino,
4-(hydroxymethyl)piperidino, 2-oxopiperidino, 4-oxopiperidino,
2,2,6,6-tetramethylpiperidino,
2,2,6,6-tetramethyl-4-hydroxypiperidino,
4-methylsulfonylpiperazinyl, 1-oxothiomorpholin-4-yl or
1,1-dioxothiomorpholin-4-yl, and 2-oxazolin-2-yl at R.sup.a22 and
R.sup.a23.
[1182] The heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from group D is that wherein the
above-defined heterocyclic group is optionally substituted by 1 to
5 substituent(s), and includes unsubstituted heterocyclic group.
The substituent(s) is(are) selected from the substituent(s) of the
above-mentioned group D (substituents shown under (a) to (q)).
[1183] Examples of the group D here include the substituent(s)
exemplified for C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D.
[1184] Examples of heterocyclic group optionally substituted by 1
to 5 substituent(s) selected from group D include 2-pyridyl,
3-pyridyl, 4-pyridyl, 3-fluoropyridin-4-yl, 3-chloropyridin-4-yl,
4-chloropyridin-3-yl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,
tetrazolyl, 2-thienyl, 3-thienyl, furyl, oxazolyl,
2-methyloxazol-4-yl, isoxazolyl, thiazolyl, 2-methylthiazol-4-yl,
2,5-dimethylthiazol-4-yl, 2,4-dimethylthiazol-5-yl, isothiazolyl,
thiadiazolyl, pyrrolinyl, pyrrolidinyl, imidazolidinyl, piperidyl,
N-methylpiperidin-4-yl, N-(tert-butoxycarbonyl)piperidin-4-yl,
N-acetylpiperidin-4-yl, N-methylsulfonylpiperidin-4-yl,
piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,
quinolyl, isoquinolyl, quinazolinyl, quinoxalyl, phthalazinyl,
cinnolinyl, naphthyridinyl, 5,6,7,8-tetrahydroquinolyl, indolinyl,
benzimidazolyl, indolinyl, benzofuranyl, benzothienyl,
benzoxazolyl, benzothiazolyl ##STR46## and the like.
[1185] In addition, the heterocyclic group may be substituted at
the 3-, 4-, 5- or 6-position of 2-pyridyl, at the 2-, 4-, 5- or
6-position of 3-pyridyl, at the 2-, 3-, 5- or 6-position of
4-pyridinyl, at the 3-, 4- or 5-position of 2-thienyl, or at the
2-, 4- or 5-position of 3-thienyl, by fluorine atom, chlorine atom,
bromine atom, nitro, methyl, tert-butyl, carboxyl, trifluoromethyl,
hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl,
methylthio, dimethylaminocarbonyl, methylsulfonyl, amino or
acetylamino.
[1186] At Z and Z', the heterocyclic moiety is preferably a
heterocyclic group which is a 5-membered or 6-membered monocyclic
group. Examples thereof include pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, 1,3,5-triazinyl, pyrrolyl, 2-oxopyrrolidinyl,
2-oxopiperidyl, pyrazolyl, imidazolyl, 2-imidazolinyl,
2-oxoimidazolidinyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl,
oxazolyl, isoxazolyl, 2-oxazolinyl, thiazolyl, isothiazolyl,
1,1-dioxoisothiazolidinyl, thiadiazolyl, pyrrolidinyl, piperidyl,
piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl,
.DELTA..sup.2-1,2,4-oxadiazolyl,
5-oxo-.DELTA..sup.2-1,2,4-oxadiazolyl,
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolinyl and
2-oxo-3H-1,2,3,5-oxathiadiazolinyl. The group D here is preferably
the above-defined halogen atom, nitro, the above-defined optionally
substituted C.sub.1-6 alkyl, --(CH.sub.2).sub.t--COOR.sup.a19,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2)--OR.sup.a20, (CH.sub.2) NR.sup.a29 CO--R.sup.a24,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 or
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26.
[1187] Examples of heterocyclic group optionally substituted by 1
to 5 substituent(s) selected from group D preferably include
piperidino, 4-hydroxypiperidino, 2-oxopiperidin-1-yl,
1-piperazinyl, 1-pyrrolidinyl, 2-oxopyrrolidin-1-yl, morpholino,
4-thiomorpholinyl, 4-tetrahydropyranyl, 3-pyridyl, 2-pyrimidinyl,
2-imidazolin-2-yl, 2-oxoimidazolidin-1-yl, 2-oxooxazolidin-1-yl,
5-tetrazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl,
2-methylthiazol-4-yl, 5-methylthiazol-2-yl, 2-aminothiazol-4-yl,
3-methyl-1,2,4-oxadiazol-5-yl, 1,1-dioxoisothiazolidin-2-yl,
4,4-dimethyl-.DELTA..sup.2-oxazolin-2-yl, 2-thienyl,
5-chlorothiophen-2-yl, 5-methyloxazol-2-yl,
5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl,
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolin-3-yl and
2-oxo-3H-1,2,3,5-oxathiazolin-4-yl.
[1188] Particularly preferably, it is pyridyl, pyrimidinyl,
tetrazolyl, thienyl, piperidyl, 2-oxopiperidin-1-yl,
2-oxopyrrolidin-1-yl, 2-imidazolin-2-yl, 2-oxoimidazolidin-1-yl,
2-oxooxazolidin-1-yl, 2-methylthiazol-4-yl, 5-methylthiazol-2-yl,
2-aminothiazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,
1,1-dioxoisothiazolidin-2-yl,
4,4-dimethyl-.DELTA..sup.2-oxazolin-2-yl, 5-chlorothiophen-2-yl,
5-methyloxazol-2-yl, 5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl,
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolin-3-yl or
2-oxo-3H-1,2,3,5-oxathiadiazolin-4-yl, more preferably
2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxoimidazolidin-1-yl,
2-oxooxazolidin-1-yl or 1,1-dioxoisothiazolidin-2-yl, most
preferably 2-oxopyrrolidin-1-yl.
[1189] The C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from group C is that wherein the
above-defined C.sub.3-8 cycloalkyl is optionally substituted by the
1 to 5 substituent(s) selected from hydroxyl group, the
above-defined halogen atom, the above-defined C.sub.1-6 alkyl and
the above-defined C.sub.1-6 alkoxy, which may be unsubstituted.
Examples thereof include cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, 4-fluorocyclohexyl, 2-methylcyclopentyl,
3-methylcyclohexyl, 4-methylcyclohexyl, 4,4-dimethylcyclohexyl,
3,5-dimethylcyclohexyl, 4-tert-butylcyclohexyl,
4-hydroxycyclohexyl, 4-methoxycyclohexyl and
2,3,4,5,6-pentafluorocyclohexyl.
[1190] The cycloalkyl moiety is preferably cyclopentyl or
cyclohexyl, particularly preferably cyclohexyl.
[1191] At the ring Cy and ring Cy', the C.sub.3-8 cycloalkyl
optionally substituted by 1 to 5 substituent(s) selected from group
C is preferably cyclopentyl, cyclohexyl, 4-fluorocyclohexyl,
4-methylcyclohexyl, 4,4-dimethylcyclohexyl, 4-tert-butylcyclohexyl,
4-hydroxycyclohexyl or 4-methoxycyclohexyl, more preferably
cyclopentyl or cyclohexyl, particularly preferably cyclohexyl.
[1192] The C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from the above group B is that wherein the
above-defined C.sub.3-8 cycloalkyl is optionally substituted by 1
to 5 substituent(s), and includes unsubstituted cycloalkyl. The
substituents are selected from the above group B.
[1193] Specific examples thereof include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, 4-fluorocyclohexyl,
2-methylcyclopentyl, 3-methylcyclohexyl, 4-methylcyclohexyl,
4,4-dimethylcyclohexyl, 3,5-dimethylcyclohexyl,
4-tert-butylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl
and 2,3,4,5,6-pentafluorocyclohexyl.
[1194] Also exemplified are those wherein cyclopentyl or cyclohexyl
is substituted by fluorine atom, chlorine atom, bromine atom,
nitro, methyl, tert-butyl, carboxyl, trifluoromethyl,
hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl,
methylthio, dimethylaminocarbonyl, methylsulfonyl or
acetylamino.
[1195] At cycloalkyl moiety, it is preferably cyclopropyl,
cyclobutyl, cyclopentyl or cyclohexyl. As the C.sub.3-8 cycloalkyl
optionally substituted by 1 to 5 substituent(s) selected from the
above group B, it is particularly preferably cyclopropyl,
cyclobutyl, cyclohexyl or 4-hydroxycyclohexyl at R.sup.a27 and
R.sup.a28.
[1196] The C.sub.3-8 cycloalkyl optionally substituted by 1 to 5
substituent(s) selected from group D is that wherein the
above-defined C.sub.3-8 cycloalkyl is optionally substituted by 1
to 5 substituent(s), and includes unsubstituted cycloalkyl. The
substituent(s) is(are) selected from the substituent(s) of the
above-mentioned group D (substituents shown under (a) to (q)).
[1197] The group D here includes the substituents recited with
regard to C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D.
[1198] Examples thereof include cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, 4-fluorocyclohexyl,
2-methylcyclopentyl, 3-methylcyclohexyl, 4-methylcyclohexyl,
4,4-dimethylcyclohexyl, 3,5-dimethylcyclohexyl,
4-tert-butylcyclohexyl, 4-hydroxycyclohexyl, 4-methoxycyclohexyl
and 2,3,4,5,6-pentafluorocyclohexyl.
[1199] The group D may be, for example, cyclopentyl or cyclohexyl
substituted by fluorine atom, chlorine atom, bromine atom, nitro,
methyl, tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl,
methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio,
dimethylaminocarbonyl, methylsulfonyl or acetylamino.
[1200] The cycloalkyl moiety is preferably cyclopentyl or
cyclohexyl, and at Z and Z', it is particularly preferably
cyclohexyl.
[1201] The optionally substituted C.sub.3-8 cycloalkenyl is that
wherein the above-defined C.sub.3-8 cycloalkenyl is optionally
substituted by substituent(s) selected from hydroxyl group, the
above-defined halogen atom, the above-defined C.sub.1-6 alkyl and
the above-defined C.sub.1-6 alkoxy, which may be unsubstituted.
Examples thereof include cyclopropenyl, cyclobutenyl,
cyclopentenyl, cyclopentadienyl, cyclohexenyl,
4-fluoro-2-cyclohexenyl, 4-methyl-2-cyclohexenyl,
4-methyl-3-cyclohexenyl, 2,4-cyclohexadien-1-yl,
2,5-cyclohexadien-1-yl, cycloheptenyl and cyclooctenyl and the
like, but do not include aryl (e.g., phenyl) or completely
saturated cycloalkyl.
[1202] The optionally substituted C.sub.3-8 cycloalkenyl is
particularly preferably cyclohexenyl at the ring Cy.
[1203] The C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted
by 1 to 5 substituent(s) selected from group B is that wherein the
above-defined C.sub.6-14 aryl C.sub.1-6 alkyl is optionally
substituted by 1 to 5 substituent(s), and includes unsubstituted
arylalkyl. The substituent(s) is(are) selected from the
above-mentioned group B.
[1204] Examples thereof include benzyl, 1-naphthylmethyl,
2-naphthylmethyl, phenethyl, 3-phenylpropyl, 2-phenylpropyl,
3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,
2,4-dichlorobenzyl, 3,5-dichlorobenzyl, pentafluorobenzyl,
4-methylbenzyl, 4-tert-butylbenzyl, 2-trifluoromethylbenzyl,
4-trifluoromethylbenzyl, 4-nitrobenzyl, 4-cyanobenzyl,
4-acetylbenzyl, 4-carboxylbenzyl, 4-carbamoylbenzyl, 4-aminobenzyl,
4-dimethylaminobenzyl, 4-acetylaminobenzyl,
4-(methylsulfonylamino)benzyl, 4-methoxybenzyl,
3,4,5-trimethoxybenzyl, 4-methylthiobenzyl, 4-methylsulfonylbenzyl,
4-aminosulfonylbenzyl, 3-nitro-4-methoxybenzyl and
4-nitro-3-methoxybenzyl.
[1205] The C.sub.6-14 aryl C.sub.1-6 alkyl moiety is preferably
benzyl or phenethyl, particularly preferably benzyl. The group B is
preferably the above-defined halogen atom, nitro, the above-defined
C.sub.1-6 alkyl, the above-defined halogenated C.sub.1-6 alkyl or
--(CH.sub.2).sub.r--OR.sup.b1. Examples thereof include fluorine
atom, chlorine atom, nitro, methyl, tert-butyl, trifluoromethyl,
methoxy or trifluoromethyloxy, particularly preferably fluorine
atom or chlorine atom.
[1206] The specific C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from group B at
R.sup.a12 and R.sup.a13 is preferably benzyl, phenethyl,
3-chlorobenzyl, 4-chlorobenzyl, 4-tert-butylbenzyl or
3-trifluoromethylbenzyl, it is preferably benzyl at R.sup.a1,
R.sup.a19, R.sup.a27, R.sup.a28, R.sup.a31 and R.sup.b5, it is
preferably benzyl, phenethyl, 4-fluorobenzyl, 2-chlorobenzyl,
3-chlorobenzyl, 4-chlorobenzyl, 4-tert-butylbenzyl or
4-trifluoromethylbenzyl at R.sup.a20, and 4-chlorobenzyl,
3,5-dichlorobenzyl or 4-trifluoromethylbenzyl at R.sup.a22 and
R.sup.a23.
[1207] It is particularly preferably benzyl at other
substituents.
[1208] The C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted
by 1 to 5 substituent(s) selected from group D is that wherein the
above-defined C.sub.6-14 aryl C.sub.1-6 alkyl is optionally
substituted by 1 to 5 substituent(s), and includes unsubstituted
aryl. The substituent(s) is(are) selected from the substituent(s)
of the above-mentioned group D (substituents shown under (a) to
(q)).
[1209] Examples of group D include fluorine atom, chlorine atom,
bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl,
tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl,
methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl,
ethoxycarbonyl, carbamoyl, methylaminocarbonyl,
isopropylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl, (2-hydroxyethyl)aminocarbonyl,
(carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy,
isopropyloxy, hydroxymethyloxy, carboxylmethyloxy,
(dimethylaminocarbonyl)methyloxy, amino, methylamino,
dimethylamino, diethylamino, acetylamino, methylsulfonylamino,
methylthio, methylsulfonyl, methylsulfinyl, aminosulfonyl,
methylaminosulfonyl and dimethylaminosulfonyl.
[1210] Examples of C.sub.6-14 aryl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from group D include
benzyl, 1-naphthylmethyl, 2-naphthylmethyl, phenethyl,
3-phenylpropyl, 2-phenylpropyl, 3-fluorobenzyl, 4-fluorobenzyl,
3-chlorobenzyl, 4-chlorobenzyl, 2,4-dichlorobenzyl,
3,5-dichlorobenzyl, 4-bromobenzyl, 4-nitrobenzyl,
pentafluorobenzyl, 4-methylbenzyl, 4-tert-butylbenzyl,
2-trifluoromethylbenzyl, 4-trifluoromethylbenzyl,
4-(hydroxymethyl)benzyl, 4-(methoxymethyl)benzyl,
4-(2-carboxylethyl)benzyl, 3-carboxylbenzyl, 4-carboxylbenzyl,
4-methoxybenzyl, 3,4,5-trimethoxybenzyl, 4-carbamoylbenzyl,
4-methylthiobenzyl, 4-(dimethylaminocarbonyl)benzyl,
4-methylsulfonylbenzyl, 4-(acetylamino)benzyl, 4-cyanobenzyl,
4-acetylbenzyl, 4-aminobenzyl, 4-dimethylaminobenzyl,
4-(methylsulfonylamino)benzyl, 4-methylsulfinylbenzyl,
4-aminosulfonylbenzyl, (3-nitro-4-methoxyphenyl)methyl and
(4-nitro-3-methoxyphenyl)methyl.
[1211] At Z and Z', the C.sub.6-14 aryl C.sub.1-6 alkyl moiety is
preferably benzyl or phenethyl, and the group D here is preferably
the above-defined halogen atom, nitro, the above-defined optionally
substituted C.sub.1-6 alkyl, --(CH.sub.2).sub.t--COOR.sup.a19,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.a20,
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 or
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26.
[1212] The C.sub.6-14 aryl C.sub.1-6 alkyl optionally substituted
by 1 to 5 substituent(s) selected from group D is preferably
benzyl, 3-fluorobenzyl, 4-fluorobenzyl, 3-chlorobenzyl,
4-chlorobenzyl, 3,5-dichlorobenzyl, 4-bromobenzyl, 4-nitrobenzyl,
4-methylbenzyl, 4-tert-butylbenzyl, 2-trifluoromethylbenzyl,
4-trifluoromethylbenzyl, 4-(hydroxymethyl)benzyl,
4-(methoxymethyl)benzyl, 4-(2-carboxylethyl)benzyl,
3-carboxylbenzyl, 4-carboxylbenzyl, 4-methoxybenzyl,
3,4,5-trimethoxybenzyl, 4-carbamoylbenzyl, 4-methylthiobenzyl,
4-(dimethylaminocarbonyl)benzyl, 4-methylsulfonylbenzyl,
4-acetylaminobenzyl, 4-methylsulfinylbenzyl or
4-aminosulfonylbenzyl.
[1213] It is particularly preferably the above-defined halogen
atom, the above-defined optionally substituted C.sub.1-6 alkyl,
(CH.sub.2).sub.t--COOR.sup.a19,
(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.20 or
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25. Examples thereof include
fluorine atom, chlorine atom, bromine atom, nitro, methyl,
tert-butyl, carboxyl, trifluoromethyl, hydroxymethyl,
methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl, methylthio,
dimethylaminocarbonyl, methylsulfonyl and acetylamino. It is more
preferably fluorine atom, chlorine atom, methyl, tert-butyl,
carboxyl, methoxy, carbamoyl, methylthio, dimethylaminocarbonyl or
methylsulfonyl, most preferably fluorine atom or chlorine atom.
[1214] The heterocycle C.sub.1-6 alkyl optionally substituted by 1
to 5 substituent(s) selected from group B is that wherein the
above-defined heterocycle C.sub.1-6 alkyl is optionally substituted
by 1 to 5 substituent(s), and includes unsubstituted heterocycle
C.sub.1-6 alkyl. The substituent(s) is(are) selected from the
above-mentioned group B.
[1215] Examples thereof include 2-pyridylmethyl, 3-pyridylmethyl,
2-chloropyridin-4-ylmethyl, 4-pyridylmethyl, pyrrolylmethyl,
imidazolylmethyl, 2-thienylmethyl, 3-thienylmethyl, 2-furylmethyl,
2-oxazolylmethyl, 5-isothiazolylmethyl, 2-methyloxazol-4-ylmethyl,
2-thiazolylmethyl, 4-thiazolylmethyl, 5-thiazolylmethyl,
2-methylthiazol-4-ylmethyl, 2-methylthiazol-5-ylmethyl,
2,5-dimethylthiazol-4-ylmethyl, 4-methylthiazol-2-ylmethyl,
2,4-dimethylthiazol-5-ylmethyl, 2-isothiazolylmethyl,
2-pyrrolinylmethyl, pyrrolidinylmethyl, piperidylmethyl,
4-piperidylmethyl, 1-methylpiperidin-4-ylmethyl,
4-hydroxypiperidinomethyl, 3-hydroxypyrrolidinylmethyl,
2-(4-hydroxypiperidino)ethyl,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl,
1-acetylpiperidin-4-ylmethyl, 1-methylsulfonylpiperidin-4-ylmethyl,
piperazinylmethyl, morpholinomethyl, thiomorpholinylmethyl,
1-tetrahydropyranylmethyl, 2-quinolylmethyl, 1-isoquinolylmethyl
and the like.
[1216] The heterocyclic moiety is preferably a heterocyclic group
which is a 5-membered or 6-membered monocyclic group. Examples
thereof include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,
1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl, 1,2,4-triazolyl,
tetrazolyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl,
isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl, piperazinyl,
morpholinyl, thiomorpholinyl and tetrahydropyranyl, and the alkyl
moiety thereof is preferably straight chain alkyl having 1 to 4
carbon atoms. The group B here is preferably the above-defined
halogen atom, the above-defined C.sub.1-6 alkyl, the above-defined
halogenated C.sub.1-6 alkyl, the above-defined C.sub.1-6 alkanoyl,
--(CH.sub.2).sub.r--COOR.sup.b1,
--(CH.sub.2).sub.r--CONR.sup.b1R.sup.b2 or
--(CH.sub.2).sub.r--OR.sup.b1.
[1217] Examples of heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from group B
preferably include 2-pyridylmethyl, 3-pyridylmethyl,
2-chloropyridin-4-ylmethyl, 4-pyridylmethyl, piperidin-4-ylmethyl,
1-methylpiperidin-4-ylmethyl, 2-(4-hydroxypiperidino)ethyl,
1-acetylpiperidin-4-ylmethyl,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl,
1-(methylsulfonyl)-piperidin-4-ylmethyl, 2-thiazolylmethyl,
4-thiazolylmethyl, 2-methylthiazolin-4-ylmethyl,
2,4-dimethylthiazolin-5-ylmethyl and 4-methylthiazol-2-ylmethyl.
Particularly preferably, it is 2-pyridylmethyl, 3-pyridylmethyl,
2-chloropyridin-4-ylmethyl, 4-pyridylmethyl, piperidin-4-ylmethyl,
1-methylpiperidin-4-ylmethyl, 2-(4-hydroxypiperidino)ethyl,
1-acetylpiperidin-4-ylmethyl,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl,
1-(methylsulfonyl)piperidin-4-ylmethyl,
2-methylthiazolin-4-ylmethyl, 2,4-dimethylthiazolin-5-ylmethyl or
4-methylthiazol-2-ylmethyl at R.sup.a20, 2-pyridylmethyl at
R.sup.a22 and R.sup.a23, and 4-pyridylmethyl or
4-methylthiazol-2-ylmethyl at R.sup.a27 and R.sup.a28.
[1218] The heterocycle C.sub.1-6 alkyl optionally substituted by 1
to 5 substituent(s) selected from group D is that wherein the
above-defined heterocycle C.sub.1-6 alkyl is optionally substituted
by 1 to 5 substituent(s), and includes unsubstituted heterocycle
C.sub.1-6 alkyl. The substituent(s) is(are) selected from the
above-mentioned group D (substituents shown under (a) to (q)).
[1219] Examples of group D here include fluorine atom, chlorine
atom, bromine atom, nitro, cyano, methyl, ethyl, propyl, isopropyl,
tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl,
methoxymethyl, 2-carboxylethyl, methoxycarbonylmethyl,
ethoxycarbonylmethyl, acetyl, carboxyl, methoxycarbonyl,
ethoxycarbonyl, carbamoyl, methylaminocarbonyl,
isopropylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl, (2-hydroxyethyl)aminocarbonyl,
(carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy,
isopropyloxy, hydroxymethyloxy, carboxylmethyloxy,
(dimethylaminocarbonyl)methyloxy, amino, methylamino,
dimethylamino, diethylamino, acetylamino, methylsulfonylamino,
methylthio, methylsulfonyl, methylsulfinyl, aminosulfonyl,
methylaminosulfonyl and dimethylaminosulfonyl.
[1220] Examples of heterocycle C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from group D include
2-pyridylmethyl, 3-pyridylmethyl, 2-chloropyridin-4-ylmethyl,
4-pyridylmethyl, pyrrolylmethyl, imidazolylmethyl, 2-thienylmethyl,
3-thienylmethyl, 2-furylmethyl, 2-oxazolylmethyl,
5-isothiazolylmethyl, 2-methyloxazol-4-ylmethyl, 2-thiazolylmethyl,
4-thiazolylmethyl, 5-thiazolylmethyl, 2-methylthiazol-4-ylmethyl,
2-methylthiazol-5-ylmethyl, 2,5-dimethylthiazol-4-ylmethyl,
4-methylthiazol-2-ylmethyl, 2,4-dimethylthiazol-5-ylmethyl,
2-isothiazolylmethyl, 2-pyrrolinylmethyl, pyrrolidinylmethyl,
piperidylmethyl, 4-piperidylmethyl, 1-methylpiperidin-4-ylmethyl,
4-hydroxypiperidinomethyl, 2-(4-hydroxypiperidino)ethyl,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl,
1-acetylpiperidin-4-ylmethyl, 1-methylsulfonylpiperidin-4-ylmethyl,
piperazinylmethyl, morpholinomethyl, thiomorpholinylmethyl,
1-tetrahydropyranylmethyl, 2-quinolylmethyl, 1-isoquinolylmethyl,
and the like.
[1221] Preferable heterocyclic moiety at Z and Z' is heterocylic
group which is 5-membered or 6-membered monocyclic group. Examples
of the heterocyclic moiety include pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, 1,3,5-triazinyl, pyrrolyl, pyrazolyl, imidazolyl,
1,2,4-triazolyl, tetrazolyl, thienyl, furyl, oxazolyl, isooxazolyl,
thiazolyl, isothiazolyl, thiadiazolyl, pyrrolidinyl, piperidyl,
piperazinyl, morpholinyl, thiomorpholinyl and tetrahydropyranyl,
and the alkyl moiety is preferably straight chain alkyl having 1 to
4 carbon atoms, particularly methyl (i.e., methylene).
[1222] Preferable group D is the above-defined halogen atom, nitro,
the above-defined optionally substituted C.sub.1-6 alkyl,
--(CH.sub.2).sub.t--COOR.sup.a19,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.a20,
--(CH.sub.2).sub.t--NR.sup.a29COR.sup.a24,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 or
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26.
