U.S. patent application number 10/840746 was filed with the patent office on 2004-10-21 for pyrrole derivatives.
This patent application is currently assigned to Sumitomo Pharmaceuticals Co., Ltd.. Invention is credited to Hume, William Ewan, Kitoh, Makoto, Nagata, Ryu, Tokunaga, Teruhisa.
Application Number | 20040209939 10/840746 |
Document ID | / |
Family ID | 18722544 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040209939 |
Kind Code |
A1 |
Tokunaga, Teruhisa ; et
al. |
October 21, 2004 |
Pyrrole derivatives
Abstract
Pyrrole derivatives represented by the following formula: 1
wherein Ring Z is an optionally substituted pyrrole ring, etc.;
W.sup.2 is --CO--, --SO.sub.2--, an optionally substituted
C.sub.1-C.sub.4 alkylene, etc.; Ar.sup.2 is an optionally
substituted aryl, etc.; W.sup.1 and Ar.sup.1 mean the following (1)
and (2): (1) W.sup.1 is an optionally substituted C.sub.1-C.sub.4
alkylene, etc.; Ar.sup.1 is an optionally substituted bicyclic
heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms: (2)
W.sup.1 is an optionally substituted C.sub.2-C.sub.5 alkylene, an
optionally substituted C.sub.2-C.sub.5 alkenylene, etc.; and
Ar.sup.1 is an aryl or monocyclic heteroaryl, which are substituted
by carboxyl, an alkoxycarbonyl, etc. at the ortho- or meta-position
thereof with respect to the binding position of W.sup.1, or a
pharmaceutically acceptable salt thereof. These compounds are
useful as medicaments such as a fibrosis inhibitor for organs or
tissues.
Inventors: |
Tokunaga, Teruhisa;
(Toyonaka-shi, JP) ; Hume, William Ewan;
(Nishinomiya-shi, JP) ; Kitoh, Makoto; (Osaka-shi,
JP) ; Nagata, Ryu; (Nishinomiya-shi, JP) |
Correspondence
Address: |
BIRCH STEWART KOLASCH & BIRCH
PO BOX 747
FALLS CHURCH
VA
22040-0747
US
|
Assignee: |
Sumitomo Pharmaceuticals Co.,
Ltd.
|
Family ID: |
18722544 |
Appl. No.: |
10/840746 |
Filed: |
May 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10840746 |
May 7, 2004 |
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10352067 |
Jan 28, 2003 |
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6759429 |
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10352067 |
Jan 28, 2003 |
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PCT/JP01/06495 |
Jul 27, 2001 |
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Current U.S.
Class: |
514/414 ;
514/422; 514/423; 514/424; 548/465; 548/517; 548/530 |
Current CPC
Class: |
C07D 403/06 20130101;
C07D 471/04 20130101; C07D 207/33 20130101; C07D 207/333 20130101;
C07D 401/06 20130101 |
Class at
Publication: |
514/414 ;
514/423; 514/422; 514/424; 548/465; 548/530; 548/517 |
International
Class: |
A61K 031/4178; A61K
031/405; A61K 031/4025; A61K 031/4015 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 28, 2000 |
JP |
2000-229423 |
Claims
1. A compound, a prodrug thereof, or a pharmaceutically acceptable
salt thereof, of the formula: 171wherein Ring Z is an optionally
substituted pyrrole ring or an optionally substituted indole ring;
W.sup.2 is --OC--, --SO.sub.2--, --CONR--, an optionally
substituted C.sub.1-C.sub.4 alkylene or an optionally substituted
C.sub.2-C.sub.4 alkenylene, and R is a hydrogen or an alkyl;
Ar.sup.2 is an optionally substituted aryl or an optionally
substituted heteroaryl; W.sup.1 and Ar.sup.1 mean the following (1)
or (2): (1) W.sup.1 is an optionally substituted C.sub.1-C.sub.4
alkylene or an optionally substituted C.sub.2-C.sub.4 alkenylene;
and Ar.sup.1 is an optionally substituted bicyclic heteroaryl
having 1 to 4 nitrogen atoms as ring-forming atoms; (2) W.sup.1 is
an optionally substituted C.sub.2-C.sub.5 alkylene, an optionally
substituted C.sub.2-C.sub.5 alkenylene, an optionally substituted
C.sub.2-C.sub.5 alkynylene, or --Y--W.sup.3--, wherein Y is an
oxygen atom or a cycloalkanediyl, and W.sup.3 is an optionally
substituted C.sub.1-C.sub.5 alkylene, an optionally substituted
C.sub.2-C.sub.5 alkenylene, or an optionally substituted
C.sub.2-C.sub.5 alkynylene; and Ar.sup.1 is an aryl or monocyclic
heteroaryl, which is substituted at the ortho- or meta-position
thereof with respect to the binding position of W.sup.1 by a group
selected from the group consisting of a carboxyl, an
alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s),
a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an
arylsulfonylcarbamoyl, an alkylsulfonyl, a sulfamoyl having
optionally alkyl-substituent(s), a cyclic aminosulfonyl,
tetrazolyl, cyano, an alkoxy and an alkylsulfonylamino, and said
aryl or monocyclic heteroaryl being optionally further substituted;
provided that when Ring Z is an optionally substituted pyrrole ring
of the formula: 172wherein the number of R.sup.1 is one or more,
and each is independently hydrogen, a halogen or an optionally
substituted alkyl, then Ar.sup.1 is not an aryl.
2. The compound, prodrug thereof, or a pharmaceutically acceptable
salt thereof according to claim 1, wherein the divalent group
including said Ring Z may be any one of the following divalent
groups (any direction of bonds are included): 173wherein the number
of R.sup.1 is one or more and each is independently hydrogen, a
halogen or an optionally substituted alkyl.
3. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 1, said compound having the
formula: 174wherein W.sup.1, W.sup.2, Ar.sup.1, Ar.sup.2 and
R.sup.1 are as defined in claim 1.
4. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 1, wherein W.sup.2 is --CO--,
--SO.sub.2--, --CONR--, methylene, or hydroxymethylene.
5. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 1, wherein Ar is a substituted
phenyl.
6. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 1, wherein Ar.sup.2 is a phenyl
which is substituted by a member selected from the group consisting
of an optionally substituted alkyl, an optionally substituted
alkoxy, hydroxy or morpholino.
7. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 1, wherein W.sup.1 is an optionally
substituted C.sub.1-C.sub.4 alkylene or an optionally substituted
C.sub.2-C.sub.4 alkenylene, and Ar.sup.1 is an optionally
substituted bicyclic heteroaryl having 1 to 4 nitrogen atoms as
ring-forming atoms.
8. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 7, wherein the bicyclic heteroaryl
having 1 to 4 nitrogen atoms as ring-forming atoms is selected from
the group consisting of indolyl, isoindolyl, inolidinyl, indazolyl,
puryl, 4-H-quinolidinyl, quinolinyl, isoquinolinyl, phthalazinyl,
naphthyridyl, quinoxalyl and quinazolyl.
9. The compound, prodrug thereof, or pharmaceutically acceptable
salt thereof according to claim 7, wherein the bicyclic heteroaryl
having 1 to 4 nitrogen atoms as ring-forming atoms is selected from
the group consisting of indolyl, indazolyl, quinolinyl and
quinoxalyl.
10. A pharmaceutical composition comprising: the compound, prodrug
thereof, or pharmaceutically acceptable salt thereof, according to
claim 1; and a pharmaceutically acceptable carrier or diluent.
11. A pharmaceutical composition comprising: the compound, prodrug
thereof, or pharmaceutically acceptable salt thereof, according to
claim 2; and a pharmaceutically acceptable carrier or diluent.
12. The pharmaceutical composition according to claim 10, which is
a TGF-.beta. inhibitor.
13. The pharmaceutical composition according to claim 10, which is
a fibrosis inhibitor.
Description
[0001] This application is a Divisional application of U.S.
application Ser. No. 10/352,067, filed Jan. 28, 2003, which is a
Continuation-In-Part application of PCT International Application
No. PCT/JP01/06495 filed on Jul. 27, 2001, which designated the
United States and on which priority is claimed under 35 U.S.C.
.sctn. 120. The entire contents of all of the above applications
are hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to pyrrole derivatives
exhibiting TGF-.beta. inhibitory activity and being useful as
fibrosis inhibitors for organs or tissues, a prodrug thereof, and
pharmaceutically acceptable salts thereof.
BACKGROUND ART
[0003] Fibrosis of organs or tissues is induced by excessive
accumulation of extracellular matrix within the organ, as repair or
defenses, when said organ is invaded or damaged by some causes. The
extracellular matrix is a substance surrounding the cells of
tissues, and representative ones thereof are, for example,
fibrinoproteins such as collagen, elastin, etc., complex
carbohydrates such as proteoglycan, etc., glycoproteins such as
fibronectin, laminin, etc. When the degree of the degeneration of
organs, etc. by invasion or injury is not serious, then the organs,
etc. can return to normality without any scarring of repair.
However, when the degree of the degeneration of organs, etc. by
invasion or injury is serious or the degeneration of organs
persists, then the fibrosis of scarring of repair will further
damage the original function of said organ, etc. And, further
fibrosis is induced by said damage. Then, it falls into a vicious
cycle thereof. Eventually, there will be caused a deficiency of
organs, and at worst, the patient will die.
[0004] TGF-.beta. (Transforming Growth Factor-.beta.) plays an
important role in the accumulation of extracellular matrix. When
TGF-.beta. is administered to normal animals, there occurred many
fibrotic events at various organs of said animals (International
Review of Experimental Pathology, 34B: 43-67, 1993). In addition,
it was reported that the fibrosis of tissues was observed in
transgenic mice which highly express TGF-.beta. (Proc. Natl. Acad.
Sci. USA, 92: 2572-2576, 1995; Laboratory Investigation, 74:
991-1003, 1995).
[0005] TGF-.beta. participates in the fibrosis of tissues in the
following manner:
[0006] (1) Acting on cells, the extracellular matrix such as
fibronectin (Journal of Biological Chemistry, 262:6443-6446, 1987),
collagen (Proc. Natl. Acad. Sci. USA, 85: 1105-1108, 1988),
proteoglycan (Journal of Biological Chemistry, 263: 3039-3045,
1988), etc. is potently produced:
[0007] (2) Decreasing the expression of an enzyme for degrading
extracellular matrix (Journal of Biological Chemistry, 263:
16999-17005, 1988) and potently promoting the expression of
inhibitors of the extracelluar matrix degrading enzyme (Cancer
Research, 49: 2533-2553, 1989), by which the degradation of
extracellular matrix is inhibited:
[0008] (3) Proliferating cells producing extracellular matrix
(American Journal of Physiology, 264: F199-F205, 1993).
[0009] Thus, the inhibition of TGF-.beta. is a useful means for
inhibiting the accumulation of extracellular matrix. In fact, it is
reported that the fibrosis is alleviated by administering antiserum
of TGF-.beta. to animal models for fibrosis (Nature, 346: 371-374,
1990).
DISCLOSURE OF INVENTION
[0010] An object of the present invention is to provide a compound
being useful as fibrosis inhibitors for organs or tissues. In order
to solve the above problems, the present inventors have intensively
studied, and found that pyrrole derivatives inhibit the fibrosis of
organs or tissues, and have accomplished the present invention.
[0011] The present invention is as follows:
[0012] [1] A pyrrole derivative of the formula: 2
[0013] wherein Ring Z is an optionally substituted pyrrole ring, an
optionally substituted indole ring, an optionally substituted
thiophene ring, an optionally substituted pyrazole ring, an
optionally substituted benzene ring, an optionally substituted
imidazole ring, or an optionally substituted isothiazole ring;
[0014] W.sup.2 is --CO--, --SO.sub.2--, --CONR--, an optionally
substituted C.sub.1-C.sub.4 alkylene or an optionally substituted
C.sub.2-C.sub.4 alkenylene, and R is hydrogen or an alkyl;
[0015] Ar.sup.2 is an optionally substituted aryl or an optionally
substituted heteroaryl;
[0016] W.sup.1 and Ar.sup.1 mean the following (1) or (2): (1)
W.sup.1 is an optionally substituted C.sub.1-C.sub.4 alkylene or an
optionally substituted C.sub.2-C.sub.4 alkenylene; Ar.sup.1 is an
optionally substituted bicyclic heteroaryl having 1 to 4 nitrogen
atoms as ring-forming atoms:
[0017] (2) W.sup.1 is an optionally substituted C.sub.2-C.sub.5
alkylene, an optionally substituted C.sub.2-C.sub.5 alkenylene, an
optionally substituted C.sub.2-C.sub.5 alkynylene, or
--Y--W.sup.3--, Y is an oxygen atom or a cycloalkanediyl, and
W.sup.3 is an optionally substituted C.sub.1-C.sub.5 alkylene, an
optionally substituted C.sub.2-C.sub.5 alkenylene, or an optionally
substituted C.sub.2-C.sub.5 alkynylene; and Ar.sup.1 is an aryl or
monocyclic heteroaryl, which is substituted at the ortho- or
meta-position thereof with respect to the binding position of
W.sup.1 by a group selected from carboxyl, an alkoxycarbonyl, a
carbamoyl having optionally alkyl-substituent(s), a cyclic
aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl,
an alkylsulfonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an
alkoxy and an alkylsulfonylamino, and said aryl or monocyclic
heteroaryl being optionally further substituted, or a prodrug
thereof, or a pharmaceutically acceptable salt thereof.
[0018] [2] The pyrrole derivative according to the above [1],
wherein the divalent group including Ring Z may be any one of the
following divalent groups (any direction of bonds is included), or
a prodrug thereof, or a pharmaceutically acceptable salt thereof.
3
[0019] wherein the number of R.sup.1 is one or more, and each is
independently hydrogen, a halogen or an optionally substituted
alkyl.
[0020] [3] The pyrrole derivative according to the above [1] or
[2], wherein Ring Z is an optionally substituted pyrrole ring, an
optionally substituted indole ring or an optionally substituted
thiophene ring, or a prodrug, or a pharmaceutically acceptable salt
thereof.
[0021] [4] The pyrrole derivative according to the above [1], which
is a compound of the formula: 4
[0022] wherein W.sup.1, W.sup.2, Ar.sup.1, Ar.sup.2 and R.sup.1 are
as defined above, or a prodrug thereof, or a pharmaceutically
acceptable salt thereof.
[0023] [5] The pyrrole derivative according to any one of the above
[1] to [4], wherein W.sup.2 is --CO--, --SO.sub.2--, --CONR--,
methylene, or hydroxymethylene, or a prodrug thereof, or a
pharmaceutically acceptable salt thereof.
[0024] [6] The pyrrole derivative according to any one of the above
[1] to [5], wherein Ar.sup.2 is a substituted phenyl, or a prodrug
thereof, or a pharmaceutically acceptable salt thereof.
[0025] [7] The pyrrole derivative according to any one of the above
[1] to [6], wherein W.sup.1 is an optionally substituted
C.sub.2-C.sub.5 alkylene, an optionally substituted C.sub.2-C.sub.5
alkenylene, or an optionally substituted C.sub.2-C.sub.5
alklynylene; and Ar.sup.1 is an aryl, which is substituted at the
ortho-position thereof with respect to the binding position of
W.sup.1 by a group selected from carboxyl, an alkoxycarbonyl, a
carbamoyl having optionally alkyl-substituent(s), a cyclic
aminocarbonyl, an alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl,
an alkylsulfonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, tetrazolyl, cyano, an
alkoxy and an alkylsulfonylamino, and said aryl being optionally
further substituted,
[0026] or a prodrug thereof, or a pharmaceutically acceptable salt
thereof.
[0027] [8] The pyrrole derivative according to any one of the above
[1] to [6], wherein W.sup.1 is an optionally substituted
trans-C.sub.3-C.sub.4 alkenylene; and Ar.sup.1 is an aryl, which is
substituted at the ortho-position thereof with respect to the
binding position of W.sup.1 by a group selected from carboxyl, an
alkoxycarbonyl, a carbamoyl having optionally alkyl-substituent(s),
a cyclic aminocarbonyl, an alkylsulfonylcarbamoyl, an
arylsulfonylcarbamoyl, tetrazolyl, cyano, an alkoxy and an
alkylsulfonylamino, and said aryl being optionally further
substituted by a halogen, cyano, an optionally substituted alkoxy
or an optionally substituted alkyl, or a prodrug thereof, or a
pharmaceutically acceptable salt thereof.
[0028] [9] The compound according to the above [1], which is a
compound of the formula: 5
[0029] wherein W.sup.4 is --CO--, --CONR-- or methylene, R is as
defined above;
[0030] R.sup.2 is a halogen, cyano, an optionally substituted
alkoxy or an optionally substituted alkyl;
[0031] R.sup.3 is hydroxyl, an alkoxy, an amino having optionally
alkyl-substituent(s), a cyclic amino or an alkylsulfonylamino;
[0032] R.sup.4 is hydrogen, a halogen or an alkyl;
[0033] R.sup.5 is an optionally substituted alkoxy or an optionally
substituted alkyl,
[0034] or a prodrug thereof, or a pharmaceutically acceptable salt
thereof.
[0035] [10] The compound according to the above [9], wherein
W.sup.4 is --CO--; R.sup.2 is a halogen, cyano, an alkoxy being
optionally substituted by a halogen or an alkoxy, or an alkyl being
optionally substituted by a halogen or an alkoxy; R.sup.4 is
hydrogen or an alkyl; R.sup.5 is an alkoxy being optionally
substituted by a halogen, an alkoxy or morpholino, or an alkyl
being optionally substituted by a halogen, an alkoxy or morpholino,
or a prodrug thereof, or a pharmaceutically acceptable salt
thereof.
[0036] [11] The compound according to the above [9] or [10], which
is a compound of the formula: 6
[0037] wherein R.sup.3 and R.sup.5 are as defined above, or a
prodrug thereof, or a pharmaceutically acceptable salt thereof.
[0038] [12] A pyrrole derivative of the formula: 7
[0039] wherein R.sup.14 and R.sup.15 are independently hydrogen or
an optionally substituted alkyl;
[0040] R.sup.11, R.sup.12 and R.sup.13 are-as follows:
[0041] (1). R.sup.11 is --W.sup.11'--Ar.sup.3 or --W.sup.12-Het,
one of R.sup.12 and R.sup.13 is --W.sup.13-A, and the other is
hydrogen or an optionally substituted alkyl, W.sup.11 is an
optionally substituted C.sub.2-C.sub.5 alkylene or an optionally
substituted C.sub.2-C.sub.5 alkenylene, W.sup.12 is an optionally
substituted C.sub.1-C.sub.4 alkylene, W.sup.13 is --CO--, an
optionally substituted C.sub.1-C.sub.6 alkylene, or an optionally
substituted C.sub.2-C.sub.5 alkenylene; or
[0042] (2) R.sup.11 is --W.sup.21-A, one of R.sup.12 and R.sup.13
is --W.sup.22--Ar.sup.3 or --W.sup.23-Het, and the other is
hydrogen or an optionally substituted alkyl, W.sup.21 is an
optionally substituted C.sub.1-C.sub.6 alkylene, an optionally
substituted C.sub.2-C.sub.5 alkenylene, or --SO.sub.2--, W.sup.22
is an optionally substituted C.sub.2-C.sub.5 alkylene, or an
optionally substituted C.sub.2-C.sub.5 alkenylene, W.sup.23 is
--CO-- or an optionally substituted C.sub.1-C.sub.4 alkylene,
Ar.sup.3 is an aryl being substituted by --COR.sup.16,
--SO.sub.2R.sup.17 or tetrazolyl, and said aryl being optionally
further substituted by hydroxy, an optionally substituted
C.sub.1-C.sub.4 alkyl, an optionally substituted C.sub.2-C.sub.4
alkenyl, an optionally substituted C.sub.2-C.sub.4 alkynyl, an
optionally substituted C.sub.1-C.sub.4 alkoxy, a halogen, cyano, a
carbamoyl having optionally alkyl-substituent(s), or a cyclic
aminocarbonyl;
[0043] Het is an optionally substituted monocyclic or bicyclic
heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms;
[0044] A is an optionally substituted aryl, or an optionally
substituted monocyclic or bicyclic heteroaryl;
[0045] R.sup.16 is hydroxyl, an alkoxy, an amino having optionally
alkyl-substituent(s), a cyclic amino, or an alkylsulfonylamino;
[0046] R.sup.17 is an alkyl, an amino having optionally
alkyl-substituent(s), or a cyclic amino;
[0047] or a pharmaceutically acceptable salt thereof.
[0048] [13] The pyrrole derivative according to the above [12],
wherein R.sup.11, R.sup.12 and R.sup.13 mean as follows:
[0049] R.sup.11 is --W.sup.11'--Ar.sup.3 or --W.sup.12-Het;
[0050] one of R.sup.12 and R.sup.13 is --W.sup.13-A, and the other
is hydrogen or an optionally substituted C.sub.1-C.sub.4 alkyl;
[0051] W.sup.11 is an optionally substituted C.sub.2-C.sub.5
alkenylene;
[0052] W.sup.12 is an optionally substituted C.sub.1-C.sub.4
alkylene;
[0053] W.sup.13 is --CO--, an optionally substituted
C.sub.1-C.sub.6 alkylene, or an optionally substituted
C.sub.2-C.sub.5 alkenylene;
[0054] Ar.sup.3 is an aryl being substituted at the ortho-position
thereof with respect to the binding position of W.sup.11 by a group
selected from --COR.sup.6, --SO.sub.2R.sup.17 and tetrazolyl, and
said aryl being optionally further substituted by a group selected
from hydroxy, an optionally substituted C.sub.1-C.sub.4 alkyl, an
optionally substituted C.sub.2-C.sub.4 alkenyl, an optionally
substituted C.sub.2-C.sub.4 alkynyl, an optionally substituted
C.sub.1-C.sub.4 alkoxy, a halogen, cyano, a carbamoyl having
optionally C.sub.1-C.sub.4 alkyl-substituent(s), and a cyclic
aminocarbonyl;
[0055] Het is an optionally substituted 3-quinolyl, an optionally
substituted 3-naphthyridinyl or an optionally substituted
2-quinoxalyl;
[0056] A is an optionally substituted aryl, or an optionally
substituted monocyclic or bicyclic heteroaryl;
[0057] R.sup.16 is hydroxy, a C.sub.1-C.sub.4 alkoxy, an amino
having optionally C.sub.1-C.sub.4 alkyl-substituent(s), a cyclic
amino, or a C.sub.1-C.sub.4 alkylsulfonylamino;
[0058] R.sup.17 is a C.sub.1-C.sub.4 alkyl, an amino having
optionally C.sub.1-C.sub.4 alkyl-substituent(s), or a cyclic
amino.
[0059] [14] A medicament containing the pyrrole derivative
according to any one of the above [1] to [13], or a prodrug
thereof, or a pharmaceutically acceptable salt thereof.
[0060] [15] The medicament according to the above [14], which is a
TGF-.beta. inhibitor.
[0061] [16] The medicament according to the above [14], which is a
fibrosis inhibitor.
[0062] The number of the substituents on the "substituted pyrrole
ring", "substituted indole ring", "substituted thiophene ring",
"substituted pyrazole ring", "substituted benzene ring",
"substituted imidazole ring" and "substituted isothiazole ring" is
1 or more, for example, 2 or 3, and the substituents include the
same groups for R.sup.1 except for hydrogen, i.e., a halogen or an
optionally substituted alkyl.
[0063] The "alkyl" includes, for example, a straight chain or
branched chain C.sub.1-C.sub.6 alkyl group, such as methyl, ethyl,
2-propyl, 2-methyl-1-propyl, butyl, 2-butyl, t-butyl, pentyl,
3-methyl-2-butyl, 2-methyl-2-butyl, hexyl, etc., and preferably a
straight chain or branched chain C.sub.1-C.sub.4 alkyl.
[0064] The substituent of the "substituted alkyl for R.sup.2 and
R.sup.5" includes, for example, hydroxy, an alkanoyloxy, a halogen,
cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino
having optionally alkyl-substituent(s), an amino having optionally
alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic
heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a
cyclic aminocarbonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The
number of the substituents may be one or more, for example, 2 or 3,
and the substituents are the same or different. The preferable
substituents of the substituted alkyl for R.sup.2 are a halogen, an
alkoxy, etc. The preferable substituents of the substituted alkyl
for R.sup.5 are a halogen, an alkoxy, morpholino, hydroxy, etc.
[0065] The substituent of the "substituted alkyl for R.sup.1,
R.sup.12, R.sup.13, R.sup.14 and R.sup.15" includes, for example, a
halogen, an alkoxy, hydroxy, oxo, etc., and the number of the
substituents are one or more, for example, 2 or 3, and the
substituents may be the same or different.
