Specification
DESCRIPTION
HALOGEN-SUBSTITUTED HETEROCYCLIC COMPOUND
5 TECHNICAL FIELD
[0001] The present invention relates to a novel a-halogen-substituted thiophene
compound or a pharmacologically acceptable salt thereof. Since the
a-halogen-substituted thiophene compound of the present invention has an antagonist
activity on a lysophosphatidic acid (LP A) receptor, it would be useful for the prevention
10 and/or the treatment of diseases caused by LP A.
BACKGROUND ART
[0002] Lysophosphatidic acid (LPA) is a physiologically active phospholipid which is
present in a living body. LPA transduces a signal in a cell and modulates the
15 proliferation, differentiation, survival, migration, adhesion, infiltration, morphogenesis
of a cell by binding to a specific G-protein-coupled receptor (LPA 1, LP A2, LPA3,
LPA4, LPA5, LPA6). Further, it has been known that LPA is involved with a disease
accompanied with fibrosis in various organs.
[0003] Regarding liver, it has been reported that LPA accelerates the proliferation or
20 contraction of stellate cell which plays an important role in the process of hepatic
fibrosis, or the migration ofmyofibroblast (refer to Non-Patent Documents 1, 2 and 3).
Regarding kidney, it has been reported that the production ofLPA or the
expression of LP A 1 is facilitated in a mouse with unilateral ureteral ligation, which is
an animal model of renal fibrosis, and that the renal fibrosis is suppressed by LPAl
25 deficiency or administration of an LPA receptor-antagonist (refer to Non-Patent
Documents 4 and 5).
[0004] Regarding lung, it has been reported that the LPA concentration in
bronchoalveolar lavage fluid of a patient with idiopathic pulmonary fibrosis is elevated;
and that LPA 1 is most expressed in fibroblast having an important role in the process of
30 pulmonary fibrosis and LPA makes the fibroblast migrate. Further, it has been
reported that fibrosis is suppressed by LPA 1 deficiency or administration of an LPA
receptor-antagonist in a mouse to which bleomycin was intratracheally administered,
which is an animal model of pulmonary fibrosis (refer to Non-Patent Documents 6 and
7).
35 [0005] Regarding skin, it has been reported that fibrosis of skin is suppressed by LPAl
deficiency or administration of an LPA receptor-antagonist in a mouse to which
-2-
bleomycin was subcutaneously administered, which is a sclerodermia animal model
(refer to Non-Patent Document 8).
[0006] It has also been known to that LPA is involved with immunological or
inflammatory diseases. It has been reported that LP A facilitates the migration of
5 human monocyte; and that LPA is involved with the proliferation or infiltration ofT
cells. Further, it has been reported that synovial cells of patient with rheumatoid
arthritis express LPA receptor and migrate or produce IL-6 and IL-8 by the LPA
stimulation; and that these actions are inhibited by an LPA receptor antagonist (refer to
Non-Patent Documents 9, 10 and 11).
10 [0007] In addition, it has been reported that LPA and LPA1 are involved with the
development of neuropathic pain (refer to Patent Document 12); that LP A is involved
with urologic diseases by contracting an extracted urethra specimen and a prostatic
specimen to increase the intraurethral pressure (refer to Patent Document 1); and that
LPA is involved with cancer-related diseases by accelerating the infiltration of cancer
15 cells, by accelerating the proliferation of ovary cancer cells, or by accelerating the
proliferation of prostate cancer cells (refer to Non-Patent Documents 13, 14 and 15).
[0008] Based on these findings, a medicament which antagonizes the LP A receptor
(particularly, LPA1 receptor) is considered to be useful for the prevention and/or
treatment of a disease accompanying fibrosis, an immunological or inflammatory
20 disease, a central or peripheral nervous system disease, an urologic disease, a
cancer-related disease, etc.
[0009] On the other hand, as a compound having antagonizing action ofLPA receptor,
([1, 1 '-biphenyl]-4-yl)acetic acid derivatives are disclosed in Patent Documents 2 to 19,
and Non-Patent Documents 7, 8, 16 and 17; (2'-methoxy-[1,1'-biphenyl]-4-yl) acetic
25 acid derivatives are disclosed in Patent Document 17; and 3-chloroisothiazole
derivatives are disclosed in Patent Document 19, but there is no disclosure on the
compound ofthe present invention.