[1223] Preferable examples of heterocycle C.sub.1-6 alkyl
optionally substituted by 1 to 5 substituent(s) selected from group
D include 2-pyridylmethyl, 3-pyridylmethyl,
2-chloropyridin-4-ylmethyl, 4-pyridylmethyl, piperidin-4-ylmethyl,
1-methylpiperidin-4-ylmethyl, 4-hydroxypiperidinomethyl,
2-(4-hydroxypiperidino)ethyl, 1-acetylpiperidin-4-ylmethyl,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyl,
1-(methylsulfonyl)piperidin-4-ylmethyl, 2-thiazolylmethyl,
4-thiazolylmethyl, 2-methylthiazolin-4-ylmethyl,
2,4-dimethylthiazolin-5-ylmethyl and
4-methylthiazol-2-ylmethyl.
[1224] Particularly preferred is 4-hydroxypiperidinomethyl.
[1225] The C.sub.3-8 cycloalkyl C.sub.1-6 alkyl optionally
substituted by 1 to 5 substituent(s) selected from the above group
B is that wherein the above-defined C.sub.3-8 cycloalkyl C.sub.1-6
alkyl is optionally substituted by 1 to 5 substituent(s), and
includes unsubstituted cycloalkylalkyl. The substituents are
selected from the above group B.
[1226] Specific examples thereof include cyclopropylmethyl,
cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl,
2-(cyclopentyl)ethyl, 2-(cyclohexyl)ethyl, cycloheptylmethyl,
4-fluorocyclohexylmethyl, 2-methylcyclopentylmethyl,
3-methylcyclohexylmethyl, 4-methylcyclohexylmethyl,
4,4-dimethylcyclohexylmethyl, 3,5-dimethylcyclohexylmethyl,
4-tert-butylcyclohexylmethyl, 4-hydroxycyclohexylmethyl,
4-methoxycyclohexylmethyl and
2,3,4,5,6-pentafluorocyclohexylmethyl.
[1227] Also exemplified are those wherein cyclopentylmethyl or
cyclohexylmethyl is substituted by fluorine atom, chlorine atom,
bromine atom, nito, methyl, tert-butyl, carboxyl, trifluoromethyl,
hydroxymethyl, methoxymethyl, 2-carboxylethyl, methoxy, carbamoyl,
methylthio, dimethylaminocarbonyl, methylsulfonyl or
acetylamino.
[1228] At cycloalkyl moiety, it is preferably cyclopentylmethyl or
cyclohexylmethyl, and at R.sup.a20, R.sup.a27 and R.sup.a28, it is
particularly preferably cyclohexylmethyl.
[1229] The carboxyl-protecting group only needs to be suitable for
reaction conditions, and is capable of protecting and deprotecting
and may be, for example, methyl; substituted methyl group such as
methoxymethyl, methylthiomethyl, 2-tetrahydropyranyl,
methoxyethoxymethyl, benzyloxymethyl, phenacyl, diacylmethyl,
phthalimidomethyl etc.; ethyl; substituted ethyl group such as
2,2,2-trichloroethyl, 2-chloroethyl, 2-(trimethylsilyl)ethyl,
2-methylthioethyl, 2-(p-toluenesulfonyl)ethyl, t-butyl etc.;
benzyl; substituted benzyl group such as diphenylmethyl,
triphenylmethyl, p-nitrobenzyl, 4-picolyl, p-methoxybenzyl,
2-(9,10-dioxo)anthrylmethyl etc.; silyl group such as
trimethylsilyl, t-butyldimethylsilyl, phenyldimethylsilyl etc.; and
the like.
[1230] Preferred are industrially effective protecting groups and
specifically preferred as R.sup.a36 are methyl and ethyl.
[1231] In formula [I], X is preferably ##STR47## wherein each
symbol is as defined above.
[1232] G.sup.1, G.sup.2, G.sup.3 and G.sup.4 are each preferably
(C--R.sup.1), (C--R.sup.2), (C--R.sup.3 and (C--R.sup.4), G.sup.5
is preferably a nitrogen atom, and G.sup.6, G.sup.8 and G.sup.9 are
preferably a carbon atom. G.sup.7 is preferably C(--R.sup.7) or
unsubstituted nitrogen atom, wherein R.sup.7 is preferably hydrogen
atom.
[1233] A preferable combination is G.sup.2 of (C--R.sup.2) and
G.sup.6 of a carbon atom, particularly preferably G.sup.2 of
(C--R.sup.2), G.sup.6 of a carbon atom and G.sup.5 of a nitrogen
atom, most preferably G.sup.2 of (C--R.sup.2), G.sup.6 of a carbon
atom, G.sup.5 of a nitrogen atom and G.sup.7 of unsubstituted
nitrogen atom.
[1234] In formulas [I] and [II], 1 to 4 of G.sup.1 to G.sup.9 in
the moiety ##STR48## is(are) preferably a nitrogen atom,
specifically preferably ##STR49## ##STR50## particularly preferably
##STR51## more preferably ##STR52## most preferably ##STR53##
[1235] It is also a preferable embodiment wherein the ##STR54##
moiety is aromatic ring.
[1236] R.sup.1 and R.sup.3 are preferably hydrogen atom or
--OR.sup.a6 (R.sup.a6 is as defined above), particularly preferably
hydrogen atom. R.sup.2 is preferably carboxyl, --COOR.sup.a1,
--CONR.sup.a2R.sup.a3, --SO.sub.2R.sup.a7 (each symbol is as
defined above) or heterocyclic group having 1 to 4 heteroatom(s)
selected from an oxygen atom, a nitrogen atom and a sulfur atom,
particularly preferably carboxyl, --COOR.sup.a1 or
--SO.sub.2R.sup.a7, more preferably carboxyl or --COOR.sup.a1, most
preferably carboxyl. R.sup.4 is preferably hydrogen atom.
[1237] R.sup.a1 is preferably optionally substituted C.sub.1-6
alkyl.
[1238] When R.sup.2 is carboxyl or --COOR.sup.a1, at least one of
R.sup.1, R.sup.3 and R.sup.4 is preferably hydroxyl group, halogen
atom (particularly fluorine atom, chlorine atom) or --OR.sup.a6
(wherein R.sup.a6 is preferably hydrogen atom or methyl).
[1239] The ring Cy and ring Cy' are preferably cyclopentyl,
cyclohexyl, cycloheptyl, tetrahydrothiopyranyl or piperidino,
particularly preferably cyclopentyl, cyclohexyl or cycloheptyl,
more preferably cyclohexyl.
[1240] The ring A and ring A' are preferably phenyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, cyclohexyl, cyclohexenyl,
furyl or thienyl, particularly preferably phenyl, pyridyl,
pyrazinyl, pyrimidinyl or pyridazinyl, more preferably phenyl or
pyridyl, and most preferably phenyl.
[1241] The ring B and ring B' are preferably C.sub.1-6 aryl or
heterocyclic group, specifically preferably, phenyl, pyridyl,
pyrazinyl, pyrimidinyl, pyridazinyl, 1,3,5-triazinyl, pyrrolyl,
pyrazolyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, thienyl, furyl,
oxazolyl, isoxazolyl, thiazolyl, isothiazolyl or thiadiazolyl,
particularly preferably phenyl, pyridyl, pyrimidinyl,
1,3,5-triazinyl or thiazolyl, more preferably, phenyl, pyridyl or
thiazolyl, and most preferably phenyl or thiazolyl.
[1242] With regard to R.sup.5 and R.sup.6, one of them is
preferably hydrogen atom and the other is halogen atom,
particularly fluorine atom. Alternatively, the both are preferably
hydrogen atoms. When ring A is phenyl, R.sup.5 and R.sup.6
preferably are present at an ortho position from G.sup.6. The same
applies to R.sup.5' and R.sup.6'.
[1243] Y is preferably --(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--,
--NHCO.sub.2--, --CONH--CHR.sup.a14--,
--(CH.sub.2).sub.m--NR.sup.a12--(CH.sub.2).sub.n--,
--CONR.sup.a13--(CH.sub.2).sub.n--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16---
(CH.sub.2).sub.n-- or --(CH.sub.2).sub.n--NR.sup.a12--CHR.sup.a15--
(each symbol is as defined above), more preferably,
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n-- or
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--,
most preferably --(CH.sub.2).sub.m--O-- (CH.sub.2).sub.n--.
[1244] The l, m and n are preferably 0 or an integer of 1 to 4,
particularly preferably 0, 1 or 2, at Y. In
--(CH.sub.2).sub.m--O--(CH.sub.2).sub.n--, m=n=0 or m=0 and n=1 is
more preferable, most preferably m=0 and n=1. In
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--,
m=n=0, m=0 and n=1, m=1 and n=0 or m=1 and n=1 is more preferable,
most preferably m=0 and n=1.
[1245] When Y is
--O--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16--(CH.sub.2).sub.n--,
R.sup.a16 is preferably hydrogen atom, R.sup.a15 is preferably
##STR55## wherein the ##STR56## moiety is preferably symmetric. The
preferable mode of n, ring B, Z and w and the preferable mode of
n', ring B', Z' and w' are the same.
[1246] When ring A is phenyl, X or Y is preferably present at the
para-position relative to G.sup.5. When ring B and ring B' are
phenyl, [1247] Z is preferably present at the ortho or
meta-position relative to Y. It is preferable that the 3-position
on phenyl have one substituent or the 2-position and the 5-position
on phenyl each have one substituent.
[1248] When ring B is bonded to Y as pyridin-2-yl, Z is preferably
substituted at the 3-position and 6-position of pyridyl; when it is
bonded to Y as pyridin-3-yl, Z is preferably substituted at the
2-position and 5-position of pyridyl; and when it is bonded to Y as
pyridin-4-yl, Z is preferably substituted at the 2-position and
5-position of pyridyl.
[1249] When ring B is thiazolyl, Y is preferably substituted at the
5-position, and Z is preferably substituted at the 2-position, the
4-position or the 2-position and the 4-position. Similarly, when
ring B' is thiazolyl, (CH.sub.2).sub.n' is also preferably
substituted at the 5-position, and Z' is preferably substituted at
the 2-position, the 4-position or the 2-position and the
4-position.
[1250] Z and Z' are preferably group D, "C.sub.6-14 aryl optionally
substituted by 1 to 5 substituent(s) selected from group D" or
"heterocyclic group optionally substituted by 1 to 5 substituent(s)
selected from group D", particularly preferably group D or
"C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from group D".
[1251] More preferably, they are the above-defined halogen atom,
nitro, the above-defined optionally substituted C.sub.1-6 alkyl,
--(CH.sub.2).sub.t--COOR.sup.a19,
--(CH.sub.2).sub.t--CONR.sup.a27R.sup.a28,
--(CH.sub.2).sub.t--OR.sup.a20,
--(CH.sub.2).sub.t--NR.sup.a29CO--R.sup.a24,
--(CH.sub.2).sub.t--S(O).sub.q--R.sup.a25 or
--(CH.sub.2).sub.t--SO.sub.2--NHR.sup.a26, or C.sub.6-14 aryl or
heterocyclic group optionally substituted by these.
[1252] With regard to Z and Z', the preferable mode of group D that
directly substitutes each ring B and ring B' and the preferable
mode of group D that substitutes C.sub.6-14 aryl, C.sub.3-8
cycloalkyl, C.sub.6-14 aryl C.sub.1-6 alkyl or heterocyclic group
are the same, wherein they may be the same with or different from
each other.
[1253] Specific examples of the substituent preferably include
fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl,
ethyl, propyl, isopropyl, tert-butyl, trifluoromethyl,
hydroxymethyl, 2-hydroxyethyl, methoxymethyl, 2-carboxylethyl,
methoxycarbonylmethyl, ethoxycarbonylmethyl,
carbamoylmethoxymethyl, (dimethylaminocarbonyl)methoxymethyl,
acetyl, isovaleryl, carboxyl, methoxycarbonyl, ethoxycarbonyl,
carbamoyl, methylaminocarbonyl, hydroxyaminocarbonyl,
ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl,
butylaminocarbonyl, isobutylaminocarbonyl, tert-butylaminocarbonyl,
(4-hydroxybutyl)aminocarbonyl, (1-hydroxypropan-2-yl)aminocarbonyl,
(2,3-dihydroxypropyl)-aminocarbonyl,
(1,3-dihydroxypropan-2-yl)aminocarbonyl, methoxyaminocarbonyl,
2-{2-(methoxy)ethoxy]ethyl}aminocarbonyl,
N-ethyl-N-methylaminocarbonyl, N-methyl-N-propylaminocarbonyl,
N-isopropyl-N-methylaminocarbonyl, dimethylaminocarbonyl,
diethylaminocarbonyl, (2-hydroxyethyl)aminocarbonyl,
(2-hydroxy-2-methylpropan-2-yl)aminocarbonyl,
(carboxylmethyl)aminocarbonyl, hydroxyl group, methoxy, ethoxy,
propyloxy, isopropyloxy, butyloxy, isopentyloxy, 2-isopentenyloxy,
3-isohexenyloxy, 4-methyl-3-pentenyloxy, 2-propynyloxy,
trifluoromethyloxy, hydroxymethyloxy, carboxylmethyloxy,
(dimethylaminocarbonyl)-methyloxy, amino, methylamino,
dimethylamino, diethylamino, acetylamino, N-acetyl-N-methylamino,
N-acetyl-N-ethylamino, N-acetyl-N-propylamino,
N-acetyl-N-isopropylamino, N-ethylcarbonyl-N-methylamino,
N-ethyl-N-(ethylcarbonyl)amino, ureido, isopropylcarbonylamino,
isobutylcarbonylamino, tert-butylcarbonylamino,
(ethylamino)carbonylamino, (isopropylamino)-carbonylamino,
(dimethylamino)carbonylamino, (4-hydroxypiperidino)carbonylamino,
[(4-hydroxypiperidino)methyl]-carbonylamino,
[(3-hydroxypyrrolidinyl)methyl]carbonylamino, methylsulfonylamino,
isopropylsulfonylamino, N-(methylsulfonyl)-N-methylamino,
N-(ethylsulfonyl)-N-methylamino,
N-(isopropylsulfonyl)-N-methylamino,
N-(methylsulfonyl)-N-ethylamino, N-(methylsulfonyl)-N-propylamino,
N-(ethylsulfonyl)-N-ethylamino, methylthio, methylsulfonyl,
isopropylsulfonyl, isobutylsulfonyl, methylsulfinyl,
isopropylsulfinyl, aminosulfonyl, methylaminosulfonyl,
dimethylaminosulfonyl, isopropylaminosulfonyl,
tert-butylaminosulfonyl, hydroxyamidino, phenyl, 3-fluorophenyl,
4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-difluorophenyl,
3,4-difluorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl,
4-chloro-3-fluorophenyl, 4-chloro-2-fluorophenyl, 4-bromophenyl,
4-nitrophenyl, 4-cyanophenyl, 4-methylphenyl, 4-ethylphenyl,
4-propylphenyl, 4-isopropylphenyl, 4-tert-butylphenyl,
2-trifluoromethylphenyl, 4-trifluoromethylphenyl,
4-(hydroxymethyl)phenyl, 4-(2-hydroxyethyl)phenyl,
4-(methoxymethyl)phenyl, 4-(2-carboxylethyl)phenyl,
4-(methoxycarbonylmethyl)phenyl, 4-(ethoxycarbonylmethyl)phenyl,
4-acetylphenyl, 3-carboxylphenyl, 4-carboxylphenyl,
4-(methoxycarbonyl)phenyl, 4-(ethoxycarbonyl)phenyl,
4-carbamoylphenyl, 4-(methylaminocarbonyl)phenyl,
4-(isopropylaminocarbonyl)phenyl, 4-(dimethylaminocarbonyl)phenyl,
4-(diethylaminocarbonyl)phenyl,
4-[(2-hydroxyethyl)aminocarbonyl]phenyl,
4-[(carboxylmethyl)aminocarbonyl]phenyl, 4-hydroxyphenyl,
4-methoxyphenyl, 3,4,5-trimethoxyphenyl, 4-ethoxyphenyl,
4-propyloxyphenyl, 4-isopropyloxyphenyl, 4-butyloxyphenyl,
4-isopentyloxyphenyl, 4-(2-isopentenyloxy)phenyl,
4-(3-isohexenyloxy)phenyl, 4-(4-methyl-3-pentenyloxy)phenyl,
4-(2-propynyloxy)phenyl, 4-(trifluoromethyloxy)phenyl,
4-(hydroxymethyloxy)phenyl, 4-(carboxylmethyloxy)phenyl,
4-[(dimethylaminocarbonyl)methyloxy]phenyl, 4-aminophenyl,
4-(methylamino)phenyl, 4-(dimethylaminophenyl),
4-(diethylamino)-phenyl, 4-(acetylamino)phenyl,
N-acetyl-N-methylamino, 4-(N-acetyl-N-methylamino)phenyl,
4-(N-acetyl-N-ethylamino)phenyl, 4-(N-acetyl-N-propylamino)phenyl,
4-(N-acetyl-N-isopropylamino)phenyl,
4-(N-ethylcarbonyl-N-methylamino)phenyl,
4-[N-ethyl-N-(ethylcarbonyl)amino]phenyl,
4-(methylsulfonylamino)phenyl, 4-(methylthio)phenyl,
4-(methylsulfonyl)phenyl, 4-(methylsulfinyl)phenyl,
4-(aminosulfonyl)phenyl, 4-(methylaminosulfonyl)phenyl,
4-(dimethylaminosulfonyl)phenyl, 4-(tert-butylaminosulfonyl)phenyl,
tetrazol-5-ylphenyl, cyclohexyl, benzyl, 4-chlorobenzyl, phenethyl,
benzyloxy, 4-fluorobenzyloxy, 2-chlorobenzyloxy, 3-chlorobenzyloxy,
4-chlorobenzyloxy, 4-tert-butylbenzyloxy,
4-trifluoromethylbenzyloxy, phenethyloxy, 2-thienyl, 2-thiazolyl,
2-pyridyl, 3-pyridyl, 4-pyridyl, 6-fluoropyridin-3-yl,
5-fluoropyridin-2-yl, 6-chloropyridin-3-yl, 6-methylpyridin-3-yl,
2-pyrimidinyl, 5-tetrazolyl, piperidino, 2-oxopiperidin-1-yl,
2-oxopyrrolidin-1-yl, 2-imidazolin-2-yl, 2-oxoimidazolidin-1-yl,
2-oxooxazolidin-1-yl, 2-methylthiazol-4-yl, 5-methylthiazol-2-yl,
2-aminothiazol-4-yl, 3-methyl-1,2,4-oxadiazol-5-yl,
1,1-dioxoisothiazolidin-2-yl,
4,4-dimethyl-.DELTA..sup.2-oxazolin-2-yl, 5-chlorothiophen-2-yl,
5-methyloxazol-2-yl, 5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl,
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolin-3-yl,
2-oxo-3H-1,2,3,5-oxathiadiazolin-4-yl, 4-hydroxypiperidinomethyl,
piperidinocarbonyl, 4-hydroxypiperidinocarbonyl,
3,4-dihydroxypiperidinocarbonyl, 1-piperazinylcarbonyl,
1-pyrrolidinylcarbonyl, morpholinocarbonyl,
4-thiomorpholinylcarbonyl, phenoxy, 2,4-dichlorophenoxy,
tetrahydropyranyloxy, 2-pyridylmethyloxy, 3-pyridylmethyloxy,
2-chloropyridin-4-ylmethyloxy, 4-pyridylmethyloxy,
2-piperidylmethyloxy, 3-piperidylmethyloxy, 4-piperidylmethyloxy,
1-methylpiperidin-4-ylmethyloxy, 1-acetylpiperidin-4-ylmethyloxy,
1-(tert-butoxycarbonyl)piperidin-4-ylmethyloxy,
1-(methylsulfonyl)piperidin-4-ylmethyloxy,
2-methylthiazolin-4-yloxy, 2,4-dimethylthiazolin-5-yloxy,
dimethylaminocarbonyl-methyloxy, piperidinocarbonylmethyloxy,
4-hydroxypiperidino-carbonylmethyloxy, 2-methylthiazol-4-yl,
(2-methylthiazol-4-yl)methyloxy,
(2,4-dimethylthiazol-5-yl)methyloxy, benzoyl, 3-fluorobenzoyl,
4-chlorobenzylamino, 3,5-dichlorobenzylamino,
4-trifluoromethylbenzylamino, 2-pyridylmethylamino, benzoylamino,
4-chlorobenzoylamino, 4-trifluoromethylbenzoylamino,
3,5-dichlorobenzoylamino, 3-nitro-4-methoxybenzoylamino,
4-nitro-3-methoxybenzoylamino, 3-pyridylcarbonylamino,
4-morpholinocarbonylamino, 2-oxazolinylamino,
4-hydroxypiperidinosulfonyl, methylphenylsulfonylamino,
2-thiazolylaminosulfonyl, 2-pyridylaminosulfonyl,
benzylaminocarbonyl, N-benzyl-N-methylaminocarbonyl,
(4-pyridylmethyl)aminocarbonyl or (cyclohexylmethyl)aminocarbonyl,
2-hydroxyethyloxy, 3-hydroxypropyloxy, 2-methoxyethoxy,
2-(2-methoxyethoxy)ethoxy, azetidinylcarbonyl,
3-hydroxypyrrolidinylcarbonyl, 3-hydroxypiperidinocarbonyl,
4-hydroxypiperidinocarbonyl, 3,4-dihydroxypiperidinocarbonyl,
4-methoxypiperidinocarbonyl, 4-carboxypiperidinocarbonyl,
4-(hydroxymethyl)piperidinocarbonyl, 2-oxopiperidinocarbonyl,
4-oxopiperidinocarbonyl, 2,6-dimethylpiperidinocarbonyl,
2,2,6,6-tetramethylpiperidinocarbonyl,
2,2,6,6-tetramethyl-4-hydroxypiperidinocarbonyl,
1-oxothiomorpholin-4-ylcarbonyl,
1,1-dioxothiomorpholin-4-ylcarbonyl,
1-(methylsulfonyl)piperidin-4-ylaminocarbonyl,
4-methylsulfonylpiperazinylcarbonyl, 4-methylpiperazinylcarbonyl,
N,N-bis(2-hydroxyethyl)aminocarbonyl, phenylaminocarbonyl,
cyclopropylaminocarbonyl, cyclobutylaminocarbonyl,
cyclohexylaminocarbonyl, 4-hydroxycyclohexylaminocarbonyl,
4-methylthiazol-2-ylmethylaminocarbonyl,
2-(4-hydroxypiperidino)ethyloxy, 2-pyridylmethylaminocarbonyl,
3-pyridylmethylaminocarbonyl,
N-methyl-N-(4-pyridylmethyl)aminocarbonyl, cyclohexylmethyloxy,
4-hydroxypiperidinocarbonylmethyloxy and
4-methylthiazol-2-ylmethyloxy.
[1254] Particularly preferable examples of the substituent include
fluorine atom, chlorine atom, bromine atom, nitro, cyano, methyl,
hydroxymethyl, carboxyl, carbamoyl, methylaminocarbonyl,
isopropylaminocarbonyl, dimethylaminocarbonyl,
diethylamino-carbonyl, (2-hydroxylethyl)aminocarbonyl,
(carboxymethyl)-aminocarbonyl, methoxy, 2-isopentenyloxy,
2-propynyloxy, methylthio, methylamino, dimethylamino, acetylamino,
N-acetyl-N-methylamino, N-acetyl-N-ethylamino,
N-acetyl-N-propylamino, N-acetyl-N-isopropylamino,
N-ethylcarbonyl-N-methylamino, N-ethyl-N-(ethylcarbonyl)amino,
methylsulfonylamino, methylsulfonyl, aminosulfonyl,
dimethylaminosulfonyl, tert-butylaminosulfonyl, phenyl,
3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl,
3,5-dichlorophenyl, 4-nitrophenyl, 4-methylphenyl,
4-tert-butylphenyl, 4-trifluoromethylphenyl,
4-(methoxymethyl)-phenyl, 4-(2-hydroxylethyl)phenyl,
3-carboxylphenyl, 4-carboxylphenyl, 4-methoxyphenyl,
4-carbamoylphenyl, 4-methylthiophenyl,
4-(dimethylaminocarbonyl)phenyl, 4-methylsulfonylphenyl, benzyl,
phenethyl, benzyloxy, 4-fluorobenzyloxy, 4-chlorobenzyloxy,
2-thiazolyl, 3-pyridyl, 4-pyridyl, 4-pyridylmethyloxy,
2-piperidylmethyloxy, 3-piperidylmethyloxy, 4-piperidylmethyloxy,
1-methylpiperidin-4-ylmethyloxy, 1-acetylpiperidin-4-ylmethyloxy,
2-chloropiperidin-4-ylmethyloxy,
1-(methylsulfonyl)piperidin-4-ylmethyloxy, 2-methylthiazol-4-yl,
(2-methylthiazol-4-yl)methyloxy,
(2,4-dimethylthiazol-5-yl)methyloxy, 5-tetrazolyl, 3-fluorobenzoyl,
piperidinocarbonyl, 4-hydroxylpiperidinocarbonyl,
1-pyrrolidinylcarbonyl, morpholinocarbonyl,
4-thiomorpholinylcarbonyl, benzylaminocarbonyl,
N-benzyl-N-methylaminocarbonyl, (4-pyridylmethyl)aminocarbonyl and
(cyclohexylmethyl)aminocarbonyl.