[0066] The "alkoxy" includes, for example, a straight chain or
branched chain C.sub.1-C.sub.6 alkoxy, such as methoxy, ethoxy,
propyloxy, 2-propyloxy, 2-methyl-2-propyloxy, butoxy, pentyloxy,
hexyloxy, etc. and preferably a straight chain or branched chain
C.sub.1-C.sub.4 alkoxy.
[0067] The substituent of the "substituted alkoxy for R.sup.2 and
R.sup.5" is, for example, hydroxy, an alkanoyloxy, a halogen,
cyano, an alkanoyl, an alkoxy, an alkoxycarbonyl, carboxy, an amino
having optionally alkyl-substituent(s), an amino having optionally
alkoxyalkyl-substituent(- s), a cyclic amino, a monocyclic
heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a
cyclic aminocarbonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The
number of the substituents may be one or more, for example, 2 or 3,
and the substituents may be the same or different. The preferable
substituents of the substituted alkoxy for R.sup.2 are a halogen,
an alkoxy, etc. The preferable substituents of the substituted
alkoxy for R.sup.5 are a halogen, an alkoxy, morpholino, hydroxy,
etc., and especially preferable substituted alkoxy is
2-morpholinoethoxy, etc.
[0068] The "alkanoyl" includes, for example, a straight chain or
branched chain C.sub.1-C.sub.6 alkanoyl, such as formyl, acetyl,
propanoyl, butanoyl, isobutanoyl, pentanoyl, hexanoyl, etc., and
preferably a straight chain or branched chain C.sub.2-C.sub.5
alkanoyl.
[0069] The "alkenyl" includes, for example, a straight chain or
branched chain C.sub.2-C.sub.6 alkenyl, such as vinyl, allyl,
isopropenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-hexenyl, etc., and
preferably a straight chain or branched chain C.sub.2-C.sub.4
alkenyl.
[0070] The "alkenyloxy" includes, for example, a straight chain or
branched chain C.sub.3-C.sub.6 alkenyloxy, such as allyloxy,
3-butenyloxy, 2-butenyloxy, etc., and preferably a straight chain
or branched chain C.sub.3-C.sub.4 alkenyloxy.
[0071] The "alkynyl" includes, for example, a straight chain or
branched chain C.sub.2-C.sub.6 alkynyl, such as ethynyl,
2-propynyl, 1-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl,
3-hexynyl, etc., and preferably a straight chain or branched chain
C.sub.2-C.sub.4 alkynyl.
[0072] The "alkynyloxy" includes, for example, a straight chain or
branched chain C.sub.3-C.sub.6 alkynyloxy, such as allyloxy,
3-butynyloxy, 2-butynyloxy, 3-pentynyloxy, etc., and preferably a
straight chain or branched chain C.sub.3-C.sub.4 alkynyloxy.
[0073] The "alkylene" includes, for example, a straight chain
alkylene having carbon atoms in a number within the scope of each
alkylene, such as methylene, ethylene, trimethylene,
tetramethylene, pentamethylene, hexamethylene, etc.
[0074] Preferable examples of the "C.sub.1-C.sub.4 alkylene for
W.sup.2" are methylene and ethylene, and especially preferable one
is methylene.
[0075] Preferable examples of the "C.sub.1-C.sub.4 alkylene for
W.sup.1 when Ar.sup.1 is an optionally substituted bicyclic
heteroaryl having 1 to 4 nitrogen atoms as ring-forming atoms" are
methylene, etc.
[0076] Preferable examples of the "C.sub.2-C.sub.5 alkylene for
W.sup.1, when Ar.sup.1 is an aryl or monocyclic heteroaryl, which
is substituted at the ortho- or meta-position thereof with respect
to the binding position of W.sup.1 by a group selected from
carboxyl, an alkoxycarbonyl, a carbamoyl having optionally
alkyl-substituent(s), a cyclic aminocarbonyl, an
alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl,
a sulfamoyl having optionally alkyl-substituent(s), a cyclic
aminosulfonyl, tetrazolyl, cyano, an alkoxy and an
alkylsulfonylamino, and said aryl or monocyclic heteroaryl being
optionally further substituted" are trimethylene, tetramethylene,
etc.
[0077] Preferable examples of "C.sub.1-C.sub.5 alkylene for
W.sup.3" are methylene, ethylene, etc.
[0078] The substituents of the "substituted alkylene" includes, for
example, an alkyl, an alkoxy, hydoxy, an alkanoyloxy, a halogen,
etc., and the substituted alkylene has 1 or 2 substituents, which
are the same or different.
[0079] The "alkenylene" includes, for example, a straight chain
alkenylene having carbon atoms in a number within the scope of each
alkenylene, such as vinylene, 1-propenylene, 2-propenylene,
1-butenylene, 2-butenylene, 3-butenylene, 1-pentenylene,
2-pentenylene, 3-pentenylene, 4-pentenylene, 2,4-pentadienylene,
etc. The configuration at the double bonds may be either
cis-configuration or trans-configuration, and preferable
configuration is trans-configuration.
[0080] Preferable examples of the "C.sub.2-C.sub.5 alkenylene for
W.sup.1, when Ar.sup.1 is an aryl or monocyclic heteroaryl, which
is substituted at the ortho- or meta-position thereof with respect
to the binding position of W.sup.1 by a group selected from
carboxyl, an alkoxycarbonyl, a carbamoyl having optionally
alkyl-substituent(s), a cyclic aminocarbonyl, an
alkylsulfonylcarbamoyl, an arylsulfonylcarbamoyl, an alkylsulfonyl,
a sulfamoyl having optionally alkyl-substituent(s), a cyclic
aminosulfonyl, tetrazolyl, cyano, an alkoxy and an
alkylsulfonylamino, and said aryl or monocyclic heteroaryl being
optionally further substituted" are a straight chain
trans-C.sub.3-C.sub.4 alkenylene, and especially preferable example
is trans-2-propenylene.
[0081] The "C.sub.2-C.sub.5 alkynylene" includes, for example, a
straight chain C.sub.2-C.sub.5 alkynylene, such as ethynylene,
2-propynylene, 2-butynylene, 3-butynylene, 2-pentynylene,
3-pentynylene, etc.
[0082] The substituents of the "substituted alkenylene" and the
"substituted alkynylene" are, for example, an alkyl, etc., and
these groups have independently 1 or 2 substituents.
[0083] The "aryl" includes, for example, a C.sub.6-C.sub.10 aryl,
such as phenyl, 1-naphthyl, 2-naphthyl, etc., and preferably one is
phenyl.
[0084] The "heteroaryl" includes, for example, a monocyclic or
bicyclic heteroaryl having 1 to 3 heteroatom selected from a
nitrogen, an oxygen and a sulfur, and these heteroatoms are the
same or different, such as a monocyclic 5-membered heteroaryl
(e.g., thiophene, furan, pyrrole, imidazole, pyrazole, thiazole,
oxazole, isothiazole, isoxazole, etc.), a monocyclic 6-membered
heteroaryl (e.g., pyridine, pyrimidine, pyrazine, pyridazine,
triazine, etc.), a bicyclic heteroaryl (e.g., indole, isoindole,
indolidine, indazole, purine, 4-H-quinolidine, quinoline,
isoquinoline, phthalazine, naphthyridine, quinoxaline, quinazoline,
benzothiazole, benzoxazole, benzisothiazole, benzisoxazole,
benzofuran, benzothiophene, etc.), etc.
[0085] The "monocyclic heteroaryl" includes monocyclic heteroaryls
among heteroaryls.
[0086] Preferable examples of the "monocyclic heteroaryl for
Ar.sup.1" are a monocyclic heteroaryl being weak basic (pKb<7),
and more preferable ones are a monocyclic 5-membered heteroaryl
containing a sulfur atom or an oxygen atom, and especially
preferable ones are thiophene, furan, thiazole, oxazole,
isothiazole, isoxazole, etc.
[0087] Preferable examples of the "heteroaryl for Ar.sup.2" are a
heteroaryl being weak basic (pKb<7), and more preferable ones
are a monocyclic 5-membered heteroaryl and bicyclic heteroaryl
containing a sulfur atom or an oxygen atom, and especially
preferable ones are thiophene, furan, thiazole, oxazole,
isothiazole, isoxazole, indole, isoindole, benzothiazole,
benzoxazole, benzisothiazole, benzisoxazole, benzofuran,
benzothiophene, etc.
[0088] The "monocyclic or bicyclic heteroaryl having 1 to 4
nitrogen atoms as ring-forming atoms" includes, for example, a
monocyclic 5-membered heteroaryl (e.g., pyrrolyl, imidazolyl,
3H-pyrazolyl, tetrazolyl, etc.), a monocyclic 6-membered heteroaryl
(e.g., pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl,
etc.), a bicyclic heteroaryl (e.g., indolyl, isoindolyl,
indolidinyl, indazolyl, puryl, 4-H-quinolidinyl, quinolinyl,
isoquinolinyl, phthalazinyl, naphthyridyl, quinoxalyl, quinazolyl,
etc.), etc. Preferable examples are a bicyclic heteroaryl, and more
preferable ones are quinolyl, quinoxalyl, naphthyridyl, etc., and
especially preferable ones are 3-quinolyl, 2-quinoxalyl,
3-naphthyridyl, etc.
[0089] The substituents of the "substituted aryl", "substituted
phenyl", "substituted heteroaryl", "substituted monocyclic or
bicyclic heteroaryl", "monocyclic or bicyclic heteroaryl having
substituted 1 to 4 nitrogen atoms", "substituted 3-quinolyl",
"substituted 3-naphthyridyl" and "substituted 2-quinoxalyl", and
the other substituents of the "substituted aryl and substituted
monocyclic heteroaryl for Ar.sup.1" are exemplified as follows.
These groups may have one or more, for example, 2 or 3
substituents, which are the same or different.
[0090] Optionally Substituted Alkyl
[0091] (the substituents of this substituted alkyl include, for
example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an
alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally
alkyl-substituent(s), an amino having optionally
alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic
heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a
cyclic aminocarbonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The
number of the substituents is 1 or more, for example, 2 or 3, and
the substituents are the same or different.)
[0092] Optionally Substituted Alkoxy:
[0093] (the substituents of this substituted alkoxy include, for
example, hydroxy, an alkanoyloxy, a halogen, cyano, an alkanoyl, an
alkoxy, an alkoxycarbonyl, carboxy, an amino having optionally
alkyl-substituent(s), an amino having optionally
alkoxyalkyl-substituent(s), a cyclic amino, a monocyclic
heteroaryl, a carbamoyl having optionally alkyl-substituent(s), a
cyclic aminocarbonyl, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, azide, etc. The
number of the substituents is 1 or more, for example, 2 or 3, and
the substituents are the same or different.)
[0094] Optionally Substituted Alkenyl, Optionally Substituted
Alkynyl:
[0095] (the substituents of these substituted alkenyl and
substituted alkynyl include, for example, an alkoxy, an
alkoxycarbonyl, an alkanoyl, hydroxy, an alkanoyloxy, a halogen,
cyano, a carbamoyl having optionally alkyl-substituent(s), a cyclic
aminocarbonyl, carboxy, an amino having optionally
alkyl-substituent(s), a cyclic amino, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, etc. The number of
the substituents is 1 or more, for example, 2 or 3, and the
substituents are the same or different.)
[0096] An alkenyloxy, hydroxy, an alkanoyl, an alkanoyloxy, a
halogen, an alkylsulfonyl, an amino having optionally
alkyl-substituent(s), a cyclic amino, a carbamoyl having optionally
alkyl-substituent(s), a cyclic aminocarbonyl, a sulfamoyl having
optionally alkyl-substituent(s), a cyclic aminosulfone, cyano,
methylenedioxy, a heteroaryl, 1,3-dioxan-2-yl, etc.
[0097] Preferable examples of the substituents of the "substituted
aryl for Ar.sup.2 and A", "substituted phenyl for Ar.sup.2",
"substituted heteroaryl for Ar.sup.2" and "substituted monocyclic
or bicyclic heteroaryl for A" are an optionally substituted alkyl,
an optionally substituted alkoxy, hydroxy, morpholino, etc. More
preferable examples are an optionally substituted alkyl (the
substituents of the substituted alkyl is a halogen, an alkoxy,
morpholino, hydroxy, etc.), a substituted alkoxy (the substituents
of the substituted alkoxy is a halogen, an alkoxy, morpholino,
hydroxy, etc.), hydroxy, etc., and especially perferable ones are
methyl, methoxy, 2-morpholinoethoxy, hydroxy, etc. When Ar.sup.1
and A are a substituted phenyl, then the substitution position of
these substituents is preferably para-position with respect to the
binding position of W.sup.13 or W.sup.21, respectively.
[0098] Preferable examples of the substituents of the "substituted
monocyclic or bicyclic heteroaryl containing 1 to 4 nitrogen atoms
as ring-forming atoms for Ar.sup.1 and Het", "substituted
3-quinolyl for Het", "substituted 3-naphthyridyl for Het", and
"substituted 2-quinoxalyl for Het", and the other substituents of
the "substituted aryl and substituted monocyclic heteroaryl for
Ar.sup.1" are a halogen, cyano, an optionally substituted alkyl, an
optionally substituted alkoxy, etc. More preferable examples are a
halogen, an optionally substituted alkyl (the substituent of the
substituted alkyl is a halogen, an alkoxy, etc.), a substituted
alkoxy (the substituent of the substituted alkyl is a halogen, an
alkoxy, etc.), cyano, etc., and especially preferable examples are
a halogen, an alkyl, an alkoxy, cyano, etc., and further most
preferable examples are chlorine, methyl, cyano, etc. When Ar.sup.1
is a substituted phenyl, the substitution position of these
substituents is preferably para-position with respect to the
binding position of W.sup.1.
[0099] The substituents of the "substituted C.sub.1-C.sub.4 alkyl,
substituted C.sub.2-C.sub.4 alkenyl, substituted C.sub.2-C.sub.4
alkynyl, and substituted C.sub.1-C.sub.4 alkoxy, which are
substituents for aryl for Ar.sup.3" are, for example, an alkoxy, an
alkoxycarbonyl, an alkanoyl, hydroxy, an alkanoyloxy, a halogen,
cyano, a carbamoyl having optionally alkyl-substituent(s), a cyclic
aminocarbonyl, carboxy, an amino having optionally
alkyl-substituent(s), a cyclic amino, a sulfamoyl having optionally
alkyl-substituent(s), a cyclic aminosulfonyl, etc. The number of
the substituents of these groups is 1 or more, for example, 2 or 3,
and the substituents are the same or different.
[0100] In the aryl or monocyclic heteroaryl for Ar.sup.1, the
ortho- or meta-position with respect to the binding position of
W.sup.1 means a position adjacent to the binding position of
W.sup.1 and further a position adjacent thereto, respectively. For
example, the ortho-, meta- and para-positions are indicated below
in cases wherein Ar.sup.1 is phenyl: 8
[0101] The "halogen" is fluorine, chlorine, bromine, etc.
[0102] The "cycloalkanediyl" includes, for example, a
C.sub.3-C.sub.6 cycloalkanediyl, such as 1,2-cyclopropanediyl,
1,2-cyclobutanediyl, 1,2-cyclopentanediyl, 1,2-cyclohexanediyl,
1,3-cyclohexanediyl, 1,4-cyclohexanediyl, etc.
[0103] In the "amino having optionally alkyl-substituent(s)",
"amino being optionally substituted by an alkoxyalkyl", "carbamoyl
having optionally alkyl-substituent(s)", and "sulfamoyl having
optionally alkyl-substituent(s)", when these groups are substituted
by an alkyl or an alkoxyalkyl, then these groups can be substituted
by 1 or 2 alkyls or alkoxyalkyls which are the same or
different.
[0104] The "cyclic amino" includes a 5- to 7-membered cyclic amino
optionally containing an oxygen atom, a sulfur atom or a nitrogen
atom as ring-forming atoms, and this cyclic amino may be further
substituted by an alkyl, hydroxy, etc., for example, pyrrolidino,
piperidino, piperazinyl, 4-methylpiperazinyl, morpholino,
thiomorpholino, 4-hydroxypiperidino, etc., and especially
preferable cyclic amino is morpholino.
[0105] The "prodrug" means a compound, which can be hydrolyzed
chemically or biochemically in the living body and converted into
the compound of the present invention. For example, when the
pyrrole derivative of the present invention has a carboxyl group,
then a compound wherein said carboxyl group is converted into a
suitable ester group is a prodrug thereof. Preferable examples of
the ester are pivaloyloxymethyl ester, acetyloxymethyl ester,
cyclohexylacetyloxymethyl ester, 1-methylcylohexylcarbonyloxymethyl
ester, ethyloxycarbonyloxy-1-ethyl ester,
cyclohexyloxycarbonyloxy-1-ethyl ester, etc.
[0106] The "pharmaceutically acceptable salt" includes, for
example, an alkali metal salt such as sodium salt, potassium salt,
etc., an alkaline earth metal salt such as calcium salt, magnesium
salt, etc., an inorganic metal salt such as zinc salt, a salt with
an organic base such as triethylamine, triethanolamine,
trihydroxymethylaminomethane, amino acid, etc., when the pyrrole
derivatives of the present invention or a pharmaceutically
acceptable salt thereof have an acidic group. When the pyrrole
derivatives of the present invention or a pharmaceutically
acceptable salt thereof have a basic group, the pharmaceutically
acceptable salt includes, for example, a salt with an inorganic
acid such as hydrochloride, hydrobromide, sulfate, phosphate,
nitrate, etc., a salt with an organic acid such as acetate,
propionate, succinate, lactate, malate, tartrate, citrate, maleate,
fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate,
ascorbate, etc.
[0107] The pyrrole derivatives of the present invention and a
pharmaceutically acceptable salt thereof exhibit TGF-.beta.
inhibitory activity and are useful as a fibrosis inhibitor for
organs or tissues. To be more precise, the present compounds are
useful as a medicament for treating the following diseases, which
is caused by the fibrosis of organs or tissues.
[0108] Kidney diseases: diabetic renal disease, glomerular
nephritis, tubulointerstitial nephritis, hereditary renal
disease
[0109] Respiratory diseases: interstitial pneumonia, chronic
obstructive pulmonary disease, asthma
[0110] Digestive diseases: cirrhosis hepatis, chronic pancreatitis,
scirrhousgastric cancer
[0111] Cardiovascular diseases: myocardial fibrosis, restenosis
after PTCA, arteriosclerosis
[0112] Bone-joint diseases: myelofibrosis, arthrorheumatism
[0113] Skin diseases: post-surgical scarring, burn scarring,
keloid, hypertrophic scar, atopic dermatitis, scleroderma
[0114] Obstetrics diseases: uterus myoma
[0115] Urinary diseases: prostatomegaly
[0116] Other diseases: Alzheimer's disease, sclerosing peritonitis,
diabetic retinopathy, type 1 diabetes mellitus, Post-surgical organ
adhesion
[0117] The pyrrole derivatives of the present invention may be
prepared, for example, by the following process. 9
[0118] wherein Ring Z, W.sup.2, Ar.sup.2, W.sup.1 and Ar.sup.1 are
as defined above.
[0119] The present pyrrole derivatives can be prepared by binding
the groups of Ar.sup.1-W.sup.1- and Ar.sup.2-W.sup.2-- to Ring Z.
The binding reaction of the groups Ar.sup.1-W.sup.1- and
Ar.sup.2-W.sup.2-- with Ring Z is carried out, for example, by the
following reactions.
[0120] (1) Friedel-Crafts reaction
[0121] (2) Reaction of a compound having a multiple bond between
carbon and carbon or an organic metal compound with an organic
halide in the presence of a palladium catalyst
[0122] (3) Nucleophilic substitution to a corresponding organic
halide
[0123] (4) Reaction of a carbonyl compound with an organic metal
compound
[0124] (5) Reaction of a carboxylic acid derivative with an organic
metal compound
[0125] (6) Wittig reaction, Horner-Emmons reaction
[0126] These reactions are listed just for illustration, and the
present derivatives can also be prepared by other processes, based
on the knowledge of a skilled person in the organic synthesis.
Besides, in this process, firstly the groups for W.sup.2 or W.sup.1
are bound to Ring Z, and then the groups for Ar.sup.1 or Ar.sup.1
are bound to the resultant. The method for binding these groups can
be the same ones as those for the reaction with Ring Z as mentioned
above.
[0127] In each reaction as mentioned above, a function group can be
protected if necessary. The protecting groups to be employed, and
the conditions for protection or deprotection are disclosed in
detail in the literature of Greene, et al., (T. W. Greene and P. G.
M. Wuts, "Protecting Groups in Organic Synthesis", 1991, JOHN WILEY
& SONS, INC.)
[0128] Double bond, hydroxy group and carbonyl group, etc. being
produced in each reaction as mentioned above are subjected to
hydrogenolysis, reduction, oxidization, etc., if necessary.
Besides, after each reaction as mentioned above, function groups
may be converted into other function groups. The conversion
reaction of these function groups is carried out, for example,
according to the following articles.
[0129] Jikken Kagaku Koza (in Japanese, i.e, Experimental Chemical
Lecture), vol. 19-26 (1992, MARUZEN CO., LTD.)
[0130] Seimitsu-Yuki-Gosei (in Japanese, i.e., Fine Organic
Synthesis) (1993, Nankodo, Co., Ltd.)
[0131] Compendium of Organic Synthetic Methods, Vol. 1-9 (John
Wiley & Sons)
[0132] Comprehensive Organic Synthesis, Vol. 1-9 (1991, Pergamon
Press)
[0133] Comprehensive Organic Transformations (1989, VCH
Publishers)
[0134] Survey of Organic Syntheses, Vol. 1-2 (1970, 1977, John
Wiley & Sons)
[0135] For example, the reduction of the hydroxy group existing at
the 1-position of the alkylene bound to Ring Z is carried out by
using a combined reducing agent such as sodium
borohydride/isopropanol, triethylsilane/trifluoroacetic acid, etc.
The reaction solvent is, for example, tetrahydrofuran (THF),
dioxane, dichloromethane, chlorobenzene, etc., and the reaction is
carried out at a temperature of from about -20.degree. C. to a
boiling point of the solvent to be used. The reduction of carbonyl
into methylene is carried out, for example, by using a combined
reducing agent such as sodium borohydride/isopropanol,
hydrazine/potassium hydroxide or sodium hydroxide, zinc
amalgam/hydrochloric acid, etc. The reaction solvent is, for
example, THF, dioxane, etc., and the reaction is carried out at a
temperature of from 0.degree. C. to a boiling point of the solvent
to be used.
[0136] For example, the oxidization of hydroxy group existing at
the 1-positin of the alkylene bound to Ring Z is carried out by
using an oxidizing reagent such as manganese dioxide, etc., a
composite oxidizing reagent such as
4-methylmorpholine-4-oxide/tetra-n-propylammonium perruthenate,
etc. The reaction solvent is, for example, THF, dioxane,
dichloromethane, chlorobenzene, chloroform, etc., and the reaction
is carried out at a temperature of from about 0.degree. C. to a
boiling point of the solvent to be used.
[0137] (1) Friedel-Crafts reaction 10
[0138] wherein Ring Z is as defined above, Q is an organic group,
and X is a chlorine, bromine, etc.
[0139] The Friedel-Crafts reaction is carried out, for example,
according to J. Org. Chem., 48, 3214-3219 (1983), to introduce Q-
on the carbon atom of Ring Z. In this reaction, preferable Q-X is,
for example, an alkyl halide, an acid halide, etc. The reaction is
carried out in the presence of a Lewis acid such as AlCl.sub.3,
BF.sub.3.OEt.sub.2, ZnCl.sub.2, SnCl.sub.4, etc., in an inert
solvent such as dichloromethane, dichloroethane, etc. and usually
at a temperature of from room temperature to a boiling point of the
solvent to be used.
[0140] When Ring Z is pyrrole ring, indole ring, pyrazole ring or
imidazole ring, the Friedel-Crafts reaction is preferably carried
out by firstly protecting the nitrogen atom at the 1-position with
a phenylsulfonyl (or toluylsulfonyl) moiety. When the 1-position is
protected with phenylsulfonyl moiety, the reaction is carried out,
for example, by reacting with phenylsulfonyl chloride, etc. in the
presence of a base such as NaH, etc. When Ring Z is a pyrrole ring
protected with phenylsulfonyl, the reaction position can be
controlled by the kind of a Lewis acid to be used. For example, by
using AlCl.sub.3, the 3-position is reacted (J. Org. Chem., 48,
3214-3219 (1983)), and by using BF.sub.3.OEt.sub.2, the 2-position
is reacted. After the Friedel-Crafts reaction, the phenylsulfonyl
is removed by hydrolysis. For example, the phenylsulfonyl is
removed by reacting in the presence of a base such as sodium
hydroxide, potassium hydroxide, etc. in a mixed solvent of water
and methanol, ethanol, etc. at a temperature of from room
temperature to a boiling point of the solvent to be use.