PRIOR ART DOCUMENTS
30 Patent Documents
35
[0010] Patent Document 1: WO 2002/062389
Patent Document 2: WO 2010/077882
Patent Document 3: WO 2010/077883
Patent Document 4: WO 20101141761
Patent Document 5: WO 2010/141768
Patent Document 6: WO 2011/017350
5
10
- 3-
Patent Document 7: WO 20111041461
Patent Document 8: WO 20111041462
Patent Document 9: WO 20111041694
Patent Document 10: WO 2011/041729
Patent Document 11: WO 2011/091167
Patent Document 12: WO 2011/159632
Patent Document 13: WO 20111159633
Patent Document 14: WO 20111159635
Patent Document 15: WO 2012/078593
Patent Document 16: WO 2012/078805
Patent Document 17: WO 2012/138648
Patent Document 18: WO 2012/138797
Patent Document 19: WO 2013/025733
15 Non-Patent Document
20
25
[00 11] Non-Patent Document 1: Biochemical and Biophysical Research
Communications, 248 (1998) 436-440
Non-Patent Document 2: Biochemical and Biophysical Research
Communications, 277 (2000) 72-78
Non-Patent Document 3: Journal of Biomedical Science, 10 (2003) 352-358
Non-Patent Document 4: Journal of the American Society ofNephrology, 18
(2007) 3110-3118
Non-Patent Document 5: The Journal of Pharmacology and Experimental
Therapeutics, 336 (2011) 693-700
Non-Patent Document 6: Nature Medicine, 14 (2008) 45-54
Non-Patent Document 7: British Journal of Pharmacology, 160 (2010)
1699-1713
Non-Patent Document 8: Arthritis & Rheumatism, 63 (2011) 1405-1415
Non-Patent Document 9: Journal of Biological Chemistry, 270 (1995)
30 25549-25556
Non-Patent Document 10: Biochimica et Biophysica Acta, 1582 (2002)
168-174
Non-Patent Document 11: Molecular Pharmacology, 73 (2008) 587-600
Non-Patent Document 12: Nature Medicine, 10 (2004) 712-718
35 Non-Patent Document 13: Biochemical and Biophysical Research
Communications, 193 (1993) 497-503
-4-
Non-Patent Document 14: Biochemical Journal, 309 (1995) 933-940
Non-Patent Document 15: The Journal of Urology, 163 (2000) 1027-1032
Non-Patent Document 16: The Journal of Pharmacology and Experimental
Therapeutics, 336 (20 11) 693-700
5 Non-Patent Document 17: Journal ofMedicinal Chemistry, 55 (2012)
7920-7939
DISCLOSURE OF THE INVENTION
Problems to be Solved by the Invention
10 [0012] The present inventors carried out a research on various halogen-substituted
heterocyclic compounds in order to develop an excellent medicament for the treatment
or prevention of a disease accompanying fibrosis, an immunological or inflammatory
disease, a central or peripheral nervous system disease, an urologic disease, a
cancer-related disease, etc., and found out that a novel a-halogen-substituted thiophene
15 compound having a specific structure has an excellent LP A receptor-antagonist action
and is useful as a medicament (particularly, for the prevention and/or treatment of a
disease accompanying fibrosis, an immunological or inflammatory disease, a central or
peripheral nervous system disease, an urologic disease, a cancer-related disease) to
accomplish the present invention.
20 [0013] The present invention provides a novel a-halogen-substituted thiophene
compound or a pharmacologically acceptable salt thereof which has a potent LP A
receptor-antagonist action and is useful as a medicament for the treatment and/or
prevention (preferably, a medicament for the treatment) of, particularly, a disease
accompanying fibrosis, an immunological or inflammatory disease, a central or
25 peripheral nervous system disease, an urologic disease or a cancer-related disease.