[1255] Most preferable substituents are fluorine atom, chlorine
atom, methyl, hydroxymethyl, carboxyl, carbamoyl,
methylaminocarbonyl, dimethylaminocarbonyl, methoxy, methylamino,
acetylamino, aminosulfonyl, dimethylaminosulfonyl,
tert-butylaminosulfonyl, phenyl, 3-fluorophenyl, 4-fluorophenyl,
3-chlorophenyl, 4-chlorophenyl, 3,5-dichlorophenyl, 4-methylphenyl,
4-tert-butylphenyl, 4-trifluoromethylphenyl, 4-carboxylphenyl,
4-methoxyphenyl, 4-carbamoylphenyl, 4-methylthiophenyl,
4-(dimethylaminocarbonyl)phenyl, 4-methylsulfonylphenyl and
2-oxopyrrolidin-1-yl.
[1256] The w is preferably 1 or 2, r and t are preferably 0, 1 or
2, particularly preferably 0 or 1, more preferably 0, p is
preferably 1, and q is preferably 0 or 2.
[1257] In formula [I], when X is ##STR57## wherein each symbol is
as defined above and w is 2 or above, one of Z is preferably
C.sub.6-14 aryl optionally substituted by 1 to 5 substituent(s)
selected from group D or heterocyclic group optionally substituted
by 1 to 5 substituent(s) selected from group D, particularly
preferably C.sub.6-14 aryl optionally substituted by 1 to 5
substituent(s) selected from group D.
[1258] When ring B is phenyl, w is 2 and phenyl is bonded to Y at
the 1-position, one of the most preferable embodiments is that
wherein Z is bonded to the 2-position and 5-position of phenyl, Z
at the 2-position is "C.sub.6-14 aryl optionally substituted by 1
to 5 substituent(s) selected from group D" and Z at the 5-position
is "heterocyclic group optionally substituted by 1 to 5
substituent(s) selected from group D".
[1259] The pharmaceutically acceptable salt may be any as long as
it forms a non-toxic salt with a compound of the above-mentioned
formula [I] or [II]. Such salt can be obtained by reacting the
compound with an inorganic acid, such as hydrochloric acid,
sulfuric acid, phosphoric acid, hydrobromic acid and the like, or
an organic acid, such as oxalic acid, malonic acid, citric acid,
fumaric acid, lactic acid, malic acid, succinic acid, tartaric
acid, acetic acid, trifluoroacetic acid, gluconic acid, ascorbic
acid, methylsulfonic acid, benzylsulfonic acid, meglumine acid and
the like, or an inorganic base, such as sodium hydroxide, potassium
hydroxide, calcium hydroxide, magnesium hydroxide, ammonium
hydroxide and the like, or an organic base, such as methylamine,
diethylamine, triethylamine, triethanolamine, ethylenediamine,
tris(hydroxymethyl)methylamine, guanidine, choline, cinchonine and
the like, with an amino acid, such as lysine, arginine, alanine and
the like. The present invention encompasses water-retaining
product, hydrate and solvate of each compound.
[1260] The compounds of the above-mentioned formula [I] or [II]
have various isomers. For example, E compound and Z compound are
present as geometric isomers, and when the compound has an
asymmetric carbon, an enantiomer and a diastereomer are present due
to the asymmetric carbon. A tautomer may be also present. The
present invention encompasses all of these isomers and mixtures
thereof.
[1261] The present invention also encompasses prodrug and
metabolite of each compound.
[1262] A prodrug means a derivative of the compound of the present
invention, which is capable of chemical or metabolic decomposition,
which shows inherent efficacy by reverting to the original compound
after administration to a body, and which includes salts and
complexes without a covalent bond.
[1263] When the inventive compound is used as a pharmaceutical
preparation, the inventive compound is generally admixed with
pharmaceutically acceptable carriers, excipients, diluents,
binders, disintegrators, stabilizers, preservatives, buffers,
emulsifiers, aromatics, coloring agents, sweeteners, thickeners,
correctives, solubilizers, and other additives such as water,
vegetable oil, alcohol such as ethanol, benzyl alcohol and the
like, polyethylene glycol, glycerol triacetate, gelatin, lactose,
carbohydrate such as starch and the like, magnesium stearate, talc,
lanolin, petrolatum and the like, and prepared into a dosage form
of tablets, pills, powders, granules, suppositories, injections,
eye drops, liquids, capsules, troches, aerosols, elixirs,
suspensions, emulsions, syrups and the like, which can be
administered systemically or topically and orally or
parenterally.
[1264] While the dose varies depending on the age, body weight,
general condition, treatment effect, administration route and the
like, it is from 0.1 mg to 1 g for an adult per dose, which is
given one to several times a day.
[1265] The prophylaxis of hepatitis C means, for example,
administration of a pharmaceutical agent to an individual found to
carry an HCV by a test and the like but without a symptom of
hepatitis C, or to an individual who shows an improved disease
state of hepatitis after a treatment of hepatitis C, but who still
carries an HCV and is associated with a risk of recurrence of
hepatitis.
[1266] The therapeutic agent for hepatitis C of the present
invention is expected to provide a synergestic effect when
concurrently used with other antiviral agents, antiinflammatory
agents or immunostimulants.
[1267] The medicaments with the prospect of synergestic effect
include, for example, interferon-.alpha., interferon-.beta.,
interferon-.gamma., interleukin-2, interleukin-8, interleukin-10,
interleukin-12, TNF.alpha., recombinant or modified products
thereof, agonists, antibodies, vaccines, ribozymes, antisense
nucleotides and the like.
[1268] As evidenced in the combination therapy of anti-HIV agents,
which is also called a cocktail therapy, the combined use of
various anti-virus agents againt viruses showing frequent genetic
mutations is expected to show effect for suppressing emergence and
increase of drug tolerant viruses. For example, 2 or 3 agents from
HCV-IRES inhibitors, HCV-NS3 protease inhibitors, HCV-NS2NS3
protease inhibitors, HCV-NS5A inhibitors and HCV polymerase
inhibitor may be used in combination. Specifically, the combined
use with Ribavirin.RTM., interferon-.alpha. (IFN-.alpha.,
Roferon.RTM., Intron A.RTM., Sumiferon.RTM., MultiFeron.RTM.,
Infergen.RTM., Omniferon.RTM., Pegasys.RTM., PEG-Intron A.RTM.),
interferon-.beta. (Frone.RTM., Rebif.RTM., AvoneX.RTM.,
IFN.beta.MOCHIDA.RTM.), interferon-.omega.,
1-.beta.-L-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide,
16.alpha.-bromo-3.beta.-hydroxy-5.alpha.-androstan-17-one,
1H-imidazole-4-ethanamide dihydrochloride, HCV ribozyme
Heptazyme.RTM., polyclonal antibody Civacir.RTM., lactoferrin
GPX-400, (1S,2R,8R,8aR)-1,2,8-trihydroxyoctahydroindolizidinium
chloride, HCV vaccine (MTH-68/B, Innivax C.RTM., Engerix B.RTM.,
antisense oligonucleotide ISIS-14803, HCV-RNA transcriptase
inhibitor VP-50406, tetrachlorodecaoxide (high concentration
Oxoferin.RTM.), tetrahydrofuran-3-yl
(S)-N-3-[3-(3-methoxy-4-oxazol-5-ylphenyl)ureido]benzylcarbamate,
4-amino-2-ethoxymethyl-.alpha.,.alpha.-dimethyl-1H-imidazo[4,5-c]quinolin-
e-1-ethanol, interleukin-2 (Proleukin.RTM.), thymosin .alpha.1 and
the like is exemplified, wherein (R) shows product names.
[1269] Furthermore, the combined use with the compounds disclosed
in JP-A-08-268890, JP-A-10-101591, JP-A-07-069899, WO99/61613 and
the like as HCV IRES inhibitors; the compounds disclosed in
WO98/22496, WO99/07733, WO99/07734, WO00/09543, WO00/09558,
WO01/59929, WO98/17679, EP932617, WO99/50230, WO00/74768,
WO97/43310, U.S. Pat. No. 5,990,276, WO01/58929, WO01/77113,
WO02/8198, WO02/8187, WO02/8244, WO02/8256, WO01/07407, WO01/40262,
WO01/64678, WO98/46630, JP-A-11-292840, JP-A-10-298151,
JP-A-11-127861, JP-A-2001-103993, WO98/46597, WO99/64442,
WO00/31129, WO01/32961, WO93/15730, U.S. Pat. No. 7,832,236,
WO00/200400, WO02/8251, WO01/16379, WO02/7761 and the like as HCV
protease inhibitors; the compounds disclosed in WO97/36554, U.S.
Pat. No. 5,830,905, WO97/36866, U.S. Pat. No. 5,633,388,
WO01/07027, WO00/24725 and the like as HCV helicase inhibitors; the
compounds disclosed in WO00/10573, WO00/13708, WO00/18231,
WO00/06529, WO02/06246, WO01/32153, WO01/60315, WO01/77091,
WO02/04425, WO02/20497, WO00/04141 and the like as HCV polymerase
inhibitors; the compounds disclosed in WO01/58877, JP-A-11-180981,
WO01/12214 and the like as interferon agonists or enhancers; and
the like is also exemplified.
[1270] Inasmuch as HCV is known to be a virus associated with many
genetic mutations, a compound effective for many genotypes is one
of the preferable modes. If a compound ensures high blood
concentration when administered as a pharmaceutical agent to an
animal infected with HCV, it is also one of the preferable modes.
From these aspects, a compound having high inhibitory activity on
both HCV type 1a and type 1b and high blood concentration, such as
2-{4-[2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy]-2-fluoropheny-
l}-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride, is
particularly preferable.
[1271] The fused ring compound of the formula [I] or [II] of the
present invention can be administered to mammals inclusive of human
for the purpose of prevention or treatment of hepatitis C or
inhibition of hepatitis C virus polymerase. The fused ring compound
of the present invention can be also administered to mammals
inclusive of human along with at least one pharmaceutical agent
(hereinafter combination drug) selected from an antiviral agent
other than the compound of the formula [I], an antiinflammatory
agent and an immunostimulant for the purpose of prevention or
treatment of hepatitis C or inhibition of hepatitis C virus
polymerase. In the case of combined administration, the compound of
the present invention can be administered simultaneously with the
combination drug or administered at certain time intervals. In the
case of combined administration, a pharmaceutical composition
containing the compound of the present invention and a combination
drug can be administered. Alternatively, a pharmaceutical
composition containing the compound of the present invention and a
pharmaceutical composition containing a combination drug may be
administered separately. The administration route may be the same
or different.
[1272] In the case of a combined administration, the compound of
the present invention can be administered once a day or several
times a day in a single dose of 0.1 mg to 1 g, or may be
administered in a smaller dose. The combination drug can be
administered in a dose generally used for the prevention or
treatment of hepatitis C or in a smaller dose.
[1273] Examples of other antiviral agent include interferons
(interferon .alpha., interferon .beta., interferon .gamma. etc.),
Ribavirin
(1-.beta.-D-ribofuranosyl-1H-1,2,4-triazole-3-carboxamide) and the
like.
[1274] Examples of the production method of the compound to be used
for the practice of the present invention are given in the
following. However, the production method of the compound of the
present invention is not limited to these examples.
[1275] Even if no directly corresponding disclosure is found in the
following Production Methods, the steps may be modified for
efficient production of the compound, such as introduction of a
protecting group into a functional group with deprotection in a
subsequent step, and changing the order of Production Methods and
steps.
[1276] The treatment after reaction in each step may be
conventional ones, for which typical methods, such as isolation and
purification, crystallization, recrystallization, silica gel
chromatography, preparative HPLC and the like, can be appropriately
selected and combined.
Production Method 1
[1277] In this Production Method, a benzimidazole compound is
formed from a nitrobenzene compound. Production Method 1-1
##STR58## wherein Hal is halogen atom, such as chlorine atom,
bromine atom and the like, R.sup.c1 is halogen atom, such as
chlorine atom, bromine atom and the like, or hydroxyl group, and
other symbols are as defined above. Step 1
[1278] A compound [1] obtained by a conventional method or a
commercially available compound [1] is reacted with amine compound
[2] in a solvent such as N,N-dimethylformamide (DMF), acetonitrile,
tetrahydrofuran (THF), toluene and the like in the presence or
absence of a base such as potassium carbonate, triethylamine,
potassium t-butoxide and the like at room temperature or with
heating to give compound [3].
Step 2
[1279] The compound [3] is hydrogenated in a solvent such as
methanol, ethanol, THF, ethyl acetate, acetic acid, water and the
like in the presence of a catalyst such as palladium carbon,
palladium hydroxide, platinum oxide, Raney nickel and the like at
room temperature or with heating to give compound [4]. In addition,
compound [3] is reduced with a reducing agent such as zinc, iron,
tin(II) chloride, sodium sulfite and the like, or reacted with
hydrazine in the presence of iron(III) chloride to give compound
[4]. The compound [4] can be also obtained by reacting compound [3]
with sodium hydrosulfite under alkaline conditions.
Step 3
[1280] The compound [4] is condensed with carboxylic acid compound
[5] in a solvent such as DMF, acetonitrile, THF, chloroform, ethyl
acetate, methylene chloride, toluene and the like using a
condensing agent such as dicyclohexylcarbodiimide,
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,
diphenylphosphoryl azide and the like and, where necessary, adding
N-hydroxysuccinimide, 1-hydroxybenzotriazole and the like to give
amide compound [6]. Alternatively, amide compound [6] can be
obtained from compound [5] as follows. The carboxylic acid compound
[5] is converted to an acid halide derived with thionyl chloride,
oxalyl chloride and the like, or an active ester (e.g., mixed acid
anhydride derived with ethyl chlorocarbonate and the like), which
is then reacted in the presence of a base, such as triethylamine,
potassium carbonate, pyridine and the like, or in an amine solvent,
such as pyridine and the like, to give amide compound [6].
Step 4
[1281] The compound [6] is heated in a solvent such as ethanol,
methanol, toluene, DMF, chloroform and the like or without a
solvent in the presence of an acid such as acetic acid, formic
acid, hydrochloric acid, dilute sulfuric acid, phosphoric acid,
polyphosphoric acid, p-toluenesulfonic acid and the like, a
halogenating agent such as zinc chloride, phosphorus oxychloride,
thionyl chloride and the like or acid anhydride such as acetic
anhydride and the like, to allow cyclization to give compound
[1-2].
Production Method 1-2
[1282] This Production Method is an alternative method for
producing compound [I-2]. ##STR59## wherein each symbol is as
defined above. Step 1
[1283] The compound [3] obtained in the same manner as in Step 1 of
Production Method 1-1 is subjected to amide condensation with
compound [5] in the same manner as in Step 3 of Production Method
1-1 to give compound [7].
Step 2
[1284] The compound [7] is reduced in the same manner as in Step 2
of Production Method 1-1 to give compound [8].
Step 3
[1285] The compound [8] is subjected to cyclization in the same
manner as in Step 4 of Production Method 1-1 to give compound
[I-2]. Production Method 1-3 ##STR60## wherein R.sup.c2 is alkyl
such as methyl, ethyl and the like, and other symbols are as
defined above.
[1286] The compound [4] is reacted with imidate compound [9] in a
solvent such as methanol, ethanol, acetic acid, DMF, THF,
chloroform and the like at room temperature or with heating to give
compound [I-2].
[1287] In addition, compound [4] may be reacted with aldehyde
compound [10] in a solvent such as acetic acid, formic acid,
acetonitrile, DMF, nitrobenzene, toluene and the like in the
presence or absence of an oxidizing agent such as benzofuroxan,
manganese dioxide, 2,3-dichloro-5,6-dicyano-p-benzoquinone, iodine,
potassium ferricyanide and the like with heating to give compound
[I-2].
[1288] Alternatively, compound [4] and carboxylic acid compound
[11] may be heated to allow reaction in the presence of
polyphosphoric acid, phosphoric acid, phosphorus oxychloride,
hydrochloric acid and the like to give compound [I-2].
Production Method 2
[1289] In this Production Method, conversion of the substituents
(R.sup.1, R.sup.2, R.sup.3, R.sup.4) on the benzene ring of
benzimidazole is shown. While a method of converting R.sup.2 when
R.sup.1, R.sup.3 and R.sup.4 are hydrogen atoms is shown, this
Production Method is applicable irrespective of the position of
substitution.
Production Method 2-1
[1290] Conversion of Carboxylic Acid Ester Moiety to Amide
##STR61## wherein E is a single bond, --(CH.sub.2)--,
--O--(CH.sub.2)-- or --NH--(CH.sub.2).sub.s-- (wherein s is an
integer of 1 to 6), R.sup.c3, R.sup.c4 and R.sup.c5 are
C.sub.1-6alkyl, and other symbols are as defined above. Step 1
[1291] The compound [I-2-1] obtained in the same manner as in the
above-mentioned Production Method is subjected to hydrolysis in a
solvent such as methanol, ethanol, THF, dioxane and the like, or in
a mixed solvent of these solvents and water under basic conditions
with sodium hydroxide, potassium hydroxide, potassium carbonate,
lithium hydroxide and the like or under acidic conditions with
hydrochloric acid, sulfuric acid and the like to give compound
[I-2-2].
Step 2
[1292] The compound [I-2-2] is reacted with compound [12] in the
same manner as in Step 3 of Production Method 1-1 to give compound
[I-2-3].
Production Method 2-2
[1293] Conversion of cyano group to substituted amidino group
##STR62## wherein each symbol is as defined above.
[1294] The compound [I-2-4] obtained in the same manner as in the
above-mentioned Production Method is reacted with hydroxylamine in
a solvent such as water, methanol, ethanol, THF, DMF and the like
to give compound [I-2-5]. When a salt of hydroxylamine such as
hydrochloride and the like is used, the reaction is carried out in
the presence of a base such as sodium hydrogencarbonate, sodium
hydroxide, triethylamine and the like.
Production Method 2-3
[1295] Conversion of sulfonic acid ester moiety to sulfonic acid
##STR63## wherein R.sup.c6 is C.sub.1-6 alkyl, and other symbols
are as defined above.
[1296] The compound [I-2-6] obtained in the same manner as in the
above-mentioned Production Method is reacted with iodide salt such
as sodium iodide, lithium iodide and the like, bromide salt such as
sodium bromide, trimethylammonium bromide and the like, amine such
as pyridine, trimethylamine, triazole and the like, phosphine such
as triphenylphosphine and the like in a solvent such as DMF,
dimethyl sulfoxide (DMSO), acetonitrile, methanol, ethanol, water
and the like with heating to give compound [I-2-7].
Production Method 3
[1297] This Production Method relates to convertion of the
substituent(s) on phenyl group at the 2-position of benzimidazole.
This Production Method can be used even when phenyl is a different
ring.
Production Method 3-1
[1298] Conversion of hydroxyl group to ether ##STR64## wherein
R.sup.c7 is optionally substituted alkyl corresponding to
R.sup.a11, G.sup.1 is a single bond, *--(CH.sub.2).sub.n--,
*--(CH.sub.2).sub.n--O--, *--(CH.sub.2)--CO-- or
*--(CH.sub.2).sub.m--CR.sup.a15R.sup.a16)--(CH.sub.2).sub.n--,
wherein * show the side to be bonded to R.sup.c1 and other symbols
are as defined above.
[1299] When R.sup.c1 of compound [13] is halogen atom, compound
[I-2-8] obtained in the same manner as in the above-mentioned
Production Method is reacted with compound [13] in a solvent such
as DMF, DMSO, acetonitrile, ethanol, THF and the like in the
presence of a base such as sodium hydride, sodium hydroxide,
potassium hydroxide, potassium carbonate, sodium ethoxide,
potassium t-butoxide and the like at room temperature or with
heating to give compound [II-2-1].
[1300] When R.sup.c1 of compound [13] is hydroxyl group, the
hydroxyl group of compound [13] is converted to halogen atom with
thionyl chloride, phosphorus tribromide, carbon
tetrabromide-triphenylphosphine and the like and reacted with
compound [I-2-8] by the aforementioned method to give compound
[II-2-1]. In this case, compound [I-2-8] may be subjected to
Mitsunobu reaction with compound [13] in a solvent such as DMF,
acetonitrile, THF and the like using triphenylphosphine-diethyl
azodicarboxylate and the like to give compound [II-2-1].
[1301] The compound [I-2-9] can be obtained in the same manner from
compound [I-2-8] and compound [14].
Production Method 3-2
[1302] Conversion of nitro to substituted amino group ##STR65##
wherein R.sup.c8 is C.sub.1-6alkyl, G.sup.2 is *--(CH.sub.2)-- or
*--CHR.sup.a15, G.sup.3 is --CO--, *--CO.sub.2--, *--CONH-- or
--SO.sub.2--, and other symbols are as defined above. Step 1
[1303] The nitro compound [I-2-10] obtained in the same manner as
in the above-mentioned Production Method is reacted in the same
manner as in Step 2 of Production Method 1-1 to give compound
[I-2-11].
Step 2
[1304] The compound [I-2-11] is alkylated with compound [15] in the
same manner as in Production Method 3-1 to give compound
[II-2-2].
Step 3
[1305] When G.sup.3 of compound [16] is --CO--, --CO.sub.2-- or
--CONH--, compound [I-2-11] is acylated with compound [16] in the
same manner as in Step 3 of Production Method 1-1 to give compound
[II-2-3].
[1306] When G.sup.3 of compound [16] is --SO.sub.2--, sulfonylation
is conducted using sulfonyl halide instead of acid halide used in
Step 3 of Production Method 1-1 to give compound [II-2-3].
[1307] The compound [I-2-11] is acylated with compound [17] in the
same manner as above to give compound [I-2-12].
[1308] This Production Method is applied in the same manner as
above to give disubstituted compounds (tertiary amine) of compound
[II-2-2], compound [II-2-3] and compound [I-2-12].
Production Method 3-3
[1309] Conversion of carboxylic acid ester moiety to amide
##STR66## wherein R.sup.c9 is C.sub.1-6 alkyl, G.sup.4 is
#--(CH.sub.2).sub.n--, #--(CH.sub.2).sub.n--NH-- or
#--CHR.sup.a14-- wherein # shows the side that is bounded to amine
and other symbols are as defined above. Step 1
[1310] The compound [I-2-13] obtained in the same manner as in the
above-mentioned Production Method is reacted in the same manner as
in Step 1 of Production Method 2-1 to give compound [I-2-14].
Step 2
[1311] The compound [I-2-14] is reacted with compound [18] in the
same manner as in Step 2 of Production Method 2-1 to give compound
[II-2-4].
[1312] The compound [I-2-15] is obtained from compound [I-2-14] and
compound [19] in the same manner as above.
Production Method 4
[1313] In this Production Method, additional substituent(s) is(are)
introduced into ring B on phenyl group that substitutes the
2-position of benzimidazole. This Production Method is applicable
even when phenyl is a different ring.
Production Method 4-1
[1314] Direct Bonding of Ring Z'' to Ring B ##STR67## wherein ring
Z''-M is aryl metal compound, ring Z'' moiety is optionally
substituted C.sub.6-14 aryl or optionally substituted heterocyclic
group corresponding to substituent Z, and the metal moiety contains
boron, zinc, tin, magnesium and the like, such as phenylboronic
acid, w'' is 0, 1 or 2, and other symbols are as defined above.
[1315] The compound [II-2-5] obtained in the same manner as in the
above-mentioned Production Method is reacted with aryl metal
compound [20] in a solvent such as DMF, acetonitrile,
1,2-dimethoxyethane, THF, toluene, water and the like in the
presence of a palladium catalyst such as
tetrakis(triphenylphosphine)-palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like, a nickel catalyst such as
nickel chloride, [1,3-bis(diphenylphosphino)-propane]nickel(II)
chloride and the like, and a base such as potassium carbonate,
potassium hydrogencarbonate, sodium hydrogen-carbonate, potassium
phosphate, triethylamine and the like at room temperature or with
heating, to give compound [II-2-6].
Production Method 4-2
[1316] Conversion of hydroxyl group to ether ##STR68## wherein
R.sup.c10 is --R.sup.a20 or --(CH.sub.2).sub.p--COR.sup.a21
corresponding to substituent Z, and other symbols are as defined
above.
[1317] The compound [II-2-7] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [21] in
the same manner as in Production Method 3-1 to give compound
[II-2-8].
Production Method 4-3
[1318] Synthesis in advance of ring B part such as compound [13] in
Production Method 3-1 ##STR69## wherein R.sup.c11 is leaving group
such as chlorine atom, bromine atom, iodine atom,
trifluoromethanesulfonyloxy and the like, R.sup.c12 is formyl,
carboxyl or carboxylic acid ester such as methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl and the like, and other symbols
are as defined above. Step 1
[1319] Commercially available compound [22] or compound [22]
obtained by a conventional method is reacted with aryl metal
compound [20] in the same manner as in Production Method 4-1 to
give compound [23].
Step 2
[1320] The compound [23] obtained in the same manner as in the
above-mentioned Production Method is reduced according to a
conventional method to give compound [24].
[1321] For example, compound [23] is reacted with in a solvent such
as methanol, ethanol, THF and the like in the presence of a
reducing agent such as lithium aluminum hydride, sodium borohydride
and the like under cooling to heating to give compound [24].