[0141] (2) Reaction of a compound having a multiple bond between
carbon and carbon or an organic metal compound with an organic
halide in the presence of a palladium catalyst 11
[0142] wherein Ring Z, Q and X are as defined above, M is a
substituted tin atom, a substituted boron atom, etc., and Q' is a
corresponding organic group.
[0143] This reaction is carried out, for example, according to the
methods disclosed in Synth. Commun., 11, 513 (1981), J. Am. Chem.
Soc., 111, 314 (1989), J. Org. Chem., 52, 422 (1987), J. Org.
Chem., 37, 2320 (1972), etc. To be more precise, the reaction is
carried out by reacting a compound having a multiple bond between
carbon and carbon or an organic metal compound with an organic
halide in an inert solvent in the presence of a palladium catalyst,
a base, etc. The palladium catalyst includes, for example, a
palladium (II) catalyst such as Pd(OAc).sub.2,
PdCl.sub.2(PPh.sub.3).sub.2, etc., and a palladium (0) catalyst
such as Pd(PPh.sub.3).sub.4, Pd(dba).sub.2, etc. The base includes,
for example, an inorganic base such as NaHCO.sub.3,
K.sub.2CO.sub.3, etc., an organic base such as NEt.sub.3,
iPr.sub.2NEt, Et.sub.2NH, etc., and the reaction can be accelerated
by addition of a phosphine ligand such as PPh.sub.3, etc., a
phase-transfer catalyst such as BnEt.sub.3NCl, etc., or an
inorganic salt such as CuI, etc. The inert solvent includes, for
example, N,N-dimethylformamide (DMF), THF, dioxane, toluene, etc.
The reaction temperature is usually in the range of from around
room temperature to a boiling point of the solvent to be used.
[0144] (3) Nucleophilic substitution to a corresponding organic
halide 12
[0145] wherein Ring Z, Q and X are as defined above, M is an alkali
metal atom, a magnesium halide, a zinc halide, etc.
[0146] This reaction is carried out according to the method
disclosed in J. Org. Chem., 26, 3202 (1961). The organic metal
compound containing Ring Z can be prepared, for example, by
halogen-metal exchange reaction, or by removing hydrogen atom using
a base, which is further reacted with Q-X.
[0147] When Ring Z is a pyrrole ring, an indole ring, a pyrazole
ring or an imidazole ring, the group Q- can be introduced on the
nitrogen atom of these rings by reacting in an inert solvent (e.g.,
THF, ether, DMF, etc.) in the presence of a base (e.g., NaH, KH,
potassium t-butoxide, ethyl-magnesium bromide, butyl lithium,
lithium 2,2,6,6-tetramethyl-piper- idine, etc.). The reaction
temperature is in the range of from about 0.degree. C. to about
80.degree. C.
[0148] (4) Reaction of a carbonyl compound with an organic metal
compound 13
[0149] wherein Ring Z, Q and X are as defined above.
[0150] This reaction is carried out, for example, by the method
disclosed in Tetrahedron, 26, 2239 (1970), J. Org. Chem., 55, 6317
(1990), etc. The organic metal compound in this reaction can be
prepared in a similar manner to the preparation of the organic
metal compound of the above (3). The organic metal compound thus
obtained is reacted, for example, with an aldehyde in an inert
solvent (e.g., THF, ether, toluene, etc.). The reaction temperature
is in the range of from about -100.degree. C. to room
temperature.
[0151] (5) Reaction of a carboxylic acid derivative with an organic
metal compound 14
[0152] wherein Ring Z, Q and M are as defined above, Y is chlorine,
an alkanoyloxy, an alkoxycarbonyloxy, an alkoxy, a dialkylamino,
2-pyridylthio, etc.
[0153] This reaction is carried out, for example, by the method
disclosed in Org. Lett., 2, 1649 (2000). The organic metal compound
in this reaction can be prepared in a similar manner to the
preparation of the organic metal compound of the above (3) &
(4). The organic metal compound thus obtained is reacted, for
example, with a compound having an activated carbonyl group in an
inert solvent (e.g., THF, ether, toluene, etc.). The reaction
temperature is in the range of from about -100.degree. C. to room
temperature.
[0154] (6) Wittig reaction, Horner-Emmons reaction 15
[0155] wherein Ring Z and Q are as dfined above, and R" is an
alkyl.
[0156] This reaction is carried out, for example, by the method
disclosed in Tetrahedron, 49, 1343 (1993). To be precise, an
organic phosphorus compound (e.g., a phosphonium salt, a phosphoric
acid ester, etc.) is treated with a base (e.g., NaH, BuLi, KOtBu,
etc.) and reacted with a carbonyl compound in an inert solvent
(e.g., THF, ether, dichloro-methane, etc.). The reaction
temperature is in the range of from about -100.degree. C. to a
boiling point of the solvent to be used.
[0157] For example, the following compound 8 is preferably prepared
as follows: 16
[0158] wherein R.sup.2, R.sup.3, R.sup.4 and R.sup.5, are as
defined above, and R' is phenyl or 4-toluyl.
[0159] The compound 3 is prepared by reacting the compound 1 with
the compound 2 in the presence of a Lewis acid in an inert solvent,
according to J. Org. Chem., 48, 3214-3219 (1983). The 2-position of
the pyrrole ring is advantageously preferentially reacted with the
compound 2 by using BF.sub.3.OEt.sub.2, ZnCl.sub.2, SnCl.sub.4 as a
Lewis acid. The inert solvent is preferably halogenated
hydrocarbons such as dichloromethane, dichloroethane, etc., and the
reaction temperature is in the range of from about 0.degree. C. to
a boiling point of the solvent to be used, and preferably around
room temperature.
[0160] The compound 3 is hydrolyzed in the presence of a base to
give the compound 4. The base includes NaOH, KOH, etc., and the
solvent includes a mixed solvent of dioxane and water, a mixed
solvent of methanol and water, etc. The reaction temperature is in
the range of from about 50.degree. C. to about 90.degree. C.
[0161] The compound 4 is reacted with an allyl halide in an inert
solvent in the presence of a base to give the compound 5. The base
is preferably KOtBu, etc., and NaH can also be used. The inert
solvent includes, for example, THF, DMF, etc., and the reaction
temperature is in the range of about 40.degree. C. to about
60.degree. C.
[0162] The compound 6 wherein R.sup.4 is methyl is prepared by
reacting the compound 5 with a Vilsmeier reagent (Org. Synth. Coll.
Vol. IV, 831, etc.), followed by subjecting the product to
reduction in a halogenated hydrocarbon solvent. The reduction is
carried out, for example, by using triethylsilane-trifluoroacetic
acid as a reducing agent, etc., and usually at a temperature of
from about 0.degree. C. to around room temperature. The compound 6
wherein R.sup.4 is an alkyl group other than methyl is prepared by
reacting the compound 5 with an alkanoyl halide in the presence of
a Lewis acid, followed by reduction of the product. The Lewis acid
includes AlCl.sub.3, etc., and the reaction is usually carried out
at a temperature of from about 0.degree. C. to a boiling point of
the solvent to be used.
[0163] The compound 8 is prepared by reacting the compound 6 and
the compound 7 in the presence of a palladium catalyst and a base
in an inert solvent. The palladium catalyst includes a palladium
(II) catalyst such as Pd(OAc).sub.2, etc., a palladium (0) catalyst
such as Pd(dba).sub.2, etc. The base includes NaHCO.sub.3,
K.sub.2CO.sub.3, triethylamine, etc., and the reaction can be
accelerated by addition of a phosphine ligand such as PPh.sub.3,
etc., a phase-transfer catalyst such as BnEt.sub.3NCl, etc. The
inert solvent includes DMF, THF, toluene, etc., and the reaction
temperature is usually in the range of from room temperature to a
boiling point of the solvent to be used.
[0164] The present invention also includes hydrates and solvates
such as ethanolates of the present pyrrole derivatives, a prodrug
thereof, and a pharmaceutically acceptable salt thereof. When the
pyrrole derivatives, etc. of the present invention exist in the
form of an optical isomer, a stereoisomer, an enatiomer, then the
present invention also includes each isomer or a mixture thereof.
In order to obtain an optical isomer of the present compound, the
present pyrrole derivatives, etc. are converted into a salt with an
optically active acid (e.g., mandelic acid, N-benzyloxyalanine,
lactic acid, tartaric acid, o-diisopropilidene tartrate, malic
acid, camphor sulfonic acid, bromo camphor sulfonic acid, etc.) or
an optically active amine (e.g., .alpha.-phenethylamine, kinin,
quinidine, cinchonidine, cinchonine, strychnine, etc.), and the
precipitated crystals are collected by filtration, and further
converted into a free compound.
[0165] The pyrrole derivative of the present invention, or a
prodrug thereof, or a pharmaceutically acceptable salt thereof can
be administered either orally or parenterally. The pharmaceutical
composition for oral administration includes, for example, tablets,
pills, granules, powders, capsules, cachets, liquids, suspensions,
emulsions, syrups, etc. The pharmaceutical composition for
parenteral administration includes, for example, injections (e.g.,
intravenous injection, intramuscular injection, etc.), percutaneous
formulations (e.g., creams, ointments, lotions, patches, matrixes,
etc.), intranasal formulations, rectal formulations (e.g.,
suppositories, etc.), etc.
[0166] These formulations are prepared by a conventional
method.
[0167] Oral solid preparations such as tablets are prepared, for
example, by mixing the present pyrrole derivative, etc., with
excipients (e.g., lactose, D-mannitol, sugar, corn starch,
cellulose, calcium hydrogen-phosphate, etc.), disintegrants (e.g.,
calcium carmerose, low substituted hydroxypropyl cellulose,
crosscarmerose sodium, sodium carboxymethyl starch,
carboxymethylcellulose sodium, starch sodium glycolate, etc.),
binders (e.g., polyvinylpyrrolidone, polyvinyl alcohol,
hydroxypropylcellulose, hydroxypropylmethylcellulose, methyl
cellulose, etc.), lubricants (e.g., magnesium stearate, talc,
magnesium stearate, etc.), flavors and corrigents, stabilizers,
coloring agents, etc., and formulated into tablets, granules,
powders, capsules, etc. by a conventional method.
[0168] Oral liquid preparations are prepared, for example, by
adding the present pyrrole derivative, etc. into water, and further
adding thereto a coloring agent, a flavor, a stabilizer, a
sweetening agent, a solubilizer, a thickening agent, etc. if
necessary. The thickening agent includes, for example, a
pharmaceutically acceptable natural or synthesized gum, resin,
methyl cellulose, sodium carboxymethyl cellulose, or a conventional
suspending agent, etc.
[0169] Injections are prepared by dissolving or suspending the
present pyrrole derivative, etc. into a pharmaceutically acceptable
carrier such as water, a physiological saline, an oil, aqueous
glucose solution, etc., and further adding thereto as a coadjuvant
a pH adjuster, a buffer, a stabilizer, a solubilizing agent, an
emulsifier, etc. if necessary.
[0170] The dosage and the frequency of administration of the
present pyrrole derivative, etc. may vary according to the
diseases, ages, weights of the patients and the administration
form, etc., but the present compounds can usually be administered
orally in a dose of about 1 to about 500 mg per day, preferably in
a dose of about 3 to about 300 mg per day, especially preferably in
a dose of about 5 to about 100 mg per day, in adult (body weight:
60 kg), once a day, or divided into several dosage units. When the
present compound is administered in an injection preparation, the
dosage thereof is in the range of about 0.1 to about 300 mg per
day, preferably in the range of about 1 to about 100 mg per day, in
an adult (body weight: 60 kg), once a day, or divided into several
dosage units, or continuously.
EXAMPLES
[0171] The present invention is illustrated by the following
Examples, but should not be construed to be limited thereto.
Reference Example 1
[0172] 17
[0173] Under nitrogen atmosphere, to a solution of
1-benzenesulfonyl-1H-py- rrole (283.9 g) in methylene chloride (1.0
L) were added p-toluoyl chloride (318 g) and boron trifluodie ether
complex (350 g), and the mixture was allowed to stand at room
temperature for 7 days. The reaction solution was washed twice with
1N hydrochloric acid (750 mL), washed with 1N aqueous sodium
hydroxide solution (750 mL) and a saturated brine (100 mL), dried,
and filtered. The filtrate was concentrated to about a half volume
thereof under atmospheric pressure, and thereto was added hexane
(500 mL). The mixture was further concentrated, and methylene
chloride was evaporated off. The resultant was cooled to 10.degree.
C., and the precipitated crystals were collected by filtration,
washed with hexane and toluene, and dried to give
(1-benzenesulfonyl-1H-pyrrol-2-yl)(4-methy- lphenyl)ketone (315 g,
71%).
[0174] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.12 (d, 2H, J=8.3
Hz), 7.75-7.78 (m, 1H), 7.72 (brd, 2H, J=7.9 Hz), 7.65 (brt, 1H,
J=7.9 Hz), 7.58 (brt, 2H, J=7.9 Hz), 7.25 (d, 2H, J=8.3 Hz),
6.69-6.72 (m, 1H), 6.35 (dd, 1H, J=3.1 and 0.5 Hz), 2.42 (s,
3H).
[0175] (1-2)
[0176] The compound (145 g) obtained in Reference Example 1-1 was
suspended in methanol (1.0 L), and thereto was added a 5N NaOH (1.1
kg), and the mixture was refluxed for 30 minutes to give a
homogenous solution. This solution was gradually cooled to
0.degree. C., and the precipitated crystals were collected by
filtration, and dried to give
(1H-pyrrol-2-yl)(4-methylphenyl)ketone (80 g, 97%).
[0177] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.52 (brs, 1H),
8.25 (d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.3 Hz), 7.12 (brs, 1H),
6.88-6.91 (m, 1H), 6.32-6.36 (m, 1H), 2.44 (s, 3H).
Reference Example 2
[0178] 18
[0179] The compound (600 mg) obtained in Reference Example 1-2 and
sodium borohydride (492 mg) were refluxed for 3 hours in 2-propanol
(15 g). The reaction solution was cooled to room temperature, and
thereto was added water (3 mL), and concentrated. The residue was
dissolved in ether, washed with water, dried, treated with
activated carbon, filtered, and the filtrate was concentrated. The
residue was purified by silica gel column chromatography to give
the title compound (465 mg, 84%) as a colorless liquid.
[0180] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.42 (brs, 1H),
7.10 (d, 2H, J=8.1 Hz), 7.08 (d, 2H, J=8.1 Hz), 6.63 (brs, 1H),
6.11-6.17 (m, 1H), 5.98 (s, 1H), 3.93 (brs, 2H), 2.32 (s, 3H).
Reference Example 3
[0181] 19
[0182] Under nitrogen atmosphere, to a suspension of aluminum
chloride (4.62 g) in dichloroethane (50 mL) was added a solution of
p-toluoyl chloride (4.91 g) in dichloroethane (5 mL) at room
temperature over a period of 10 minutes. After stirring for 30
minutes, to the mixture was added a solution of
1-benzenesulfonyl-1H-pyrrole (6.00 g) in dichloroethane (10 mL)
over a period of 10 minutes. The mixture was stirred at room
temperature for 2 hours, and the reaction mixture was poured into
ice water, and the aqueous layer was extracted twice with methylene
chloride. The organic layers were combined, dried, filtered and
concentrated. The residue was purified by silica gel column
chromatography to give
(1-benzenesulfonyl-1H-pyrrol-2-yl)(4-methylphenyl) ketone (9.9 g,
100%).
[0183] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.89 (brd, 2H,
J=7.9 Hz), 7.73 (d, 2H, J=8.0 Hz), 7.65 (brt, 1H, J=7.9 Hz), 7.65
(brs, 1H), 7.34 (brt, 2H, J=7.9 Hz), 7.29 (d, 2H, J=8.0 Hz), 7.22
(dd, 1H, J=2.2 and 2.8 Hz), 6.80 (dd, 1H, J=1.5 and 2.8 Hz), 2.44
(s, 3H).
[0184] (3-2)
[0185] The compound (6.50 g) obtained in Reference Example 3-1 and
5N aqueous NaOH solution (70 mL) and THF (70 mL) were stirred at
45.degree. C. for 6 hours. The organic layer was concentrated till
the solvent was reduced to 5 mL, and then allowed to stand at room
temperature for 2 days. The precipitated crystals were collected by
filtration to give (1H-pyrrol-3-yl)(4-methylphenyl)ketone (3.1 g,
84%).
[0186] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.76 (d, 2H, J=8.1
Hz), 7.35 (brquint., 1H, J=1.5 Hz), 7.26 (d, 2H, J=8.1 Hz), 6.84
(brq, 1H, J=1.5 Hz), 6.76 (brs, 1H), 2.43 (s, 3H).
Example 1
[0187] 20
[0188] A solution of 3-methylquinoline (275 mg), N-bromosuccinimide
(343 mg) and 2,2'-azobis(isobutyronitrile) (31.6 mg) in carbon
tetrachloride (8.0 g) was heated under reflux for 2 hours. The
mixture was cooled to room temperature, and the insoluble materials
were removed by filtration, and thereto was added toluene, and the
mixture was concentrated under reduced pressure. To the residue was
added toluene (5 mL) to give a solution of 3-bromomethylquinoline
in toluene. To a 60% suspension of NaH (70 mg) in THF (2 mL) was
added dropwise a solution of the compound (300 mg) obtained in
Reference Example 3-2 in THF (3 mL). To the solution was added the
solution of 3-bromomethylquinoline in toluene as mentioned above,
and the mixture was stirred at 35.degree. C. for one hour. Water
was added to the reaction solution, and the organic layer was
separated, dried, filtered and concentrated. The residue was
purified by silica gel column chromatography to give the title
compound (460 mg, 74%).
[0189] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.77 (d, 1H, J=2.2
Hz), 8.11 (d, 1H, J=8.6 Hz), 7.86 (brs, 1H), 7.71-7.81 (series of
m, 2H), 7.75 (d, 2H, J=8.1 Hz), 7.57 (brt, 1H, J=8.0 Hz), 7.34
(brt, 1H, J=1.8 Hz), 7.25 (d, 2H, J=8.1 Hz), 6.75 (brs, 1H), 6.74
(brs, 1H), 5.26 (s, 2H), 3.38 (s, 3H).
Example 2
[0190] 21
[0191] The title compound was obtained from 3-methylquinoline and
the compound obtained in Reference Example 1 in a similar manner to
Example 1.
[0192] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.06 (d, 1H, J=8.6 Hz), 7.93 (brs, 1H), 7.74 (brd, 1H, J=8.1
Hz), 7.68 (d, 2H, J=8.1 Hz), 7.66 (brt, 1H, J=8.1 and 1.1 Hz), 7.51
(ddd, 1H, J=8.6, 8.1 and 1.1 Hz), 7.23 (d, 2H, J=8.1 Hz), 7.10 (dd,
1H, J=1.7 and 2.6 Hz), 6.82 (dd, 1H, J=1.7 and 4.0 Hz), 6.26 (dd,
1H, J=2.6 and 4.0 Hz), 5.84 (s, 2H), 2.38 (s, 3H).
Example 3
[0193] 22
[0194] The title compound was obtained from 4-methylquinoline and
the compound obtained in Reference Example 1 in a similar manner to
Example 1.
[0195] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.78 (d, 1H, J=4.6
Hz), 8.14 (brd, 1H, J=7.7 Hz), 8.04 (brd, 1H, J=8.4 Hz), 7.74 (ddd,
1H, J=8.4, 7.7 and 1.5 Hz), 7.71 (d, 2H, J=8.1 Hz), 7.61 (ddd, 1H,
J=8.4, 7.7 and 1.3 Hz), 7.24 (d, 2H, J=8.1 Hz), 7.00 (dd, 1H, J=1.7
and 2.6 Hz), 6.91 (dd, 1H, J=1.7 and 4.0 Hz), 6.33 (dd, 1H, J=2.6
and 4.0 Hz), 6.18 (s, 2H), 2.41 (s, 3H).
Example 4
[0196] 23
[0197] After converting 2-chloromethylquinoline hydrochloride into
a free compound, the title compound was obtained from the free
compound and the compound obtained in Reference Example 1 in a
similar manner to Example 1.
[0198] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.07 (d, 1H, J=8.4
Hz), 8.06 (brd, 1H, J=8.4 Hz), 8.04 (brd, 1H, J=8.4 Hz), 7.74 (d,
2H, J=8.1 Hz), 7.66-7.79 (m, 2H), 7.50 (ddd, 1H, J=8.4, 7.7 and 1.3
Hz), 7.25 (d, 2H, J=8.1 Hz), 7.17 (d, 1H, J=8.4 Hz), 7.15 (dd, 1H,
J=1.7 and 2.6 Hz), 6.83 (dd, 1H, J=1.7 and 4.0 Hz), 6.26 (dd, 1H,
J=2.6 and 4.0 Hz), 5.94 (s, 2H), 2.42 (s, 3H).
Example 5
[0199] 24
[0200] After converting 2-chloromethylquinoline hydrochloride into
a free compound, the title compound was obtained from the free
compound and the compound obtained in Reference Example 2 in a
similar manner to Example 1.
[0201] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.03 (brd, 1H,
J=8.4 Hz), 7.96 (d, 1H, J=8.4 Hz), 7.76 (brd, 1H, J=8.4 Hz), 7.72
(ddd, 1H, J=8.4, 7.5 and 1.3 Hz), 7.52 (ddd, 1H, J=8.4, 7.5 and 1.3
Hz), 6.95 (d, 2H, J=8.1 Hz), 6.93 (d, 2H, J=8.1 Hz), 6.74 (dd, 1H,
J=1.7 and 2.6 Hz), 6.60 (d, 1H, J=8.4 Hz), 6.20 (dd, 1H, J=1.7 and
4.0 Hz), 6.00 (dd, 1H, J=2.6 and 4.0 Hz), 5.26 (s, 2H), 3.81 (brs,
2H), 2.20 (s, 3H).
Example 6
[0202] 25
[0203] To a suspension of 60% NaH (3.13 g) in THF (20 mL) was added
dropwise a solution of pyrrole (5.00 g) in THF (20 mL). The mixture
was stirred for 30 minutes, and thereto was added a solution of
p-toluene sulfonylchloride (14.2 g) in THF (20 mL), and the mixture
was stirred at room temperature for 3 hours. Water was added to the
reaction solution, and the organic layer was separated, dried,
filtered, and concentrated. The residue was recrystallized from a
mixed solvent of methanol and water (each 35 mL), and the resulting
crystals were collected by filtration, and dried to give
1-p-toluenesulfonyl-1H-pyrrole (16.3 g, 99%).
[0204] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.73 (dt, 2H,
J=8.4 and 2.0 Hz), 7.27 (dt, 2H, J=8.4 and 2.0 Hz), 7.15 (dd, 2H,
J=2.2 and 2.4 Hz), 6.28 (dd, 2H, J=2.2 and 2.4 Hz), 2.40 (s,
3H).
[0205] (6-2)
[0206] A solution of 2,2,6,6-tetramethylpiperidine (1.34 g) in THF
(20 mL) was cooled to -70.degree. C. under nitrogen atmosphere, and
thereto was added dropwise a 1.5 M n-butyl lithium in hexane (6.40
mL), and the mixture was stirred for 20 minutes. To the solution
was added dropwise a solution of the compound (2.0 g) obtained in
Example 6-1 in THF (10 mL) over a period of 15 minutes, and the
mixture was stirred at -70.degree. C. for one hour to give a
solution of the lithiatied compound of Example 6-1. A solution of
3-quinolinecarboxyaldehyde (1.42 g) in THF (10 mL) was cooled to
-78.degree. C., and thereto was added dropwise a solution of the
lithiatied compound of Example 6-1 via a cannula. The mixture was
warmed to room temperature, and thereto was added water. The
aqueous layer was extracted twice with ethyl acetate, and the
combined organic layer was dried, filtered, and concentrated. The
residue was purified by silica gel column chromatography to give
(1-p-toluenesulfonyl-1H-pyrrol-2- -yl)(3-quinolyl)methanol (1.68 g,
49%) and (1H-pyrrol-2-yl)(3-quinolyl)met- hanol (150 mg, 7.4%).