Means for Solving the Problems
[0014] The present invention provides:
[0015] (1) A compound represented by the general formula (I):
30 [0016] [Chemical Formula 1]
- 5-
(I)
X
[00 17] wherein
A represents, a phenyl ring, a thiophene ring, or an isothiazole ring;
R1 is the same or different, and represents a halogen atom, or a C1-C3 alkyl
5 group;
R2 represents a hydrogen atom, or a C1-C6 alkyl group;
p represents an integer of 0 to 5;
V represents CR3 wherein R3 represents a hydrogen atom, an amino group, a
nitro group, or a C1-C3 alkoxy group, or V represents a nitrogen atom;
10 X represents a halogen atom,
15
and, a pharmacologically acceptable salt thereof.
[0018] (2) The compound according to (1) which is represented by the general formula
(Ia):
[0019] [Chemical Formula 2]
{I a)
[0020] wherein
R 1 is the same or different, and represents a halogen atom, or a C 1-C3 alkyl
group,
R2 represents a hydrogen atom, or a C1-C6 alkyl group;
- 6-
p represents an integer of 0 to 5;
V represents CH or a nitrogen atom;
X represents a halogen atom,
and, a pharmacologically acceptable salt thereof.
5 [0021] (3) The compound according to (2) wherein, in the general formula (Ia), the
group:
[0022] [Chemical Formula 3]
(R'),-~
is selected from a group consisting of the groups:
10 [0023] [Chemical Formula 4]
Cl ~ ~c1J) ..
uh F-· F~u- -.Fu0 -. FuF~.., FFu~F_-. Fh0 -. F {5\Me F& F'd.: ~ I~ I~
I ..& b Cl and b M
Cl F e
[0024] and, a pharmacologically acceptable salt thereof.
[0025] (4) The compound according to (2) wherein, in the general formula (Ia), the
group:
15 [0026] [Chemical Formula 5]
(R'), ~
[0027]
is selected from a group consisting of the groups:
[Chemical Formula 6]
Cl
~
b
Me F& I~
and ,&; F
20 [0028] and, a pharmacologically acceptable salt thereof.
[0029] (5) The compound according to (2) which is selected from a group consisting
of:
- 7-
(RS)-1- { 4 1
-[ 5-bromo-3-( {[ 1-(2-chlorophenyl)ethoxy ]carbonyl} amino)thiophen-
2-yl]-[ 1, 11 -biphenyl ]-4-yl} cyclopropanecarboxylic acid,
(RS)-1- {4'-[5-chloro-3-( {[1-(2-chlorophenyl)ethoxy]carbonyl }amino)thiophen-
2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
5 (R)-1-{ 4' -[ 5-chloro-3-( {[ 1-(2-chlorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-[ 41-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino} thiophen-2-yl)-[ 1,1 'biphenyl
]-4-yl]cyclopropanecarboxylic acid,
(R)-1- {4'-[5-chloro-3-( {[1-(2-fluorophenyl)ethoxy]carbonyl} amino )thiophen-
10 2-yl]-[1,1 1-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[1-(3-fluoropheny1)ethoxy]carbonyl} amino )thiophen-
2-y1 ]-[ 1, 1 '-biphenyl ]-4-y1} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[ 5 -chloro-3-( { [ 1-( 4-fluorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl ]-[ 1,1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid,
15 (R)-1-{ 4'-[ 5-chloro-3-( { [ 1-( 4-chlorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl ]-[ 1,1 1 -biphenyl ]-4-yl} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[ 1-( o-tolyl)ethoxy]carbonyl} amino )thiophen-2-y1][
1,1 '-bipheny1]-4-yl} cyclopropanecarboxylic acid,
(R)-1- {4'-[5-chloro-3-( {[1-(2,4-difluorophenyl)ethoxy ]carbonyl }amino)-
20 thiophen-2-yl]-[ 1,1 '-biphenyl]-4-y1 }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[1-(2,5-difluorophenyl)ethoxy]carbonyl }amino)thiophen-