Step 3
[1322] The compound [24] obtained in the same manner as in the
above-mentioned Production Method is reacted in a solvent such as
1,4-dioxane, diethyl ether, THF, dichloromethane, chloroform,
toluene and the like with a halogenating agent, such as phosphorus
pentachloride, phosphorus tribromide, thionyl chloride and the
like, to give compound [25]. For an accerelated reaction, the
reaction may be carried out in the presence of a tertiary amine
such as DMF, pyridine and the like, or under heating.
Step 4
[1323] The compound [24] or [25] obtained in the same manner as in
the above-mentioned Production Method is reacted with compound
[I-2-8] in the same manner as in Production Method 3-1 to give
compound [II-2-9]. Production Method 4-4 ##STR70## wherein M' is a
metal such as magnesium, lithium, zinc and the like, and other
symbols are as defined above. Step 1
[1324] Commercially available compound [41] or compound [41]
obtained by a conventional method is converted to aryl metal
reagent by a conventional method to give compound [42].
[1325] For example, when M' is magnesium, magnesium is reacted with
compound [41] in a solvent such as THF, diethyl ether, benzene,
toluene and the like, preferably THF, from cooling to heating
preferably at -100.degree. C. to 100.degree. C. to give compound
[42].
Step 2
[1326] The compound [42] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [43] to
give compound [44].
[1327] The compound [42] is reacted in a solvent such as diethyl
ether, benzene, toluene, THF and the like, preferably THF, from
cooling to room temperature, preferably at -100.degree. C. to
30.degree. C. to give compound [44].
Step 3
[1328] The compound [44] obtained in the same manner as in the
above-mentioned Production Method is halogenated in the same manner
as in Step 3 of Production Method 4-3 to give compound [45].
[1329] The compound [44] is reacted with thionyl chloride and
pyridine preferably in toluene solvent to give compound [45].
[1330] When compound [45] is symmetric, namely, when the ring
B-(Z)w moiety and the ring B'-(Z')w' moiety are the same, compound
[42] is reacted with formate such as methyl formate, ethyl formate
and the like, preferably ethyl formate, in a solvent such as
diethyl ether, benzene, toluene, THF and the like, preferably THF,
from cooling to room temperature, preferably at -100.degree. C. to
30.degree. C., to give compound [45].
Production Method 4-5
[1331] Method including steps to introduce a protecting group into
a functional group ##STR71## ##STR72## wherein R.sup.c13 is
carboxylic acid protecting group such as tert-butyl and the like,
R.sup.c14 is carboxylic acid protecting group such as methyl and
the like and other symbols are as defined above. Step 1
[1332] Commercially available compound [26] or compound [26]
obtained by a conventional method is protected by a conventional
method to give compound [27].
[1333] For example, when R.sup.c13 is tert-butyl, compound [26] is
converted to acid halide with thionyl chloride, oxalyl chloride and
the like in a solvent such as THF, chloroform, dichloromethane,
toluene and the like, and reacted with potassium tert-butoxide to
give compound [27].
[1334] As used herein, R.sup.c13 may be a different protecting
group as long as it is not removed during the Step 2 or Step 3 but
removed in Step 4 without affecting --CO.sub.2R.sup.c14.
Step 2
[1335] The methyl group of compound [27] obtained in the same
manner as in the above-mentioned Production Method is converted to
bromomethyl with N-bromosuccinimide and N,N'-azobisisobutyronitrile
and reacted with compound [I-2-16] in the same manner as in
Production Method 3-1 to give compound [II-2-10].
Step 3
[1336] The compound [II-2-10] obtained in the same manner as in the
above-mentioned Production Method is reacted with aryl metal
compound [20] in the same manner as in Production Method 4-1 to
give compound [II-2-11].
Step 4
[1337] The R.sup.c13 of the compound [II-2-11] obtained in the same
manner as in the above-mentioned Production Method is removed by a
conventional method to give compound [II-2-12].
[1338] The protecting group of carboxylic acid can be removed by a
conventional deprotection method according to the protecting group.
In this Step, the conditions free from reaction of R.sup.c14 are
preferable. For example, when R.sup.c13 is tert-butyl, compound
[II-2-11] is treated with trifluoroacetic acid in a solvent such as
dichloromethane, chloroform and the like to give compound
[II-2-12].
Step 5
[1339] The compound [II-2-12] obtained in the same manner as in the
above-mentioned Production Method is subjected to amide
condensation with compound [28] in the same manner as in Step 3 of
Production Method 1-1 to give compound [II-2-13].
Step 6
[1340] The compound [II-2-13] obtained in the same manner as in the
above-mentioned Production Method is deprotected in the same manner
as in Step 1 of Production Method 2-1 to give compound
[II-2-14].
[1341] As used herein, R.sup.c14 is preferably a protecting group
that does not react during the Step 1 through Step 5 but removed in
this Step.
[1342] For example, when R.sup.c14 is methyl, compound [II-2-13] is
reacted in an alcohol solvent such as methanol, ethanol,
n-propanol, isopropanol and the like or a mixed solvent of alcohol
solvent and water in the presence of a base such as potassium
carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide,
potassium hydroxide and the like from cooling to heating for
deprotection, followed by acidifying the reaction solution to give
compound [II-2-14]. Production Method 4-6 ##STR73## wherein g is an
integer of 1 to 5, and other sumbols are as defined above. Step
1
[1343] The compound [I-2-16] obtained by the above-mentioned
Production Method is reacted with toluene derivative [41] in the
same manner as in Step 2 of Production Method 4-5 to give compound
[II-2-17].
Step 2
[1344] The compound [II-2-17] obtained by the above-mentioned
Production Method is reacted with aryl metal compound [20] in the
same manner as in Production Method 4-1 to give compound
[II-2-18].
Step 3
[1345] The compound [II-2-18] obtained by the above-mentioned
Production Method is reduced in the same manner as in Step 2 of
Production Method 1-1 to give compound [II-2-19].
Step 4
[1346] The compound [II-2-19] obtained by the above-mentioned
Production Method is amide condensed with compound [42] in the same
manner as in Step 3 of Production Method 1-1 and subjected to
cyclization in the same manner as in Step 1 of Production Method
1-1 to give compound [II-2-20].
Step 5
[1347] The compound [II-2-20] obtained by the above-mentioned
Production Method is hydrolyzed in the same manner as in Step 1 of
Production Method 2-1 to give compound [II-2-21]. Production Method
4-7 ##STR74## ##STR75## wherein each symbol is as defined above.
Step 1
[1348] Commercially available product or compound [46] obtained by
a conventional method is reacted with compound [20] in the same
manner as in Production Method 4-1 to give compound [47].
Step 2
[1349] The compound [47] obtained in the same manner as in the
above-mentioned Production Method is reduced in the same manner as
in the above-mentioned Production Method 4-3 Step 2 to give
compound [48].
Step 3
[1350] The compound [48] obtained in the same manner as in the
above-mentioned Production Method is reduced in the same manner as
in the above-mentioned Production Method 1-1 Step 2 to give
compound [49].
Step 4
[1351] The compound [49] obtained in the same manner as in the
above-mentioned Production Method is reacted with compound [42] in
a solvent such as DMF, acetonitrile, THF, chloroform, ethyl
acetate, methylene chloride and toluene to give compound [50]. To
enhance the reaction selectivity for amino group, acetic acid and
sodium acetate may be added in an equivalent amount ratio.
Step 5
[1352] The compound [50] obtained in the same manner as in the
above-mentioned Production Method is subjected to cyclization
reaction in the same manner as in the above-mentioned Production
Method 1-1 Step 1 to give compound [51].
Step 6
[1353] The compound [51] obtained in the same manner as in the
above-mentioned Production Method is halogenated in the same manner
as in the above-mentioned Production Method 4-3 Step 3 to give
compound [52].
Step 7
[1354] The compound [52] obtained in the same manner as in the
above-mentioned Production Method is reacted in the same manner as
in the above-mentioned Production Method 3-1 with compound [I-2-16]
obtained in the same manner as in the above-mentioned Production
Method to give compound [II-2-20].
Step 8
[1355] The compound [II-2-20] obtained in the same manner as in the
above-mentioned Production Method is hydrolyzed in the same manner
as in the above-mentioned Production Method 2-1 Step 1 to give
compound [II-2-21].
Production Method 5
[1356] Formation of indole ring ##STR76## wherein R.sup.C15 is
protecting group such as trimethylsilyl, tert-butyldimethylsilyl,
tert-butyldiphenylsilyl and the like, and other symbols are as
defined above. Step 1
[1357] The compound [29] obtained in the same manner as in the
above-mentioned Production Method or conventional method is reacted
with compound [30] in a solvent such as DMF, acetonitrile,
1,2-dimethoxyethane, THF, toluene, water and the like using a
palladium catalyst such as tetrakis(triphenylphosphine)palladium,
bis(triphenylphosphine)palladium(II) dichloride, palladium
acetate-triphenylphosphine and the like, a copper catalyst such as
copper(I) iodide and the like or a mixture thereof, and in the
presence of a base such as potassium carbonate, potassium
hydrogencarbonate, sodium hydrogencarbonate, potassium phosphate,
triethylamine and the like to give compound [31].
Step 2
[1358] The compound [31] obtained in the same manner as in the
above-mentioned Production Method is reacted in an alcohol solvent
such as methanol, ethanol and the like or a mixed solvent of an
alcohol solvent and a solvent such as DMF, acetonitrile, THF,
chloroform, dichloromethane, ethyl acetate, methylene chloride,
toluene and the like in the presence of a base such as potassium
carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide,
potassium hydroxide, lithium hydride, sodium hydride, potassium
hydride and the like at room temperature or with heating for
deprotection, and reacted with compound [32] obtained in the same
manner as in Step 1 of Production Method 1-1 in the same manner as
in Step 1 of Production Method 5 to give compound [33].
step 3
[1359] The compound [33] obtained in the same manner as in the
above-mentioned Production Method was subjected to cyclization in a
solvent such as DMF, acetonitrile, THF, chloroform,
dichloromethane, ethyl acetate, methylene chloride, toluene and the
like in the presence of a copper catalyst such as copper(I) iodide
and the like or a palladium catalyst such as palladium(II) chloride
and the like at room temperature or with heating to give compound
[II-2-15].
Production Method 6
[1360] Formation of imidazo[1,2-a]pyridine ring ##STR77## wherein
R.sup.c16 and R.sup.c17 are each independently alkyl, such as
methyl, ethyl and the like, and other symbols are as defined above.
Step 1
[1361] The compound [34] obtained by the above-mentioned Production
Method or a conventional method is subjected to amide condensation
with compound [35] in the same manner as in Step 3 of Production
Method 1-1 to give compound [36].
Step 2
[1362] The compound [36] obtained by the above-mentioned Production
Method is reacted with Grignard reagent [37] obtained by a
conventional method to give compound [38].
[1363] Alternatively, an acid halide of compound [34] may be used
instead of compound [36].
Step 3
[1364] The compound [38] obtained by the above-mentioned Production
Method is subjected to halogenation by a conventional method to
give compound [39].
[1365] For example, when Hal is a bromine atom, compound [38] is
reacted with bromine under cooling or at room temperature in a
solvent such as DMF, acetonitrile, THF, chloroform,
dichloromethane, ethyl acetate, toluene and the like to give
compound [39].
[1366] Alternatively, a halogenating agent such as hypohalite
(e.g., hypochlorite and the like), N-bromosuccinimide and the like
may be used instead of bromine for halogenation.
Step 4
[1367] The compound [39] obtained by the above-mentioned Production
Method is subjected to cyclization with compound [40] obtained by a
conventional or known method (JP-A-8-48651) in the presence of a
base such as potassium carbonate, sodium carbonate, lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium hydride,
sodium hydride, potassium hydride and the like in a solvent or
without a solvent at room temperature or with heating to give
compound [II-2-16].
[1368] In the compounds of the formulas [I] and [II], a desired
heterocyclic group can be formed according to a method similar to
the methods disclosed in known publications. Examples of such
heterocyclic group and reference publications are recited in the
following. [1369] 5-oxo-.DELTA..sup.2-1,2,4-oxadiazolin-3-yl (or
2,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl),
5-oxo-.DELTA..sup.2-1,2,4-thiadiazolin-3-yl (or
2,5-dihydro-5-oxo-4H-1,2,4-thiadiazol-3-yl),
2-oxo-.DELTA..sup.3-1,2,3,5-oxathiadiazolin-4-yl (or
2-oxo-.DELTA..sup.3-1,2,4-oxathiadiazol-4-yl): Journal of Medicinal
Chemistry, 39(26), 5228-35, 1996, [1370]
5-oxo-.DELTA..sup.2-1,2,4-triazolin-3-yl: J Org Chem, 61(24),
8397-8401, 1996, [1371]
1-oxo-.DELTA..sup.3-1,2,3,5-thiatriazolin-4-yl: Liebigs Ann Chem,
1376, 1980, [1372] 3-oxo-.DELTA..sup.4-1,2,4-oxadiazolin-5-yl:
EP145095, [1373] 5-oxo-.DELTA..sup.2-1,3,4-oxadiazolin-2-yl: J Org
Chem, 20, 412, 1955, [1374]
5-oxo-.DELTA..sup.3-1,2,4-dioxazolin-3-yl: J Prakt Chem, 314, 145,
1972, [1375] 3-oxo-.DELTA..sup.4-1,2,4-thiadiazolin-5-yl:
JP-A-61-275271, [1376] 5-oxo-.DELTA..sup.3-1,2,4-dithiazolin-3-yl:
J Org Chem, 61(19), 6639-6645, 1996, [1377]
2-oxo-.DELTA..sup.4-1,3,4-dioxazolin-5-yl: J Org Chem, 39, 2472,
1974, [1378] 2-oxo-.DELTA..sup.4-1,3,4-oxathiazolin-5-yl: J Med
Chem, 35(20), 3691-98, 1992, [1379]
5-oxo-.DELTA..sup.2-1,3,4-thiadiazolin-2-yl: J Prakt Chem, 332(1),
55, 1990, [1380] 5-oxo-.DELTA..sup.2-1,4,2-oxathiazolin-3-yl: J Org
Chem, 31, 2417, 1966, [1381]
2-oxo-.DELTA..sup.4-1,3,4-dithiazolin-5-yl: Tetrahedron Lett, 23,
5453, 1982, [1382] 2-oxo-.DELTA..sup.4-1,3,2,4-dioxathiazolin-5-yl:
Tetrahedron Lett, 319, 1968, [1383] 3,5-dioxoisooxazolidin-4-yl:
Helv Chim Acta, 1973, 48, 1965, [1384] 2,5-dioxoimidazolidin-4-yl:
Heterocycles, 43(1), 49-52, 1996, [1385]
5-oxo-2-thioxoimidazolidin-4-yl: Heterocycles, 5, 391, 1983, [1386]
2,4-dioxooxazolidin-5-yl: J Am Chem Soc, 73, 4752, 1951, [1387]
4-oxo-2-thioxooxazolidin-5-yl: Chem Ber, 91, 300, 1958, [1388]
2,4-dioxothiazolidin-5-yl: JP-A-57-123175, [1389]
4-oxo-2-thioxothiazolidin-5-yl: Chem Pharm Bull, 30, 3563,
1982,
[1390] The Production Methods shown in the above-mentioned
Production Methods 2 to 4 can be used for the synthesis of
compounds other than benzimidazole of the formulas [I] and [II],
such as compounds [II-2-15] and [II-2-16].
[1391] The compounds of the formulas [I], [II] and [III],
4-(4-fluorophenyl)-5-hydroxymethyl-2-methylthiazole and
4-(4-fluorophenyl)-5-chloromethyl-2-methylthiazole and production
methods thereof of the present invention are explained in detail in
the following by way of Examples. It is needless to say that the
present invention is not limited by these Examples.
EXAMPLE 1
Production of ethyl
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
Step 1: Production of ethyl 4-chloro-3-nitrobenzoate
[1392] 4-Chloro-3-nitrobenzoic acid (300 g) was dissolved in ethyl
alcohol (1500 ml) and concentrated sulfuric acid (100 ml) was added
with ice-cooling. The mixture was refluxed under heating for 7 hr.
The reaction mixture was poured into ice-cold water and the
precipitated crystals were collected by filtration to give the
title compound (332 g, yield 97%).
[1393] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.50(1H, d, J=2.1 Hz),
8.16(1H, dd, J=8.4, 2.1 Hz), 7.63(1H, d, J=8.4 Hz), 4.43(2H, q,
J=7.5 Hz), 1.42(3H, t, J=7.5 Hz)
Step 2: Production of ethyl 4-cyclohexylamino-3-nitrobenzoate
[1394] Ethyl 4-chloro-3-nitrobenzoate (330 g) obtained in the
previous step was dissolved in acetonitrile (1500 ml), and
cyclohexylamine (220 g) and triethylamine (195 g) were added. The
mixture was refluxed under heating overnight. The reaction mixture
was poured into ice-cold water and the precipitated crystals were
collected by filtration to give the title compound (400 g, yield
94%).
[1395] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.87(1H, d, J=2.1 Hz),
8.35-8.46(1H, m), 8.02(1H, dd, J=9.1, 2.1 Hz), 6.87(1H, d, J=9.1
Hz), 4.35(2H, q, J=7.1 Hz), 3.65-3.50(1H, m), 2.14-1.29(10H, m),
1.38(3H, t, J=7.1 Hz)
Step 3: Production of ethyl 3-amino-4-cyclohexylaminobenzoate
[1396] Ethyl 4-cyclohexylamino-3-nitrobenzoate (400 g) obtained in
the previous step was dissolved in ethyl acetate (1500 ml) and
ethyl alcohol (500 ml), and 7.5% palladium carbon (50% wet, 40 g)
was added. The mixture was hydrogenated for 7 hr at atmospheric
pressure. The catalyst was filtered off and the filtrate was
concentrated under reduced pressure. Diisopropyl ether was added to
the residue and the precipitated crystals were collected by
filtration to give the title compound (289 g, yield 80%).
[1397] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.57(1H, dd, J=8.4, 1.9
Hz), 7.41(1H, d, J=1.9 Hz), 6.59(1H, d, J=8.4 Hz), 4.30(2H, q,
J=7.1 Hz), 3.40-3.30(1H, m), 2.18-2.02(2H, m), 1.88-1.15(8H, m),
1.35(3H, t, J=7.1 Hz)
Step 4: Production of ethyl
3-[4-(3-bromophenoxy)benzoyl]amino-4-cyclohexylaminobenzoate
[1398] 4-(3-Bromophenoxy)benzoic acid (74 g) was dissolved in
chloroform (500 ml), and oxalyl chloride (33 ml) and
dimethylformamide (catalytic amount) were added. The mixture was
stirred for 4 hr at room temperature. The reaction mixture was
concentrated under reduced pressure and dissolved in
dichloromethane (150 ml). The resulting solution was added dropwise
to a solution of ethyl 3-amino-4-cyclohexylaminobenzoate (66 g)
obtained in the previous step in dichloromethane (500 ml) and
triethylamine (71 ml), and the mixture was stirred for 1 hr at room
temperature. The reaction mixture was poured into water and
extracted with dichloromethane. The organic layer was washed with
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. Diethyl ether was added to the
residue for crystallization and the crystals were collected by
filtration to give the title compound (129 g, yield 95%).
[1399] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.00-7.78(4H, m),
7.66(1H, brs), 7.37-7.18(3H, m), 7.13-6.59(3H, m), 6.72(1H, d,
J=8.7 Hz), 4.50(1H, brs), 4.29(2H, q, J=7.2 Hz), 3.36(1H, m),
2.12-1.96(2H, m), 1.83-1.56(3H, m), 1.47-1.12(5H, m), 1.37(3H, t,
J=7.2 Hz)
Step 5: Production of ethyl
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
[1400] Ethyl
3-[4-(3-bromophenoxy)benzoyl]amino-4-cyclohexylaminobenzoate (129
g) obtained in the previous step was suspended in acetic acid (600
ml) and the resulting suspension was refluxed under heating for 3
hr. The reaction mixture was concentrated under reduced pressure.
Water was added to the residue and the precipitated crystals were
collected by filtration to give the title compound (124 g, yield
99%).
[1401] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.51(1H, d, J=1.5 Hz),
8.00(1H, dd, J=8.4, 1.5 Hz), 7.67(1H, d, J=8.4 Hz), 7.63(2H, d,
J=8.7 Hz), 7.35-7.21(3H, m), 7.17(2H, d, J=8.7 Hz), 7.14(1H, m),
4.42(2H, q, J=7.2 Hz), 4.38(1H, m), 2.43-2.22(2H, m), 2.07-1.87(4H,
m), 1.80(1H, m), 1.42(3H, t, J=7.2 Hz), 1.40-1.27(3H, m)
EXAMPLE 2
Production of
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexyl-benzimidazole-5-carboxylic
acid
[1402] Ethyl
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexyl-benzimidazole-5-carboxylate
(1.0 g) obtained in Example 1 was dissolved in tetrahydrofuran (10
ml) and ethyl alcohol (10 ml), and 4N sodium hydroxide (10 ml) was
added. The mixture was refluxed under heating for 1 hr. The
reaction mixture was concentrated under reduced pressure and water
was added to the residue. The mixture was acidified with 6N
hydrochloric acid and the precipitated crystals were collected by
filtration to give the title compound (0.9 g, yield 96%).
[1403] melting point: 255-256.degree. C.
[1404] FAB-Ms: 491(MH+)
[1405] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): (12.75(1H, brs),
8.24(1H, s), 7.96(1H, d, J=8.7 Hz), 7.86(1H, d, J=8.7 Hz), 7.71(2H,
d, J=8.6 Hz), 7.47-7.34(3H, m), 7.24(2H, d, J=8.6 Hz), 7.20(1H, m),
4.31(1H, m), 2.38-2.18(2H, m), 2.02-1.79(4H, m), 1.65(1H, m),
1.44-1.20(3H, m)
EXAMPLE 3
Production of ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate
[1406] Ethyl 3-amino-4-cyclohexylaminobenzoate (130 g) obtained in
Example 1, Step 3, and methyl 4-hydroxybenzimidate hydrochloride
(139 g) were added to methyl alcohol (1500 ml), and the mixture was
refluxed under heating for 4 hr. The reaction mixture was allowed
to cool and the precipitated crystals were collected by filtration
to give the title compound (131 g, yield 72%).
[1407] .sup.1H-NMR (300 MHz, CDCl.sub.3): 10.02(1H, brs), 8.21(1H,
d, J=1.4 Hz), 7.93(1H, d, J=8.6 Hz), 7.83(1H, dd, J=8.6, 1.4 Hz),
7.48(2H, d, J=8.6 Hz), 6.95(2H, d, J=8.6 Hz), 4.39-4.25(1H, m),
4.33(1H, q, J=7.0 Hz), 2.35-2.18(2H, m), 1.98-1.79(4H, m),
1.70-1.60(1H, m), 1.46-1.19(3H, m), 1.35(3H, t, J=7.0 Hz)
EXAMPLE 4
Production of ethyl
2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylate
[1408] 2-Bromo-5-chlorobenzyl bromide prepared from
2-bromo-5-chlorotoluene (50 g), N-bromosuccinimide and
N,N'-azobisisobutyronitrile, and ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (50 g)
obtained in Example 3 were suspended in dimethylformamide (300 ml).
Potassium carbonate (38 g) was added and the mixture was stirred
for 1 hr at 80.degree. C. with heating. The reaction mixture was
allowed to cool and then added to a mixed solvent of water-ethyl
acetate. The precipitated crystals were collected by filtration to
give the title compound (50 g, yield 64%).
[1409] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.50(1H, d, J=1.4 Hz),
7.97(1H, dd, J=8.6, 1.4 Hz), 7.70-7.57(5H, m), 7.20(1H, dd, J=8.4,
2.5 Hz), 7.14(2H, d, J=8.7 Hz), 5.17(2H, s), 4.46-4.30(1H, m),
4.41(2H, q, J=7.1 Hz), 2.40-2.20(2H, m), 2.02-1.21(8H, m), 1.42(3H,
t, J=7.1 Hz)
EXAMPLE 5
Production of ethyl
2-{4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]-phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate
[1410] Ethyl
2-[4-(2-bromo-5-chlorobenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carbo-
xylate (49 g) obtained in Example 4,4-chlorophenylboronic acid (18
g) and tetrakis-(triphenylphosphine)palladium (10 g) were suspended
in 1,2-dimethoxyethane (600 ml). Saturated aqueous sodium
hydrogencarbonate solution (300 ml) was added and the mixture was
refluxed under heating for 2 hr. Chloroform was added to the
reaction mixture. The organic layer was washed successively with
saturated aqueous sodium hydrogencarbonate solution, water and
saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel flash chromatography (developing solvent,
chloroform:ethyl acetate=97:3). Ethyl acetate and diisopropyl ether
were added to the resulting oil for crystallization and the
resulting crystals were collected by filtration to give the title
compound (44 g, yield 85%).
[1411] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.4 Hz),
7.97(1H, dd, J=8.6, 1.6 Hz), 7.70-7.60(2H, m), 7.55(2H, d, J=8.7
Hz), 4.95(2H, s), 4.48-4.28(1H, m), 4.40(2H, m), 2.02-1.20(8H, m),
1.41(3H, t, J=7.1 Hz)
EXAMPLE 6
Production of
2-{4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylic acid
[1412] Ethyl
2-{4-[2-(4-chlorophenyl)-5-chlorobenzyloxy]phenyl}-1-cyclohexylbenzimidaz-
ole-5-carboxylate (43 g) obtained in Example 5 was treated in the
same manner as in Example 2 to give the title compound (33 g, yield
76%).
[1413] melting point: 243-244.degree. C.