(1-p-toluenesulfonyl-1H-pyrrol-2-yl)(3-quinolyl)meth- anol:
[0207] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.55 (d, 1H, J=2.2
Hz), 8.04 (d, 1H, J=2.2 Hz), 8.02 (brd, 1H, J=8.4 Hz), 7.62-7.72
(m, 2H), 7.52 (brt, 1H, J=7.0 Hz), 7.49 (d, 2H, J=8.4 Hz), 7.37
(dd, 1H, J=3.1 and 1.7 Hz), 7.07 (brd, 2H, J=8.4 Hz), 6.30 (brs,
1H), 6.21 (t, 1H, J=3.5 Hz), 5.94 (brquint., 1H, J=1.7 Hz), 4.25
(brs, 1H), 2.25 (s, 3H). (1H-pyrrol-2-yl)(3-quinolyl)methanol:
[0208] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.87 (d, 1H, J=2.0
Hz), 8.19 (brs, 1H), 8.08 (brd, 1H, J=8.4 Hz), 7.79 (brd, 1H, J=8.4
Hz), 7.70 (brt, 1H, J=8.4 Hz), 7.55 (brt, 1H, J=8.4 Hz), 6.80 (brd,
1H, J=1.5 Hz), 6.16 (brq, 1H, J=2.8 Hz), 6.11 (brs, 1H), 6.04 (brs,
1H).
Example 7
[0209] 26
[0210] To a solution of (1H-pyrrol-2-yl)(3-quinolyl)methanol (40.0
mg) in 2-propanol (3 mL) was added sodium borohydride (33.9 mg),
and the mixture was refluxed for one hour. To the mixture was added
water, and the mixture was concentrated. The residue was separated
using water and ethyl acetate, and the organic layer was dried,
filtered, and concentrated. The residue was purified by silica gel
column chromatography to give 2-(3-quinolylmethyl)-1H-pyrrole (30.0
mg, 75%).
[0211] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.68 (d, 1H, J=2.2
Hz), 8.57 (brs, 1H), 8.04 (d, 1H, J=8.4 Hz), 7.86 (brs, 1H), 7.69
(brd, 1H, J=8.1 Hz), 7.63 (ddd, 1H, J=8.4, 7.0 and 1.5 Hz), 7.49
(ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 6.75 (brdd, 1H, J=2.9 and 4.0
Hz), 6.18 (brq, 1H, J=2.9 Hz), 6.04 (brs, 1H), 4.12 (s, 2H).
[0212] (7-2)
[0213] To a suspension of 60% NaH (5.3 mg) in DMF (1 mL) was added
dropwise a solution of the compound of Example 7-1 (25.0 mg) in DMF
(1.5 mL) at room temperature under nitrogen atmosphere. The mixture
was stirred for 30 minutes, and thereto was added a solution of
p-methylbenzyl bromide (26.6 mg) in DMF (1 mL), and the mixture was
stirred at room temperature for 30 minutes. Water was added to the
reaction solution, and the mixture was extracted with diethyl
ether, and the ether layer was dried, filtered, and concentrated.
The residue was purified by silica gel column chromatography to
give 1-(4-methyl-benzyl)-2-(3-quinolylmethyl)-1H-pyrrole (8.0 mg,
21%).
[0214] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.70 (d, 1H, J=2.2
Hz), 8.06 (brd, 1H, J=8.4 Hz), 7.70 (d, 1H, J=1.7 Hz), 7.66 (d, 1H,
J=8.2 Hz), 7.59-7.65 (m, 1H), 7.49 (ddd, 1H, J=8.2, 7.0 and 1.1
Hz), 7.01 (brd, 2H, J=8.4 Hz), 6.81 (brd, 2H, J=8.4 Hz), 6.72 (brt,
1H, J=2.4 Hz), 6.17 (t, 1H, J=3.0 Hz), 5.97 (brs, 1H), 4.92 (s,
2H), 3.99 (s, 2H), 2.23 (s, 3H).
Example 8
[0215] 27
[0216] 2,3-Diaminopyridine (2.0 g) and a 40% aqueous pyruvic
aldehyde solution (3.30 g) were refluxed in ethanol for 20 minutes.
The reaction solution was concentrated, and the residue was
recrystallized from 2-propanol, collected by filtration, and dried
to give 3-methylpyrido[2,3-b]pyrazine (1.61 g, 60%).
[0217] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.15 (dd, 1H,
J=4.2 and 1.9 Hz), 8.85 (s, 1H), 8.45 (dd, 1H, J=8.3 and 1.9 Hz),
7.68 (dd, 1H, J=8.3 and 4.2 Hz), 2.88 (s, 3H).
[0218] (8-2)
[0219] The title compound was obtained from the compound of Example
8-1 and the compound of Reference Example 1 in a similar manner to
Example 1.
[0220] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.17 (dd, 1H,
J=4.2 and 1.9 Hz), 8.88 (s, 1H), 8.46 (dd, 1H, J=8.3 and 1.9 Hz),
7.72 (dd, 1H, J=8.3 and 4.2 Hz), 7.71 (d, 2H, J=8.0 Hz), 7.27 (dd,
1H, J=2.6 and 1.6 Hz), 7.25 (d, 2H, J=8.0 Hz), 6.87 (dd, 1H, J=4.1
and 1.6 Hz), 6.31 (dd, 1H, J=4.1 and 2.6 Hz), 6.01 (s, 2H), 2.42
(s, 3H).
Example 9
[0221] 28
[0222] To a solution of methyl 2-bromo-5-chlorobenzoate (6.30 g),
tri-o-tolylphosphine (P(o-tol).sub.3) (770 mg), tri-n-butylamine
(9.38 g) and acrylic acid (3.64 g) in toluene (20 mL) was added
palladium acetate (284 mg) under nitrogen atmosphere, and the
mixture was heated at 110.degree. C. for 3 hours. The mixture was
washed with 1N HCl, dried, filtered, and concentrated. The residue
was purified by silica gel column chromatography, and the fractions
containing the desired compound were combined, dissolved in ethyl
acetate, and extracted with a saturated aqueous sodium hydrogen
carbonate solution. The aqueous layer was acidified with
hydrochloric acid, extracted with ethyl acetate, and the organic
layer was dried, filtered, and concentrated to give
2-(4-chloro-2-methoxycarbonylphenyl)acrylic acid (4.0 g, 66%).
[0223] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.51 (d, 1H,
J=15.9 Hz), 7.98 (d, 1H, J=1.9 Hz), 7.58 (d, 1H, J=8.4 Hz), 7.53
(dd, 1H, J=8.4 and 1.9 Hz), 6.31 (d, 1H, J=15.9 Hz), 3.95 (s,
3H).
[0224] (9-2)
[0225] To a solution of 2-(4-chloro-2-methoxycarbonylphenyl)acrylic
acid (1.40 g) and triethylamine (705 mg) in THF (20 mL) was added
dropwise a solution of ethyl chloroformate (694 mg) in THF (10 mL)
at 0.degree. C. under nitrogen atmosphere. The mixture was stirred
for 30 minutes, and the insoluble materials were removed by
filtration to give a solution of a mixed acid anhydride. To a
solution of sodium borohydride (212 mg) in THF (10 mL) and (5 mL)
was added dropwise 93% of the solution of mixed acid anhydride
prepared above at 0.degree. C. under nitrogen atmosphere. To the
solution was added sodium borohydride (210 mg). To the reaction
solution was added 3N HCl, and the mixture was extracted with
diethyl ether. The extract was washed with a saturated aqueous
sodium hydrogen carbonate solution, dried, filtered, and
concentrated to give 3-(4-chloro-2-methoxycarbonylphenyl)propenol
(880 mg, 70%, containing a saturate compound in about 15%).
[0226] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.88 (d, 1H, J=2.2
Hz), 7.50 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H, J=8.5 and 2.2 Hz), 7.35
(brd, 1H, J=15.9 Hz), 6.26 (dt, 1H, J=15.9 and 5.6 Hz), 4.36 (brd,
2H, J=5.6 Hz), 3.91 (s, 3H).
[0227] (9-3)
[0228] To a solution of the compound (870 mg) of Example 9-2 and
triphenylphosphine (PPh.sub.3) (1.01 g) in methylene chloride (20
mL) was added N-bromosuccinimide (683 mg) at 0.degree. C. in
portions. The mixture was stirred for 10 minutes, and the reaction
solution was concentrated, and the residue was purified by silica
gel column chromatography to give a bromide (942 mg, 85%). To a
suspension of 60% NaH (167 mg) in THF (5 mL) was added dropwise a
solution of the compound (774 mg) of Reference Example 1 in THF (15
mL). To the solution was slowly added dropwise a solution of the
above bromide (930 mg) in THF (20 mL), which was previously heated
to 55.degree. C. The mixture was stirred for 2 hours, and thereto
was added 3N HCl. The mixture was extracted with diethyl ether, and
the extract was dried, filtered, and concentrated. The residue was
purified by silica gel column chromatography to give a mixture of a
methyl ester of the title compound and the comound of Reference
Example 1 (1.4 g, molar ratio; 3:7). This mixture was dissolved in
a mixture of THF (7 mL) and methanol (7 mL), and thereto was added
1N aqueous NaOH solution (7 mL), and the mixture was stirred at
40.degree. C. for 15 minutes under nitrogen atmosphere. The organic
solvent was evaporated under reduced pressure, and the residue was
washed with ether. The ether layer was extracted twice with 1N
aqueous NaOH solution, and the combined aqueous layer was washed
with hexane and acidified with hydrochloric acid. The resultant was
extracted with ethyl acetate, dried, treated with activated carbon,
filtered, and concentrated to give the title compound (320 mg,
60%). To the title compound (596 mg) were added 1N aqueous NaOH
solution (1.52 mL) and THF (2 mL), and the mixture was subjected to
supersonic treatment. The mixture was concentrated with toluene,
and the residue was washed with diethyl ether, and dried to give a
sodium salt of the title compound (520 mg, 83%).
[0229] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.67 (d, 2H,
J=8.1 Hz), 7.46 (brd, 1H, J=16.2 Hz), 7.40 (brd, 1H, J=8.5 Hz),
7.39 (brs, 1H), 7.33 (dd, 1H, J=1.7 and 2.4 Hz), 7.31 (d, 2H, J=8.1
Hz), 7.13 (brdd, 1H, J=8.4 and 2.3 Hz), 6.65 (dd, 1H, J=1.7 and 4.0
Hz), 6.25 (dt, 1H, J=16.2 and 6.4 Hz), 6.20 (dd, 1H, J=2.4 and 4.0
Hz), 5.10 (brd, 1H, J=6.4 Hz), 2.38 (s, 3H).
Example 10
[0230] 29
[0231] To a mixture of methyl 4-allyloxybenzoate (10.0 g), THF (50
mL) and methanol (50 mL) was added 2N aqueous NaOH solution (50
mL), and the mixture was stirred at 50.degree. C. for 40 minutes.
The reaction solution was concentrated to about 50 g, washed with
hexane, and acidified with conc. hydrochloric acid. The
precipitated crystals were collected by filtration, dissolved in
ethyl acetate, dried over magnesium sulfate, and the solvent was
evaproated under reduced prssure to give crude crystals of
4-allyloxybenzoic acid (4.68 g, 50%). To the crystals were added
dichloroethane (50 mL) and DMF (2 drops), and the mixture was
heated to 80.degree. C., and thereto was added dropwise thionyl
chloride (4.61 g) over a period of 10 minutes. The mixture was
stirred for 30 minutes, and the reaction solution was concentrated
to give an oily acid chloride (5.3 g). The compound (3.81 g) of
Example 6-1 and the above acid chloride (5.07 g) were dissolved in
methylene chloride (50 mL), and thereto was added boron trifluoride
diethyl ether complex (4.39 g), and the mixture was allowed to
stand at room temperature for 5 days. The reaction solution was
washed successively with aqueous hydrochloric acid, water, and
aqueous sodium hydroxide solution, dried, filtered, and
concentrated. The residue was purified by silica gel chromatography
to give a mixture of
(1-p-toluenesulfonyl-1H-pyrrol-2-yl)(4-allyloxyphenyl) ketone and
4-allyloxybenzoic acid. This mixture was dissolved in 1N aqueous
NaOH solution, and extracted three time with ethyl acetate. The
combined oil layer was dried and concentrated to give crude
crystals of
(1-p-toluenesulfonyl-1H-pyrrol-2-yl)(4-allyloxyphenyl)ketone (5.79
g), which was dissolved in methanol (70 mL), and thereto was added
5N aqueous NaOH solution (70 mL), and the mixture was heated for
1.5 hour. The methanol was evaporated under reduced pressure, and
extracted with ethyl acetate, dried, and concentrated. The residue
was purified by silica gel column chromatography to give
(1H-pyrrol-2-yl) (4-allyloxyphenyl)ketone (2.51 g, 43%).
[0232] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.51(brs, 1H),
7.92 (dt, 2H, J=8.4 and 2.0 Hz), 7.12 (dt, 1H, J=1.3 and 2.7 Hz),
6.99 (dt, 2H, J=8.4 and 2.0 Hz), 6.89 (ddd, 1H, J=3.8, 2.4 and 1.3
Hz), 6.35 (dt, 1H, J=3.8 and 2.7 Hz), 6.08 (ddt, 1H, J=17.3, 10.6
and 5.0 Hz), 5.45 (ddt, 1H, J=17.3, 1.6 and 1.6 Hz), 5.33 (ddt, 1H,
J=10.6, 1.6 and 1.6 Hz), 4.63 (ddd, 2H, J=5.0, 1.6 and 1.6 Hz).
[0233] (10-2)
[0234] The title compound was obtained from 3-methylquinoline and
the compound of Example 10-1 in a similar manner to Example 1.
[0235] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4 and 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0 and 1.5 Hz), 7.52 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.09 (dd,
1H, J=1.7 and 2.5 Hz), 6.99 (dt, 2H, J=8.4 and 2.0 Hz), 6.83 (dd,
1H, J=1.7 and 4.0 Hz), 6.28 (dd, 1H, J=2, 5 and 4.0 Hz), 6.06 (ddt,
1H, J=17.3, 10.6 and 5.0 Hz), 5.84 (brs, 2H), 5.43 (ddt, 1H,
J=17.3, 1.6 and 1.6 Hz), 5.32 (ddt, 1H, J=10.6, 1.6 and 1.6 Hz),
4.59 (ddd, 2H, J=5.0, 1.6 and 1.6 Hz).
Example 11
[0236] 30
[0237] To a solution of 2,3-dimethyl-2-buten (37.8 mg) in THF (1
mL) was added dropwise a solution of borane dimethylsulfide complex
(31.0 mg) in THF (1.5 mL) at -10.degree. C. over a period of 10
minutes, and the mixture was stirred at the same temperature for 2
hours. To the solution was added a solution of the compound of
Example 10 (50.0 mg) in THF (1.5 mL) over a period of 10 minutes,
and the mixture was stirred for one hour. To this solution were
added a 30% aqueous hydrogen peroxide solution (1 mL) and a 3N
aquoues NaOH solution (1 mL), and the mixture was stirred for 30
minutes. The reaction solution was extracted with ethyl acetate,
and the organic layer was washed with an aqueous sodium thiosulfate
solution, dried, filtered, and concentrated. The residue was
purified by silica gel column chromatography to give the compound
of Example 11 (24 mg, 46%) and the compound of Example 12 (4.2 mg,
8%).
[0238] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.77 (dt, 2H,
J=8.4 and 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.67 (ddd, 1H, J=8.4,
7.0 and 1.5 Hz), 7.51 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.08 (dd,
1H, J=1.7 and 2.5 Hz), 6.91 (dt, 2H, J=8.4 and 2.0 Hz), 6.81 (dd,
1H, J=1.7 and 4.0 Hz), 6.27 (dd, 1H, J=2.5 and 4.0 Hz), 5.82 (brs,
2H), 4.16 (t, 2H, J=6.0 Hz), 3.86 (brt, 2H, J=6.0 Hz), 2.12 (brs,
1H), 2.06 (quint, 2H, J=6.0 Hz).
Example 12
[0239] 31
[0240] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4 and 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0 and 1.5 Hz), 7.52 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.10 (dd,
1H, J=1.7 and 2.5 Hz), 6.93 (dt, 2H, J=8.4 and 2.0 Hz), 6.81 (dd,
1H, J=1.7 and 4.0 Hz), 6.28 (dd, 1H, J=2.5 and 4.0 Hz), 5.84 (brs,
2H), 4.23 (brddd, 1H, J=7.7, 6.4 and 3.2 Hz), 3.99 (dd, 1H, J=9.3
and 3.2 Hz), 3.86 (dd, 1H, J=9.3 and 7.7 Hz), 1.30 (d, 3H, J=6.4
Hz).
Example 13
[0241] 32
[0242] To a solution of the compound (74.0 mg) of Example 10 in
(0.5 mL) and acetonitrile (0.5 mL) were added
N-methylmorpholine-N-oxide (30.6 mg), osmium tetraoxide
microcapsules (purity; 10%, 25.4 mg) and water (0.5 mL), and the
mixure was stirred at room temperature for 20 hours. The reaction
solution was filtered, and the filtrate was concentrated. The
residue was purified by silica gel column chromatography to give
the title compound (38.0 mg, 44%).
[0243] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.79 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.73-7.78
(series of m, 3H), 7.67 (ddd, 1H, J=8.4, 7.0 and 1.5 Hz), 7.51
(ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.09 (dd, 1H, J=1.7 and 2.5 Hz),
6.89 (brd, 2H, J=8.4 Hz), 6.80 (dd, 1H, J=1.7 and 4.0 Hz), 6.27
(dd, 1H, J=2.5 and 4.0 Hz), 5.82 (brs, 2H), 4.04-4.16 (m, 3H), 3.84
(dd, 1H, J=11.4 and 3.8 Hz), 3.75 (dd, 1H, J=11.4 and 5.5 Hz).
Example 14
[0244] 33
[0245] The compound of Example 10 (200 mg) and pyrrolidine (77.2
mg) were dissolved in a mixture of THF (1 mL) and ethanol (3 mL),
and thereto was added P(PPh.sub.3).sub.4 (62.7 mg), and the mixture
was stirred at room temperature for 30 minutes. The reaction
solution was concentrated, and the residue was purified by silica
gel column chromatography to give the title compound (190 mg,
100%).
[0246] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.61 (brs, 1H),
8.07 (brd, 1H, J=8.4 Hz), 8.05 (brs, 1H), 7.79 (brd, 1H, J=8.1 Hz),
7.68 (ddd, 1H, J=8.4, 7.0 and 1.5 Hz), 7.66 (dt, 2H, J=8.4 and 2.0
Hz), 7.54 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.12 (dd, 1H, J=1.7 and
2.5 Hz), 6.81 (dd, 1H, J=1.7 and 4.0 Hz), 6.79 (dt, 2H, J=8.4 and
2.0 Hz), 6.27 (dd, 1H, J=2.5 and 4.0 Hz), 5.86 (brs, 2H).
Example 15
[0247] 34
[0248] To a suspension of 60% NaH (7.3 mg) in THF (1 mL) was added
dropwise a solution of the compound of Example 14 (50.0 mg) in THF
(1.5 mL). The mixture was stirred for 30 minutes, and thereto was
added a solution of ethyl bromoacetate (29.2 mg) in THF (1 mL), and
the mixture was stirred at room temperature for one hour. Water was
added to the reaction solution, and the mixture was extracted with
ethyl acetate, dried, filtered and concentrated. The residue was
purified by silica gel column chromatography to give the title
compound (46.4 mg, 74%).
[0249] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4 and 2.0 Hz), 7.75 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0 and 1.5 Hz), 7.51 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.10 (dd,
1H, J=1.7 and 2.5 Hz), 6.92 (dt, 2H, J=8.4 and 2.0 Hz), 6.82 (dd,
1H, J=1.7 and 4.0 Hz), 6.27 (dd, 1H, J=2.5 and 4.0 Hz), 5.83 (brs,
2H), 4.67 (s, 2H), 4.28 (q, 2H, J=7.1 Hz), 1.30 (t, 3H, J=7.1
Hz).
Example 16
[0250] 35
[0251] To a mixture of the compound of Example 15 (23.0 mg), THF (1
mL) and methanol (1 mL) was added 1N aqueous NaOH solution (1 mL),
and the mixture was stirred at 40.degree. C. for 40 minutes. The
reaction solution was concentrated to about 1.0 g, and diluted with
water. The mixture was washed with hexane, and acidified with
hydrochloric acid. The mixture was extracted with ethyl acetate,
dried over magnesium sulfate, and the solvent was evaporated under
reduced pressure to give the title compound (19.4 mg, 91%).
[0252] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.78 (d, 1H, J=2.2
Hz), 8.12 (d, 1H, J=8.4 Hz), 8.04 (brs, 1H), 7.78 (brd, 1H, J=8.1
Hz), 7.76 (brd, 2H, J=8.4 Hz), 7.68 (ddd, 1H, J=8.4, 7.0 and 1.5
Hz), 7.54 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.11 (dd, 1H, J=1.7 and
2.5 Hz), 6.93 (brd, 2H, J=8.4 Hz), 6.82 (dd, 1H, J=1.7 and 4.0 Hz),
6.28 (dd, 1H, J=2.5 and 4.0 Hz), 5.81 (brs, 2H), 4.73 (s, 2H).
Example 17
[0253] 36
[0254] To a suspension of 60% NaH (7.3 mg) in THF (1 mL) was added
dropwise a solution of the compound of Example 14 (50.0 mg) in THF
(1.5 mL). The mixture was stirred for 30 minutes, and thereto was
added 2-bromoacetamide (25.2 mg) in THF (1 mL), and the mixture was
stirred at room temperature for one hour. To the reaction solution
was added water, and the mixture was extracted twice with ethyl
acetate. The organic layer was dried, filtered, and concentrated.
The residue was purified by silica gel column chromatography to
give the title compound (40.0 mg, 68%).
[0255] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.80 (dt, 2H,
J=8.4 and 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0 and 1.5 Hz), 7.52 (ddd, 1H, J=8.1, 7.0 and 1.1 Hz), 7.12 (dd,
1H, J=1.7 and 2.5 Hz), 6.94 (dt, 2H, J=8.4 and 2.0 Hz), 6.81 (dd,
1H, J=1.7 and 4.0 Hz), 6.55 (brs, 1H), 6.29 (dd, 1H, J=2.5 and 4.0
Hz), 5.92 (brs, 1H), 5.84 (brs, 2H), 4.55 (s, 2H).
Example 18
[0256] 37
[0257] To a solution of ethyl o-bromobenzoate (20.0 g),
P(o-tol).sub.3 (2.66 g), triethylamine (17.6 g) and acrylic acid
(12.6 g) in toluene (70 mL) was added palladium acetate (980 mg)
under nitrogen atmosphere, and the mixture was heated at
110.degree. C. for one hour. The reaction solution was filtered,
and extracted with a saturated aqueous sodium hydrogen carbonate
solution. The aqueous layer was acidified with hydrochloric acid,
extracted with ethyl acetate, dried, filtered, and concentrated to
give 3-(2-ethoxycarbonylphenyl)acrylic acid (19.8 g, 103%).
[0258] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.58 (d, 1H,
J=15.9 Hz), 7.99 (dd, 1H, J=1.2 and 7.7 Hz), 7.62 (brd, 1H, J=7.7
Hz), 7.56 (dt, 1H, J=1.1 and 7.7 Hz), 7.47 (dt, 1H, J=1.2 and 7.7
Hz), 6.31 (d, 1H, J=15.9 Hz), 4.41 (q, 2H, J=7.2 Hz), 1.42 (t, 3H,
J=7.2 Hz).
[0259] (18-2)
[0260] To a solution of the compound of Example 18-1 (11.7 g) and
triethylamine (5.91 g) in THF (150 mL) was added dropwise a
solution of ethyl chloroformate (6.34 g) in THF (75 mL) at
0.degree. C. under nitrogen atmosphere. The mixture was stirred for
30 minutes, and the insoluble materials were removed by filtration
to give a solution of a mixed acid anhydride. To a solution of
sodium borohydride (2.03 g) in THF (10 mL) and water (5 mL) was
added dropwise the above solution of the mixed acid anhydride at
0.degree. C. under nitrogen atmosphere. To the solution was added
sodium borohydride (2.00 g), and thereto was added 3N HCl, and the
mixture was extracted with diethyl ether. The extract was washed
with a saturated aqueous sodium hydrogen carbonate solution, dried,
filtered, and concentrated to give 3-(2-ethoxycarbonylphenyl)prope-
nol (8.82 g, 81%, containing a saturated compound in about
15%).
[0261] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.89 (dd, 1H,
J=1.2 and 7.7 Hz), 7.56 (brd, 1H, J=7.7 Hz), 7.47 (dt, 1H, J=1.1
and 7.7 Hz), 7.38 (brd, 1H, J=15.9 Hz), 7.32 (dt, 1H, J=1.2 and 7.7
Hz), 6.26 (dt, 1H, J=15.9 and 5.6 Hz), 4.36 (brd, 2H, J=5.6 Hz),
4.35 (q, 2H, J=7.2 Hz), 1.39 (t, 3H, J=7.2 Hz).