2-yl]-[ 1,1 '-biphenyl]-4-y1 }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[1-(3,4-difluorophenyl)ethoxy]carbonyl }amino)thiophen-
2-yl]-[1 ,1 '-biphenyl]-4-yl}cyclopropanecarboxylic acid,
25 (R)-1- {41-[5-chloro-3-( {[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl }amino)-
thiophen-2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4-[ 5-(5-chloro-3-{[(1-phenylethoxy)carbonyl]amino} thiophen-2-yl)pyridin-
2-yl ]phenyl} cyclopropanecarboxylic acid,
(R)-1-[ 4' -( 5-fluoro-3-{[ ( 1-phenylethoxy)carbonyl] amino} thiophen-2-yl)[ 1, 1 '-
30 bipheny1]-4-yl]cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-fluoro-3-( {[1-(2-fluorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{ 4'-[ 5-fluoro-3-( {[1-( 4-fluorophenyl)ethoxy ]carbonyl }amino )thiophen-
2-yl]-[1 ,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
35 (R)-1- {4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl} amino )-5-fluorothiophen-
2-yl] -[ 1, 1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid,
- 8 -
(R)-1-{4'-[3-( {[1-( 4-chlorophenyl)ethoxy]carbonyl }amino )-5-fluorothiophen-
2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{4'-[5-fluoro-3-( {[ 1-( o-tolyl)ethoxy]carbonyl}amino )thiophen-2-yl][
1, 1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid,
5 (R)-1-{4'-[3-( {[1-(3,4-difluorophenyl)ethoxy]carbonyl }amino )-5-fluorothiophen-
2-yl]-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{4'-[3-( {[1-(2,4-difluorophenyl)ethoxy]carbonyl }amino )-5-fluorothiophen-
2-yl]-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[3-( {[1-(2-chloro-4-fluorophenyl)ethoxy]carbonyl }amino )-5-fluoro-
10 thiophen-2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1- {4'-[3-( {[ 1-( 4-chloro-2-fluorophenyl)ethoxy]carbonyl }amino )-5-
fluorothiophen-2-yl]-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[ 5-fluoro-3-( { [ 1-(2,4,5-trifluorophenyl)ethoxy ]carbonyl} amino)thiophen-
2-yl] -[ 1, !'-biphenyl ]-4-yl} cyclopropanecarboxylic acid,
15 and, a phannacologically acceptable salt thereof.
[0030] (6) The compound according to (1) wherein, in the general formula (I), V
represents CR3 in which R3 represents a hydrogen atom, an amino group, a nitro group,
or a Ct-C3 alkoxy group, or V represents a nitrogen atom with the proviso that in a case
where A represents a phenyl ring, V is not CH or a nitrogen atom,
20 and, a phannacologically acceptable salt thereof.
[0031] (7) The compound according to (6) which is represented by the general formula
(Ib):
[0032] [Chemical Formula 7]
25 [0033] wherein
R1 is the same or different, and represents a halogen atom, or a C1-C3 alkyl
group;
- 9-
R2 represents a hydrogen atom or a C1-C6 alkyl group;
p represents an integer of 0 to 5;
X represents a halogen atom,
and, a pharmacologically acceptable salt thereof.
5 [0034] (8) The compound according to (7) wherein, in the general formula (lb ), the
group:
[0035] [Chemical Formula 8]
(R'), ~
is selected from a group consisting of the groups:
10 [0036] [Chemical Formula 9]
[0037] and, a pharmacologically acceptable salt thereof.
[0038] (9) The compound according to (7) wherein, in the general formula (lb ), the
group:
15 [0039] [Chemical Formula 10]
(R1
)p ~
is selected from a group consisting of the groups:
[0040] [Chemical Formula 11]
b_
V -·and
20 [0041] and, a pharmacologically acceptable salt thereof.