[1414] FAB-Ms: 571(MH+)
[1415] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.32(1H, s), 8.28(1H,
d, J=8.9 Hz), 8.05(1H, d, J=8.8 Hz), 7.76-7.72(3H, m),
7.58-7.46(5H, m), 7.40(1H, d, J=8.3 Hz), 7.24(2H, d, J=8.9 Hz),
5.11(2H, s), 4.36(1H, m), 2.40-2.15(2H, m), 2.15-1.95(2H, m),
1.95-1.75(2H, m), 1.75-1.55(1H, m), 1.55-1.15(3H, m)
EXAMPLE 7
Production of ethyl
2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carb-
oxylate
[1416] Ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate
obtained in Example 3 and 2-bromo-5-methoxybenzyl bromide were
treated in the same manner as in Example 4 to give the title
compound (59 g).
EXAMPLE 8
Production of ethyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]-phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylate
[1417] Ethyl
2-[4-(2-bromo-5-methoxybenzyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carb-
oxylate obtained in Example 7 was treated in the same manner as in
Example 5 to give the title compound (48 g, yield 77%).
[1418] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.4 Hz),
7.97(1H, dd, J=8.6, 1.4 Hz), 7.64(1H, d, J=8.6 Hz), 7.54(2H, d,
J=8.7 Hz), 7.37(2H, d, J=8.6 Hz), 7.31(2H, d, J=8.6 Hz), 7.25(1H,
d, J=8.4 Hz), 7.19(1H, d, J=2.7 Hz), 7.00(2H, d, J=8.7 Hz),
6.97(1H, dd, J=8.4, 2.7 Hz), 4.98(2H, s), 4.41(2H, q, J=7.1 Hz),
4.42-4.29(1H, m), 3.88(3H, s), 2.40-2.20(2H, m), 2.01-1.88(4H, m),
1.83-1.73(1H, m), 1.42(3H, t, J=7.1 Hz), 1.41-1.25(3H, m)
EXAMPLE 9
Production of
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid
[1419] Ethyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate (52 g) obtained in Example 8 was treated in the
same manner as in Example 2 to give the title compound (44 g, yield
89%).
[1420] melting point: 248-249.degree. C.
[1421] FAB-Ms: 568(MH+)
[1422] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.20(1H, s), 7.88(1H,
d, J=8.7 Hz), 7.85(1H, d, J=8.7 Hz), 7.57(d, 2H, J=8.6 Hz),
7.46(2H, d, J=8.6 Hz), 7.44(2H, d, J=8.6 Hz), 7.29(1H, d, J=8.5
Hz), 7.24(1H, d, J=2.6 Hz), 7.11(2H, d, J=8.6 Hz), 7.06(1H, dd,
J=8.5, 2.6 Hz), 5.04(2H, s), 4.26(1H, m), 3.83(3H, s),
2.38-2.29(2H, m)
EXAMPLE 10
Production of ethyl
1-cyclohexyl-2-{4-[(E)-2-phenylvinyl]phenyl}-benzimidazole-5-carboxylate
[1423] Ethyl 3-amino-4-cyclohexylaminobenzoate (500 mg) obtained in
Example 1, Step 3, was dissolved in methyl alcohol (6 ml) and
trans-4-stilbenecarbaldehyde (397 mg) was added under ice-cooling.
The mixture was stirred overnight at room temperature. The reaction
mixture was ice-cooled and benzofuroxan (259 mg) dissolved in
acetonitrile (2 ml) was added. The mixture was stirred for 7 hr at
50.degree. C. The reaction mixture was ice-cooled. After 1N sodium
hydroxide was added, ethyl acetate was added and the mixture was
extracted. The organic layer was washed with water and saturated
brine, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
flash chromatography (developing solvent, n-hexane:ethyl
acetate=4:1) to give the title compound (540 mg, yield 63%).
[1424] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.28(1H, d, J=1.4 Hz),
8.01(1H, d, J=8.7 Hz), 7.90-7.80(3H, m), 7.75-7.65(4H, m),
7.50-7.25(5H, m), 4.35(2H, q, J=7.0 Hz), 4.31(1H, m), 2.40-2.20(2H,
m), 2.00-1.80(4H, m), 1.63(1H, m), 1.40-1.20(3H, m), 1.36(3H, t,
J=7.0 Hz)
EXAMPLE 11
Production of
1-cyclohexyl-2-{4-[(E)-2-phenylvinyl]phenyl}-benzimidazole-5-carboxylic
acid
[1425] Ethyl
1-cyclohexyl-2-{4-[(E)-2-phenylvinyl]phenyl}-benzimidazole-5-carboxylate
(127 mg) obtained in Example 10 was treated in the same manner as
in Example 2 to give the title compound (116 mg, yield 97%).
[1426] melting point: not lower than 300.degree. C.
[1427] FAB-Ms: 423(MH+)
[1428] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.25(1H, s),
7.96-7.29(13H, m), 4.33(1H, brt), 2.41-2.23(2H, m), 2.03-1.78(4H,
m), 1.71-1.59(1H, m), 1.49-1.20(3H, m)
EXAMPLE 12
Production of
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid
[1429] In the same manner as in Examples 1 and 2, the title
compound (700 mg) was obtained.
[1430] FAB-Ms: 413(MH+)
[1431] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.60(1H, s), 8.04(1H, d,
J=9.0 Hz), 7.63(2H, d, J=8.4 Hz), 7.51-7.32(6H, m), 7.14(2H, d,
J=9.0 Hz), 5.16(2H, s), 5.03-4.89(1H, m), 2.41-1.63(8H, m)
EXAMPLE 13
Production of
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxamide
[1432]
2-(4-Benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxylic acid
(700 mg) obtained in Example 12 was dissolved in dimethylformamide
(10 ml), and ammonium chloride (108 mg),
1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (390
mg), 1-hydroxybenzotriazole (275 mg) and triethylamine (0.3 ml)
were added. The mixture was stirred overnight at room temperature.
Water was added to the reaction mixture and the mixture was
extracted with ethyl acetate. The organic layer was washed
successively with saturated aqueous sodium hydrogencarbonate, water
and saturated brine, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure. Ethyl acetate and diisopropyl
ether were added to the residue for crystallization and the
crystals were collected by filtration to give the title compound
(571 mg, yield 81%).
[1433] melting point: 232-233.degree. C.
[1434] FAB-Ms: 412(MH+)
[1435] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.23(1H, d, =1.5 Hz),
7.86(1H, dd, J=8.5, 1.5 Hz), 7.65-7.30(8H, m), 7.13(2H, d, J=8.8
Hz), 5.16(2H, s), 4.93(1H, quint, J=8.8 Hz), 2.40-1.60(8H, m)
EXAMPLE 14
Production of
2-(4-benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole
[1436] In the same manner as in Example 1, the title compound (400
mg) was obtained.
[1437] FAB-Ms: 394(MH+)
[1438] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.11(1H, s),
7.68-7.30(9H, m), 7.13(2H, s), 5.16(2H, s), 4.94(1H, quint, J=8.9
Hz), 2.35-1.60(8H, m)
EXAMPLE 15
Production of
2-(4-benzyloxyphenyl)-1-cyclopentylbenzimidazole-5-carboxamide
oxime
[1439] 2-(4-Benzyloxyphenyl)-5-cyano-1-cyclopentylbenzimidazole
(400 mg) obtained in Example 14 was suspended in ethyl alcohol (3
ml) and water (1.5 ml), and hydroxylamine hydrochloride (141 mg)
and sodium hydrogencarbonate (170 mg) were added. The mixture was
refluxed under heating overnight. The reaction mixture was allowed
to cool and the precipitated crystals were collected by filtration
to give the title compound (312 mg, yield 71%).
[1440] melting point: 225-226.degree. C.
[1441] FAB-Ms: 456(MH+)
[1442] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.20(1H, s),
7.50-7.31(9H, m), 7.12(2H, d, J=8.7 Hz), 5.15(2H, s), 4.94(1H,
quint, J=8.7 Hz), 3.61(3H, s), 3.40(3H, s), 2.41-1.42(8H, m)
EXAMPLE 16
Production of ethyl
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-methyl-5-thiazolyl}methoxy]pheny-
l}benzimidazole-5-carboxylate
Step 1: Production of
4-(4-fluorophenyl)-5-hydroxymethyl-2-methylthiazole
[1443] Ethyl 4-(4-fluorophenyl)-2-methyl-5-thiazolecarboxylate (59
g) prepared by a known method (Chem. Pharm. Bull., 43(6), 947,
1995) was dissolved in tetrahydrofuran (700 ml). Lithium aluminum
hydride (13 g) was added under ice-cooling and the mixture was
stirred for 30 min. Water (13 ml), 15% sodium hydroxide (13 ml) and
water (39 ml) were added successively to the reaction mixture, and
the precipitated insoluble materials were filtered off. The
filtrate was concentrated under reduced pressure to give the title
compound (37 g, yield 71%).
[1444] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.60(2H, dd, J=8.7, 6.6
Hz), 7.11(2H, t, J=8.7 Hz), 4.80(2H, s), 2.70(3H, s)
Step 2: Production of
5-chloromethyl-4-(4-fluorophenyl)-2-methylthiazole
[1445] 4-(4-Fluorophenyl)-5-hydroxymethyl-2-methylthiazole (37 g)
obtained in the previous step was dissolved in chloroform (500 ml),
and thionyl chloride (24 ml) and pyridine (2 ml) were added. The
mixture was stirred for 3 hr at room temperature. The reaction
mixture was poured into ice-cold water. The mixture was extracted
with chloroform, and washed with water and saturated brine. The
organic layer was dried over sodium sulfate, and concentrated under
reduced pressure to give the title compound (29 g, yield 76%).
[1446] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.67(2H, dd, J=8.8, 5.4
Hz), 7.16(2H, t, J=8.7 Hz), 4.79(2H, s), 2.73(3H, s)
Step 3: Production of ethyl
1-cyclohexyl-2-{4-[{-4-(4-fluorophenyl)-2-methyl-5-thiazolyl}methoxy]phen-
yl}benzimidazole-5-carboxylate
[1447] 5-Chloromethyl-4-(4-fluorophenyl)-2-methylthiazole (28 g)
obtained in the previous step and ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (36 g)
obtained in Example 3 were treated in the same manner as in Example
4 to give the title compound (61 g, yield 100%).
[1448] APCI-Ms: 570(MH+)
[1449] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.25(1H, d, J=1.5 Hz),
7.97(1H, d, J=8.7 Hz), 7.86(1H, dd, J=8.6, 1.6 Hz), 7.74(2H, dd,
J=8.8, 5.5 Hz), 7.62(2H, d, J=8.7 Hz), 7.33(2H, t, J=8.9 Hz),
7.22(2H, t, J=8.9 Hz), 5.41(2H, s), 4.34(2H, q, J=7.1 Hz), 4.31(1H,
m), 2.71(3H, s), 2.40-2.15(2H, m), 2.05-1.75(4H, m), 1.55-1.15(3H,
m), 1.36(3H, t, J=7.1 Hz)
EXAMPLE 17
Production of
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-methyl-5-thiazolyl}methoxy]pheny-
l}benzimidazole-5-carboxylic acid
[1450] Ethyl
1-cyclohexyl-2-{4-[{4-(4-fluorophenyl)-2-methyl-5-thiazolyl}methoxy]pheny-
l}benzimidazole-5-carboxylate (60 g) obtained in Example 16 was
treated in the same manner as in Example 2 to give the title
compound (39 g, yield 69%).
[1451] melting point: 196-198.degree. C.
[1452] FAB-Ms: 542(MH+)
[1453] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 13.1(1H, brs), 8.34(1H,
s), 8.29(1H, d, J=8.8 Hz), 8.06(1H, d, J=8.7 Hz), 7.80-7.72(4H, m),
7.36-7.31(4H, m), 5.46(2H, s), 4.38(1H, m), 2.72(3H, s),
2.45-2.15(2H, m), 2.15-1.95(2H, m), 1.95-1.75(2H, m), 1.75-1.55(1H,
m), 1.55-1.20(3H, m)
EXAMPLE 18
Production of ethyl
1-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)-benzimidazole-5-carboxylate
[1454] In the same manner as in Example 3, the title compound (50
g) was obtained.
EXAMPLE 19
Production of ethyl
2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylate
Step 1: Production of 3,3'-difluorobenzhydrol
[1455] To a stirred solution of magnesium strip (35.4 g) in THF
(200 ml), iodine strip was added and the mixture was heated with
stirring under nitrogen stream until most of color of iodine was
disappeared. A solution of 3-fluoro-bromobenzene (250.0 g) in THF
(1000 ml) was added dropwise over 2.5 hr while the temperature of
the solution was maintained at 60.degree. C. After the completion
of the addition of the solution, the resulting mixture was refluxed
for 1 hr with heating. The resulting Grignard solution was
ice-cooled and a solution of ethyl formate (63.2 g) in THF (200 ml)
was added dropwise over 1 hr. After a stirring of the reaction
solution for an additional 30 min, saturated aqueous ammonium
chloride solution (700 ml) was added dropwise with ice-cooling and
water (300 ml) was added. The mixture was stirred for 10 min. The
organic layer and water layer were separated. Water layer was
extracted with ethyl acetate, and the combined organic layer was
washed with 2N hydrochloric acid, saturated aqueous sodium
hydrogencarbonate and saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and the solvent was
evaporated off under reduced pressure to give the title compound
(156.2 g, yield 99%).
[1456] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.31(2H, td, J=7.9, 5.8
Hz), 7.15-7.80(4H, m), 6.97-6.94(2H, m), 5.82(1H, d, J=3.3 Hz),
2.30(1H, d, J=3.3 Hz)
Step 2: Production of 3,3'-difluorobenzhydryl chloride
[1457] To a solution of 3,3'-difluorobenzhydrol (150.0 g) obtained
in the previous step in toluene (400 ml), pyridine (539 mg) was
added at room temperature. To the solution, thionyl chloride (89.1
g) was added dropwise over 1 hr at room temperature and the
resulting solution was stirred for an additional 2 hr. The solution
was heated so that the temperature of the solution was at
40.degree. C., and then stirred for an additional 1.5 hr. Thionyl
chloride (8.1 g) was added again and the mixture was stirred for 30
min. To the reaction mixture, water was added. The organic layer
was separated, and washed with water, saturated aqueous sodium
hydrogencarbonate and saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, filtered, the solvent was
evaporated off under reduced pressure to give the title compound
(158.2 g, yield 97%).
[1458] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.32(2H, td, J=8.0, 5.9
Hz), 7.18-7.10(4H, m), 7.01(2H, tdd, J=8.2, 2.5, 1.2 Hz), 6.05(1H,
s)
Step 3: Production of ethyl
2-{4-(bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylate
[1459] Ethyl
1-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)-benzimidazole-5-carboxylate
(50 g) obtained in Example 18 and 3,3'-difluorobenzhydryl chloride
(34 g) obtained in the previous step were treated in the same
manner as in Example 4 to give the title compound (76 g, yield
99%).
[1460] FAB-Ms: 585(MH+)
[1461] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.24(1H, d, J=1.4 Hz),
7.98(1H, d, J=8.7 Hz), 7.88(1H, d, J=8.7 Hz), 7.56(1H, t, J=8.6
Hz), 7.50-7.40(6H, m), 6.82(1H, s), 4.34(2H, q, J=7.1 Hz), 3.95(1H,
m), 2.20-2.10(2H, m), 1.90-1.80(4H, m), 1.6(1H, m), 1.35(3H, t,
J=7.2 Hz), 1.30-1.20(3H, mz)
EXAMPLE 20
Production of
2-{4-(bis[3-fluorophenyl]methoxy)-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylic acid
[1462] Ethyl
2-{4-[bis(3-fluorophenyl)methoxy]-2-fluorophenyl}-1-cyclohexylbenzimidazo-
le-5-carboxylate (75 g) obtained in Example 19 was treated in the
same manner as in Example 2 to give the title compound (48 g, yield
62%).
[1463] melting point: 242-243.degree. C.
[1464] FAB-Ms: 557(MH+)
[1465] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.29(1H, s), 8.16(1H,
d, J=8.8 Hz), 7.99(1H, d, J=8.7 Hz), 7.66(1H, t, J=8.7 Hz),
7.51-7.40(6H, m), 7.30(1H, d, J=12.1 Hz), 7.20-7.14(3H, m),
6.88(1H, s), 4.07(1H, m), 2.40-2.10(2H, m), 2.00-1.75(4H, m),
1.70-1.55(1H, m), 1.50-1.15(3H, m)
EXAMPLE 21
Production of ethyl
1-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5-carboxylate
[1466] In the same manner as in Example 1, the title compound (12
g) was obtained.
EXAMPLE 22
Production of ethyl
2-(4-aminophenyl)-1-cyclopentylbenzimidazole-5-carboxylate
[1467] Ethyl
1-cyclopentyl-2-(4-nitrophenyl)benzimidazole-5-carboxylate (12 g)
obtained in Example 21 was dissolved in tetrahydrofuran (200 ml)
and ethyl alcohol (50 ml), 7.5% palladium carbon (50% wet, 1 g) was
added. The mixture was hydrogenated for 1 hr at atmospheric
pressure. The catalyst was filtered off and the filtrate was
concentrated under reduced pressure. Tetrahydrofuran was added to
the residue to allow crystallization and the crystals were
collected by filtration to give the title compound (11 g, yield
98%).
[1468] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.3 Hz),
7.95(1H, dd, J=8.5, 1.3 Hz), 7.50-7.40(3H, m), 6.79(2H, d, J=4.6
Hz), 4.97(1H, quint, J=8.9 Hz), 4.40(2H, q, J=7.1 Hz), 3.74(2H,
brs), 2.40-1.60(8H, m), 1.41(3H, t, J=7.1 Hz)
EXAMPLE 23
Production of ethyl
2-(4-benzoylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylate
[1469] Ethyl
1-cyclopentyl-2-(4-aminophenyl)benzimidazole-5-carboxylate (300 mg)
obtained in Example 22 was dissolved in pyridine (3 ml) and
chloroform (3 ml), and benzoyl chloride (127 mg) was added. The
mixture was stirred for 30 min at room temperature. The reaction
mixture was concentrated under reduced pressure and water was added
to the residue to allow crystallization. The crystals were
collected by filtration to give the title compound (403 mg, yield
100%).
[1470] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.58(1H, s), 8.00(1H, d,
J=9.0 Hz), 7.84(2H, d, J=7.5 Hz), 7.60-7.40(6H, m), 7.14(2H, d,
J=7.5 Hz), 4.84(1H, quint, J=8.7 Hz), 4.41(2H, q, J=7.5 Hz),
2.20-1.30(8H, m), 1.41(3H, t, J=7.5 Hz)
EXAMPLE 24
Production of
2-(4-benzoylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylic
acid
[1471] Ethyl
2-(4-benzoylaminophenyl)-1-cyclopentylbenzimidazole-5-carboxylate
(200 mg) obtained in Example 23 was treated in the same manner as
in Example 2 to give the title compound (131 mg, yield 70%).
[1472] melting point: not lower than 300.degree. C.
[1473] FAB-Ms: 426(MH+)
[1474] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 10.75(1H, s), 8.35(1H,
s), 8.15 and 7.85(4H, ABq, J=8.9 Hz), 8.10-7.98(4H, m),
7.70-7.55(3H, m), 5.02(1H, quint, J=8.7 Hz), 2.36-2.15(4H, m),
2.14-1.95(2H, m), 1.80-1.62(2H, m)
EXAMPLE 25
Production of ethyl
2-{4-[3-(3-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylate
[1475] Ethyl
2-[4-(3-bromophenoxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
(65 g) obtained in Example 1 and 3-chlorophenylboronic acid (23 g)
were treated in the same manner as in Example 5 to give the title
compound (59 g, yield 85%).
[1476] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.51(1H, d, J=1.8 Hz),
7.99(1H, dd, J=8.7, 1.8 Hz), 7.71-7.55(4H, m), 7.51-7.43(2H, m),
7.43-7.27(4H, m), 7.19(1H, d, J=8.4 Hz), 7.12(1H, m), 4.41(2H, q,
J=7.2 Hz), 4.39(1H, m), 2.42-2.22(2H, m), 2.03-1.87(4H, m),
1.79(1H, m), 1.42(3H, t, J=7.2 Hz), 1.39-1.29(3H, m)
EXAMPLE 26
Production of
2-{4-[3-(3-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylic acid
[1477] Ethyl
2-{4-[3-(3-chlorophenyl)phenoxy]phenyl}-1-cyclohexylbenzimidazole-5-carbo-
xylate (59 g) obtained in Example 25 was treated in the same manner
as in Example 2 to give the title compound (43 g, yield 76%).
[1478] melting point: 253-254.degree. C.
FAB-Ms: 523(MH+)
[1479] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 12.82(1H, brs),
8.24(1H, d, J=1.3 Hz), 7.98(1H, d, J=8.7 Hz), 7.89(1H, dd, J=8.7,
1.3 Hz), 7.78(1H, s), 7.72(2H, d, J=9.7 Hz), 7.70(1H, m),
7.64-7.42(5H, m), 7.25(2H, d, J=8.7 Hz), 7.20(1H, m), 4.33(1H, m),
2.39-2.17(2H, m), 2.00-1.76(4H, m), 1.65(1H, m), 1.50-1.22(3H,
m)
EXAMPLE 27
Production of ethyl
2-[4-(3-acetoxyphenyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
[1480] In the same manner as in Example 1, the title compound (87
g) was obtained.
EXAMPLE 28
Production of ethyl
1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)-phenyl]benzimidazole-5-carboxylate
[1481] Ethyl
2-[4-(3-acetoxyphenyloxy)phenyl]-1-cyclohexylbenzimidazole-5-carboxylate
(87 g) obtained in Example 27 was dissolved in methyl alcohol (250
ml) and tetrahydrofuran (250 ml), and potassium carbonate (31 g)
was added. The mixture was stirred for 30 min at room temperature.
The insoluble materials were filtered off and the filtrate was
concentrated under reduced pressure. Water was added to the residue
and the mixture was neutralized with 2N hydrochloric acid. The
precipitated crystals were collected by filtration to give the
title compound (78 g, yield 97%).
[1482] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 9.71(1H, s), 7.98(1H,
d, J=8.7 Hz), 7.87(1H, d, J=8.7 Hz), 7.68(2H, d, J=8.6 Hz),
7.24(1H, t, J=8.1 Hz), 7.18(2H, d, J=8.6 Hz), 6.63(1H, d, J=8.1
Hz), 6.57(1H, d, J=8.1 Hz), 6.51(1H, s), 4.38-4.23(1H, m), 4.35(2H,
q, J=6.9 Hz), 2.36-2.18(2H, m), 1.99-1.78(4H, m), 1.71-1.59(1H, m),
1.45-1.20(3H, m), 1.36(3H, t, J=6.9 Hz)
EXAMPLE 29
Production of ethyl
1-cyclohexyl-2-{4-[3-(4-pyridylmethoxy)-phenyloxy]phenyl}benzimidazole-5--
carboxylate
[1483] Ethyl
1-cyclohexyl-2-[4-(3-hydroxyphenyloxy)phenyl]-benzimidazole-5-carboxylate
(78 g) obtained in Example 28 was suspended in dimethylformamide
(800 ml), and sodium hydride (60% oil, 14 g) was added under
ice-cooling. The mixture was stirred for 1 hr at room temperature.
After the reaction mixture was ice-cooled, 4-chloromethylpyridine
hydrochloride (29 g) was added and the mixture was stirred for 30
min. The mixture was then stirred overnight at room temperature.
Water was added to the reaction mixture and the precipitated
crystals were collected by filtration. The resulting crystals were
recrystallized from ethyl alcohol to give the title compound (77 g,
yield 82%).
[1484] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.63(2H, d, J=6.0 Hz),
8.51(1H, s), 7.99(1H, d, J=8.7 Hz), 7.66(2H, d, J=8.7 Hz), 7.62(2H,
d, J=8.7 Hz), 7.36(2H, d, J=8.7 Hz), 7.31(1H, t, J=8.2 Hz),
7.26(1H, s), 7.16(2H, d, J=8.7 Hz), 6.79-6.70(3H, m), 5.09(2H, s),
4.47-4.31(1H, m), 4.42(2H, q, J=7.0 Hz), 2.42-2.22(2H, m),
2.04-1.71(5H, m), 1.45-1.25(3H, m), 1.42(3H, t, J=7.0 Hz)
EXAMPLE 30
Production of
1-cyclohexyl-2-{4-[3-(4-pyridylmethoxy)phenyloxy]-phenyl}benzimidazole-5--
carboxylic acid
[1485] Ethyl
1-cyclohexyl-2-{4-[3-(4-pyridylmethoxy)phenyloxy]-phenyl}benzimidazole-5--
carboxylate (60 g) obtained in Example 29 was treated in the same
manner as in Example 2 to give the title compound (54 g, yield
75%).
[1486] melting point: 235-237.degree. C.