[0262] (18-3)
[0263] To a solution of the compound of Example 18-2 (8.87 g) and
PPh.sub.3 (12.3 g) in methylene chloride (40 mL) was added
N-bromosuccinimide (8.37 g) at 0.degree. C. in portions, and the
reaction solution was stirred for 10 minutes, and concentrated. The
residue was purified by silica gel column chromatography to give a
bromide compound (8.40 g, 73%). To a solution of the compound of
Reference Example 1 (4.05 g) in THF (40 mL) was added potassium
t-butoxide (2.45 g), and the mixture was stirred at 40.degree. C.
for one hour. To the solution was added slowly a solution of the
above bromide compound (8.40 g) in THF (120 mL), and the mixture
was stirred for one hour. Water was added to the reaction solution,
and the mixture was extracted with diethyl ether. The extract was
dried, filtered, and concentrated. The residue was purified by
silica gel column chromatography to give the title compound (6.90
g, 85%).
[0264] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.87 (dd, 1H,
J=1.2 and 7.7 Hz), 7.74 (dt, 2H, J=8.4 and 2.0 Hz), 7.54 (brd, 1H,
J=7.7 Hz), 7.43 (dt, 1H, J=1.1 and 7.7 Hz), 7.30 (brd, 1H, J=15.7
Hz), 7.29 (dt, 1H, J=1.2 and 7.7 Hz), 7.25 (brd, 2H, J=8.4 Hz),
7.11 (dd, 1H, J=1.7 and 2.5 Hz), 6.76 (dd, 1H, J=1.7 and 4.0 Hz),
6.36 (dt, 1H, J=15.7 and 5.6 Hz), 6.21 (dd, 1H, J=2.5 and 4.0 Hz),
5.23 (dd, 2H, J=6.2 and 1.4 Hz), 4.34 (q, 2H, J=7.2 Hz), 2.43 (s,
3H), 1.37 (t, 3H, J=7.2 Hz).
Example 19
[0265] 38
[0266] The compound of Example 18 (2.00 g) was dissolved in THF (20
mL) and methanol (20 mL), and thereto was added 1N aqueous NaOH
solution (20 mL). The mixture was stirred at 40.degree. C. for one
hour under nitrogen atmosphere. The organic solvent was evaporated
under reduced pressure, and the residue was washed with ether. The
ether layer was extracted with 1N aqueous NaOH solution, and the
combined aqueous layer was washed with hexane and acidified with
hydrochloric acid. The mixture was extracted with ethyl acetate,
and the extract was dried, and treated with activated carbon,
filtered, and concentrated to give the title compound (1.55 g,
84%).
[0267] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (dd, 1H,
J=1.2 and 7.7 Hz), 7.74 (brd, 2H, J=8.4 Hz), 7.57 (brd, 1H, J=7.7
Hz), 7.50 (dt, 1H, J=1.1 and 7.7 Hz), 7.36 (brd, 1H, J=15.7 Hz),
7.34 (dt, 1H, J=1.2 and 7.7 Hz), 7.24 (brd, 2H, J=8.4 Hz), 7.11
(dd, 1H, J=1.7 and 2.5 Hz), 6.78 (dd, 1H, J=1.7 and 4.0 Hz), 6.38
(dt, 1H, J=15.7 and 5.6 Hz), 6.22 (dd, 1H, J=2.5 and 4.0 Hz), 5.25
(dd, 2H, J=6.2 and 1.4 Hz), 2.40 (s, 3H).
Example 20
[0268] 39
[0269] To a solution of 3-methylquinoline (11.0 ml) in carbon
tetrachloride (290 ml) were added N-bromosuccinimide (14.7 g) and
2,2'-azobis(isobutyronitrile) (1.13 g) under nitrogen atmosphere,
and the mixture was refluxed for 1.5 hour. The reaction solution
was cooled to room temperature, and the insoluble materials were
removed by filtration, and the solvent was evaporated under reduced
pressure to about 80 ml. Toluene was added to the mixture, and
further evaporated under reduced pressure to about 80 ml, and this
procedure was repeated three time to give a solution of a crude
bromo compound in toluene.
[0270] A suspension of 60% NaH (3.28 g) in THF (400 ml) was cooled
to 0.degree. C. under nitrogen atmosphere, and thereto was added
pyrrol-2-carbaldehyde (7.81 g) in portions. To the mixture was
added a solution of the above crude bromo compound in toluene, and
the mixture was stirred at room temperature for 0.5 hour, and
stirred at 40.degree. C. for one hour, and further stirred at
50.degree. C. for 2 hours. The mixture was cooled to room
temperature, and poured into water, and extracted with ethyl
acetate. The extract was washed with a saturated brine, dried over
magnesium sulfate, and the solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1.fwdarw.2/1.fwdarw.1/1) to give
1-(3-quinolylmethyl)-1H-pyrrol-2-carbaldehyde (10.5 g, 54%).
[0271] .sup.1H NMR (CDCl.sub.3, 270 MHz) .delta. 9.57 (d, 1H, J=1.3
Hz), 8.80 (d, 1H, J=2.3 Hz), 8.08 (d, 1H, J=7.9 Hz), 7.87 (d, 1H,
J=2.3 Hz), 7.76 (d, 1H, J=7.9 Hz), 7.70 (dd, 1H, J=7.9 and 7.9 Hz),
7.53 (dd, 1H, J=7.9 and 7.9 Hz), 7.08 (m, 1H), 7.02 (dd, 1H, J=1.7
and 4.0 Hz), 6.33 (dd, 1H, J=2.6 and 4.0 Hz), 5.76 (s, 2H).
[0272] (20-2)
[0273] Ether (10 ml) was added to magnesium (1.05 g) under nitrogen
atmosphere, and thereto was added dropwise a solution of
4-bromotoluene (5.3 ml) in ether (80 ml) under reflux. The mixture
was further refluxed for another hour to give 0.452 N Grignard
reagent.
[0274] A solution of the compound of Example 20-1 (6.00 g) in THF
(130 ml) was cooled to 0.degree. C. under nitrogen atmosphere, and
thereto was added dropwise the above 0.452N Grignard reagent (62.5
ml), and the mixture was stirred at the same temperature. One hour
thereafter, the 0.452N Grignard reagent (10 ml) was added, and the
mixture was further stirred for one hour. The reaction solution was
poured into water, and extracted twice with ethyl acetate. The
extract was washed three times with a saturated aqueous sodium
hydrogen carbonate solution, and washed with a saturated brine,
dried over magnesium sulfate, and filtered. The solvent was
evaporated under reduced pressure, and the precipitated solid was
suspended in ethyl acetate, and collected by filtration to give
[1-(3-quinolylmethyl)-1H-pyrrol-2-yl](4-methylphenyl)methanol (6.80
g, 81%).
[0275] .sup.1H NMR (CDCl.sub.3, 270 MHz) .delta. 8.63 (d, 1H, J=2.3
Hz), 8.06 (d, 1H, J=8.3 Hz), 7.65-7.71 (m, 2H), 7.49-7.54 (m, 2H),
7.20 (d, 2H, J=8.1 Hz), 7.03 (d, 2H, J=8.1 Hz), 6.71 (dd, 1H, J=1.7
and 2.7 Hz), 6.15 (dd, 1H, J=2.7, 3.5 Hz), 5.99 (dd, 1H, J=1.7, 3.5
Hz), 5.81 (d, 1H, J=4.3 Hz), 5.37 (d, 1H, J=16.3 Hz), 5.28 (d, 1H,
J=16.3 Hz), 2.36 (d, 1H, J=4.3 Hz), 2.21 (s, 3H).
Example 21
[0276] 40
[0277] To the compound of Example 20-2 (4.16 g) were added at
0.degree. C. trifluoroacetic acid (32 ml) and triethylsilane (1.70
ml) under nitrogen atmosphere, and the mixture was stirred at room
temperature for 20 minutes. The solvent in the reaction solution
was evaporated under reduced pressure, and the residue was
neutralized with a saturated aqueous sodium hydrogen carbonate
solution, and extracted with ethyl acetate. The extract was washed
with a saturated aqueous sodium hydrogen carbonate solution, dried
over magnesium sulfate, filtered, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
column (hexane/ethyl acetate=5/1.fwdarw.4/1.fwdarw.3/1) to give the
title compound (1.35 g, 34%).
[0278] .sup.1H NMR (CDCl.sub.3, 270 MHz) .delta. 8.60 (d, 1H, J=1.8
Hz), 8.07 (d, 1H, J=7.7 Hz), 7.63-7.71 (m, 2H), 7.51 (dd, 1H, J=7.7
and 7.7 Hz), 7.38 (d, 1H, J=1.8 Hz), 6.96 (s, 4H), 6.68 (dd, 1H,
J=1.8 and 2.8 Hz), 6.20 (m, 1H), 6.06 (m, 1H), 5.09 (s, 2H), 3.84
(s, 2H), 2.18 (s, 3H).
Example 22
[0279] 41
[0280] (22-1)
[0281] A 2.0N solution of ethylmagnesium chloride in THF (100 ml)
was cooled to 0.degree. C. under nitrogen atmosphere, and thereto
was added dropwise a solution of 2-cyanoaniline (7.90 g) in THF (65
ml) over a period of 50 minutes. The mixture was stirred at room
temperature for 20 minutes, and refluxed for 3 hours. The reaction
solution was cooled to 0.degree. C., and thereto was added a 4N
aqueous hydrochloric acid solution (80 ml) over a period of 40
minutes, and the mixture was further refluxed for 3 hours. The
solvent in the reaction solution was evaporated under reduced
pressure, and the resultant was added to a saturated aqueous sodium
hydrogen carbonate solution for neutralization. The mixture was
extracted three times with ethyl acetate, and the extract was
washed with a saturated brine, dried over magnesium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=8/1) to give 1-(2-aminophenyl)-1-propanone (6.78 g,
68%).
[0282] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.75 (dd, 1H,
J=1.5, 8.6 Hz), 7.25 (ddd, 1H, J=1.5, 7.7 and 7.7 Hz), 6.62-6.67
(m, 2H), 6.28 (brs, 2H), 2.98 (q, 2H, J=7.3 Hz), 1.21 (t, 3H, J=7.3
Hz).
[0283] (22-2)
[0284] To a solution of the compound of Example 22-1 (5.12 g) in
THF (200 ml) was added triethylamine (5.80 ml) under nitrogen
atmosphere, and the mixture was cooled to 0.degree. C. To the
mixture was added dropwise acetyl chloride (2.55 ml), and the
mixture was stirred for 30 minutes. Acetyl chloride (0.50 ml) was
further added thereto, and the mixture was stirred at room
temperature for 30 minutes. The reaction solution was poured into
water, and extracted three times with ethyl acetate. The extract
was washed with a saturated brine, dried over magnesium sulfate,
filtered, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column (hexane/ethyl
acetate=5/1.fwdarw.3/1) to give 1-(2-acetylaminophenyl)-1-propanone
(5.13 g, 78%).
[0285] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 11.76 (brs, 1H),
8.74 (d, 1H, J=7.9 Hz), 7.93 (d, 1H, J=7.9 Hz), 7.54 (dd, 1H, J=7.9
and 7.9 Hz), 7.11 (dd, 1H, J=7.9 and 7.9 Hz), 3.08 (q, 2H, J=7.2
Hz), 2.24 (s, 3H), 1.23 (t, 3H, J=7.2 Hz).
[0286] (22-3)
[0287] A solution of the compound of Example 22-2 (4.20 g) in DMF
(21 mL) was cooled to 0.degree. C. under nitrogen atmosphere, and
thereto was added dropwise phosphorus oxychloride (16.2 mL). The
mixture was stirred at room temperature for 40 minutes, and further
stirred at 90.degree. C. for 5 hours. The reaction solution was
poured into ice water-aqueous sodium hydrogen carbonate solution
for neutralization. The mixture was extracted three times with
ethyl acetate, and the extract was washed with a saturated aqueous
sodium hydrogen carbonate solution, dried over magnesium sulfate,
filtered, and evaporated under reduced pressure. The residue was
purified by silica gel column (hexane/ethyl acetate=3/1) to give
4-chloro-3-methylquinoline (3.58 g, 92%).
[0288] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.75 (s, 1H), 8.24
(d, 1H, J=7.7 Hz), 8.09 (d, 1H, J=7.7 Hz), 7.72 (dd, 1H, J=7.7 and
7.7 Hz), 7.63 (dd, 1H, J=7.7 and 7.7 Hz), 2.58 (s, 3H).
[0289] (22-4)
[0290] To a solution of the compound of Example 22-3 (500 mg) in
carbon tetrachloride (15 mL) were added N-bromosuccinimide (508 mg)
and 2,2'-azobis(isobutyronitrile) (30.1 mg) under nitrogen
atmosphere, and the mixture was refluxed for one hour. The reaction
solution was cooled to room temperature, and the insoluble
materials were removed by filtration, and the solvent was
evaporated under reduced pressure to about 5 mL. Toluene was added
to the resultant, and the mixture was evaporated under reduced
pressure to about 5 mL, which was repeated five times to give an
about 0.56N solution of a crude bromo compound in toluene.
[0291] A solution of the compound of Reference Example 1 (90.1 mg)
in THF (2.0 mL) was cooled to 0.degree. C. under nitrogen
atmosphere, and thereto was added 60% NaH (21.3 mg) in portions.
Then, to the mixture was added the above 0.56 N solution of the
crude bromo compound in toluene (1.05 mL), and the mixture was
stirred at 50.degree. C. for one hour. The reaction solution was
cooled to room temperature, and thereto was added a saturated
aqueous sodium hydrogen carbonate solution. The mixture was
extracted with ethyl acetate, and the extract was dried over
magnesium sulfate, filtered, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
(hexane/ethyl acetate=8/1.fwdarw.6/1.fwdarw.3/1) to give the title
compound (92.1 mg, 43%, 2 steps).
[0292] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.26-8.29 (m, 2H),
8.06 (d, 1H, J=7.9 Hz), 7.63-7.76 (m, 4H), 7.23 (d, 2H, J=7.9 Hz),
7.07 (dd, 1H, J=1.7, 2.6 Hz), 6.86 (dd, 1H, J=1.7 and 4.1 Hz), 6.29
(dd, 1H, J=2.6 and 4.1 Hz), 5.99 (s, 2H), 2.41(s, 3H).
Example 23
[0293] 42
[0294] To the compound of Example 22 (47.1 mg) and 60% zinc cyanide
(28.4 mg) were added DMF (1.3 mL),
bis(dibenzylideneacetone)palladium (0) (32.1 mg), and a 2.47 N
solution of tri-t-butylphosphine in toluene (120 .mu.l) under
nitrogen atmosphere, and the mixture was stirred at 110.degree. C.
for 6 hours. The reaction solution was cooled to room temperature,
and thereto was added a saturated aqueous sodium hydrogen carbonate
solution. The mixture was extracted with ethyl acetate-toluene, and
the extract was washed twice with a saturated aqueous sodium
hydrogen carbonate solution, dried over magnesium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=5/1) to the title compound (5.1 mg, 11%).
[0295] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.65 (s, 1H), 8.22
(d, 1H, J=7.9 Hz), 8.15 (d, 1H, J=7.9 Hz), 7.83 (dd, 1H, J=7.9, 7.9
Hz), 7.76 (dd, 1H, J=7.9, 7.9 Hz), 7.69 (d, 2H, J=8.0 Hz), 7.24 (d,
2H, J=8.0 Hz), 7.17 (dd, 1H, J=1.7, 2.6 Hz), 6.89 (dd, 1H, J=1.7,
4.1 Hz), 6.33 (dd, 1H, J=2.6, 4.1 Hz), 6.08 (s, 2H), 2.41 (s,
3H).
Example 24
[0296] 43
[0297] To the compound of Example 23 (4.4 mg) was added t-butanol
(1.0 mL) under nitrogen atmosphere, and the mixture was warmed to
50.degree. C. To the mixture was added potassium hydroxide powder
(25.0 mg), and the mixture was stirred at 50.degree. C. for 30
minutes. The reaction solution was cooled to room temperature,
filtered, and the insoluble materials were removed by filtration.
Ethyl acetate was added to the filtrate, and the mixture was
filtered again. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column (hexane/ethyl
acetate=1/1.fwdarw.0/1) to give the title compound (6.7 mg,
quantitatively).
[0298] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.19 (s, 1H),
8.01-8.04 (m, 2H), 7.81 (brs, 1H), 7.70 (dd, 1H, J=7.2, 7.2 Hz),
7.60 (dd, 1H, J=7.2, 7.2 Hz), 7.54 (d, 2H, J=8.0 Hz), 7.30 (dd, 1H,
J=1.7, 2.6 Hz), 7.17 (d, 2H, J=8.0 Hz), 6.92 (dd, 1H, J=1.7, 4.0
Hz), 6.36 (dd, 1H, J=2.6, 4.0 Hz), 6.23 (brs, 1H), 5.84 (brs, 2H),
2.37 (s, 3H).
Example 25
[0299] 44
[0300] A solution of the compound of Reference Example 2 (80.2 mg)
in DMF (2.0 ml) was cooled to 0.degree. C. under nitrogen
atmosphere, and thereto was added 60% NaH (22.0 mg), and the
mixture was stirred at 50.degree. C. for 30 minutes. The solution
(about 0.56 N) of the crude bromo compound obtained from the
compound of Example 22-3 in toluene (1.0 mL) was added thereto, and
the mixture was stirred at 50.degree. C. for one hour. The reaction
solution was cooled to room temperature, and thereto was added a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted three times with ethyl acetate-toluene. The
extract was washed with a saturated aqueous sodium hydrogen
carbonate solution and a saturated brine, dried over magnesium
sulfate, filtered, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
(hexane/ethyl acetate=8/1.fwdarw.6/1) to give the title compound
(27.0 mg, 27%, 2 stesp).
[0301] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.20 (d, 1H, J=7.2
Hz), 8.04 (d, 1H, J=7.2 Hz), 7.88 (s, 1H), 7.74 (dd, 1H, J=7.2, 7.2
Hz), 7.64 (dd, 1H, J=7.2, 7.2 Hz), 6.94 (d, 2H, J=7.9 Hz), 6.87 (d,
2H, J=7.9 Hz), 6.69 (dd, 1H, J=1.8, 3.1 Hz), 6.20 (dd, 1H, J=3.1,
3.1 Hz), 6.06 (dd, 1H, J=1.8, 3.1 Hz), 5.21 (s, 2H), 3.86 (s, 2H),
2.06 (s, 3H).
Example 26
[0302] 45
[0303] To the compound of Example 25 (37.3 mg) and 60% zinc cyanide
(24.0 mg) were added DMF (1.0 mL),
bis(dibenzilidenacetone)palladium (0) (52.1 mg) and a 2.47N
solution of tri-t-butylphosphine in toluene (150 .mu.L) under
nitrogen atmosphere, and the mixture was stirred at 110.degree. C.
for 3 hours. The reaction solution was cooled to room temperature,
and thereto was added a saturated aqueous sodium hydrogen carbonate
solution. The mixture was extracted with ethyl acetate-toluene, and
the extract was washed twice with a saturated aqueous sodium
hydrogen carbonate solution, dried over magnesium sulfate,
filtered, and the solvent was evaporated under reduced pressure.
The residue was purified by silica gel column (hexane/ethyl
acetate=10/1.fwdarw.7/1) to give the title compound (29.0 mg,
80%).
[0304] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.17 (s, 1H), 8.10
(d, 1H, J=7.4 Hz), 8.07 (d, 1H, J=7.4 Hz), 7.80 (dd, 1H, J=7.4, 7.4
Hz), 7.73 (dd, 1H, J=7.4, 7.4 Hz), 6.87 (d, 2H, J=7.9 Hz), 6.77
(dd, 1H, J=1.8, 3.1 Hz), 6.72 (d, 2H, J=7.9 Hz), 6.25 (dd, 1H,
J=3.1, 3.1 Hz), 6.12 (dd, 1H, J=1.8, 3.1 Hz), 5.32 (s, 2H), 3.92
(s, 2H), 1.87 (s, 3H).
Example 27
[0305] 46
[0306] The title compound (22.4 mg, 80%) was obtained from the
compound of Example 26 (26.2 mg) in a similar manner to the
preparation of the compound of Example 24.
[0307] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.34 (s, 1H), 8.09
(d, 1H, J=7.6 Hz), 7.91 (d, 1H, J=7.6 Hz), 7.74 (dd, 1H, J=7.6, 7.6
Hz), 7.59 (dd, 1H, J=7.6, 7.6 Hz), 6.90-6.96 (m, 4H), 6.58 (dd, 1H,
J=2.0, 3.1 Hz), 6.15 (dd, 1H, J=3.1, 3.1 Hz), 6.01 (dd, 1H, J=2.0,
3.1 Hz), 5.90 (brs, 1H), 5.57 (brs, 1H), 5.14 (s, 2H), 3.88 (s,
2H), 2.15 (s, 3H).
Example 28
[0308] 47
[0309] 2-Bromo-6-nitrobenzaldehyde was synthesized by the method
disclosed in J. Chem. Soc., Perkin Trans. 1, 1996, 1699.
[0310] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 10.29 (s, 1H),
8.02 (d, 1H, J=7.8 Hz), 7.94 (d, 1H, J=7.8 Hz), 7.54 (dd, 1H,
J=7.8, 7.8 Hz).
[0311] (28-2)
[0312] A solution of triethyl 2-phosphonopropionate (3.60 mL) in
THF (50 mL) was cooled to 0.degree. C. under nitrogen atmosphere,
and thereto was added potassium t-butoxide (1.88 g). The mixture
was stirred at the same temperature for 10 minutes, and thereto was
added the compound of Example 28-1 (3.00 g), and the mixture was
stirred at 60.degree. C. for 3 hours. To the reaction solution was
added a 5% aqueous potassium hydrogen sulfate solution, and the
mixture was extracted three times with ethyl acetate. The extract
was washed with water and a saturated brine, dried over magnesium
sulfate, and filtered. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=8/1.fwdarw.6/1) to give ethyl
2-methyl-3-(2-bromo-6-nitorphenyl)acrylate (4.04 g, 99%).
[0313] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.89-7.97 (m,
3.times.1/2H), 7.83 (dd, 1.times.1/2H, J=1.2, 7.9 Hz), 7.62 (s,
1.times.1/2H), 7.38 (dd, 1.times.1/2H, J=8.4, 8.4 Hz), 7.31 (dd,
1.times.1/2H, J=7.9, 7.9 Hz), 6.89 (s, 1.times.1/2H), 4.30 (q,
2.times.1/2H, J=7.1 Hz), 3.94 (q, 2.times.1/2H, J=7.2 Hz), 2.14 (s,
3.times.1/2H), 1.67 (s, 3.times.1/2H), 1.37 (t, 3.times.1/2H, J=7.1
Hz), 0.95 (t, 3.times.1/2H, J=7.2 Hz).
[0314] (28-3)
[0315] A solution of the compound of Example 28-2 (3.80 g) in
toluene (75 ml) was cooled to -78.degree. C. under nitrogen
atmosphere, and thereto was added dropwise a 1.01N solution of
diisobutyl aluminium hydride in toluene (25.5 mL) over a period of
30 minutes. The mixture was stirred at -78.degree. C. for 2 hours.
To the reaction solution were added water and a 1N aqueous
hydrochloric acid, and the mixture was extracted twice with ethyl
acetate. The extract was washed with a 1N aqueous hydrochloric acid
solution, water and a saturated brine, dried over magnesium
sulfate, filtered, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
(hexane/ethyl acetate=3/1) to give
2-methyl-3-(2-bromo-6-nitrophenyl)propenol (2.89 g, 88%).
[0316] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 7.73-7.86 (m, 2H),
7.30 (dd, 1.times.1/2H, J=8.1, 8.1 Hz), 7.29 (dd, 1.times.1/2H,
J=8.1, 8.1 Hz), 6.47 (s, 1.times.1/2H), 6.22 (s, 1.times.1/2H),
4.21 (s, 2.times.1/2H), 3.85 (s, 2.times.1/2H), 2.01 (s,
3.times.1/2H), 1.48 (s, 3.times.1/2H).
[0317] (28-4)
[0318] To a solution of the compound of Example 28-3 (2.72 g) in
chloroform (50 mL) was added manganese dioxide (22.3 g) under
nitrogen atmosphere, and the mixture was stirred at room
temperature. Further, to the mixture was added manganese dioxide
(total; 7.29 g), and the mixture was stirred at room temperature
for 7 hours. The reaction solution was filtered, and the solvent
was evaporated under reduced pressure to give
2-methyl-3-(2-bromo-6-nitrophenyl)propenal (2.53 g, 94%).
[0319] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 9.74 (s,
1.times.1/2H), 9.41 (s, 1.times.1/2H), 7.92-8.06 (m, 2H), 7.43-7.47
(m, 2H), 2.02 (s, 3.times.1/2H), 1.59 (s, 3.times.1/2H).