F& l,p
F
[0042] (10) The compound according to (7) which is selected from a group consisting
of:
- 10-
(R)-1-[ 4' -( 5-chloro-3- { [ ( 1-phenylethoxy)carbonyl ]amino} thiophen-2-yl)-2'methoxy-[
1, 1 '-biphenyl]-4-yl]cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[1-(2-fluorophenyl)ethoxy]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid,
5 (R)-1-{ 4'-[ 5-chloro-3-( {[ 1-(3-fluorophenyl)ethoxy]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[ 1-( 4-fluorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[ 1-(2-chlorophenyl)ethoxy]carbonyl} amino )thiophen-
10 2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{ 4'-[ 5-chloro-3-( {[ 1-( 4-chlorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylicacid,
(R)-1-{ 4'-[5-chloro-3-( {[ 1-( o-tolyl)ethoxy]carbonyl }amino )thiophen-2-yl]-2'methoxy-[
1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid,
15 (R)-1-{ 4'-[5-chloro-3-( {[1-(3,4-difluorophenyl)ethoxy]carbonyl} amino)-
thiophen-2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[ 5-chloro-3-( {[ 1-(2,5-difluorophenyl )ethoxy ]carbonyl} amino)thiophen-
2-yl]-2'-methoxy-[1,1 '-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{ 4 '-[ 5-chloro-3 -( { [ 1-(2, 4-difluorophenyl)ethox y ]carbonyl} amino)-
20 thiophen-2-yl]-2'-methoxy-[ 1, 1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[5-chloro-3-( {[1-(2-chloro-5-fluorophenyl)ethoxy]carbonyl }amino
)thiophen-2-yl]-2'-methoxy-[1 ,1'-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(R )-1-{ 4 '-[ 5-chloro-3-( {[ 1-(2-chloro-4-fluorophenyl)ethoxy ]carbonyl} amino)thiophen-
2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
25 (RS )-1-{ 4'-[ 5-chloro-3-( {[ 1-( 5-fluoro-2-methylphenyl)ethoxy ]carbonyl}-
amino)thiophen-2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-chloro-3-( {[1-(4-fluoro-2-methylphenyl)ethoxy]carbonyl}amino)
thiophen-2-yl]-2'-methoxy-[1,1 '-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-[4'-(5-fluoro-3-{[(1-phenylethoxy)carbonyl]amino}thiophen-2-yl)-2'-
30 methoxy-[1,1 '-biphenyl]-4-yl]cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-fluoro-3-( {[1-(2-fluorophenyl)ethoxy]carbonyl} amino )thiophen-
2-yl ]-2 '-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid,
(R )-1- { 4 '-[ 5-fluoro-3-( { [ 1-(3-fluorophenyl )ethoxy ]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
3 5 (R)-1- { 4 '-[ 5-fluoro-3-( {[ 1-( 4-fluorophenyl )ethoxy ]carbonyl} amino )thiophen-
2-yl ]-2'-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid,
- 11 -
(R)-1-{ 4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl} amino )-5-fluorothiophen-
2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{41-[3-({[1-(4-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-
2-yl]-2' -methoxy-[ 1, 1 1 -biphenyl ]-4-yl} cyclopropanecarboxylic acid,
5 (R)-1-{ 41-[5-fluoro-3-( {[1-( o-tolyl)ethoxy]carbonyl }amino )thiophen-2-yl]-21
-
methoxy-[ 1,1 1 -biphenyl]-4-yl} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[3-( {[ 1-(3,4-difluorophenyl)ethoxy]carbonyl }amino )-5-fluorothiophen-
2-yl]-2'-methoxy-[ 1,1 1-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4'-(3-( {[ 1-(2,5-difluorophenyl)ethoxy ]carbonyl }amino )-5-fluoro-
1 0 thiophen-2-yl]-2'-methoxy-[ 1,1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[3-( {[1-(2,4-difluorophenyl)ethoxy]carbonyl }amino )-5-fluorothiophen-
2-yl]-2'-methoxy-[ 1,1 1-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(RS)-1-{ 4 1-(3-( {[ 1-(2-chloro-5-fluorophenyl)ethoxy ]carbonyl }amino )-5-
fluorothiophen-2-yl]-2'-methoxy-[ 1, 1'-biphenyl ]-4-yl} cyclopropanecarboxylic acid,
15 (R)-1-{ 41-[3-( {[1-(2-chloro-4-fluorophenyl)ethoxy ]carbonyl }amino )-5-fluoro-
20
thiophen-2-yl]-2'-methoxy-(1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[5-fluoro-3-( {( 1-(5-fluoro-2-methylphenyl)ethoxy]carbonyl }amino
)thiophen-2-yl ]-2'-methoxy-[ 1,1 '-biphenyl] -4-yl} cyclopropanecarboxylic acid,
and
(RS)-1-{4'-[ 5-fluoro-3-( {[1-( 4-fluoro-2-methylphenyl)ethoxy ]carbonyl}amino
)thiophen-2-yl]-2'-methoxy-[1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
and, a pharmacologically acceptable salt thereof.