[1487] FAB-Ms: 520(MH+)
[1488] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.58(2H, d, J=6.0 Hz),
8.23(1H, s), 7.96 and 7.86(2H, ABq, J=8.7 Hz), 7.68 and 7.17(4H,
A'B'q, J=8.7 Hz), 7.44(2H, d, J=8.7 Hz), 7.39(1H, t, J=8.3 Hz),
6.90(1H, d, J=8.1 Hz), 6.84(1H, s), 6.75(1H, d, J=8.1 Hz), 5.22(2H,
s), 4.40-4.22(1H, m), 2.40-2.19(2H, m), 2.00-1.80(4H, m)
EXAMPLE 241
Production of methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate
Step 1: Production of 2-bromo-5-methoxybenzaldehyde
[1489] 3-Methoxybenzaldehyde (15 g) was dissolved in acetic acid
(75 ml), and a solution of bromine (5.7 ml) dissolved in acetic
acid (15 ml) was added dropwise. The mixture was stirred overnight
at room temperature and water (150 ml) was added to the reaction
mixture. The precipitated crystals were collected by filtration,
washed with water and dried under reduced pressure to give the
title compound (21 g, yield 88%).
[1490] .sup.1H-NMR (300 MHz, CDCl.sub.3): 10.31(1H, s), 7.52(1H, d,
J=8.8 Hz), 7.41(1H, d, J=3.3 Hz), 7.03(1H, dd, J=8.8, 3.3 Hz),
3.48(3H, s)
Step 2: Production of 2-(4-chlorophenyl)-5-methoxybenzaldehyde
[1491] 2-Bromo-5-methoxybenzaldehyde (10 g) obtained in the
previous step was treated in the same method as in Example 5 to
give the title compound (11 g, yield 96%).
[1492] .sup.1H-NMR (300 MHz, CDCl.sub.3): 9.92(1H, s), 7.50(1H, d,
J=2.6 Hz), 7.48-7.14(6H, m), 3.90(3H, s)
Step 3: Production of 2-(4-chlorophenyl)-5-methoxybenzyl
alcohol
[1493] 2-(4-Chlorophenyl)-5-methoxybenzaldehyde (10 g) obtained in
the previous step was dissolved in tetrahydrofuran (30 ml). The
solution was added dropwise to a suspension of sodium borohydride
(620 mg) in isopropyl alcohol (50 ml) and the mixture was stirred
for 1 hr. The solvent was evaporated under reduced pressure and
water was added to the residue. The precipitated crystals were
collected by filtration and dried under reduced pressure. The
resulting crystals were recrystallized from a mixture of methanol
and water to give the title compound (9.2 g, yield 91%).
[1494] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.37(2H, d, J=8.6 Hz),
7.27(2H, d, J=8.6 Hz), 7.17(1H, d, J=8.6 Hz), 7.11(1H, d, J=2.6
Hz), 6.89(1H, dd, J=8.6, 2.6 Hz), 4.57(2H, s), 3.86(3H, s)
Step 4: Production of 2-(4-chlorophenyl)-5-methoxybenzyl
chloride
[1495] 2-(4-Chlorophenyl)-5-methoxybenzyl alcohol (20 g) obtained
in the previous step was dissolved in ethyl acetate (100 ml) and
pyridine (0.5 ml), and thionyl chloride (11 ml) was added dropwise.
The mixture was stirred for 1 hr. Water was added to the reaction
mixture and the mixture was extracted with ethyl acetate. The
organic layer was washed with water, saturated aqueous sodium
hydrogencarbonate, water and saturated brine, dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure.
Isopropyl alcohol was added to the residue to allow
crystallization. The resulting crystals were collected by
filtration and dried under reduced pressure to give the title
compound (16 g, yield 74%).
[1496] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.43-7.29(4H, m),
7.17(1H, d, J=8.6 Hz), 7.05(1H, d, J=2.6 Hz), 6.96-6.89(1H, m),
4.46(2H, s), 3.86(3H, s)
Step 5: Production of methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate
[1497] 2-(4-Chlorophenyl)-5-methoxybenzyl chloride (4.0 g) obtained
in the previous step and methyl
1-cyclohexyl-2-(4-hydroxyphenyl)-benzimidazole-5-carboxylate (5.0
g) obtained in the same manner as in Example 3 were treated in the
same manner as in Example 4 to give the title compound (6.0 g,
yield 72%).
[1498] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.48(1H, s),
8.00-7.93(1H, m), 7.68-7.62(1H, m), 7.54(2H, d, J=9.0 Hz),
7.41-7.16(6H, m), 7.04-6.93(3H, m), 4.97(2H, s), 4.36(1H, m),
3.94(3H, s), 3.87(3H, s), 2.39-2.21(2H, m), 2.02-1.88(4H, m),
1.85-1.45(4H, m)
EXAMPLE 242
Production of
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylic acid hydrochloride
[1499] Methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate (5.0 g) obtained in Example 241 was treated in
the same manner as in Example 2 to give the title compound (5.1 g,
yield 98%).
[1500] APCI-Ms: 568(MH+)
[1501] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.30(1H, d, J=1.4 Hz),
8.24(1H, d, J=8.7 Hz), 8.03(1H, d, J=8.7 Hz), 7.72(2H, d, J=8.7
Hz), 7.51-7.39(4H, m), 7.34-7.18(4H, m), 7.11-7.03(1H, m), 5.08(2H,
s), 4.35(1H, m), 3.83(3H, m), 2.40-2.18(2H, m), 2.10-1.96(2H, m),
1.93-1.78(2Hm), 1.72-1.18(4H, m)
EXAMPLE 243
Production of ethyl
2-{4-[3-(4-chlorophenyl)pyridin-2-ylmethoxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate
Step 1: Production of methyl 3-hydroxypicolinate
[1502] 3-Hydroxypicolinic acid (1.0 g) was suspended in methanol
(10 ml) and concentrated sulfuric acid (1.0 ml) was added. The
mixture was refluxed under heating for 5 hr. The reaction mixture
was ice-cooled, neutralized with saturated aqueous sodium
hydrogencarbonate, and extracted with chloroform. The organic layer
was washed with water and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated under reduced
pressure to give the title compound (711 mg, yield 64%).
[1503] .sup.1H-NMR (300 MHz, CDCl.sub.3): 10.63(1H, s), 8.28(1H,
dd, J=3.7, 1.8 Hz), 7.47-7.35(2H, m), 4.06(3H, s)
Step 2: Production of methyl
3-(trifluoromethylsulfonyloxy)-pyridine-2-carboxylate
[1504] Methyl 3-hydroxypicolinate (710 mg) obtained in the previous
step and triethylamine (0.77 ml) were dissolved in dichloromethane
(7 ml), and trifluoromethanesulfonic anhydride (0.86 ml) was added
under ice-cooling. The reaction mixture was allowed to warm to room
temperature and the mixture was stirred for 2 hr. Water was added
to the reaction mixture and the mixture was extracted with ethyl
acetate. The organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
under reduced pressure to give the title compound (1.2 g, yield
90%).
[1505] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.80-8.73(1H, m),
7.75-7.70(1H, m), 7.63(1H, dd, J=8.2, 4.5 Hz), 4.05(3H, s)
Step 3: Production of methyl
3-(4-chlorophenyl)pyridine-2-carboxylate
[1506] Methyl 3-(trifluoromethylsulfonyloxy)pyridine-2-carboxylate
(1.2 g) obtained in the previous step was treated in the same
manner as in Example 5 to give the title compound (728 mg, yield
69%).
[1507] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.73-8.66(1H, m),
7.77-7.68(1H, m), 7.49(1H, dd, J=7.8, 4.5 Hz), 7.46-7.37(2H, m),
7.32-7.23(2H, m), 3.80(3H, s)
Step 4: Production of [3-(4-chlorophenyl)pyridin-2-yl]methanol
[1508] Methyl 3-(4-chlorophenyl)pyridine-2-carboxylate (720 mg)
obtained in the previous step was dissolved in tetrahydrofuran (10
ml) and the solution was ice-cooled. Lithium aluminum hydride (160
mg) was added to the solution and the mixture was stirred for 1 hr.
To the reaction mixture were added successively water (1.6 ml), 15%
sodium hydroxide (1.6 ml) and water (4.8 ml). The insoluble
materials were filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography (developing solvent, n-hexane:ethyl acetate=1:1) to
give the title compound (208 mg, yield 32%).
[1509] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.60(1H, dd, J=4.8, 1.5
Hz), 7.60-7.55(1H, m), 7.40-7.48(2H, m), 7.29-7.36(1H, m),
7.27-7.20(3H, m), 4.63(2H, s)
Step 5: Production of ethyl
2-{4-[3-(4-chlorophenyl)pyridin-2-ylmethoxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate
[1510] [3-(4-Chlorophenyl)pyridin-2-yl]methanol (200 mg) obtained
in the previous step was dissolved in chloroform (3 ml), and
thionyl chloride (0.13 ml) and pyridine (catalytic amount) were
added. The mixture was stirred for 1 hr at room temperature and
concentrated under reduced pressure. The residue was dissolved in
dimethylformamide (3 ml), and ethyl
1-cyclohexyl-2-(4-hydroxyphenyl)benzimidazole-5-carboxylate (232
mg) obtained in the same manner as in Example 3 and potassium
carbonate (250 mg) were added. The mixture was stirred for 3 hr
with heating at 80.degree. C. The reaction mixture was then allowed
to cool. Water was added and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. The residue was purified by silica gel
flash chromatography (developing solvent, n-hexane:ethyl
acetate=1:2) to give the title compound (246 mg, yield 68%).
[1511] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.71(1H, dd, J=4.7, 1.4
Hz), 8.49(1H, d, J=2.1 Hz), 7.96(1H, d, J=10.2 Hz), 7.71-7.62(2H,
m), 7.53(2H, d, J=8.7 Hz), 7.45-7.34(5H, m), 7.04(2H, d, J=8.7 Hz),
5.14(2H, s), 4.48-4.29(3H, m), 2.38-2.19(2H, m), 2.02-1.22(11H,
m)
EXAMPLE 244
Production of methyl
2-[4-(2-bromo-5-tert-butoxycarbonyl-benzyloxy)phenyl]-1-cyclohexylbenzimi-
dazole-5-carboxylate
Step 1: Production of tert-butyl 4-bromo-3-methylbenzoate
[1512] 4-Bromo-3-methylbenzoic acid (25 g) was suspended in
dichloromethane (200 ml), and oxalyl chloride (12 ml) and
dimethylformamide (catalytic amount) were added. The mixture was
stirred for 2 hr at room temperature and the solvent was evaporated
under reduced pressure. The residue was dissolved in
tetrahydrofuran (200 ml) and the solution was ice-cooled. To the
solution was added dropwise a solution of potassium tert-butoxide
dissolved in tetrahydrofuran (150 ml) and the mixture was stirred
for 30 min. Water was added to the reaction mixture and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated under reduced pressure to give
the title compound (27 g, yield 85%).
[1513] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.83(1H, d, J=2.2 Hz),
7.67-7.53(2H, m), 2.43(3H, s), 1.58(9H, s)
Step 2: Production of methyl
2-[4-(2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl]-1-cyclohexylbenzimid-
azole-5-carboxylate
[1514] tert-Butyl 4-bromo-3-methylbenzoate (7.0 g) obtained in the
previous step and methyl
1-cyclohexyl-2-(4-hydroxyphenyl)-benzimidazole-5-carboxylate (6.3
g) obtained in the same manner as in Example 3 were treated in the
same manner as in Example 4 to give the title compound (8.8 g,
yield 77%).
[1515] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.5 Hz),
8.21(1H, d, J=2.1 Hz), 7.97(1H, d, J=10.2 Hz), 7.82(1H, d, J=10.2
Hz), 7.71-7.58(4H, m), 7.16(2H, d, J=8.7 Hz), 5.23(2H, s), 4.38(1H,
m), 3.95(3H, s), 2.40-2.23(2H, m), 2.04-1.90(4H, m), 1.84-1.73(1H,
m), 1.59(9H, s), 1.44-1.27(3H, m)
EXAMPLE 245
Production of methyl
2-{4-[5-tert-butoxycarbonyl-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohe-
xylbenzimidazole-5-carboxylate
[1516] Methyl
2-[4-(2-bromo-5-tert-butoxycarbonylbenzyloxy)phenyl]-1-cyclohexylbenzimid-
azole-5-carboxylate (4.5 g) obtained in Example 244 was treated in
the same manner as in Example 5 to give the title compound (3.6 g,
yield 76%).
[1517] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.48(1H, s), 8.27(1H, d,
J=1.8 Hz), 8.04(1H, dd, J=7.9, 1.5 Hz), 7.96(1H, dd, J=7.0, 1.5
Hz), 7.65(1H, d, J=8.6 Hz), 7.55(2H, d, J=8.6 Hz), 7.43-7.32(5H,
m), 7.01(2H, d, J=8.6 Hz), 4.99(2H, s), 4.43-4.29(1H, m), 3.95(3H,
s), 2.41-2.21(2H, m), 2.02-1.89(4H, m), 1.82-1.73(1H, m), 1.62(9H,
s), 1.46-1.28(3H, m)
EXAMPLE 246
Production of methyl
2-{4-[5-carboxy-2-(4-chlorophenyl)-benzyloxy]phenyl}-1-cyclohexylbenzimid-
azole-5-carboxylate hydrochloride
[1518] Methyl
2-{4-[5-tert-butoxycarbonyl-2-(4-chlorophenyl)-benzyloxy]phenyl}-1-cycloh-
exylbenzimidazole-5-carboxylate (3.5 g) obtained in Example 245 was
dissolved in dichloromethane (35 ml), and trifluoroacetic acid (35
ml) was added. The mixture was stirred for 1 hr at room temperature
and the reaction mixture was concentrated under reduced pressure.
The residue was dissolved in ethyl acetate, and 4N hydrochloric
acid-ethyl acetate was added. The precipitated crystals were
collected by filtration and dried under reduced pressure to give
the title compound (3.3 g, yield 97%).
[1519] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.33(1H, d, J=1.5 Hz),
8.29(1H, s), 8.24(1H, d, J=1.8 Hz), 8.09-8.00(2H, m), 7.74(2H, d,
J=8.6 Hz), 7.61-7.44(5H, m), 7.24(2H, d, J=8.6 Hz), 5.19(2H, s),
4.36(1H, m), 3.93(3H, s), 2.37-1.21(10H, m)
EXAMPLE 247
Production of methyl
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoyl-benzyloxy]phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylate
[1520] Methyl
2-{4-[5-carboxy-2-(4-chlorophenyl)benzyloxy]phenyl}-1-cyclohexylbenzimida-
zole-5-carboxylate hydrochloride (400 mg) obtained in Example 246
was suspended in dichloromethane (5 ml), and oxalyl chloride (0.08
ml) and dimethylformamide (catalytic amount) were added. The
mixture was stirred for 2 hr at room temperature. The reaction
mixture was concentrated under reduced pressure and the residue was
dissolved in dichloromethane (5 ml). The resulting solution was
added dropwise to a mixed solution of 40% aqueous methylamine
solution (5 ml) and tetrahydrofuran (5 ml) under ice-cooling. The
reaction mixture was stirred for 1 hr and concentrated under
reduced pressure. Water was added to the residue and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water, saturated aqueous sodium hydrogencarbonate and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated under reduced pressure and the residue was crystallized
from ethyl acetate and diisopropyl ether. The crystals were
collected by filtration and dried under reduced pressure to give
the title compound (335 mg, yield 86%).
[1521] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.47(1H, s), 8.06(1H, d,
J=1.8 Hz), 7.96(1H, dd, J=8.6, 1.5 Hz), 7.82(1H, dd, J=8.2, 2.2
Hz), 7.64(1H, d, J=8.6 Hz), 7.54(2H, d, J=9.0 Hz), 7.44-7.31(5H,
m), 6.99(2H, d, J=9.0 Hz), 6.35-6.26(1H, m), 5.00(2H, s), 4.35(1H,
m), 3.95(3H, s), 3.05(3H, d, J=4.8 Hz), 2.40-1.24(10H, m)
EXAMPLE 248
Production of
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]phenyl}-1-cyclohexylb-
enzimidazole-5-carboxylate hydrochloride
[1522] Methyl
2-{4-[2-(4-chlorophenyl)-5-methylcarbamoylbenzyloxy]-phenyl}-1-cyclohexyl-
benzimidazole-5-carboxylate (150 mg) obtained in Example 247 and
tetrahydrofuran (2 ml) were treated in the same manner as in
Example 2 to give the title compound (141 mg, yield 90%).
[1523] APCI-Ms: 594(MH+)
[1524] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.65-8.58(1H, m),
8.27(1H, d, J=1.5 Hz), 8.21(1H, d, J=8.2 Hz), 8.15(1H, d, J=1.5
Hz), 8.05-7.90(2H, m), 7.70(2H, d, J=8.6 Hz), 7.56-7.43(5H, m),
7.21(2H, d, J=8.6 Hz), 5.14(2H, s), 4.34(1H, m), 2.81(3H, d, J=4.5
Hz), 2.39-1.19(10H, m)
EXAMPLE 336
Production of methyl
2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazble-
-5-carboxylate
[1525] Commercially available 2-bromo-5-nitrotoluene was dissolved
in carbon tetrachloride (30 ml), and N-bromosuccinimide (2.9 g) and
N,N'-azobisisobutyronitrile (228 mg) were added, which was followed
by refluxing under heating overnight. The reaction mixture was
allowed to cool, water was added and the mixture was extracted with
chloroform. The organic layer was dried over magnesium sulfate and
concentrated under reduced pressure. The residue was dissolved in
dimethylformamide (30 ml) and methyl
2-(2-fluoro-4-hydroxyphenyl)-1-cyclohexylbenzimidazole-5-carboxylate
(3.8 g) obtained in the same manner as in Example 3 and potassium
carbonate (3.8 g) were added, which was followed by stirring at
80.degree. C. for 1 hr. The reaction mixture was allowed to cool,
water was added and the mixture was extracted with ethyl acetate.
The organic layer was washed with water and saturated brine, dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel flash
chromatography (n-hexane:ethyl acetate=1:1) to give the title
compound (3.7 g, yield 61%).
[1526] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.55-8.45 (2H, m),
8.15-8.05 (1H, m), 7.99(1H, dd, J=8.6 Hz, 1.5 Hz), 7.70-7.55(2H,
m), 7.05-6.85(2H, m), 5.24(2H, s), 4.06(1H, m), 3.95(3H, s),
2.35-2.15(2H, m), 2.05-1.85(4H, m), 1.80-1.70(1H, m), 1.45-1.20(3H,
m)
EXAMPLE 337
Production of methyl
2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate
[1527] Methyl
2-[4-(2-bromo-5-nitrobenzyloxy)-2-fluorophenyl]-1-cyclohexylbenzimidazole-
-5-carboxylate (2.0 g) obtained in Example 336,
4-chlorophenylboronic acid (590 mg) and
tetrakis(triphenylphosphine)palladium (396 mg) were suspended in
dimethoxyethane (40 ml), and saturated aqueous sodium
hydrogencarbonate solution (20 ml) was added, which was followed by
refluxing under heating for 1 hr. The reaction mixture was allowed
to cool, water was added and the mixture was extracted with
chloroform. The organic layer was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel flash chromatography (n-hexane:ethyl
acatate=2:1) to give the title compound (1.9 g, yield 90%).
[1528] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.55(1H, d, J=2.3 Hz),
8.49(1H, d, J=1.4 Hz), 8.29(1H, dd, J=8.4 Hz, 2.3 Hz), 7.98(1H, dd,
J=8.6 Hz, 1.5 Hz), 7.60-7.30(6H, m), 6.85-6.70(2H, m), 5.03(2H, s),
4.02(1H, m), 3.95(3H, s), 2.35-2.10(2H, m), 2.05-1.70(5H, m),
1.40-1.20(3H, m)
EXAMPLE 338
Production of methyl
2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate
[1529] Methyl
2-[4-{2-(4-chlorophenyl)-5-nitrobenzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate (1.9 g) obtained in Example 337 was
suspended in ethanol (40 ml), and tin(II) chloride dihydrate (3.5
g) was added, which was followed by refluxing under heating for 30
min. The reaction mixture was concentrated under reduced pressure,
4N sodium hydroxide was added and the mixture was extracted with
chloroform. The organic layer was washed with 2N sodium hydroxide
and water, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. Diisopropyl ether was added to the residue,
and the precipitated crystals were collected by filtration to give
the title compound (1.5 g, yield 82%).
[1530] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.2 Hz),
7.98(1H, dd, J=9.0, 1.5 Hz), 7.66(1H, d, J=8.7 Hz), 7.49(1H, t,
J=8.4 Hz), 7.40-7.20(3H, m), 7.13(1H, d, J=8.1 Hz), 6.92(1H, d,
J=2.7 Hz), 6.85-6.65(4H, m), 4.92(2H, s), 4.03(1H, m), 3.95(3H, s),
3.82(2H, brs), 2.30-2.10(2H, m), 2.05-1.80(4H, m), 1.80-1.70(1H,
m), 1.40-1.10(3H, m)
EXAMPLE 339
Production of methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate
[1531] Methyl
2-[4-{5-amino-2-(4-chlorophenyl)benzyloxy}-2-fluorophenyl]-1-cyclohexylbe-
nzimidazole-5-carboxylate (500 mg) obtained in Example 338 and
triethylamine (0.14 ml) were dissolved in chloroform (5 ml), and
commercially available chlorobutyryl chloride (0.1 ml) was added
under ice-cooling, which was followed by stirring at room
temperature for 3 hr. Water was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed with water and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. The
residue was dissolved in dimethylformamide (6 ml) and potassium
carbonate (244 mg) was added, which was followed by stirring at
80.degree. C. for 1 hr. The reaction mixture was allowed to cool,
water was added and the precipitated crystals were collected by
filtration to give the title compound (502 mg, yield 89%).
[1532] .sup.1H-NMR (300 MHz, CDCl.sub.3): 4.89(1H, d, J=1.5 Hz),
7.98(1H, dd, J=8.6 Hz, 1.6 Hz), 7.72(1H, d, J=2.2 Hz),
7.75-7.65(2H, m), 7.49(1H, t, J=8.3 Hz), 7.45-7.20(5H, m),
6.85-7.65(2H, m), 4.99(2H, s), 4.10-3.85(6H, m), 2.66(2H, t, J=7.8
Hz), 2.30-2.15(4H, m), 2.00-1.85(4H, m), 1.80-1.70(1H, m),
1.45-1.20(3H, m)
EXAMPLE 340
Production of
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
[1533] Methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate (200 mg) obtained in
Example 339 was treated in the same manner as in Example 2 to give
the title compound (182 mg, yield 87%).
[1534] Ms: 638(M+1)
[1535] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.28(1H, d, J=1.3 Hz),
8.10(1H, d, J=8.7 Hz), 8.05-7.90(2H, m), 7.77(1H, dd, J=8.4 Hz, 2.2
Hz), 7.61(1H, t, J=8.5 Hz), 7.55-7.35(5H, m), 7.00-7.20(2H, m),
5.09(2H, s), 4.06(1H, m), 3.90(2H, t, J=6.9 Hz), 2.60-2.45(2H, m),
2.30-2.00(4H, m), 1.95-1.75(4H, m), 1.70-1.55(1H, m), 1.45-1.15(3H,
m)
EXAMPLE 340-2
Step 1: Production of 4'-chloro-4-nitro-biphenyl-2-carbaldehyde
[1536] To a solution of 2-chloro-5-nitrobenzaldehyde (100 g) in
1,2-dimethoxyethane (1000 ml) were added 4-chlorophenylboronic acid
(93 g), bistriphenylphosphine palladium(II) dichloride (380 mg),
sodium hydrogencarbonate (68 g) and water (500 ml), and the mixture
was refluxed for 1 hr. The reaction mixture was cooled to
50.degree. C., ethyl acetate (1000 ml) was added thereto and the
mixture was stirred. The aqueous layer was separated and the
organic layer was washed with water (500 ml), 1N aqueous sodium
hydroxide solution (500 ml), water (500 ml), 28% aqueous ammonia
(500 ml), water (500 ml), 2N hydrochloric acid (500 ml) and
saturated brine (500 ml), dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was suspended
in diisopropyl ether (500 ml), filtrated and vacuum dried to give
the title compound (120 g, yield 85%).
[1537] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 9.92(1H, s), 8.61 (1H,
d, J=2.5 Hz), 8.53(1H, dd, J=2.6 Hz, 8.5 Hz), 7.82(1H, d, J=8.5
Hz), 7.64(2H, d, J=8.7 Hz), 7.59(2H, d, J=8.7 Hz)
Step 2: Production of (4'-chloro-4-nitro-biphenyl-2-yl)methanol
[1538] A solution of 4'-chloro-4-nitro-biphenyl-2-carbaldehyde (120
g) obtained in the previous step in tetrahydrofuran (900 ml) was
added dropwise to a suspension of sodium borohydride (47 g) in
2-propanol (600 ml), over 70 min under water-cooling. The reaction
mixture was stirred at room temperature for 1 hr, and 2N
hydrochloric acid (185 ml) was dropwise added thereto over 40 min
under water-cooling. The mixture was stirred at room temperature
for 30 min and concentrated under reduced pressure. The residue was
suspended in 2-propanol (300 ml), and water (1000 ml) was added
with stirring. After stirring the mixture for 30 min, the crystals
were collected by filtration and vacuum dried to give the title
compound (116 g, yield 96%).
[1539] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.43(1H, d, J=2.5 Hz),
8.19(1H, dd, J=2.6 Hz, 8.4 Hz), 7.57(2H, d, J=8.5 Hz), 7.52(1H, d,
J=8.4 Hz), 7.47(2H, d, J=8.6 Hz), 5.59(1H, brs), 4.48(2H, s)
Step 3: Production of (4-amino-4'-chloro-biphenyl-2-yl)methanol
[1540] To a suspension of (4'-chloro-4-nitro-biphenyl-2-yl)methanol
(1.0 g) obtained in the previous step and sodium hydrosulfite (2.0
g) in N,N-dimethylformamide (4 ml) and methanol (1 ml) was added
water (0.3 ml, 50 .mu.l each time in 6 portions) every 20 min at
100.degree. C. Water (5 ml) was added threto at room temperature.