[0320] (28-5)
[0321] To a 20% aqueous titanium trichloride solution (10.8 g) was
added water (10 mL) under nitrogen atmosphere, and the mixture was
cooled to 0.degree. C., and thereto was added dropwise a solution
of the compound of Example 28-4 (540 mg) in ethanol (20 mL). The
mixture was stirred at room temperature for one hours, and heated
under reflux for 3 hours. To the reaction solution was added a
saturated aqueous sodium hydrogen carbonate solution for
neutralization, and the mixture was extracted three times with
ethyl acetate. The extract was washed with a saturated aqueous
sodium hydrogen carbonate solution and a saturated brine, dried
over magnesium sulfate, filtered, and the solvent was evaporated
under reduced pressure. The residue was purified by silica gel
column (hexane/ethyl acetate=3/1) to give 5-bromo-3-methylquinoline
(206 mg, 46%).
[0322] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.79 (d, 1H, J=2.2
Hz), 8.30 (d, 1H, J=2.2 Hz), 8.05 (d, 1H, J=8.2 Hz), 7.80 (d, 1H,
J=8.2 Hz), 7.50 (dd, 1H, J=8.2, 8.2 Hz), 2.59 (s, 3H).
[0323] (28-6)
[0324] To a solution of the compound of Example 28-5 (194 mg) in
carbon tetrachloride (5.0 mL) were added N-bromosuccinimide (156
mg) and 2,2'-azobis(isobutyronitrile) (16.3 mg) under nitrogen
atmosphere, and the mixture was heated under reflux for 2 hours.
The reaction solution was cooled to room temperature, and the
insoluble materials were removed by filtration. The solvent was
evaporated under reduced pressure to about 3 ml. Further, toluene
was added thereto, and the mixture was evaporated under reduced
pressure to about 3 mL. This procedure was repeated five times to
give a solution of a crude bromo compound in toluene.
[0325] Under nitrogen atmosphere, a solution of the compound of
Reference Example 1 (158 mg) in THF (5.0 mL) was cooled to
0.degree. C., and thereto was added 60% NaH (37.06 mg). Further,
thereto was added the solution of the crude bromo compound in
toluene, and the mixture was stirred at 50.degree. C. for 2 hours.
The reaction solution was cooled to room temperature, and water was
added to the mixture, and further extracted twice with ethyl
acetate. The extract was washed with water and a saturated brine,
dried over magnesium sulfate, filtered, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column (hexane/ethyl acetate=3/1.fwdarw.1/1) to give the
title compound (90.9 mg, 26%).
[0326] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (d, 1H, J=2.1
Hz), 8.20 (d, 1H, J=2.1 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.80 (d, 1H,
J=7.5 Hz), 7.70 (d, 2H, J=8.0 Hz), 7.53 (dd, 1H, J=7.5, 8.4 Hz),
7.23 (d, 2H, J=8.0 Hz), 7.11 (dd, 1H, J=1.7, 2.5 Hz), 6.86 (dd, 1H,
J=1.7, 4.0 Hz), 6.31 (dd, 1H, J=2.5, 4.0 Hz), 5.91 (s, 2H), 2.41
(s, 3H).
Example 29
[0327] 48
[0328] Under nitrogen atmosphere, to the compound of Example 28-5
(269 mg) and 60% zinc cyanide (243 mg) were added DMF (6.0 ml), and
P(PPh.sub.3).sub.4 (620 mg), and the mixture was stirred at
100.degree. C. for 2 hours. The reaction solution was cooled to
room temperature, and thereto was added a saturated aqueous sodium
hydrogen carbonate solution. The mixture was extracted three times
with ethyl acetate-toluene, and the extract was washed twice with a
saturated aqueous sodium hydrogen carbonate solution, and then
washed with a saturated brine, dried over magnesium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl acetate
3/1.fwdarw.2/1) to give 5-cyano-3-methylquinoline (190 mg,
93%).
[0329] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.90 (d, 1H, J=2.0
Hz), 8.30-8.33 (m, 2H), 7.96 (d, 1H, J=7.3 Hz), 7.71 (dd, 1H,
J=7.3, 7.3 Hz), 2.62 (s, 3H).
[0330] (29-2)
[0331] In a similar manner to Example 22-4, a solution (about 0.71
N) of a crude bromo compound in toluene was obtained from the
compound of Example 29-1, and the title compound (59.9 mg, 32%, 2
steps) was obtained from said solution (about 0.71 N) of the crude
bromo compound (750 .mu.l) and the compound of Reference Example 1
(91.7 mg).
[0332] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.90 (d, 1H, J=2.2
Hz), 8.32 (d, 1H, J=7.9 Hz), 8.13 (d, 1H, J=2.2 Hz), 7.95 (d, 1H,
J=7.9 Hz), 7.69-7.76 (m, 3H), 7.24 (d, 2H, J=7.9 Hz), 7.12 (dd, 1H,
J=1.7 and 2.6 Hz), 6.89 (dd, 1H, J=1.7 and 4.0 Hz), 6.34 (dd, 1H,
J=2.6 and 4.0 Hz), 5.93 (s, 2H), 2.41 (s, 3H).
Example 30
[0333] 49
[0334] In a similar manner to the preparation of the compound of
Example 25, the title compound (5.5 mg, 3.5%, 2 steps) was obtained
from a solution (about 0.71 N) of a crude bromo compound in toluene
(650 pL) obtained from the compound of Example 29-1 and the
compound of Reference Example 2 (66.9 mg).
[0335] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.57 (d, 1H, J=2.0
Hz), 8.29 (d, 1H, J=8.6 Hz), 7.94 (d, 1H, J=7.2 Hz), 7.78 (d, 1H,
J=2.0 Hz), 7.27 (dd, 1H, J=7.2 and 8.6 Hz), 6.90 (d, 2H, J=8.2 Hz),
6.85 (d, 2H, J=8.2 Hz), 6.72 (dd, 1H, J=1.8 and 3.0 Hz), 6.24 (dd,
1H, J=3.0 and 3.0 Hz), 6.12 (dd, 1H, J=1.8 and 3.0 Hz), 5.15 (s,
2H), 3.87 (s, 2H), 2.03 (s, 3H).
Example 31
[0336] 50
[0337] Under nitrogen atmosphere, to the compound of Example 29
(27.5 mg) was added t-butanol (3.0 mL), and the mixture was warmed
to 50.degree. C. To the mixture wad added potassium hydroxide
powder (140 mg), and the mixture was stirred at 50.degree. C. for
1.5 hour. The reaction solution was cooled to room temperature, and
the insoluble materials were removed by filtration. Water was added
to the filtrate, and the mixture was extracted with ethyl acetate.
The extract was washed with a saturated brine, dried over magnesium
sulfate, filtered, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column (ethyl
acetate) to give the title compound (5.0 mg, 17%).
[0338] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.79 (d, 1H, J=1.7
Hz), 8.32 (d, 1H, J=7.9 Hz), 8.13 (d, 1H, J=2.2 Hz), 7.95 (d, 1H,
J=7.9 Hz), 7.69-7.76 (m, 3H), 7.24 (d, 2H, J=7.9 Hz), 7.12 (dd, 1H,
J=1.7, 2.6 Hz), 6.89 (dd, 1H, J=1.7, 4.0 Hz), 6.34 (dd, 1H, J=2.6,
4.0 Hz), 5.93 (s, 2H), 2.41 (s, 3H).
Example 32
[0339] The title compound (5.5 mg, quantitatively) was obtained
from the compound of Example 30 (4.8 mg) in a similar manner to
Example 51
[0340] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.52 (d, 1H, J=2.2
Hz), 8.38 (d, 1H, J=2.2 Hz), 8.18 (d, 1H, J=8.4 Hz), 7.79 (d, 1H,
J=7.0 Hz), 7.68 (dd, 1H, J=7.0, 8.4 Hz), 6.95 (s, 4H), 6.69 (dd,
1H, J=1.8, 3.1 Hz), 6.18 (dd, 1H, J=3.1, 3.1 Hz), 6.03 (dd, 1H,
J=1.8, 3.1 Hz), 5.86 (brs, 2H), 5.10 (s, 2H), 3.85 (s, 2H), 2.17
(s, 3H).
Example 33
[0341] 52
[0342] Under nitrogen atmosphere, to a solution of
2-amino-4-chlorobenzald- ehyde (467 mg) in ethanol (10 mL) were
added propanal (250 .mu.L) and piperidine (50 .mu.l), and the
mixture was heated under reflux. Further, to the mixture were added
propanal (800 .mu.L) and piperidine (250 .mu.L) in several
portions, and the mixture was heated under reflux for total 9
hours. The solvent was evaporated under reduced pressure, and the
residue was purified by silica gel column (hexane/ethyl
acetate=6/1) to give 7-chloro-3-methylquinoline (401 mg, 75%).
[0343] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.77 (d, 1H, J=2.0
Hz), 8.06 (d, 1H, J=2.1 Hz), 7.90 (d, 1H, J=2.0 Hz), 6.68 (d, 1H,
J=8.7 Hz), 7.47 (dd, 1H, J=2.1, 8.7 Hz), 2.51 (s, 3H).
[0344] (33-2)
[0345] Under nitrogen atmosphere, to a solution of the compound of
Example 33-1 (100 mg) in carbon tetrachloride (5.0 mL) were added
N-bromosuccinimide (105 mg) and 2,2'-azobis(isobutyronitrile) (11.8
mg), and the mixture was heated under reflux for 2 hours. The
reaction solution was cooled to room temperature, and the insoluble
materials were removed by filtration. The solvent was evaporated
under reduced pressure to about 1 mL. Then, to the resultant was
added toluene, and the mixture was evaporated under reduced
pressure to about 1 mL. This procedure was repeated three times to
give a solution of a crude bromo compound in toluene.
[0346] Under nitrogen atmosphere, the solution of the compound of
Reference Example 1 (89.4 mg) in THF (2.0 mL) was cooled to
0.degree. C., and thereto was added 60% NaH (20.6 mg). Further,
thereto was added the solution of the crude bromo compound in
toluene, and the mixture was stirred at 50.degree. C. for 2 hours.
The reaction solution was cooled to room temperature, and thereto
was added a saturated aqueous sodium hydrogen carbonate solution.
The mixture was extracted with ethyl acetate, dried over magnesium
sulfate, filtered, and the solvent was evaporated under reduced
pressure. The residue was purified by silica gel column
(hexane/ethyl acetate=3/1.fwdarw.2/1) to give the title compound
(54.7 mg, 31%).
[0347] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=1.7
Hz), 8.07 (d, 1H, J=2.0 Hz), 7.90 (d, 1H, J=1.7 Hz), 7.69 (d, 1H,
J=8.7 Hz), 7.67 (d, 2H, J=8.2 Hz), 7.47 (dd, 1H, J=2.0, 8.7 Hz),
7.23 (d, 2H, J=8.2 Hz), 7.11 (dd, 1H, J=1.7, 2.5 Hz), 6.84 (dd, 1H,
J=1.7, 4.0 Hz), 6.29 (dd, 1H, J=2.5, 4.0 Hz), 5.83 (s, 2H), 2.41
(s, 3H).
Example 34
[0348] 53
[0349] In a similar manner to the preparation of the compound of
Example 33-1,6-bromo-3-methylquinoline (1.04 g, 75%) was obtained
from 2-amino-5-bromobenzaldehyde (1.25 g).
[0350] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.77 (d, 1H, J=2.0
Hz), 7.93 (d, 1H, J=9.0 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.83 (d, 1H,
J=2.0 Hz), 7.71 (dd, 1H, J=2.2, 9.0 Hz), 2.53 (s, 3H).
[0351] (34-2)
[0352] Under nitrogen atmosphere, to a solution of the compound of
Example 34-1 (150 mg) in monochlorobenzene (5.0 mL) were added
N-bromosuccinimide (123 mg) and 2,2'-azobis(isobutyronitrile) (13.1
mg), and the mixture was stirred at 110.degree. C. for 2 hours. The
solvent in the reaction solution was evaporated under reduced
pressure to about a half volume thereof, and thereto was added
toluene-hexane. The insoluble materials were removed by filtration,
and the filtrate was evaporated under reduced pressure to about 2
mL to a solution of the crude bromo compound in toluene.
[0353] Under nitrogen atmosphere, a solution of the compound of
Reference Example 1 (59.4 mg) in THF (1.5 mL) was cooled to
0.degree. C., and thereto was added 60% NaH (15.9 mg). To the
mixture was added the solution of the crude bromo compound in
toluene, and the mixture was stirred at 50.degree. C. for 4 hours.
The reaction solution was cooled to room temperature, and thereto
was added water. The mixture was extracted with ethyl acetate, and
the extract was dried over magnesium sulfate, filtered, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column (hexane/ethyl acetate=3/1.fwdarw.2/1)
to give the title compound (62.5 mg, 48%).
[0354] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 7.93 (d, 1H, J=9.1 Hz), 7.91 (d, 1H, J=2.2 Hz), 7.78 (d, 1H,
J=2.2 Hz), 7.73 (dd, 1H, J=2.2, 9.1 Hz), 7.67 (d, 2H, J=8.1 Hz),
7.23 (d, 2H, J=8.1 Hz), 7.10 (dd, 1H, J=1.7, 2.6 Hz), 6.84 (dd, 1H,
J=1.7, 4.1 Hz), 6.29 (dd, 1H, J=2.6, 4.1 Hz), 5.84 (s, 2H), 2.41
(s, 3H).
Example 35
[0355] 54
[0356] In a similar manner to the preparation of the compound of
Example 33-1,8-chloro-3-methylquinoline (1.09 g, 95%) was obtained
from 2-amino-3-chlorobenzaldehyde (1.00 g).
[0357] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.90 (d, 1H, J=2.2
Hz), 7.95 (d, 1H, J=2.2 Hz), 7.77 (dd, 1H, J=1.6, 7.5 Hz), 7.68
(dd, 1H, J=1.6, 7.5 Hz), 7.43 (dd, 1H, J=7.5, 7.5 Hz), 2.55 (s,
3H).
[0358] (35-2)
[0359] In a similar manner to the preparation of the compound of
Example 33, the title compound (92.4 mg, 69%) was obtained from the
compound of Example 35-1 (134 mg) and the compound of Reference
Example 1 (69.0 mg).
[0360] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.89 (d, 1H, J=2.2
Hz), 7.97 (d, 1H, J=2.2 Hz), 7.80 (dd, 1H, J=1.3, 7.7 Hz),
7.65-7.71 (m, 3H), 7.44 (dd, 1H, J=7.7, 7.7 Hz), 7.22 (d, 2H, J=8.1
Hz), 7.11 (dd, 1H, J=1.7, 2.6 Hz), 6.84 (dd, 1H, J=1.7, 4.0 Hz),
6.29 (dd, 1H, J=2.6, 4.0 Hz), 5.87 (s, 2H), 2.41 (s, 3H).
Example 36
[0361] 55
[0362] Under nitrogen atmosphere, to the compound of Example 34-2
(50.0 mg) and 60% zinc cyanide (38.6 mg) were added DMF (11.0 mL)
and P(PPh.sub.3).sub.4 (63.1 mg), and the mixture was stirred at
100.degree. C. for 2 hours. The reaction solution was cooled to
room temperature, and thereto was added a saturated aqueous sodium
hydrogen carbonate solution. The mixture was extracted three times
with ethyl acetate-toluene, and the extract was washed twice with a
saturated aqueous sodium hydrogen carbonate solution, dried over
magnesium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1.fwdarw.1/1) to give the title compound
(37.3 mg, 86%).
[0363] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.94 (d, 1H, J=2.2
Hz), 8.14-8.17 (m, 2H), 7.90 (d, 1H, J=2.2 Hz), 7.81 (dd, 1H,
J=1.7, 8.8 Hz), 7.66 (d, 2H, J=7.9 Hz), 7.23 (d, 2H, J=7.9 Hz),
7.13 (dd, 1H, J=1.7, 2.6 Hz), 6.87 (dd, 1H, J=1.7, 4.0 Hz), 6.32
(dd, 1H, J=2.6, 4.0 Hz), 5.86 (s, 2H), 2.41 (s, 3H).
Example 37
[0364] 56
[0365] Under nitrogen atmosphere, to the compound of Example 33
(39.5 mg) and 60% zinc cyanide (30.4 mg) were DMF (1.0 mL),
bis(dibenzilidenacetone- )palladium (0) (32.5 mg) and a 2.47N
solution of tri-t-butylphosphine in toluene (100 .mu.L), and the
mixture was stirred at 120.degree. C. for 5 hours. The reaction
solution was filtered to remove the insoluble materials, and to the
filtrate was added a saturated aqueous sodium hydrogen carbonate
solution. The mixture was extracted twice with ethyl
acetate-toluene, and the extract was washed twice with a saturated
aqueous sodium hydrogen carbonate solution, and washed with a
saturated brine, dried over magnesium sulfate, and filtered. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.2/1.fwdarw.1/1) to give the title compound (33.8
mg, 88%).
[0366] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.90 (d, 1H, J=2.2
Hz), 8.44 (s, 1H), 7.91 (d, 1H, J=2.2 Hz), 7.85 (d, 1H, J=8.4 Hz),
7.65-7.67 (m, 3H), 7.23 (d, 2H, J=7.9 Hz), 7.13 (dd, 1H, J=1.7, 2.6
Hz), 6.87 (dd, 1H, J=1.7, 4.0 Hz), 6.32 (dd, 1H, J=2.6, 4.0 Hz),
5.86 (s, 2H), 2.41 (s, 3H).
Example 38
[0367] 57
[0368] In a similar manner to the preparation of the compound of
Example 37, the title compound (32.3 mg, 55%) was obtained from the
compound of Example 35 (60.0 mg), while the purification was
carried out as follows. That is, after the purification of silica
gel column, the product was suspended in ethyl acetate, and the
precipitates were collected by filtration, and dried.
[0369] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.93 (d, 1H, J=2.2
Hz), 8.09 (dd, 1H, J=1.2, 7.6 Hz), 8.00-8.03 (m, 2H), 7.66 (d, 2H,
J=8.1 Hz), 7.58 (dd, 1H, J=7.6, 7.6 Hz), 7.23 (d, 2H, J=8.1 Hz),
7.14 (dd, 1H, J=1.7, 2.6 Hz), 6.86 (dd, 1H, J=1.7, 4.0 Hz), 6.31
(dd, 1H, J=2.6, 4.0 Hz), 5.87 (s, 2H), 2.41 (s, 3H).
Example 39
[0370] 58
[0371] Under nitrogen atmosphere, t-butanol (5.0 mL) was added to
the compound of Example 36 (30.0 mg), and the mixture was warmed to
50.degree. C. Potassium hydroxide powder (150 mg) was added
thereto, and the mixture was stirred at 50.degree. C. for 1 hour.
The reaction solution was cooled to room temperature, and filtered
to remove the insoluble materials. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(ethyl acetate.fwdarw.ethyl acetate/ethanol=20/1) to give the title
compound (29.3 mg, 93%).
[0372] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.88 (d, 1H,
J=2.2 Hz), 8.45 (d, 1H, J=1.9 Hz), 8.16 (brs, 1H), 8.14 (dd, 1H,
J=1.9, 8.8 Hz), 8.03 (d, 1H, J=8.8 Hz), 7.98 (d, 1H, J=2.2 Hz),
7.59-7.62 (m, 3H), 7.55 (brs, 1H), 7.28 (d, 2H, J=7.9 Hz), 6.79
(dd, 1H, J=1.7, 4.0 Hz), 6.34 (dd, 1H, J=2.5, 4.0 Hz), 5.86 (s,
2H), 2.36 (s, 3H).
Example 40
[0373] 59
[0374] In a similar manner to the preparation of the compound of
Example 39, the title compound (15.7 mg, 59%) was obtained from the
compound of Example 37 (25.5 mg).
[0375] .sup.1H NMR (DMSO-d.sub.6, 300 MHz) .delta. 8.85 (d, 1H,
J=2.0 Hz), 8.54 (s, 1H), 8.26 (brs, 1H), 7.97-8.03 (m, 3H),
7.58-7.61 (m, 4H), 7.28 (d, 2H, J=7.9 Hz), 6.78 (dd, 1H, J=1.7, 3.9
Hz), 6.34 (dd, 1H, J=2.6, 3.9 Hz), 5.85 (s, 2H), 2.36 (s, 3H).
Example 41
[0376] 60
[0377] Under nitrogen atmosphere, t-butanol (4.0 mL) and THF (3.0
mL) were added to the compound of Example 38 (24.3 mg), and the
mixture was warmed to 50.degree. C. Potassium hydroxide powder (120
mg) was added thereto, and the mixture was stirred at 50.degree. C.
for 15 hours. The reaction solution was cooled to room temperature,
and filtered to remove the insoluble materials, which was duly
washed with THF. The solvent in the filtrate was evaporated under
reduced pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=1/1.fwdarw.0/1) to give the title compound
(24.2 mg, 95%).
[0378] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 10.04 (brs, 1H),
8.92 (d, 1H, J=2.3 Hz), 8.51 (dd, 1H, J=1.5, 7.5 Hz), 8.13-8.16 (m,
2H), 7.90 (brs, 1H), 7.70 (dd, 1H, J=7.5, 7.5 Hz), 7.59-7.62 (m,
3H), 7.28 (d, 2H, J=7.9 Hz), 6.79 (dd, 1H, J=1.6, 4.0 Hz), 6.34
(dd, 1H, J=2.6, 4.0 Hz), 5.88 (s, 2H), 2.36 (s, 3H).
Example 42
[0379] 61
[0380] Under nitrogen atmosphere, to a solution of the compound of
Example 28-5 (300 mg) in toluene (3.5 mL)-ethanol (3.5 ml) were
added triethylamine (400 .mu.l), and dichlorobistriphenylphosphine
palladium (158 mg), and the mixture was stirred at 100.degree. C.
under carbon monoxide atmosphere. To the mixture were added
triethylamine (300 .mu.L), and dichlorobistriphenylphosphine
palladium (43.2 mg), and the mixture was stirred for total 10
hours. Water was added to the reaction solution, and the mixture
was extracted with ethyl acetate. The extract was dried over
magnesium sulfate, filtered, and the solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1) to give
5-ethoxycarbonyl-3-methylquinoline (100 mg, 34%). The starting
compound (150 mg, 50%) was recovered as well.
[0381] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.12 (d, 1H, J=2.0
Hz), 8.81 (d, 1H, J=2.0 Hz), 8.24-8.27 (m, 2H), 7.67 (dd, 1H,
J=7.4, 8.3 Hz), 4.47 (q, 2H, J=7.1 Hz), 2.57 (s, 3H), 1.47 (t, 3H,
J=7.1 Hz).
[0382] (42-2)
[0383] Under nitrogen atmosphere, to a solution of the compound of
Example 42-1 (93.0 mg) in monochlorobenzene (4.0 mL) were added
N-bromosuccinimide (79.7 mg) and 2,2'-azobis(isobutyronitrile) (9.6
mg), and the mixture was stirred at 100.degree. C. for 5 hours. The
solvent in the reaction solution was evaporated under reduced
pressure to about a half volume thereof, and thereto was added
toluene-hexane. The insoluble materials were removed by filtration,
and the solvent was evaporated under reduced pressure to about 2 ml
to give a solution of a crude bromo compound in toluene.
[0384] Under nitrogen atmosphere, a solution of the compound of
Reference Example 1 (79.3 mg) in THF (2.0 mL) was cooled to
0.degree. C., and thereto was added 60% NaH (17.9 mg). Further, to
the mixture was added the solution of crude bromo compound in
toluene, and the mixture was stirred at 50.degree. C. for 3 hours.
The mixture was cooled to room temperature, and the reaction
solution was poured into a 5% aqueous potassium hydrogen sulfate
solution, and the mixture was extracted with ethyl acetate. The
aqueous layer was neutralized with a saturated aqueous sodium
hydrogen carbonate solution, and extracted with ethyl acetate. The
organic layers were combined, dried over magnesium sulfate, and
filtered. The solvent was evaporated under reduced pressure
(hexane/ethyl acetate=3/1.fwdarw.2/1.fwdarw.1/1) to give
{1-[(5-ethoxycarbonyl-3-quinol- yl)methyl]-1H-pyrrol-2-yl}
(4-methylphenyl) ketone (50.6 mg, 29%).
[0385] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.10 (d, 1H, J=2.1
Hz), 8.82 (d, 1H, J=2.1 Hz), 8.24-8.28 (m, 2H), 7.70 (dd, 1H,
J=7.4, 8.3 Hz), 7.70 (d, 2H, J=8.0 Hz), 7.22 (d, 2H, J=8.0 Hz),
7.11 (dd, 1H, J=1.7, 2.5 Hz), 6.85 (dd, 1H, J=1.7, 4.0 Hz), 6.29
(dd, 1H, J=2.5, 4.0 Hz), 5.90 (s, 2H), 4.43 (q, 2H, J=7.1 Hz), 2.41
(s, 3H), 1.42 (t, 3H, J=7.1 Hz).