[0043] (11) The compound according to (6) wherein, in the general formula (I), V
represents CR3 in which R3 represents a hydrogen atom or a methoxy group, or V
25 represents a nitrogen atom; and
the group:
[0044] (Chemical Formula 12]
is selected from a group consisting of the groups:
30 (0045] (Chemical Formula 13]
c0Mb\t:C S S S Me
c0 N,._l).
s-N and ~J ...,.
5
- 12-
[0046] and, a pharmacologically acceptable salt thereof.
[0047] (12) The compound according to (6) wherein, in the general formula (I), the
group:
[0048] [Chemical Formula 14]
(R1)P'A[0049]
is selected from a group consisting of the groups:
[Chemical Formula 15]
a\ S and
MeL~ --Js
(J1 ~ s
and, a pharmacologically acceptable salt thereof.
13. The compound according to Claim 11 which is selected from a group
consisting of:
(RS)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl}amino)thiophen-
2-yl ]-[ 1, 1 '-biphenyl] -4-y1} cyclopropanecarboxylic acid,
15 (R)-1- {4'-[5-chloro-3-( {[1-(thiophen-3-y1)ethoxy]carbonyl }amino )thiophen-2-
yl]-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl} amino )thiophen-
2-yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{ 4'-[5-chloro-3-( {[ 1-(thiophen-3-yl)ethoxy]carbonyl }amino )thiophen-2-
20 yl]-2'-methoxy-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-chloro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}amino)thiophen-
2-yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(R)-1-{ 4' -[ 5-chloro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)thiophen-
2-yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxy1ic acid,
25 (RS)-1-{ 4' -[ 5-chloro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)-
thiophen-2-yl]-2'-methoxy-[ 1,1 '-bipheny1]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[5-chloro-3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl }amino)thiophen-
2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[5-chloro-3-( {[(1-(isothiazol-3-yl)ethoxy]carbonyl }amino )thio-
294-
phen-2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-chloro-3-( {[l-(isothiazo1-4-yl)ethoxy]carbonyl} amino )thiophen-
2-yl]-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-( 4-{ 5-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl }amino )thio-
5 ph en-2-yl ]pyridin-2-yl} phenyl)cyclopropanecarboxylic acid,
(RS)-1-( 4-{ 5-[5-chloro-3-( {[ 1-( 4-methylthiophen-3-yl)ethoxy]carbonyl}amino
)thiophen-2-yl]pyridin-2-yl }pheny1)cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[5-fluoro-3-( {[ 1-(thiophen-3-yl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
10 (R)-1-{4'-[5-fluoro-3-( {[1-(thiophen-3-y1)ethoxy]carbonyl }amino )thiophen-2-
yl]-[1,1'-bipheny1]-4-y1}cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-fluoro-3-( {[1-(thiophen-3-yl)ethoxy ]carbonyl }amino )thiophen-
2-yl]-2'-methoxy-[1 ,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-fluoro-3-( {[1-( 4-methylthiophen-3-yl)ethoxy]carbonyl} amino)-
15 thiophen-2-yl] -[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(R)-1-{ 4'-[ 5-fluoro-3-( { [ 1-( 4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)thiophen-
2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(RS)-1-{4'-[5-fluoro-3-( {[1-(2-methylthiophen-3-yl)ethoxy]carbonyl }amino)thiophen-
2-yl]-[1, 1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
20 (RS)-1-{ 4'-[5-fluoro-3-( {[1-(4-methylthiophen-3-yl)ethoxy ]carbonyl} amino)-
thiophen-2-yl]-2'-methoxy-[1,1 '-biphenyl]-4-y1}cyclopropanecarboxylic acid,
(RS)-1-{4'-[3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl}amino )-5-fluorothiophen-
2-yl]-[ 1, 1'-biphenyl]-4-yl}cyclopropanecarboxylic acid,
(RS)-1-{ 4'-[3-( {[1-( 4-chlorothiophen-3-yl)ethoxy]carbonyl }amino )-5-fluoro-
25 thiophen-2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
(R)-1-{4'-[5-chloro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl}amino)thiophen-2-
yl]-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylicacid,
(R)-1-{4'-[5-chloro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl }amino )thiophen-2-
yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl }cyclopropanecarboxylic acid,
30 (R)-1-{ 4'-[5-fluoro-3-( {[ 1-(thiophen-2-yl)ethoxy]carbonyl} amino )thiophen-2-
yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid,
(R)-1-{4'-[5-fluoro-3-( {[1-(thiophen-2-yl)ethoxy]carbonyl}amino)thiophen-2-
yl]-2'-methoxy-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid,
and, a pharmacologically acceptable salt thereof.