Conc. hydrochloric acid (2.5 ml) was added threto at room
temperature. The mixture was stirred at 55.degree. C. for 2.5 hr,
and a solution of sodium hydroxide (1.2 g) in water (3 ml) was
added under ice-cooling. Water (5 ml) was added and the mixture was
stirred at room temperature for 1 hr. The precipitate was filtrated
and washed with water (3 ml). The crystals were vacuum dried to
give the title compound (700 mg, yield 79%).
[1541] .sup.1H-NMR (400 MHz, DMSO-d.sub.6): 7.39(2H, d, J=8.5 Hz),
7.35(2H, d, J=8.5 Hz), 6.90(1H, d, J=8.4 Hz), 6.82(1H, s), 6.56(1H,
d, J=8.4 Hz), 5.20(2H, brs), 5.04(1H, t, J=5.4 Hz), 4.29(2H, d,
J=5.4 Hz)
Step 4: Production of
4-chloro-N-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)butyramide
[1542] To a solution of (4-amino-4'-chloro-biphenyl-2-yl)-methanol
(1.0 g) obtained in the previous step in tetrahydrofuran (10 ml)
were added sodium acetate (390 mg) and acetic acid (0.27 ml) at
room temperature.
[1543] 4-Chlorobutyryl chloride (0.48 ml) was gradually added
dropwise under ice-cooling. After stirring the mixture at room
temperature for 30 min, water (20 ml) and ethyl acetate (20 ml)
were added to the reaction mixture and the organic layer was
separated. The organic layer was washed with saturated aqueous
sodium hydrogencarbonate (20 ml) and saturated brine (20 ml). The
organic layer was dried over sodium sulfate, filtrated and the
solvent was evaporated to give the title compound (1.44 g, yield
99%).
[1544] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.68(1H, s), 7.55(1H, d,
J=8.4 Hz), 7.39(2H, d, J=8.5 Hz), 7.28(2H, d, J=8.5 Hz), 7.22(1H,
d, J=8.3 Hz), 4.58(2H, s), 3.69(2H, t, J=6.1 Hz), 2.60(2H, t, J=7.0
Hz), 2.22(2H, m)
Step 5: Production of
1-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)-2-pyrrolidinone
[1545] To a solution of
4-chloro-N-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)butyramide
(1.44 g) obtained in the previous step in N,N-dimethylformamide (15
ml) was added potassium carbonate (710 mg) at room temperature.
After stirring the mixture at 100.degree. C. for 90 min, 1N
hydrochloric acid (5 ml) and water (20 ml) were added at room
temperature and the precipitated crystals were collected by
filtration and washed with water (5 ml). The crystals were vacuum
dried to give the title compound (970 mg, yield 76%).
[1546] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.76(1H, d, J=2.3 Hz),
7.62(1H, dd, J=2.4 Hz, 8.3 Hz), 7.38(2H, d, J=8.5 Hz), 7.29(2H, d,
J=8.5 Hz), 7.25(1H, d, J=8.3 Hz), 4.61(2H, s), 3.91(2H, t, J=7.0
Hz), 2.62(2H, t, J=7.8 Hz), 2.18(2H, m)
Step 6: Production of
1-(4'-chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone
[1547] To a mixed solution of
1-(4'-chloro-2-hydroxymethyl-biphenyl-4-yl)-2-pyrrolidinone (900
mg) obtained in the previous step in N,N-dimethylformamide (2 ml)
and toluene (7 ml) was dropwise added thionyl chloride (0.26 ml)
under ice-cooling. After stirring the mixture at room temperature
for 3 hr, the reaction mixture was diluted with ethyl acetate (20
ml) and washed with water (20 ml), saturated aqueous sodium
hydrogencarbonate (20 ml) and saturated brine (20 ml). The organic
layer was dried over sodium sulfate, filtrated and the solvent was
evaporated under reduced pressure to give the title compound (954
mg, yield 99%).
[1548] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.77(1H, d, J=2.3 Hz),
7.69(1H, dd, J=2.4 Hz, 8.5 Hz), 7.42(2H, d, J=8.6 Hz), 7.34(2H, d,
J=8.6 Hz), 7.26(1H, d, J=8.4 Hz), 4.50(2H, s), 3.92(2H, t, J=7.0
Hz), 2.65(2H, t, J=7.8 Hz), 2.20(2H, m)
Step 7: Production of methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate
[1549] To a suspension of methyl
1-cyclohexyl-2-(2-fluoro-4-hydroxyphenyl)benzimidazole-5-carboxylate
(915 mg) obtained in Example 18 in N,N-dimethylformamide (6 ml) was
added 1-(4'-chloro-2-chloromethyl-biphenyl-4-yl)-2-pyrrolidinone
(954 mg) obtained in the previous step and potassium carbonate (415
mg) at room temperature. After stirring the mixture at 100.degree.
C. for 1 hr, 1N hydrochloric acid (3 ml) and water (8 ml) were
added at room temperature and the precipitated crystals were
collected by filtration and washed with water (5 ml). The crystals
were vacuum dried to give the title compound (1.6 g, yield
100%).
[1550] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.49(1H, d, J=1.5 Hz),
7.98(1H, dd, J=1.6 Hz, 8.6 Hz), 7.90(1H, d, J=2.2 Hz),
7.72-7.65(2H, m), 7.49(1H, t, J=8.3 Hz), 7.40(2H, d, J=8.5 Hz),
7.34(1H, d, J=8.7 Hz), 7.31(2H, d, J=8.6 Hz), 6.80 (1H, d, J=8.6
Hz), 6.71(1H, d, J=11.6 Hz), 4.99(2H, s), 4.04(1H, m), 3.95(3H, s),
3.93(2H, t, J=7.1 Hz), 2.66(2H, t, J=7.8 Hz), 2.30-2.15(4H, m),
2.00-1.85(4H, m), 1.80-1.70(1H, m), 1.45-1.20(3H, m)
Step 8: Production of
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylic acid
[1551] Methyl
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylate (2.0 g) obtained in the
previous step was suspended in methanol (4.0 ml) and
tetrahydrofuran (8.0 ml), and 2N aqueous sodium hydroxide solution
(2.3 ml) was added. The mixture was heated under reflux for 3 hr.
The reaction mixture was allowed to cool and tetrahydrofuran (1.0
ml) and water (5.0 ml) were added. 2N Hydrochloric acid (2.3 ml)
was gradually added at room temperature. After stirring the mixture
at room temperature for 2 hr, the precipitated crystals were
collected by filtration and washed successively with methanol-water
(1:1) mixed solution (6.0 ml), water (6.0 ml) and methanol-water
(1:1) mixed solution (6.0 ml), and vacuum dried to give the title
compound (1.84 g, yield 94%).
[1552] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 12.75(1H, brs),
8.26(1H, s), 7.99(1H, s), 7.96(1H, d, J=9.0 Hz), 7.89(1H, d, J=9.0
Hz), 7.78(1H, dd, J=2.1 Hz, 8.4 Hz), 7.54(1H, t, J=9.0 Hz),
7.49(2H, d, J=8.7 Hz), 7.45(2H, d, J=8.4 Hz), 7.38(1H, d, J=8.4
Hz), 7.08(1H, dd, J=2.1 Hz, 12.0 Hz), 6.96(1H, dd, J=2.1 Hz, 8.7
Hz), 5.09(2H, s), 3.99(1H, m), 3.91(2H, t, J=6.6 Hz), 2.54(2H, t,
J=7.8 Hz), 2.30-2.00(4H, m), 1.95-1.50(5H, m), 1.45-1.20(3H, m)
Step 9: Production of
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidine-1-yl)benzyloxy}-2-fluorophen-
yl]-1-cyclohexylbenzimidazole-5-carboxylic acid hydrochloride
[1553] To 4N hydrochloric acid (50 ml) were successively added
2-[4-{2-(4-chlorophenyl)-5-(2-oxopyrrolidin-1-yl)benzyloxy}-2-fluoropheny-
l]-1-cyclohexylbenzimidazole-5-carboxylic acid (10.0 g) obtained in
the previous step and acetone-methyl ethyl ketone (3:2) mixed
solution (20 ml). The mixture was stirred at 60.degree. C. for 3 hr
and at room temperature for 1 hr. The crystals were collected by
filtration, washed twice with acetone (10 ml) and vacuum dried to
give the title compound (9.62 g, yield 91%).
[1554] melting point: 243-246.degree. C.
[1555] Ms: 638(M+1)
[1556] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.33(1H, d, J=1.1 Hz),
8.21(1H, d, J=8.8 Hz), 8.02(1H, d, J=8.8 Hz), 8.00(1H, d, J=2.2
Hz), 7.77(1H, dd, J=2.2 Hz, 8.4 Hz), 7.68(1H, t, J=8.4 Hz),
7.50(2H, d, J=8.4 Hz), 7.45(2H, d, J=8.4 Hz), 7.39(1H, d, J=8.4
Hz), 7.20(1H, dd, J=2.2 Hz, 12.1 Hz), 7.06(1H, dd, J=2.2 Hz, 8.8
Hz), 5.11(2H, s), 4.13(1H, m), 3.91(2H, t, J=7.0 Hz), 2.54(2H, t,
J=8.1 Hz), 2.40-2.05(4H, m), 2.00-1.75(4H, m), 1.70-1.55(1H, m),
1.50-1.20(3H, m)
[1557] In the same manner as in Examples 1-30, 241-248 and 336-340
and optionally using other conventional methods, where necessary,
the compounds of Examples 31-240, 249-335, 341-471, 701-703 and
1001-1559 were obtained. The chemical structures and properties are
shown in Table 1 to 177, 185 to 212, 219 to 221 and 225 to 269.
EXAMPLE 501
Production of methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylate
Step 1: Production of methyl 3-bromo-4-cyclohexylaminobenzoate
[1558] 3-Bromo-4-fluorobenzoic acid (2.0 g) was dissolved in
methanol (20 ml) and concentrated sulfuric acid (2 ml) was added.
The mixture was refluxed for 3 hr. The reaction mixture was poured
into ice-cold water and extracted with ethyl acetate (50 ml). The
organic layer was washed with water (30 ml) and saturated brine (30
ml), and dried over sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure. The residue was dissolved in
dimethyl sulfoxide (20 ml) and cyclohexylamine (10.3 ml) was added.
The mixture was stirred overnight at 120.degree. C. The reaction
mixture was poured into 10% aqueous citric acid solution (100 ml)
and extracted with ethyl acetate (100 ml). The organic layer was
washed with water (50 ml) and saturated brine (50 ml), and dried
over sodium sulfate. After filtration, the solvent was evaporated
under reduced pressure and the residue was purified by silica gel
flash chromatography (developing solvent, n-hexane:ethyl
acetate=10:1) to give the title compound (2.6 g, yield 92%).
[1559] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.10(1H, d, J=1.9 Hz),
7.83(1H, dd, J=1.9 Hz, 8.6 Hz), 6.59(1H, d, J=8.7 Hz), 4.73(1H,
brd, J=7.3 Hz), 3.85(3H, s), 3.38(1H, m), 2.10-2.00(2H, m),
1.90-1.20(8H, m)
Step 2: Production of
4'-chloro-2-(4-iodophenoxymethyl)-4-methoxybiphenyl
[1560] 4-Iodophenol (5.0 g) was dissolved in acetone (50 ml), and
potassium carbonate (4.7 g) and
4'-chloro-2-chloromethyl-4-methoxybiphenyl (6.0 g) obtained in
Example 241, Step 4 were added. The mixture was refluxed for 10 hr.
The reaction mixture was concentrated and 4N aqueous sodium
hydroxide solution (50 ml) was added. The precipitated crystals
were collected by filtration, washed with water, and dried under
reduced pressure to give the title compound (10.0 g, yield
98%).
[1561] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.52(2H, d, J=8.9 Hz),
7.35(2H, d, J=8.5 Hz), 7.27-7.20(3H, m), 7.12(1H, s), 6.95(1H, d,
J=8.5 Hz), 6.62(2H, d, J=8.9 Hz), 4.84(2H, s), 3.85(3H, s)
Step 3: Production of
[4-(4'-chloro-4-methoxybiphenyl-2-ylmethoxy)phenylethynyl]trimethylsilane
[1562] 4'-Chloro-2-(4-iodophenoxymethyl)-4-methoxybiphenyl (7.0 g)
obtained in the previous step was dissolved in acetonitrile (50
ml), and trimethylsilylacetylene (2.3 g),
tetrakis-(triphenylphosphine)palladium complex (1.8 g), copper(I)
iodide (0.6 g) and triethylamine (50 ml) were added. The mixture
was stirred overnight at room temperature and concentrated. Water
(30 ml) was added and the mixture was extracted with ethyl acetate
(50 ml). The organic layer was washed with water (30 ml) and
saturated brine (30 ml) and dried over sodium sulfate. After
filtration, the solvent was evaporated under reduced pressure and
the residue was purified by silica gel flash chromatography
(developing solvent, n-hexane:ethyl acetate=10:1) to give the title
compound (5.1 g, yield 79%).
[1563] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.37(2H, d, J=8.9 Hz),
7.34(2H, d, J=8.2 Hz), 7.28-7.21(3H, m), 7.13(1H, s), 6.94(1H, d,
J=8.2 Hz), 6.75(2H, d, J=8.9 Hz), 4.87(2H, s), 3.85(3H, s),
0.23(9H, s)
Step 4: Production of methyl
3-[4-(4'-chloro-4-methoxybiphenyl-2-ylmethoxy)phenylethynyl]-4-cyclohexyl-
aminobenzoate
[1564]
[4-(4'-Chloro-4-methoxybiphenyl-2-ylmethoxy)phenylethynyl]-trimeth-
ylsilane (5.1 g) obtained in the previous step was dissolved in
methanol (50 ml) and chloroform (50 ml), and potassium carbonate
(2.5 g) was added. The mixture was stirred for 3 hr at room
temperature and concentrated. Water (30 ml) was added and the
mixture was extracted with ethyl acetate (50 ml). The organic layer
was washed with water (30 ml) and saturated brine (30 ml) and dried
over sodium sulfate. After filtration, the solvent was evaporated
under reduced pressure to give white crystals (3.8 g). The white
crystals (2.3 g) were dissolved in acetonitrile (10 ml), and methyl
3-bromo-4-cyclohexylamino-benzoate (1.0 g) obtained in Step 1,
tetrakis(triphenyl-phosphine)palladium complex (0.4 g), copper(I)
iodide (0.1 g) and triethylamine (10 ml) were added. The mixture
was stirred overnight at 100.degree. C. and concentrated under
reduced pressure. Water (30 ml) was added and the mixture was
extracted with ethyl acetate (50 ml). The organic layer was washed
with water (30 ml) and saturated brine (30 ml), and dried over
sodium sulfate. After filtration, the solvent was evaporated under
reduced pressure and the residue was purified by silica gel flash
chromatography (developing solvent, n-hexane:ethyl acetate=8:1) to
give the title compound (0.9 g, yield 49%).
[1565] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.03(1H, s), 7.84(1H, d,
J=8.7 Hz), 7.42-7.22(7H, m), 7.15(1H, s), 6.95(1H, d, J=8.2 Hz),
6.85(2H, d, J=8.8 Hz), 6.59(1H, d, J=8.8 Hz), 5.07(1H, brs),
4.91(2H, s), 3.86(3H, s), 3.85(3H, s), 3.42(1H, m), 2.15-2.00(2H,
m), 1.80-1.20(8H, m)
Step 5: Production of methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylate
[1566] Methyl
3-[4-(4'-chloro-4-methoxybiphenyl-2-ylmethoxy)phenyl-ethynyl]-4-cyclohexy-
laminobenzoate (0.5 g) obtained in the previous step was dissolved
in N,N-dimethylformamide (5 ml), and copper(I) iodide (0.17 g) was
added. The mixture was refluxed for 3 hr at 180.degree. C. The
insoluble materials were removed by filtration. Water (10 ml) was
added and the mixture was extracted with ethyl acetate (30 ml). The
organic layer was washed with water (10 ml) and saturated brine (10
ml), and dried over sodium sulfate. After filtration, the solvent
was evaporated under reduced pressure and the residue was purified
by silica gel flash chromatography (developing solvent,
n-hexane:ethyl acetate=8:1) to give the title compound (0.27 g,
yield 55%).
[1567] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.34(1H, s), 7.85(1H, d,
J=8.8 Hz), 7.62(1H, d, J=8.8 Hz), 7.40-7.18(8H, m), 7.00-6.94(3H,
m), 6.48(1H, s), 4.95(2H, m), 4.18(1H, m), 3.93(3H, s), 3.88(3H,
s), 2.45-2.25(2H, m), 1.95-1.20(8H, m)
EXAMPLE 502
Production of
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylic acid
[1568] Methyl
2-{4-[2-(4-chlorophenyl)-5-methoxybenzyloxy]phenyl}-1-cyclohexyl-1H-indol-
e-5-carboxylate (0.27 g) obtained in Example 501 was treated in the
same manner as in Example 2 to give the title compound (0.19 g,
yield 71%).
[1569] APCI-Ms: 566(MH+)
[1570] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 12.43(1H, brs),
8.20(1H, s), 7.79(1H, d, J=9.3 Hz), 7.72(1H, d, J=9.0 Hz),
7.50-7.20(8H, m), 7.07-7.03(3H, m), 6.53(1H, s), 5.01(2H, s),
4.13(1H, m), 3.83(3H, m), 2.35-2.25(2H, m), 1.85-1.10(8H, m)
[1571] In the same manner as in Examples 501 and 502, and
optionally using other conventional methods where necessary, the
compound of Example 503 was obtained. The chemical structure and
properties are shown in Table 207.
EXAMPLE 601
Production of ethyl
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo-[1,2-a]pyridine-7-carboxylate
Step 1: Production of 4-benzyloxy-N-methoxy-N-methylbenzamide
[1572] 4-Benzyloxybenzoic acid (5.0 g) and
N,O-dimethyl-hydroxylamine hydrochloride (2.5 g) were suspended in
dimethylformamide (50 ml), and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (5.0
g), 1-hydroxybenzotriazole (3.5 g) and triethylamine (3.6 ml) were
added. The mixture was stirred overnight at room temperature. Water
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The organic layer was washed successively with
water, saturated aqueous sodium hydrogencarbonate, water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure to give the title
compound (5.6 g, yield 94%).
[1573] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.22, 2H, d, J=8.8 Hz),
7.28-7.46(5H, m), 6.97(2H, d, J=8.8 Hz), 5.10(2H, s), 3.56(3H, s),
3.35(3H, s)
Step 2: Production of
1-(4-benzyloxyphenyl)-2-cyclohexylethanone
[1574] Magnesium (470 mg) was suspended in tetrahydrofuran (2 ml)
and cyclohexylmethyl bromide (3.4 g) was added dropwise at room
temperature. After the addition, the reaction mixture was stirred
for 30 min at 60.degree. C. The reaction mixture was allowed to
cool and diluted with tetrahydrofuran (5 ml). Separately,
4-benzyloxy-N-methoxy-N-methylbenzamide (3.4 g) obtained in the
previous step was dissolved in tetrahydrofuran (10 ml) and the
solution was added dropwise to the reaction mixture at room
temperature. The mixture was stirred for 2 hr and saturated aqueous
ammonium chloride solution was added to the reaction mixture. The
mixture was extracted with diethyl ether. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate, and the solvent was evaporated under reduced pressure. The
residue was purified by silica gel flash chromatography (developing
solvent, n-hexane:ethyl acetate=9:1) to give the title compound
(3.8 g, yield 66%).
[1575] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.93(2H, d, J=8.8 Hz),
7.28-7.46(5H, m), 7.00(2H, d, J=8.8 Hz), 5.13(2H, s), 2.76(2H, d,
J=6.8 Hz), 1.95(1H, m), 0.78-1.82(10H, m)
Step 3: Production of
1-(4-benzyloxyphenyl)-2-bromo-2-cyclohexylethanone
[1576] 1-(4-Benzyloxyphenyl)-2-cyclohexylethanone (1.0 g) obtained
in the previous step was dissolved in 1,4-dioxane (10 ml) and
bromine (0.17 ml) was added. The mixture was stirred for 10 min at
room temperature. Saturated aqueous sodium hydrogencarbonate was
added to the reaction mixture and the mixture was extracted with
diethyl ether. The organic layer was washed with water and
saturated brine and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel flash chromatography (developing solvent,
n-hexane:ethyl acetate=9:1) to give the title compound (696 mg,
yield 55%).
[1577] .sup.1H-NMR (300 MHz, CDCl.sub.3): 7.98(2H, d, J=8.9 Hz),
7.28-7.48(5H, m), 7.02(2H, d, J=8.9 Hz), 5.14(2H, s), 4.89(1H, d,
J=9.3 Hz), 0.86-3.30(11H, m)
Step 4: Production of ethyl
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2-a]pyridine-7-carboxylate
[1578] Ethyl 2-aminopyridine-4-carboxylate (214 mg) prepared
according to JP-A-8-48651,
1-(4-benzyloxyphenyl)-2-bromo-2-cyclohexylethanone (500 mg)
obtained in the previous step and potassium carbonate (356 mg) were
stirred for 5 hr with heating at 140.degree. C. The reaction
mixture was allowed to cool and chloroform was added. The insoluble
materials were filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel flash
chromatography (developing solvent, n-hexane:ethyl acetate=1:1) to
give the title compound (95 mg, yield 16%).
[1579] APCI-MS: 455(MH+)
[1580] .sup.1H-NMR (300 MHz, CDCl.sub.3): 8.33(1H, s), 8.21(1H, d,
J=7.5 Hz), 7.55(2H, d, J=8.7 Hz), 7.25-7.50(6H, m), 5.13(2H, s),
4.41(2H, q, J=7.1 Hz), 3.25(1H, m), 1.41(3H, t, J=7.1 Hz),
1.15-2.00(10H, m)
EXAMPLE 602
Production of
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2-a]pyridine-7-carboxylic
acid
[1581] Ethyl
2-(4-benzyloxyphenyl)-3-cyclohexylimidazo[1,2-a]pyridine-7-carboxylate
(95 mg) obtained in the previous step was treated in the same
manner as in Example 2 to give the title compound (33 mg, 37%).
[1582] APCI-MS: 427(MH+)
[1583] .sup.1H-NMR (300 MHz, DMSO-d.sub.6): 8.67(1H, d, J=7.3 Hz),
8.08(1H, s), 7.25-7.58(8H, m), 7.13(2H, d, J=8.7 Hz), 5.17(2H, s),
3.23(1H, m), 1.25-2.10(10H, m)
[1584] The compounds shown in Tables 213 to 218 can be further
obtained in the same manner as in Examples 1 to 703 or by other
conventional method employed as necessary.
[1585] The evaluation of the HCV polymerase inhibitory activity of
the compound of the present invention is explained in the
following. This polymerase is an enzyme coded for by the
non-structural protein region called NS5B on the RNA gene of HCV
(EMBO J., 15:12-22, 1996).
EXPERIMENTAL EXAMPLE [I]
i) Preparation of Enzyme (HCV Polymerase)
[1586] Using, as a template, a cDNA clone corresponding to the full
length RNA gene of HCV BK strain obtained from the blood of a
patient with hepatitis C, a region encoding NS5B (591 amino acids;
J Virol 1991 March, 65(3), 1105-13) was amplified by PCR. The
objective gene was prepared by adding a 6 His tag {base pair
encoding 6 continuous histidine (His)} to the 5' end thereof and
transformed to Escherichia coli. The Escherichia coli capable of
producing the objective protein was cultured. The obtained cells
were suspended in a buffer solution containing a surfactant and
crushed in a microfluidizer. The supernatant was obtained by
centrifugation and applied to various column chromatographys
{poly[U]-Sepharose, Sephacryl S-200, mono-S (Pharmacia)}, inclusive
of metal chelate chromatography, to give a standard enzyme
product.
ii) Synthesis of Substrate RNA
[1587] Using a synthetic primer designed based on the sequence of
HCV genomic 3' untranslated region, a DNA fragment (148 bp)
containing polyU and 3'X sequence was entirely synthesized and
cloned into plasmid pBluescript SK II(+) (Stratagene). The cDNA
encoding full length NS5B, which was prepared in i) above, was
digested with restriction enzyme KpnI to give a cDNA fragment
containing the nucleotide sequence of from the restriction enzyme
cleavage site to the termination codon. This cDNA fragment was
inserted into the upstream of 3' untranslated region of the DNA in
pBluescript SK II(+) and ligated. The about 450 bp inserted DNA
sequence was used as a template in the preparation of substrate
RNA. This plasmid was cleaved immediately after the 3'X sequence,
linearized and purified by phenol-chloroform treatment and ethanol
precipitation to give DNA.
[1588] RNA was synthesized (37.degree. C., 3 hr) by run-off method
using this purified DNA as a template, a promoter of pBluescript SK
II(+), MEGAscript RNA synthesis kit (Ambion) and T7 RNA polymerase.
DNaseI was added and the mixture was incubated for 1 hr. The
template DNA was removed by decomposition to give a crude RNA
product. This product was treated with phenol-chloroform and
purified by ethanol precipitation to give the objective substrate
RNA.