Example 43
[0386] 62
[0387] Under nitrogen atmosphere, to the compound of Example 42
(45.0 mg) are added acetic acid (2.0 mL), water (1.0 mL) and conc.
hydrochloric acid (1.0 mL), and the mixture was stirred at
100.degree. C. for 4 hours. Toluene was added to the mixture, and
the solvent was evaporated under reduced pressure to give the title
compound (60.8 mg, quantitatively).
[0388] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 9.85 (s, 1H), 9.27
(s, 1H), 8.63 (d, 1H, J=7.6 Hz), 8.38 (d, 1H, J=8.4 Hz), 8.17 (dd,
1H, J=7.6, 8.4 Hz), 7.62 (d, 2H, J=8.0 Hz), 7.51 (dd, 1H, J=1.5,
2.6 Hz), 7.26 (d, 2H, J=8.0 Hz), 6.94 (dd, 1H, J=1.5, 4.0 Hz), 6.42
(dd, 1H, J=2.6, 4.0 Hz), 6.00 (s, 2H), 2.39 (s, 3H).
Example 44
[0389] 63
[0390] Under nitrogen atmosphere, to a solution of the compound of
Example 43 (13.1 mg) in DMF (0.65 mL) were added successively
morpholine (10 .mu.L), 1-hydroxybenzotriazole (7.2 mg),
1-(3-dimethylaminopropyl)-3-ethy- lcarbodiimide hydrochloride (12.9
mg), and triethylamine (15 .mu.L), and the mixture was stirred at
room temperature for 15 hours. To the reaction solution was added a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted with ethyl acetate-toluene. The extract was
washed twice with a saturated aqueous sodium hydrogen carbonate
solution, and washed with a saturated brine, dried over magnesium
sulfate, and filtered. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column (ethyl
acetate) to give the title compound (2.4 mg, 17%).
[0391] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87 (d, 1H, J=2.1
Hz), 8.12 (d, 1H, J=8.5 Hz), 7.88 (d, 1H, J=2.1 Hz), 7.70 (dd, 1H,
J=7.0, 8.5 Hz), 7.67 (d, 2H, J=8.1 Hz), 7.47 (d, 1H, J=7.0 Hz),
7.23 (d, 2H, J=8.1 Hz), 7.13 (dd, 1H, J=1.6, 2.5 Hz), 6.86 (dd, 1H,
J=1.6, 4.0 Hz), 6.31 (dd, 1H, J=2.5, 4.0 Hz), 5.83 (m, 2H),
3.68-3.97 (m, 4H), 3.23-3.41 (m, 2H), 2.96-3.11 (m, 2H), 2.40 (s,
3H).
Example 45
[0392] 64
[0393] In a similar manner to the preparation of the compound of
Example 44, the title compound (10.0 mg, 69%) was obtained from the
compound of Example 43 (13.1 mg) and N-methylpiperazine (5.7
mg).
[0394] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.85 (d, 1H, J=2.1
Hz), 8.13 (d, 1H, J=8.4 Hz), 7.92 (brs, 1H), 7.70 (dd, 1H, J=7.1,
8.4 Hz), 7.63 (brd, 2H, J=7.9 Hz), 7.47 (d, 1H, J=7.1 Hz), 7.22 (d,
2H, J=7.9 Hz), 7.13 (brs, 1H), 6.83 (dd, 1H, J=1.5, 4.0 Hz), 6.30
(dd, 1H, J=2.6, 4.0 Hz), 5.82 (m, 2H), 2.23-3.79 (m, 8H), 2.41 (s,
3H), 2.33 (brs, 3H).
Example 46
[0395] 65
[0396] In a similar manner to the preparation of the compound of
Example 44, the title compound (11.9 mg, 93%) was obtained from the
compound of Example 43 (13.1 mg) and dimethylamine hydrochloride
(12.0 mg).
[0397] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (d, 1H, J=2.2
Hz), 8.18 (brd, 1H, J=8.4 Hz), 7.93 (brs, 1H), 7.72 (dd, 1H, J=7.1,
8.4 Hz), 7.66 (d, 2H, J=8.0 Hz), 7.52 (d, 1H, J=7.1 Hz), 7.23 (d,
2H, J=8.0 Hz), 7.09 (dd, 1H, J=1.7, 2.5 Hz), 6.85 (dd, 1H, J=1.7,
4.0 Hz), 6.29 (dd, 1H, J=2.5, 4.0 Hz), 5.84 (s, 2H), 3.18 (s, 3H),
2.69 (s, 3H), 2.41 (s, 3H).
Example 47
[0398] 66
[0399] In a similar manner to the preparation of the compound of
Example 44, the title compound (4.4 mg, 36%) was obtained from the
compound of Example 43 (13.1 mg) and methylamine hydrochloride
(37.0 mg).
[0400] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.74 (d, 1H, J=1.9
Hz), 8.59 (d, 1H, J=1.9 Hz), 8.13 (d, 1H, J=8.2 Hz), 7.69 (d, 2H,
J=8.0 Hz), 7.60-7.67 (m, 2H), 7.23 (d, 2H, J=8.0 Hz), 7.10 (dd, 1H,
J=1.7, 2.5 Hz), 6.84 (dd, 1H, J=1.7, 4.0 Hz), 6.28 (dd, 1H, J=2.5,
4.0 Hz), 6.17 (brs, 2H), 5.84 (s, 2H), 3.06 (d, 3H, J=4.9 Hz), 2.41
(s, 3H).
Example 48
[0401] 67
[0402] Under nitrogen atmosphere, to a solution of the compound of
Example 28 (41.2 mg) and 3-diethylamino-1-propine (30 .mu.L) in
triethylamine (0.9 mL) were added dichlorobistriphenylphosphine
palladium (14.6 mg) and cupper iodide (2.5 mg), and the mixture was
stirred at 70.degree. C. for 2.5 hours. To the mixture was added
water, and the mixture was extracted with ethyl acetate. The
extract was washed with a saturated aqueous sodium hydrogen
carbonate solution, dried over magnesium sulfate, and filtered. The
solvent was purified by silica gel column (ethyl
acetate.fwdarw.ethyl acetate/ethanol=10/1) and further purified by
silica gel column (chloroform/methanol=60/1.fwdarw.40/1) to give
the title compound (28.7 mg, 65%).
[0403] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.83 (d, 1H, J=2.1
Hz), 8.31 (d, 1H, J=2.1 Hz), 8.04 (d, 1H, J=8.4 Hz), 7.68 (d, 1H,
J=7.2 Hz), 7.68 (d, 2H, J=8.1 Hz), 7.60 (dd, 1H, J=7.2, 8.4 Hz),
7.23 (d, 2H, J=8.1 Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz), 6.83 (dd, 1H,
J=1.7, 4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.89 (s, 2H), 3.79
(s, 2H), 2.66-2.70 (brs, 4H), 2.41(s, 3H), 1.17 (t, 6H, J=7.1
Hz).
Example 49
[0404] 68
[0405] In a similar manner to the preparation of the compound of
Example 48, the title compound (23.4 mg, 67%) was obtained from the
compound of Example 28 (29.7 mg) and t-butyl 4-pentynate (32.6
mg).
[0406] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (d, 1H, J=2.1
Hz), 8.35 (brs, 1H), 8.05 (brd, 1H, J=7.5 Hz), 7.70 (d, 2H, J=8.0
Hz), 7.58-7.63 (m, 2H), 7.24 (d, 2H, J=8.0 Hz), 7.12 (dd, 1H,
J=1.7, 2.5 Hz), 6.85 (dd, 1H, J=1.7, 4.0 Hz), 6.29 (dd, 1H, J=2.5,
4.0 Hz), 5.91 (s, 2H), 2.77 (t, 2H, J=7.4 Hz), 2.59 (t, 2H, J=7.4
Hz), 2.41 (s, 3H), 1.48 (s, 9H).
Example 50
[0407] 69
[0408] Under nitrogen atmosphere, to the compound of Example 49
(17.4 mg) was added a 4N solution of hydrochloric acid in dioxane
(1.0 mL), and the the mixture was stirred at 50.degree. C. for 8
hours. To the reaction solution was added toluene, and the solvent
was evaporated 20 under reduced pressure to give the title compound
(14.3 mg, 86%).
[0409] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.00 (s, 1H),
8.33 (s, 1H), 8.08 (d, 1H, J=8.0 Hz), 7.87 (dd, 1H, J=8.0, 8.0 Hz),
7.60-7.62 (m, 3H), 7.29 (d, 2H, J=7.7 Hz), 6.78 (s, 1H), 6.32 (s,
1H), 5.86 (m, 3H), 2.83 (t, 2H, J=6.5 Hz), 2.40 (t, 2H, J=6.5 Hz),
2.37 (s, 3H).
Example 51
[0410] 70
[0411] Methyl 2-amino-3-formylbenzoate was obtained according to
the methods disclosed in J. Med. Chem., 40, 2040 (1997) and Synth.
Commun., 29, 4223 (1999).
[0412] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.88 (s, 1H), 8.41
(brs, 2H), 8.14 (t, 1H, J=7.7 Hz), 7.67 (t, 1H, J=7.7 Hz), 6.70 (t,
1H, J=7.7 Hz), 3.89 (s, 3H).
[0413] (51-2)
[0414] Under nitrogen atmosphere, to a solution of methyl
2-amino-3-formylbenzoate (3.00 g) in methanol (80 ml) were added
propanal (1.50 mL) and piperidine (800 .mu.L), and the mixture was
heated under reflux. To the mixture were further added propanal
(700 .mu.L) and piperidine (400 .mu.L), and the mixture was further
heated under reflux for total 4 hours. The solvent in the reaction
solution was evaporated under reduced pressure, and water was added
to the residue. The mixture was extracted with ethyl acetate, and
the extract was washed twice with water, and washed with a
saturated brine, dried over magnesium sulfate, and filtered. The
solvent was evaporated under reduced pressure, and the residue was
purified twice by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.2/1.fwdarw.1/1) and silica gel column
(hexane/ethyl acetate=3/1.fwdarw.2/1) to give
3-methyl-8-methoxycarbonylquinoline (2.21 g, 66%).
[0415] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.93 (d, 1H, J=2.1
Hz), 8.00 (dd, 1H, J=1.2, 7.2 Hz), 7.96 (d, 1H, J=2.1 Hz), 7.89
(dd, 1H, J=1.2, 8.2 Hz), 7.54 (dd, 1H, J=7.2, 8.2 Hz), 4.06 (s,
3H), 2.54 (s, 3H).
[0416] (51-3)
[0417] Under nitrogen atmospher, to a solution of the compound of
Example 51-2 (2.11 g) in monochlorobenzene (60 ml) were added
N-bromosuccinimide (1.87 g) and 2,2'-azobis(isobutyronitrile) (144
mg), and the mixture was stirred at 100.degree. C. for 2 hours. The
solvent in the reaction solution was evaporated under reduced
pressure to about 20 mL, and thereto was added toluene-hexane, and
the insoluble materials were removed by filtration to about 20 ml
to give a solution of a crude bromo compound.
[0418] Under nitrogen atmosphere, the solution of the compound of
Reference Example 1 (1.94 g) in THF(30 ml) was cooled to 0.degree.
C., and thereto was added 60% NaH (440 mg). Thereto was added the
solution of the crude bromo compound, and the mixture was further
stirred at 50.degree. C. for 2 hours. The mixture was cooled to
room temperature, and poured into a 5% aqueous potassium hydrogen
sulfate solution, and the mixture was made weak basic by addition
of sodium hydrogen carbonate thereto. The mixture was extracted
twice with ethyl acetate, and the extract was washed with water and
a saturated brine, and dried over magnesium sulfate, and filtered.
The solvent was purified by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.2/1.fwdarw.3/2) to give the title compound (1.40
g, 35%). The starting compound (686 mg, 33%) was also
recovered.
[0419] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.95 (d, 1H, J=2.0
Hz), 8.02-8.04 (m, 2H), 7.91 (d, 1H, J=7.9 Hz), 7.66 (d, 2H, J=7.8
Hz), 7.55 (dd, 1H, J=7.9, 7.9 Hz), 7.22 (d, 2H, J=7.8 Hz), 7.11
(brs, 1H), 6.82 (dd, 1H, J=1.1, 2.8 Hz), 6.27 (dd, 1H, J=2.8, 3.3
Hz), 5.86 (s, 2H), 4.04 (s, 3H), 2.40 (s, 3H).
Example 52
[0420] 71
[0421] Under nitrogen atmosphere, to the compound of Example 51
(1.74 g) were added successively methanol (4.1 mL), THF (4.1 ml)
and 1N aqueous NaOH solution (4.07 mL), and the mixture was stirred
at 45.degree. C. for 2 hours. The reaction solution was cooled to
room temperature, and the precipitated solid was suspended in
ether, and collected by filtration to give the title compound (1.67
g, 94%).
[0422] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.71 (d, 1H,
J=2.2 Hz), 7.88 (d, 1H, J=2.2 Hz), 7.56-7.63 (m, 4H), 7.38-7.43 (m,
2H), 7.27 (d, 2H, J=7.9 Hz), 6.74 (dd, 1H, J=1.6, 4.0 Hz), 6.30
(dd, 1H, J=2.6, 4.0 Hz), 5.81 (s, 2H), 2.36 (s, 3H).
Example 53
[0423] 72
[0424] Under nitrogen atmosphere, to a suspension of the compound
of Example 52 (30.0 mg) in THF (1.0 mL) was added pivaloyl chloride
(10 .mu.L), and the mixture was stirred at room temperature for 3
hours. To the mixture were added diethylamine hydrochloride (12.4
mg) and triethylamine (30 .mu.L), and the mixture was stirred at
room temperature. Further, thereto were added diethylamine
hydrochloride (16.5 mg) and triethylamine (40 .mu.l), and the
mixture was stirred for 4.5 hours. Water was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
extract was washed with a saturated aqueous sodium hydrogen
carbonate solution and a saturated brine, dried over magnesium
sulfate, and filtered. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column (ethyl
acetate/ethanol=1/0.fwdarw.20/1) to give the title compound (21.2
mg, 70%).
[0425] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.0
Hz), 7.97 (d, 1H, J=2.0 Hz), 7.79 (dd, 1H, J=1.4, 8.1 Hz), 7.67 (d,
2H, J=8.0 Hz), 7.63 (dd, 1H, J=1.4, 7.1 Hz), 7.54 (dd, 1H, J=7.1,
8.1 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.09 (dd, 1H, J=1.6, 2.6 Hz), 6.83
(dd, 1H, J=1.6, 4.0 Hz), 6.27 (dd, 1H, J=2.6, 4.0 Hz), 5.85 (s,
2H), 3.26 (s, 3H), 2.78 (s, 3H), 2.41 (s, 3H).
Example 54
[0426] 73
[0427] Under nitrogen atmosphere, to a suspension of the compound
of Example 52 (30.0 mg) in THF (1.0 ml) was added pivaloyl chloride
(10 .mu.L), and the mixture was stirred at room temperature for 2
hours. To the mixture was added morpholine (25 .mu.L), and the
mixture was at room temperature overnight. To the reaction solution
was added a saturated aqueous sodium hydrogen carbonate solution,
and the mixture was extracted with ethyl acetate. The extract was
washed with a saturated brine, dried over magnesium sulfate, and
filtered. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (ethyl
acetate/ethanol=1/0.fwdarw.20/1) to give the title compound (22.5
mg, 67%).
[0428] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (s, 1H), 7.94
(s, 1H), 7.80 (dd, 1H, J=1.3, 8.1 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.64
(dd, 1H, J=1.3, 7.1 Hz), 7.54 (dd, 1H, J=7.1, 8.1 Hz), 7.23 (d, 2H,
J=8.0 Hz), 7.10 (dd, 1H, J=1.6, 2.6 Hz), 6.84 (dd, 1H, J=1.6, 4.0
Hz), 6.29 (dd, 1H, J=2.6, 4.0 Hz), 5.85 (s, 2H), 3.85-3.96 (m, 4H),
3.55 (m, 2H), 3.13-3.16 (m, 2H), 2.41 (s, 3H).
Example 55
[0429] 74
[0430] In a similar manner to the preparation of the compound of
Example 54, the title compound (22.2 mg, 68%) was obtained from the
compound of Example 52 (30.0 mg) and 2-methylaminoethanol, except
that the purification of the product was carried out by silica gel
column (chloroform/methanol=40/1.fwdarw.30/1).
[0431] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (d, 1H, J=1.9
Hz), 8.03 (d, 1H, J=1.9 Hz), 7.82 (dd, 1H, J=1.2, 8.2 Hz), 7.75
(dd, 1H, J=1.2, 7.0 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.58 (dd, 1H,
J=7.0, 8.2 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.11 (dd, 1H, J=1.5, 2.6
Hz), 6.84 (dd, 1H, J=1.5, 4.0 Hz), 6.29 (dd, 1H, J=2.6, 4.0 Hz),
5.83 (s, 2H), 4.00 (m, 2H), 3.80 (t, 1H, J=5.1 Hz), 3.55 (t, 1H,
J=5.1 Hz), 2.78 (s, 3H), 2.41 (s, 3H).
Example 56
[0432] 75
[0433] In a similar manner to the preparation of the compound of
Example 54, the title compound (24.4 mg, 70%) was obtained from the
compound of Example 52 (30.0 mg) and 1-methylpiperazine, provided
that the purification of the product was carried out by silica gel
column (chloroform/methanol=30/1.fwdarw.20/1).
[0434] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 7.92 (d, 1H, J=2.2 Hz), 7.78 (dd, 1H, J=1.4, 8.1 Hz), 7.67 (d,
2H, J=8.0 Hz), 7.62 (dd, 1H, J=1.4, 7.1 Hz), 7.53 (dd, 1H, J=7.1,
8.1 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.10 (dd, 1H, J=1.6, 2.6 Hz), 6.83
(dd, 1H, J=1.6, 4.0 Hz), 6.28 (dd, 1H, J=2.6, 4.0 Hz), 5.89 (d, 1H,
J=15.5 Hz), 5.80 (d, 1H, J=15.5 Hz), 4.00 (m, 2H), 3.68 (m, 1H),
3.18-3.20 (m, 2H), 2.67-2.72 (m, 1H), 2.51-2.54 (m, 1H), 2.41 (s,
3H), 2.34 (s, 3H), 2.23 (m, 3H).
Example 57
[0435] 76
[0436] In a similar manner to the preparation of methyl
2-amino-3-formylbenzoate, 2-amino-3-bromobenzaldehyde (3.28 g,
quantitatively) was obtained from (2-amino-3-bromophenyl)methanol
(3.27 g).
[0437] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.83 (s, 1H), 7.62
(dd, 1H, J=1.5, 7.7 Hz), 7.48 (dd, 1H, J=1.5, 7.7 Hz), 6.67 (t, 1H,
J=7.7 Hz).
[0438] (57-2)
[0439] In a similar manner to Example
51-2,8-bromo-3-methylquinoline (3.23 g, 94%) was obtained from the
compound of Example 57-1 (3.10 g).
[0440] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.90 (d, 1H, J=1.5
Hz), 7.99 (dd, 1H, J=1.2, 7.5 Hz), 7.94 (d, 1H, J=1.5 Hz), 7.73
(dd, 1H, J=1.2, 8.2 Hz), 7.38 (dd, 1H, J=7.5, 8.2 Hz), 2.56 (s,
3H).
[0441] (57-3)
[0442] Under nitrogen atmosphere, to a solution of the compound of
Example 57-2 (1.01 g) in carbon tetrachloride (25 mL) were added
N-bromosuccinimide (810 mg) and 2,2'-azobis(isobutyronitrile) (68.0
mg), and the mixture was heated under reflux for 2 hours. The
reaction solution was cooled to room temperature, and the insoluble
materials were removed by filtration, and the solvent in the
filtrate was evaporated under reduced pressure to about 10 ml. To
the resultant was added toluene, and the mixture was evaporated
under reduced pressure to about 10 ml. This procedure was repeated
total four times to give a solution of a crude bromo compound in
toluene.
[0443] Under nitrogen atmosphere, a solution of the compound of 20.
Reference Example 1 (844 mg) in THF (13 mL) was cooled to 0.degree.
C., and thereto was added 60% NaH (191 mg). Then, the above
solution of the crude bromo compound was added thereto, and the
mixture was stirred at 50.degree. C. for 6 hours. The reaction
solution was cooled to room temperature, and thereto was added
water. The mixture was extracted 25 three times with ethyl acetate,
and the extract was washed with water and a saturated brine, dried
over magnesium sulfate, and filtered. The solvent was evaporated
under reduced pressure, and the residue was purified by silica gel
column (hexane/ethyl acetate=8/1.fwdarw.3/1.fwdarw-
.hexane/acetone=2/1.fwdarw.1/1) to give the title compound (950 mg,
52%).
[0444] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.91 (d, 1H, J=2.1
Hz), 8.01-8.04 (m, 2H), 7.76 (dd, 1H, J=1.0, 8.1 Hz), 7.66 (d, 2H,
J=8.0 Hz), 7.39 (dd, 1H, J=7.5, 8.1 Hz), 7.23 (d, 2H, J=8.0 Hz),
7.11 (dd, 1H, J=1.6, 2.6 Hz), 6.84 (dd, 1H, J=1.6, 4.0 Hz), 6.29
(dd, 1H, J=2.6, 4.0 Hz), 5.87 (s, 2H), 2.41 (s, 3H).
Example 58
[0445] 77
[0446] Under nitrogen atmosphere, to the compound of Example 57
(45.0 mg) and 3-diethylamino-1-propine (30 .mu.L) were added
triethylamine (1.0 ml) and THF (1.0 ml), and thereto were added
dichlorobistriphenylphosphine palladium (17.7 mg) and cupper iodide
(3.5 mg), and the mixture was stirred at 45.degree. C. for 4 hours,
and then stirred at 50.degree. C. for 3 hours. To the reaction
solution was added a saturated aqueous sodium hydrogen carbonate
solution, and the mixture was extracted with ethyl acetate. The
extract was dried over magnesium sulfate, and filtered. The solvent
was evaporated under reduced pressure, and the residue was purified
by silica gel column (ethyl acetate.fwdarw.ethyl
acetate/ethanol=20/1.fwdarw.chloroform/methanol=20/1) to give the
title compound (19.1 mg, 40%).
[0447] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.88 (d, 1H, J=2.2
Hz), 7.97 (d, 1H, J=2.2 Hz), 7.86 (dd, 1H, J=1.2, 7.3 Hz), 7.73
(dd, 1H, J=1.2, 8.1 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.45 (dd, 1H,
J=7.3, 8.1 Hz), 7.22 (d, 2H, J=8.0 Hz), 7.10 (dd, 1H, J=1.6, 2.6
Hz), 6.82 (dd, 1H, J=1.6, 4.0 Hz), 6.27 (dd, 1H, J=2.6, 4.0 Hz),
5.85 (s, 2H), 3.89 (s, 2H), 2.80 (brs, 4H), 2.41 (s, 3H), 1.20 (t,
6H, J=7.1 Hz).
Example 59
[0448] 78
[0449] Under nitrogen atmosphere, to a mixture of the compound of
Example 57 (50.0 mg), bis(dibenzylideneacetone)palladium (14.1 mg)
and cesium carbonate (66.0 mg) were added dioxane (1.0 mL), t-butyl
acrylate (30 .mu.L) and a 2.47 N solution of tri-t-butylphosphine
in toluene (20 .mu.L), and the mixture was stirred at 100.degree.
C. for 3 hours. Water was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The extract was washed
with a saturated brine, dried over magnesium sulfate, and filtered.
The solvent was purified by silica gel column (ethyl
acetate/hexane=5/1.fwdarw.3/1) to give the title compound (48.6 mg,
87%).
[0450] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87 (d, 1H, J=2.2
Hz), 8.74 (d, 1H, J=16.2 Hz), 7.98 (d, 1H, J=2.2 Hz), 7.92 (dd, 1H,
J=1.0, 7.3 Hz), 7.79 (dd, 1H, J=1.0, 8.2 Hz), 7.67 (d, 2H, J=8.0
Hz), 7.53 (dd, 1H, J=7.3, 8.2 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.11
(dd, 1H, J=1.7, 2.5 Hz), 6.83 (dd, 1H, J=1.7, 4.0 Hz), 6.72 (d, 1H,
J=16.2 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.86 (s, 2H), 2.41 (s,
3H), 1.56 (s, 9H).
Example 60
[0451] 79
[0452] Under nitrogen atmosphere, to a solution of the compound of
Example 59 (19.0 mg) in dioxane (1.0 mL) was added a 4N solution of
hydrochloric acid in dioxane (0.7 mL), and the mixture was stirred
at 50.degree. C. for 5 hours. The solvent in the reaction solution
was evaporated under reduced pressure, and the precipitated solid
was collected by filtration, and dried to give the title compound
(17.9 mg, 98%).