35 14. (R)-1-{ 4'-[5-chloro-3-( {[1-(2-chlorophenyl)ethoxy ]carbonyl} amino )thiophen-
2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically
-295-
acceptable salt thereof.
15. (R)-1-{4'-[5-chloro-3-( {[1-(3-fluorophenyl)ethoxy]carbonyl}amino)thiophen-
2-yl]-[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically
acceptable salt thereof.
5 16. (R)-1-{4'-[3-({[1-(2-chlorophenyl)ethoxy]carbonyl}amino)-5-fluorothiophen-
2-yl]-[1, 1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically
acceptable salt thereof.
17. (R)-1-{4'-[5-fluoro-3-( {[1-(o-tolyl)ethoxy]carbonyl }amino)thiophen-2-yl]-
[ 1,1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid, and, a pharmacologically acceptable
10 salt thereof.
18. (R)-1-[ 4' -( 5-chloro-3- { [ ( 1-phenylethoxy )carbonyl ]amino} thiophen-2-y1)-
2'-methoxy-[ 1, 1'-biphenyl ]-4-yl]cyclopropanecarboxylic acid, and, a pharmacologically
acceptable salt thereof.
19. (R)-1-{ 4'-[ 5-chloro-3-( {[ 1-(2,5-difluorophenyl)ethoxy ]carbonyl}-
15 amino )thiophen-2-yl]-2'-methoxy-[1, 1 '-biphenyl]-4-yl }cyclopropanecarboxylic acid,
and, a pharmacologically acceptable salt thereof.
20. (R)-1- {4'-[3-( {[1-(2-chlorophenyl)ethoxy]carbonyl}amino )-5-fluorothiophen-
2-yl]-2'-methoxy-[ 1,1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a
pharmacologically acceptable salt thereof.
20 21. (R)-1- {4'-[5-chloro-3-( {[ 1-(thiophen-3-yl)ethoxy]carbonyl}amino )thiophen-
2-yl]-[ 1, 1 '-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a pharmacologically
acceptable salt thereof.
22. (R)-1-{4'-[5-chloro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl}amino)thiophen-
2-yl]-2'-methoxy-[1,1'-biphenyl]-4-yl}cyclopropanecarboxylic acid, and, a
25 pharmacologically acceptable salt thereof.
23. (R)-1-{4'-[5-chloro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}-
amino )thiophen-2-yl ]-[ 1, 1 '-bipheny1)-4-yl} cyclopropanecarboxylic acid, and, a
pharmacologically acceptable salt thereof.
24. (R)-1-{ 4'-[5-fluoro-3-( {[1-(thiophen-3-yl)ethoxy]carbonyl }amino )thio-
30 phen-2-yl]-[1,1 '-biphenyl]-4-yl}cyclopropanecarboxylic acid, and, a pharmacologically
acceptable salt thereof.
25. (R)-1-{4'-[5-fluoro-3-( {[1-(4-methylthiophen-3-yl)ethoxy]carbonyl}-
amino )thiophen-2-yl]-[ 1, 1'-biphenyl]-4-yl} cyclopropanecarboxylic acid, and, a
pharmacologically acceptable salt thereof.
35 26. An LP A receptor antagonist comprising the compound or a pharmacologically
acceptable salt thereof according to anyone of Claims 1 to 25 as an active ingredient.
27. A pharmaceutical composition comprising the compound or a
pharmacologically acceptable salt thereof according to anyone of Claims 1 to 25 as an
active ingredient.
28. The pharmaceutical composition according to Claim 27 for the treatment or
prevention of a disease accompanying fibrosis, an immunological or inflammatory
disease, a central or peripheral nervous system disease, an urologic disease or a
cancer-related disease.