[1589] This RNA was applied to formaldehyde denaturation agarose
gel electrophoresis to confirm the quality thereof and preserved at
-80.degree. C.
iii) Assay of Enzyme (HCV Polymerase) Inhibitory Activity
[1590] A test substance (compound of the present invention) and a
reaction mixture (30 .mu.l) having the following composition were
reacted at 25.degree. C. for 90 min.
[1591] 10% Trichloroacetic acid at 4.degree. C. and 1% sodium
pyrophosphate solution (150 .mu.l) were added to this reaction
mixture to stop the reaction. The reaction mixture was left
standing in ice for 15 min to insolubilize RNA. This RNA was
trapped on a glass filter (Whatman GF/C and the like) upon
filtration by suction. This filter was washed with a solution
containing 1% trichloroacetic acid and 0.1% sodium pyrophosphate,
washed with 90% ethanol and dried. A liquid scintillation cocktail
(Packard) was added and the radioactivity of RNA synthesized by the
enzyme reaction was measured on a liquid scintillation counter.
[1592] The HCV polymerase inhibitory activity (IC.sub.50) of the
compound of the present invention was calculated from the values of
radioactivity of the enzyme reaction with and without the test
substance.
[1593] The results are shown in Tables 178-184 and 222-224.
[1594] Reaction mixture: HCV polymerase (5 .mu.g/ml) obtained in
i), substrate RNA (10 .mu.g/ml) obtained in ii), ATP (50 .mu.M),
GTP (50 .mu.M), CTP (50 .mu.M), UTP (2 .mu.M), [5,6-.sup.3H]UTP (46
Ci/mmol (Amersham), 1.5 .mu.Ci) 20 mM Tris-HCl (pH 7.5), EDTA (1
mM), MgCl.sub.2 (5 mM), NaCl (50 mM), DTT (1 mM), BSA (0.01%)
[1595] Formulation Example is given in the following. This example
is merely for the purpose of exemplification and does not limit the
invention.
FORMULATION EXAMPLE
[1596] TABLE-US-00001 (a) compound of Example 1 10 g (b) lactose 50
g (c) corn starch 15 g (d) sodium carboxymethylcellulose 44 g (e)
magnesium stearate 1 g
[1597] The entire amounts of (a), (b) and (c) and 30 g of (d) are
kneaded with water, dried in vacuo and granulated. The obtained
granules are mixed with 14 g of (d) and 1 g of (e) and processed
into tablets with a tableting machine to give 1000 tablets each
containing 10 mg of (a). TABLE-US-00002 LENGTHY TABLE REFERENCED
HERE US20070032497A1-20070208-T00001 Please refer to the end of the
specification for access instructions.
TABLE-US-00003 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00002 Please refer to the end of the
specification for access instructions.
TABLE-US-00004 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00003 Please refer to the end of the
specification for access instructions.
TABLE-US-00005 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00004 Please refer to the end of the
specification for access instructions.
TABLE-US-00006 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00005 Please refer to the end of the
specification for access instructions.
TABLE-US-00007 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00006 Please refer to the end of the
specification for access instructions.
TABLE-US-00008 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00007 Please refer to the end of the
specification for access instructions.
TABLE-US-00009 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00008 Please refer to the end of the
specification for access instructions.
TABLE-US-00010 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00009 Please refer to the end of the
specification for access instructions.
TABLE-US-00011 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00010 Please refer to the end of the
specification for access instructions.
TABLE-US-00012 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00011 Please refer to the end of the
specification for access instructions.
TABLE-US-00013 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00012 Please refer to the end of the
specification for access instructions.
TABLE-US-00014 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00013 Please refer to the end of the
specification for access instructions.
TABLE-US-00015 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00014 Please refer to the end of the
specification for access instructions.
TABLE-US-00016 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00015 Please refer to the end of the
specification for access instructions.
TABLE-US-00017 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00016 Please refer to the end of the
specification for access instructions.
TABLE-US-00018 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00017 Please refer to the end of the
specification for access instructions.
TABLE-US-00019 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00018 Please refer to the end of the
specification for access instructions.
TABLE-US-00020 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00019 Please refer to the end of the
specification for access instructions.
TABLE-US-00021 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00020 Please refer to the end of the
specification for access instructions.
TABLE-US-00022 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00021 Please refer to the end of the
specification for access instructions.
TABLE-US-00023 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00022 Please refer to the end of the
specification for access instructions.
TABLE-US-00024 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00023 Please refer to the end of the
specification for access instructions.
TABLE-US-00025 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00024 Please refer to the end of the
specification for access instructions.
TABLE-US-00026 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00025 Please refer to the end of the
specification for access instructions.
TABLE-US-00027 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00026 Please refer to the end of the
specification for access instructions.
TABLE-US-00028 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00027 Please refer to the end of the
specification for access instructions.
TABLE-US-00029 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00028 Please refer to the end of the
specification for access instructions.
TABLE-US-00030 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00029 Please refer to the end of the
specification for access instructions.
TABLE-US-00031 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00030 Please refer to the end of the
specification for access instructions.
TABLE-US-00032 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00031 Please refer to the end of the
specification for access instructions.
TABLE-US-00033 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00032 Please refer to the end of the
specification for access instructions.
TABLE-US-00034 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00033 Please refer to the end of the
specification for access instructions.
TABLE-US-00035 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00034 Please refer to the end of the
specification for access instructions.
TABLE-US-00036 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00035 Please refer to the end of the
specification for access instructions.
TABLE-US-00037 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00036 Please refer to the end of the
specification for access instructions.
TABLE-US-00038 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00037 Please refer to the end of the
specification for access instructions.
TABLE-US-00039 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00038 Please refer to the end of the
specification for access instructions.
TABLE-US-00040 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00039 Please refer to the end of the
specification for access instructions.
TABLE-US-00041 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00040 Please refer to the end of the
specification for access instructions.
TABLE-US-00042 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00041 Please refer to the end of the
specification for access instructions.
TABLE-US-00043 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00042 Please refer to the end of the
specification for access instructions.
TABLE-US-00044 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00043 Please refer to the end of the
specification for access instructions.
TABLE-US-00045 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00044 Please refer to the end of the
specification for access instructions.
TABLE-US-00046 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00045 Please refer to the end of the
specification for access instructions.
TABLE-US-00047 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00046 Please refer to the end of the
specification for access instructions.
TABLE-US-00048 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00047 Please refer to the end of the
specification for access instructions.
TABLE-US-00049 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00048 Please refer to the end of the
specification for access instructions.
TABLE-US-00050 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00049 Please refer to the end of the
specification for access instructions.
TABLE-US-00051 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00050 Please refer to the end of the
specification for access instructions.
TABLE-US-00052 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00051 Please refer to the end of the
specification for access instructions.
TABLE-US-00053 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00052 Please refer to the end of the
specification for access instructions.
TABLE-US-00054 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00053 Please refer to the end of the
specification for access instructions.
TABLE-US-00055 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00054 Please refer to the end of the
specification for access instructions.
TABLE-US-00056 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00055 Please refer to the end of the
specification for access instructions.
TABLE-US-00057 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00056 Please refer to the end of the
specification for access instructions.
TABLE-US-00058 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00057 Please refer to the end of the
specification for access instructions.
TABLE-US-00059 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00058 Please refer to the end of the
specification for access instructions.
TABLE-US-00060 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00059 Please refer to the end of the
specification for access instructions.
TABLE-US-00061 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00060 Please refer to the end of the
specification for access instructions.
TABLE-US-00062 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00061 Please refer to the end of the
specification for access instructions.
TABLE-US-00063 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00062 Please refer to the end of the
specification for access instructions.
TABLE-US-00064 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00063 Please refer to the end of the
specification for access instructions.
TABLE-US-00065 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00064 Please refer to the end of the
specification for access instructions.
TABLE-US-00066 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00065 Please refer to the end of the
specification for access instructions.
TABLE-US-00067 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00066 Please refer to the end of the
specification for access instructions.
TABLE-US-00068 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00067 Please refer to the end of the
specification for access instructions.
TABLE-US-00069 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00068 Please refer to the end of the
specification for access instructions.
TABLE-US-00070 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00069 Please refer to the end of the
specification for access instructions.
TABLE-US-00071 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00070 Please refer to the end of the
specification for access instructions.
TABLE-US-00072 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00071 Please refer to the end of the
specification for access instructions.
TABLE-US-00073 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00072 Please refer to the end of the
specification for access instructions.
TABLE-US-00074 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00073 Please refer to the end of the
specification for access instructions.
TABLE-US-00075 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00074 Please refer to the end of the
specification for access instructions.
TABLE-US-00076 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00075 Please refer to the end of the
specification for access instructions.
TABLE-US-00077 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00076 Please refer to the end of the
specification for access instructions.
TABLE-US-00078 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00077 Please refer to the end of the
specification for access instructions.
TABLE-US-00079 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00078 Please refer to the end of the
specification for access instructions.
TABLE-US-00080 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00079 Please refer to the end of the
specification for access instructions.
TABLE-US-00081 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00080 Please refer to the end of the
specification for access instructions.
TABLE-US-00082 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00081 Please refer to the end of the
specification for access instructions.
TABLE-US-00083 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00082 Please refer to the end of the
specification for access instructions.
TABLE-US-00084 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00083 Please refer to the end of the
specification for access instructions.
TABLE-US-00085 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00084 Please refer to the end of the
specification for access instructions.
TABLE-US-00086 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00085 Please refer to the end of the
specification for access instructions.
TABLE-US-00087 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00086 Please refer to the end of the
specification for access instructions.
TABLE-US-00088 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00087 Please refer to the end of the
specification for access instructions.
TABLE-US-00089 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00088 Please refer to the end of the
specification for access instructions.
TABLE-US-00090 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00089 Please refer to the end of the
specification for access instructions.
TABLE-US-00091 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00090 Please refer to the end of the
specification for access instructions.
TABLE-US-00092 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00091 Please refer to the end of the
specification for access instructions.
TABLE-US-00093 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00092 Please refer to the end of the
specification for access instructions.
TABLE-US-00094 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00093 Please refer to the end of the
specification for access instructions.
TABLE-US-00095 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00094 Please refer to the end of the
specification for access instructions.
TABLE-US-00096 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00095 Please refer to the end of the
specification for access instructions.
TABLE-US-00097 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00096 Please refer to the end of the
specification for access instructions.
TABLE-US-00098 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00097 Please refer to the end of the
specification for access instructions.
TABLE-US-00099 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00098 Please refer to the end of the
specification for access instructions.
TABLE-US-00100 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00099 Please refer to the end of the
specification for access instructions.
TABLE-US-00101 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00100 Please refer to the end of the
specification for access instructions.
TABLE-US-00102 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00101 Please refer to the end of the
specification for access instructions.
TABLE-US-00103 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00102 Please refer to the end of the
specification for access instructions.
TABLE-US-00104 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00103 Please refer to the end of the
specification for access instructions.
TABLE-US-00105 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00104 Please refer to the end of the
specification for access instructions.
TABLE-US-00106 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00105 Please refer to the end of the
specification for access instructions.
TABLE-US-00107 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00106 Please refer to the end of the
specification for access instructions.
TABLE-US-00108 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00107 Please refer to the end of the
specification for access instructions.
TABLE-US-00109 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00108 Please refer to the end of the
specification for access instructions.
TABLE-US-00110 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00109 Please refer to the end of the
specification for access instructions.
TABLE-US-00111 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00110 Please refer to the end of the
specification for access instructions.
TABLE-US-00112 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00111 Please refer to the end of the
specification for access instructions.
TABLE-US-00113 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00112 Please refer to the end of the
specification for access instructions.
TABLE-US-00114 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00113 Please refer to the end of the
specification for access instructions.
TABLE-US-00115 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00114 Please refer to the end of the
specification for access instructions.
TABLE-US-00116 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00115 Please refer to the end of the
specification for access instructions.
TABLE-US-00117 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00116 Please refer to the end of the
specification for access instructions.
TABLE-US-00118 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00117 Please refer to the end of the
specification for access instructions.
TABLE-US-00119 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00118 Please refer to the end of the
specification for access instructions.
TABLE-US-00120 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00119 Please refer to the end of the
specification for access instructions.
TABLE-US-00121 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00120 Please refer to the end of the
specification for access instructions.
TABLE-US-00122 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00121 Please refer to the end of the
specification for access instructions.
TABLE-US-00123 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00122 Please refer to the end of the
specification for access instructions.
TABLE-US-00124 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00123 Please refer to the end of the
specification for access instructions.
TABLE-US-00125 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00124 Please refer to the end of the
specification for access instructions.
TABLE-US-00126 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00125 Please refer to the end of the
specification for access instructions.
TABLE-US-00127 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00126 Please refer to the end of the
specification for access instructions.
TABLE-US-00128 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00127 Please refer to the end of the
specification for access instructions.
TABLE-US-00129 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00128 Please refer to the end of the
specification for access instructions.
TABLE-US-00130 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00129 Please refer to the end of the
specification for access instructions.
TABLE-US-00131 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00130 Please refer to the end of the
specification for access instructions.
TABLE-US-00132 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00131 Please refer to the end of the
specification for access instructions.
TABLE-US-00133 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00132 Please refer to the end of the
specification for access instructions.
TABLE-US-00134 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00133 Please refer to the end of the
specification for access instructions.
TABLE-US-00135 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00134 Please refer to the end of the
specification for access instructions.
TABLE-US-00136 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00135 Please refer to the end of the
specification for access instructions.
TABLE-US-00137 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00136 Please refer to the end of the
specification for access instructions.
TABLE-US-00138 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00137 Please refer to the end of the
specification for access instructions.
TABLE-US-00139 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00138 Please refer to the end of the
specification for access instructions.
TABLE-US-00140 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00139 Please refer to the end of the
specification for access instructions.
TABLE-US-00141 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00140 Please refer to the end of the
specification for access instructions.
TABLE-US-00142 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00141 Please refer to the end of the
specification for access instructions.
TABLE-US-00143 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00142 Please refer to the end of the
specification for access instructions.
TABLE-US-00144 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00143 Please refer to the end of the
specification for access instructions.
TABLE-US-00145 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00144 Please refer to the end of the
specification for access instructions.
TABLE-US-00146 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00145 Please refer to the end of the
specification for access instructions.
TABLE-US-00147 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00146 Please refer to the end of the
specification for access instructions.
TABLE-US-00148 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00147 Please refer to the end of the
specification for access instructions.
TABLE-US-00149 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00148 Please refer to the end of the
specification for access instructions.
TABLE-US-00150 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00149 Please refer to the end of the
specification for access instructions.
TABLE-US-00151 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00150 Please refer to the end of the
specification for access instructions.
TABLE-US-00152 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00151 Please refer to the end of the
specification for access instructions.
TABLE-US-00153 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00152 Please refer to the end of the
specification for access instructions.
TABLE-US-00154 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00153 Please refer to the end of the
specification for access instructions.
TABLE-US-00155 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00154 Please refer to the end of the
specification for access instructions.
TABLE-US-00156 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00155 Please refer to the end of the
specification for access instructions.
TABLE-US-00157 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00156 Please refer to the end of the
specification for access instructions.
TABLE-US-00158 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00157 Please refer to the end of the
specification for access instructions.
TABLE-US-00159 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00158 Please refer to the end of the
specification for access instructions.
TABLE-US-00160 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00159 Please refer to the end of the
specification for access instructions.
TABLE-US-00161 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00160 Please refer to the end of the
specification for access instructions.
TABLE-US-00162 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00161 Please refer to the end of the
specification for access instructions.
TABLE-US-00163 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00162 Please refer to the end of the
specification for access instructions.
TABLE-US-00164 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00163 Please refer to the end of the
specification for access instructions.
TABLE-US-00165 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00164 Please refer to the end of the
specification for access instructions.
TABLE-US-00166 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00165 Please refer to the end of the
specification for access instructions.
TABLE-US-00167 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00166 Please refer to the end of the
specification for access instructions.
TABLE-US-00168 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00167 Please refer to the end of the
specification for access instructions.
TABLE-US-00169 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00168 Please refer to the end of the
specification for access instructions.
TABLE-US-00170 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00169 Please refer to the end of the
specification for access instructions.
TABLE-US-00171 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00170 Please refer to the end of the
specification for access instructions.
TABLE-US-00172 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00171 Please refer to the end of the
specification for access instructions.
TABLE-US-00173 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00172 Please refer to the end of the
specification for access instructions.
TABLE-US-00174 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00173 Please refer to the end of the
specification for access instructions.
TABLE-US-00175 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00174 Please refer to the end of the
specification for access instructions.
TABLE-US-00176 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00175 Please refer to the end of the
specification for access instructions.
TABLE-US-00177 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00176 Please refer to the end of the
specification for access instructions.
TABLE-US-00178 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00177 Please refer to the end of the
specification for access instructions.
TABLE-US-00179 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00178 Please refer to the end of the
specification for access instructions.
TABLE-US-00180 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00179 Please refer to the end of the
specification for access instructions.
TABLE-US-00181 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00180 Please refer to the end of the
specification for access instructions.
TABLE-US-00182 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00181 Please refer to the end of the
specification for access instructions.
TABLE-US-00183 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00182 Please refer to the end of the
specification for access instructions.
TABLE-US-00184 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00183 Please refer to the end of the
specification for access instructions.
TABLE-US-00185 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00184 Please refer to the end of the
specification for access instructions.
TABLE-US-00186 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00185 Please refer to the end of the
specification for access instructions.
TABLE-US-00187 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00186 Please refer to the end of the
specification for access instructions.
TABLE-US-00188 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00187 Please refer to the end of the
specification for access instructions.
TABLE-US-00189 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00188 Please refer to the end of the
specification for access instructions.
TABLE-US-00190 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00189 Please refer to the end of the
specification for access instructions.
TABLE-US-00191 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00190 Please refer to the end of the
specification for access instructions.
TABLE-US-00192 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00191 Please refer to the end of the
specification for access instructions.
TABLE-US-00193 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00192 Please refer to the end of the
specification for access instructions.
TABLE-US-00194 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00193 Please refer to the end of the
specification for access instructions.
TABLE-US-00195 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00194 Please refer to the end of the
specification for access instructions.
TABLE-US-00196 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00195 Please refer to the end of the
specification for access instructions.
TABLE-US-00197 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00196 Please refer to the end of the
specification for access instructions.
TABLE-US-00198 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00197 Please refer to the end of the
specification for access instructions.
TABLE-US-00199 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00198 Please refer to the end of the
specification for access instructions.
TABLE-US-00200 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00199 Please refer to the end of the
specification for access instructions.
TABLE-US-00201 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00200 Please refer to the end of the
specification for access instructions.
TABLE-US-00202 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00201 Please refer to the end of the
specification for access instructions.
TABLE-US-00203 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00202 Please refer to the end of the
specification for access instructions.
TABLE-US-00204 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00203 Please refer to the end of the
specification for access instructions.
TABLE-US-00205 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00204 Please refer to the end of the
specification for access instructions.
TABLE-US-00206 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00205 Please refer to the end of the
specification for access instructions.
TABLE-US-00207 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00206 Please refer to the end of the
specification for access instructions.
TABLE-US-00208 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00207 Please refer to the end of the
specification for access instructions.
TABLE-US-00209 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00208 Please refer to the end of the
specification for access instructions.
TABLE-US-00210 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00209 Please refer to the end of the
specification for access instructions.
TABLE-US-00211 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00210 Please refer to the end of the
specification for access instructions.
TABLE-US-00212 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00211 Please refer to the end of the
specification for access instructions.
TABLE-US-00213 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00212 Please refer to the end of the
specification for access instructions.
TABLE-US-00214 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00213 Please refer to the end of the
specification for access instructions.
TABLE-US-00215 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00214 Please refer to the end of the
specification for access instructions.
TABLE-US-00216 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00215 Please refer to the end of the
specification for access instructions.
TABLE-US-00217 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00216 Please refer to the end of the
specification for access instructions.
TABLE-US-00218 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00217 Please refer to the end of the
specification for access instructions.
TABLE-US-00219 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00218 Please refer to the end of the
specification for access instructions.
TABLE-US-00220 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00219 Please refer to the end of the
specification for access instructions.
TABLE-US-00221 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00220 Please refer to the end of the
specification for access instructions.
TABLE-US-00222 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00221 Please refer to the end of the
specification for access instructions.
TABLE-US-00223 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00222 Please refer to the end of the
specification for access instructions.
TABLE-US-00224 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00223 Please refer to the end of the
specification for access instructions.
TABLE-US-00225 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00224 Please refer to the end of the
specification for access instructions.
TABLE-US-00226 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00225 Please refer to the end of the
specification for access instructions.
TABLE-US-00227 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00226 Please refer to the end of the
specification for access instructions.
TABLE-US-00228 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00227 Please refer to the end of the
specification for access instructions.
TABLE-US-00229 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00228 Please refer to the end of the
specification for access instructions.
TABLE-US-00230 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00229 Please refer to the end of the
specification for access instructions.
TABLE-US-00231 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00230 Please refer to the end of the
specification for access instructions.
TABLE-US-00232 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00231 Please refer to the end of the
specification for access instructions.
TABLE-US-00233 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00232 Please refer to the end of the
specification for access instructions.
TABLE-US-00234 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00233 Please refer to the end of the
specification for access instructions.
TABLE-US-00235 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00234 Please refer to the end of the
specification for access instructions.
TABLE-US-00236 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00235 Please refer to the end of the
specification for access instructions.
TABLE-US-00237 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00236 Please refer to the end of the
specification for access instructions.
TABLE-US-00238 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00237 Please refer to the end of the
specification for access instructions.
TABLE-US-00239 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00238 Please refer to the end of the
specification for access instructions.
TABLE-US-00240 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00239 Please refer to the end of the
specification for access instructions.
TABLE-US-00241 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00240 Please refer to the end of the
specification for access instructions.
TABLE-US-00242 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00241 Please refer to the end of the
specification for access instructions.
TABLE-US-00243 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00242 Please refer to the end of the
specification for access instructions.
TABLE-US-00244 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00243 Please refer to the end of the
specification for access instructions.
TABLE-US-00245 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00244 Please refer to the end of the
specification for access instructions.
TABLE-US-00246 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00245 Please refer to the end of the
specification for access instructions.
TABLE-US-00247 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00246 Please refer to the end of the
specification for access instructions.
TABLE-US-00248 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00247 Please refer to the end of the
specification for access instructions.
TABLE-US-00249 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00248 Please refer to the end of the
specification for access instructions.
TABLE-US-00250 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00249 Please refer to the end of the
specification for access instructions.
TABLE-US-00251 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00250 Please refer to the end of the
specification for access instructions.
TABLE-US-00252 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00251 Please refer to the end of the
specification for access instructions.
TABLE-US-00253 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00252 Please refer to the end of the
specification for access instructions.
TABLE-US-00254 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00253 Please refer to the end of the
specification for access instructions.
TABLE-US-00255 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00254 Please refer to the end of the
specification for access instructions.
TABLE-US-00256 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00255 Please refer to the end of the
specification for access instructions.
TABLE-US-00257 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00256 Please refer to the end of the
specification for access instructions.
TABLE-US-00258 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00257 Please refer to the end of the
specification for access instructions.
TABLE-US-00259 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00258 Please refer to the end of the
specification for access instructions.
TABLE-US-00260 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00259 Please refer to the end of the
specification for access instructions.
TABLE-US-00261 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00260 Please refer to the end of the
specification for access instructions.
TABLE-US-00262 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00261 Please refer to the end of the
specification for access instructions.
TABLE-US-00263 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00262 Please refer to the end of the
specification for access instructions.
TABLE-US-00264 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00263 Please refer to the end of the
specification for access instructions.
TABLE-US-00265 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00264 Please refer to the end of the
specification for access instructions.
TABLE-US-00266 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00265 Please refer to the end of the
specification for access instructions.
TABLE-US-00267 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00266 Please refer to the end of the
specification for access instructions.
TABLE-US-00268 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00267 Please refer to the end of the
specification for access instructions.
TABLE-US-00269 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00268 Please refer to the end of the
specification for access instructions.
TABLE-US-00270 LENGTHY TABLE REFERENCED HERE
US20070032497A1-20070208-T00269 Please refer to the end of the
specification for access instructions.
INDUSTRIAL APPLICABILITY
[1598] As is evident from the above-mentioned results, the compound
of the present invention shows a high inhibitory activity against
HCV polymerase.
[1599] Therefore, the compound of the present invention can provide
a pharmaceutical agent effective for the prophylaxis or treatment
of hepatitis C, based on the anti-HCV effect afforded by the HCV
polymerase inhibitory activity. When used concurrently with a
different anti-HCV agent, such as interferon, and/or an
anti-inflammatory agent and the like, it can provide a
pharmaceutical agent more effective for the prophylaxis or
treatment of hepatitis C. Its high inhibitory activity specific to
HCV polymerase suggests the possibility of the compound being a
pharmaceutical agent with slight side effects, which can be used
safely for humans.
[1600] This application is based on patent application Nos.
369008/1999, 391904/2000, 193786/2001 and 351537/2001 filed in
Japan, international application No. PCT/JP00/09181 and U.S. patent
application Ser. No. 09/939,374, the contents of which are hereby
incorporated by reference. TABLE-US-00271 LENGTHY TABLE The patent
application contains a lengthy table section. A copy of the table
is available in electronic form from the USPTO web site
(http://seqdata.uspto.gov/?pageRequest=docDetail&DocID=US20070032497A1)
An electronic copy of the table will also be available from the
USPTO upon request and payment of the fee set forth in 37 CFR
1.19(b)(3).
* * * * *
References