[0453] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.88 (d, 1H,
J=2.2 Hz), 8.77 (d, 1H, J=16.3 Hz), 7.21 (d, 1H, J=7.3 Hz),
8.00-8.03 (m, 2H), 7.59-7.65 (m, 4H), 7.27 (d, 2H, J=7.9 Hz), 6.81
(d, 1H, J=16.3 Hz), 6.78 (dd, 1H, J=1.6, 4.0 Hz), 6.33 (dd, 1H,
J=2.6, 4.0 Hz), 5.86 (s, 2H), 2.36 (s, 3H).
Example 61
[0454] 80
[0455] Under nitrogen atmosphere, to a mixture of the compound of
Example 57 (50.0 mg), N,N-dimethylacrylamide (30 .mu.L),
bis(dibenzylideneacetone- )palladium (15.0 mg) and cesium carbonate
(67.6 mg) were added dioxane (1.0 mL) and a 2.47 N solution of
tri-t-butylphosphine in toluene (20 .mu.L), and the mixture was
stirred at 100.degree. C. for 3.5 hours. Water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The extract was washed with a saturated brine, dried over
magnesium sulfate, and filtered. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(ethyl acetate/hexane=1/1.fwdarw.1/3.fwdarw.0/1) to give the title
compound (44.6 mg, 86%).
[0456] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87 (d, 1H, J=2.2
Hz), 8.53 (d, 1H, J=15.6 Hz), 7.96 (d, 1H, J=2.2 Hz), 7.87 (dd, 1H,
J=1.2, 7.1 Hz), 7.74 (dd, 1H, J=1.2, 8.1 Hz), 7.67 (d, 2H, J=8.0
Hz), 7.51 (dd, 1H, J=7.1, 8.1 Hz), 7.49 (d, 1H, J=15.6 Hz), 7.22
(d, 2H, J=8.0 Hz), 7.12 (dd, 1H, J=1.7, 2.5 Hz), 6.83 (dd, 1H,
J=1.7, 4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.85 (s, 2H), 3.21
(s, 3H), 3.09 (s, 3H), 2.40 (s, 3H).
Example 62
[0457] 81
[0458] Under nitrogen atmosphere, a mixture of the compound of
Example 57 (76.8 mg), sodium t-butoxide (30.8 mg) and
bis(dibenzylideneacetone)palla- dium (18.9 mg) were added toluene
(1.0 mL) and a 2.47N solution of tri-t-butylphosphine in toluene
(20 .mu.L), and the mixture was stirred at 100.degree. C. for 9
hours. Water was added to the reaction solution, and the mixture
was extracted with ethyl acetate. The extract was washed with a
saturated brine, dried over magnesium sulfate, and filtered. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (ethyl acetate/hexane=3/1.fwdarw.2/1)
to give the title compound (12.8 mg, 17%).
[0459] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=1.8
Hz), 7.93 (d, 1H, J=1.8 z), 7.68 (d, 2H, J=8.0 Hz), 7.45 (dd, 1H,
J=1.5, 8.1 Hz), 7.40 (dd, 1H, J=7.4, 8.1 Hz), 7.31 (dd, 1H, J=1.5,
7.4 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.08 (dd, 1H, J=1.6, 2.6 Hz), 6.81
(dd, 1H, J=1.6, 4.0 Hz), 6.25 (dd, 1H, J=2.6, 4.0 Hz), 5.84 (s,
2H), 2.41 (s, 3H), 1.49 (s, 9H).
Example 63
[0460] 82
[0461] Under nitrogen atmosphere, to the compound of Example 62
(8.7 mg) were added toluene (0.5 mL) and a solution (500 .mu.L),
wherein trifluoroacetic acid (100 .mu.L) and
trifluoromethanesulfonic acid (110 .mu.L) were dissolved in toluene
(10 mL), and the mixture was stirred at room temperature for 30
minutes. The reaction solution was poured into a saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
with ethyl acetate. The extract was dried over magnesium sulfate,
and filtered. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column (ethyl
acetate/hexane=3/1.fwdarw.2/1) to give the title compound (2.4 mg,
32%).
[0462] .sup.1H NMR (CDCl.sub.3, 300 MHz) .delta. 8.68 (s, 1H), 7.99
(s, 1H), 7.67 (d, 2H, J=8.1 Hz), 7.45 (dd, 1H, J=8.0, 8.1 Hz), 7.23
(d, 2H, J=8.1 Hz), 7.17-7.30 (m, 2H), 7.11 (dd, 1H, J=1.7, 2.5 Hz),
6.84 (dd, 1H, J=1.7, 4.0 Hz), 6.29 (dd, 1H, J=2.5, 4.0 Hz), 5.85
(s, 2H), 2.41 (s, 3H).
Example 64
[0463] 83
[0464] The title compound was obtained in a similar manner to
Example 1 from 2-methylquinoxaline and the compound of Reference
Example 1.
[0465] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H),
8.00-8.10 (m, 2H), 7.70-7.80 (m, 2H), 7.71 (d, 2H, J=8.0 Hz), 7.25
(d, 2H, J=8.0 Hz), 7.19 (dd, 1H, J=2.5, 1.7 Hz), 6.86 (dd, 1H,
J=4.1, 1.7 Hz), 6.30 (dd, 1H, J=4.1, 2.5 Hz), 5.96 (s, 2H), 2.42
(s, 3H).
Example 65
[0466] 84
[0467] To a solution of 3-nitro-1,2-phenylenediamine (5.02 g) in
ethanol (500 mL) was added at 60.degree. C. a 40% aqueous solution
of pyruvic aldehyde (17.72 g). The reaction solution was refluxed
for 10 minutes, and thereto was added water (300 mL). The mixture
was cooled to room temperature, and concentrated under reduced
pressure. The precipitated crystals were collected by filtration,
washed with cold water, and dried under reduced pressure to give
2-methyl-8-nitroquinoxaline (4.17 g, 67%) as orange crystals.
[0468] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H), 8.30
(dd, 1H, J=8.4, 1.3 Hz), 8.10 (dd, 1H, J=7.5, 1.3 Hz), 7.77 (t, 1H,
J=8.1 Hz), 2.84 (s, 3H).
[0469] (65-2)
[0470] To a solution of 2-methyl-8-nitroquinoxaline (3.50 g) in
MeOH (350 mL) was added dropwise a 20% aqueous solution of titanium
trichloride (88.64 g) at 0.degree. C. After the addition, the
reaction solution was warmed to room temperature, and the mixture
was stirred for another hour, and then concentrated under reduced
pressure. The resultant was neutralized by addition of an aqueous
sodium carbonate solution, and the mixture was extracted five times
with ethyl acetate (200 mL). The organic layers were combined,
dried over magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (chloroform) to give 2-methyl-8-aminoquinoxalin- e
(2.27 g, 77%) as red oil.
[0471] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (s, 1H), 7.47
(t, 1H, J=7.5 Hz), 7.39 (dd, 1H, J=8.3, 1.3 Hz), 6.92 (dd, 1H,
J=7.3, 1.3 Hz), 4.95 (brs, 1H), 2.73 (s, 3H).
[0472] (65-3)
[0473] A mixture of 2-methyl-8-aminoquinoxaline (2.27 g), conc.
hydrochloric acid (7.87 g) and water (10 mL) was cooled to
0.degree. C., and vigorously stirred. To the mixture was added an
aqueous solution of sodium nitrite (1.03 g) in water (10 mL) in
such a manner that the temperature of the mixture was not raised
over 5.degree. C. After the addition, the mixture was further
stirred for 10 minutes, and thereto was added slowly a solution of
KI, which was prepared by dissolving KI (2.37 g) in water (10 mL)
in such a manner that that the temperature of the reaction mixture
was not raised over 5.degree. C. After the addition, the mixture
was stirred for 10 minutes, and the reaction solution was warmed to
room temperature, and further stirred for one hour. The reaction
solution was neutralized with a 2N NaOH, and extracted twice with
chloroform. The organic layers were combined, dried over magnesium
sulfate, filtered, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography
(hexane/ethyl acetate=10/1) to give 2-methyl-8-iodoquinoxaline (743
mg, 19%) as pale brown solid.
[0474] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (s, 1H), 8.34
(dd, 1H, J=7.5, 1.3 Hz), 8.07 (dd, 1H, J=8.3, 1.1 Hz), 7.44 (t, 1H,
J=7.7 Hz), 2.86 (s, 3H).
[0475] (65-4)
[0476] A suspension of 2-methyl-8-iodoquinoxaline (730 mg),
Zn(CN).sub.2 (423 mg) and Pd(PPh.sub.3).sub.4 (313 mg) in DMF (5
mL) was stirred at 60.degree. C. for 5 hours. The reaction solution
was cooled, and thereto was added water (10 mL), and the mixture
was extracted twice with a mixture of toluene and ethyl acetate
(1:1) (50 mL). The organic layers were combined, dried over
magnesium sulfate, filtered, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=5/1.fwdarw.4/1) to give
2-methyl-8-cyanoquinoxaline (422 mg, 93%) as red brown solid.
[0477] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.86 (s, 1H), 8.32
(dd, 1H, J=8.4, 1.3 Hz), 8.15 (dd, 1H, J=7.3, 1.3 Hz), 7.77 (dd,
1H, J=8.3, 7.3 Hz), 2.88 (s, 3H).
[0478] (65-5)
[0479] The title compound was obtained in a similar manner to
Example 1 from the compound of Example 65-4 and the compound of
Reference Example 1.
[0480] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.84 (s, 1H), 8.33
(dd, 1H, J=8.4, 1.3 Hz), 8.15 (dd, 1H, J=7.3, 1.5 Hz), 7.80 (dd,
1H, J=8.6, 7.3 Hz), 7.72 (d, 2H, J=8.1 Hz), 7.25 (m, 3H), 6.89 (dd,
1H, J=4.0, 1.7 Hz), 6.33 (dd, 1H, J=4.0, 2.8 Hz), 6.01 (s, 2H),
2.42 (s, 3H).
Example 66
[0481] 85
[0482] To a solution of 3-nitro-1,2-phenylenediamine (2.67 g) and a
2N KOH (8.7 mL) in ethanol (250 mL) was added a 40% aqueous
solution of pyruvic aldehyde (17.72 g) at 60.degree. C. The mixture
was heated under reflux for 10 minutes, and thereto was added water
(150 mL). The mixture was cooled to room temperature, and
concentrated under reduced pressure. The precipitated crystals were
collected by filtration, washed with cold water, and dried under
reduced pressure to give 2-methyl-5-nitroquinoxali- ne (2.21 g,
67%) as pale brown solid.
[0483] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.91 (s, 1H), 8.26
(dd, 1H, J=8.6, 1.2 Hz), 8.12 (d, 1H, J=7.7 Hz), 7.83 (t, 1H, J=7.7
Hz), 2.84 (s, 3H).
[0484] (66-2)
[0485] To a solution of 2-methyl-5-nitroquinoxaline (3.67 g) in
MeOH (350 mL) was added dropwise a 20% aqueous titanium trichloride
(92.9 g) at room temperature. After the addition, the mixture was
further stirred for one hour, and concentrated under reduced
pressure. The resultant was neutralized by addition of aqueous
sodium carbonate solution, and the mixture was extracted four times
with ethyl acetate (150 mL). The organic layers were combined, and
dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (chloroform) to give 2-methyl-5-aminoquinoxaline
(2.44 g, 79%) as orange crystals.
[0486] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.55 (s, 1H), 7.51
(t, 1H, J=7.7 Hz), 7.33 (dd, 1H, J=8.4, 0.9 Hz), 6.89 (d, 1H, J=7.7
Hz), 2.75 (s, 3H).
[0487] (66-3)
[0488] 2-Methyl-5-iodoquinoxaline was obtained from
2-methyl-5-aminoquinoxaline in a similar manner to Reference
Example 3.
[0489] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.78 (s, 1H), 8.31
(dd, 1H, J=7.3, 1.1 Hz), 8.02 (dd, 1H, J=8.4, 1.1 Hz), 7.48 (dd,
1H, J=8.3, 7.5 Hz), 2.82 (s, 3H).
[0490] (66-4) 2-Methyl-5-cyanoquinoxaline was obtained from
2-methyl 5-iodoquinoxaline in a similar manner to Example 65-4.
[0491] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.91 (s, 1H), 8.27
(dd, 1H, J=8.4, 1.3 Hz), 8.12 (dd, 1H, J=7.2, 1.3 Hz), 7.82 (dd,
1H, J=8.2, 7.2 Hz), 2.77 (s, 3H).
[0492] (66-5)
[0493] The title compound was obtained from the compound of Example
66-4 and the compound of Reference Example 1 in a similar manner to
Example 1.
[0494] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.73 (s, 1H), 8.29
(dd, 1H, J-8.4, 1.1 Hz), 8.14 (dd, 1H, J=7.3, 1.5 Hz), 7.82 (dd,
1H, J=8.4, 7.3 Hz), 7.69 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.1 Hz),
7.18 (dd, 1H. J=2.4, 1.5 Hz), 6.90 (dd, 1H, J=4.0, 1.5 Hz), 6.34
(dd, 1H, J=4.0, 2.4 Hz), 5.97 (s, 2H), 2.42 (s, 3H).
Example 67
[0495] 86
[0496] To a suspension of 4-nitro-1,2-phenylenediamine (10.0 g) in
water (150 mL) was added dropwise a 40% aqueous solution of pyruvic
aldehyde (11.76 g) at room temperature. The reaction solution was
stirred at 80.degree. C. for 4 hours, and cooled to room
temperature. Water (200 mL) was added to the mixture, and the
mixture was extracted with chloroform (150 mL.times.3). The organic
layers were combined, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residual solid was
recrystallized from ethanol, collected by filtration, and dried to
give 2-methyl-6-nitroquinoxaline (7.38 g, 60%) as red solid.
[0497] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.99 (d, 1H, J=2.4
Hz), 8.90 (s, 1H), 8.52 (dd, 1H, J=9.2, 2.4 Hz), 8.18 (d, 1H, J=9.2
Hz), 2.84 (s, 3H).
[0498] (67-2)
[0499] To a suspension of 2-methyl-5-nitroquinoxaline (5.00 g) in
MeOH (500 mL) was added dropwise a 20% aqueous solution of titanium
trichloride (126.6 g) at room temperature. After the addition, the
mixture was stirred for 1.5 hour, and concentrated under reduced
pressure. To the mixture was added water (200 mL), and the mixture
was neutralized by addition of aqueous sodium carbonate solution,
and extracted with ethyl acetate (250 mL.times.8). The organic
layers were combined, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (1% MeOH/chloroform) to give
2-methyl-6-aminoquinoxaline (2.88 g, 68%) as yellow solid.
[0500] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.53 (s, 1H), 7.80
(d, 1H, J=8.8 Hz), 7.16 (m, 2H), 4.13 (brs, 2H), 2.69 (s, 3H).
[0501] (67-3)
[0502] 2-Methyl-6-iodoquinoxaline was prepared from
2-methyl-6-aminoquinixaline in a similar manner to Reference
Example 3.
[0503] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.72 (s, 1H), 8.49
(d, 1H, J=2.0 Hz), 7.99 (dd, 1H, J=8.8, 1.8 Hz), 7.73 (d, 1H, J=8.8
Hz), 2.76 (s, 3H).
[0504] (67-4)
[0505] 2-Methyl-6-cyanoquinoxaline was prepared from
2-methyl-6-iodoquinoxaline in a similar manner to Reference Example
4.
[0506] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.86 (s, 1H), 8.46
(d, 1H, J=1.7 Hz), 8.11 (d, 1H, J=8.6 Hz), 7.90 (dd, 1H, J=8.2, 1.8
Hz), 2.83 (s, 3H).
[0507] (67-5)
[0508] The title compound was obtained from the compound of Example
67-4 and the compound of Reference Example 1 in a similar manner to
Example 1.
[0509] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.73 (s, 1H), 8.46
(d, 1H, J=1.5 Hz), 8.13 (d, 1H, J=8.4 Hz), 7.89 (dd, 1H, J=8.6, 1.6
Hz), 7.69 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.19 (dd, 1H,
J=2.4, 1.5 Hz), 6.90 (dd, 1H, J=4.0, 1.5 Hz), 6.34 (dd, 1H, J=4.0,
2.4 Hz), 5.94 (s, 2H), 2.42(s, 3H).
Example 68
[0510] 87
[0511] To a suspension of 1,2,4-triaminobenzene dihydrochloride
(5.0 g) in a 10% aqueous Na.sub.2CO.sub.3 solution (60 mL) was
added a 40% aqueous pyruvic aldehyde solution (4.59 g) at room
temperature. The reaction solution was heated under reflux for 2
hours, and extracted with chloroform (60 mL.times.3). The organic
layers were combined, dried over magnesium sulfate, filtered, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (2-3% methanol in chloroform) to
give 2-methyl-7-aminoquinoxaline (3.17 g, 78%) as yellow solid.
[0512] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.46 (s, 1H), 7.83
(d, 1H, J=8.8 Hz), 7.11 (dd, 1H, J=8.8, 2.6 Hz), 7.06 (d, 1H, J=2.6
Hz), 2.69 (s, 3H).
[0513] (68-2)
[0514] 2-Methyl-7-idoquinoxaline was prepared from
2-methyl-7-aminoquinixa- line in a similar manner to Reference
Example 3.
[0515] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.74 (s, 1H), 8.44
(d, 1H, J=1.8 Hz), 7.95 (dd, 1H, J=8.6, 1.8 Hz), 7.78 (d, 1H, J=8.8
Hz), 2.77 (s, 3H).
[0516] (68-3)
[0517] 2-Methyl-7-cyanoquinoxaline was prepared from
2-methyl-7-iodoquinixaline in a similar manner to Reference Example
4.
[0518] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H), 8.39
(d, 1H, J=1.8 Hz), 8.17 (d, 1H, J=8.6 Hz), 7.86 (dd, 1H, J=8.6, 1.8
Hz), 2.83 (s, 3H).
[0519] (68-4)
[0520] The title compound was obtained from the compound of Example
68-3 and the compound of Reference Example 1 in a similar manner to
Example 1.
[0521] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.80 (s, 1H), 8.41
(d, 1H, J=1.3 Hz), 8.18 (d, 1H, J=8.8 Hz), 7.87 (dd, 1H, J=8.6, 1.7
Hz), 7.69 (d, 2H, J=8.1 Hz), 7.21 (m, 3H), 6.89 (dd, 1H, J=4.0, 1.7
Hz), 6.34 (dd, 1H, J=4.0, 2.6 Hz), 5.94 (s, 2H), 2.42 (s, 3H).
Example 69
[0522] 88
[0523] To a solution of 2-methyl-6-aminoquinoxaline (15.8 g) in
acetic acid (150 mL) was added dropwise a solution of bromine
(15.88 g) in acetic acid (11 mL) at 0.degree. C. After the
addition, the reaction solution was stirred at 0.degree. C. for one
hour, and the precipitates were collected by filtration, washed
with ether, and dried to give 2-methyl-6-amino-5-bromoquinoxaline
hydrobromide (29.86 g, 94%), which was neutralized to give
2-methyl-6-amino-5-bromoquinoxaline.
[0524] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.70 (s, 1H), 7.79
(d, 1H, J=9.0 Hz), 7.26 (d, 1H, J=9.0 Hz), 4.67 (brs, 2H), 2.73 (s,
3H).
[0525] (69-2)
[0526] A mixture of the compound of Example 69-1 (1.0 g), conc.
hydrochloric acid (3 mL) and water (15 mL) was cooled to 0.degree.
C., and stirred vigorously, and thereto was added slowly a solution
of sodium nitrite (299 mg) in water (5 mL) in such a manner that
the temperature of the mixture was not raised over 5.degree. C.
After the addition, the mixture was stirred for 20 minutes, and
thereto was added slowly a 36% aqueous H.sub.3PO.sub.2 solution (10
mL) which was cooled to 0.degree. C. After the addition, the
mixture was stirred at 0.degree. C. for 10 hours, and the reaction
solution was warmed to room temperature, and allowed to stand
overnight. The mixture was extracted twice with ethyl acetate, and
the organic layers were combined, dried over magnesium sulfate,
filtered, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=20/1.fwdarw.8/1) to give 2-methyl-5-bromoquinoxaline (475
mg, 51%) as pink solid.
[0527] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.85 (s, 1H), 8.03
(dd, 1H, J=7.6, 1.2 Hz), 8.01 (dd, 1H, J=8.6, 1.2 Hz), 7.62 (dd,
1H, J=8.6, 7.6 Hz), 2.83 (s, 3H).
[0528] (69-3)
[0529] The title compound was obtained from the compound of
Reference Example 1 and the compound of Example 69-2 in a similar
manner to Example 1.
[0530] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.67 (s, 1H), 8.05
(dd, 1H, J=7.6, 1.2 Hz), 8.03 (dd, 1H, J=8.6, 1.2 Hz), 7.70 (d, 2H,
J=8.0 Hz), 7.63 (dd, 1H, J=8.6, 7.6 Hz), 7.25 (d, 2H, J=8.0 Hz),
7.17 (dd, 1H, J=2.5, 1.7 Hz), 6.88 (dd, 1H, J=4.1, 1.7 Hz), 6.32
(dd, 1H, J=4.1, 2.5 Hz), 5.98 (s, 2H), 2.42 (s, 3H).
Example 70
[0531] 89
[0532] The title compound was obtained from the compound of Example
65 in a similar manner to the preparation of the compound of
Example 39.
[0533] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 9.49 (brs, 1H),
8.93 (s, 1H), 8.51 (dd, 1H, J=7.5, 1.5 Hz), 8.26 (dd, 1H, J=8.3,
1.5 Hz), 7.84 (t, 1H, J=8.3 Hz), 7.62 (d, 2H, J=8.1 Hz), 7.21 (d,
2H, J=8.1 Hz), 7.19 (m, 1H), 6.98 (dd, 1H, J=4.0, 1.5 Hz), 6.38
(dd, 1H, J=4.0, 2.7 Hz), 6.05 (s, 2H), 2.39 s, 3H).
Example 71
[0534] 90
[0535] The title compound was obtained from the compound of Example
67 in a similar manner to the preparation of the compound of
Example 39.
[0536] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.73 (s, 1H), 8.45
(d, 1H, J=1.8 Hz), 8.23 (dd, 1H, J=8.9, 2.1 Hz), 8.11 (d, 1H, J=8.6
Hz), 7.71 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.20 (dd, 1H,
J=2.6, 1.7 Hz), 6.89 (dd, 1H, J=4.0, 1.7 Hz), 6.33 (dd, 1H, J=4.0,
2.6 Hz), 6.29 (brs, 1H), 5.96 (s, 2H), 5.72 (brs, 1H), 2.42 (s,
3H).
Example 72
[0537] 91
[0538] The title compound was obtained from the compound of Example
68 in a similar manner to the preparation of the compound of
Example 39.
[0539] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 8.74 (s, 1H), 8.42
(d, 1H, J=1.7 Hz), 8.18 (dd, 1H, J=8.7, 1.9 Hz), 8.12 (d, 1H, J=8.7
Hz), 7.69 (d, 2H, J=8.1 Hz), 7.24 (d, 2H, J=8.1 Hz), 7.21 (dd, 1H,
J=2.6, 1.7 Hz), 6.89 (dd, 1H, J=4.0, 1.7 Hz), 6.46 (brs, 1H), 6.33
(dd, 1H, J=4.0, 2.6 Hz), 5.95 (s, 2H), 2.42 (s, 3H).
Example 73
[0540] 92
[0541] The title compound was obtained from
2-methylpyrido[2,3-b]-pyrazine and the compound of Reference
Example 1 in a similar manner to the preparation of the compound of
Example 1.
[0542] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. 9.15 (dd, 1H,
J=4.2, 1.9 Hz), 8.84 (s, 1H), 8.41 (dd, 1H, J=8.4, 1.9 Hz), 7.71
(dd, 1H, J=8.4, 4.2 Hz), 7.70 (dd, 2H, J=8.0 Hz), 7.25 (d, 2H,
J=8.0 Hz), 7.19 (dd, 1H, J=2.5, 1.7 Hz), 6.89 (dd, 1H, J=4.0, 1.7
Hz), 6.33 (dd, 1H, J=4.0, 2.5 Hz), 5.98 (s, 2H), 2.42 (s, 3H).
Reference Example 4-1
[0543] Methyl 4-[(2-pyridylsulfanyl)carbonyl]benzoate
[0544] A solution of monomethyl terephthalate (1.50 g),
2,2'-dipyridyl disulfide (3.67 g) and triphenylphosphine (4.37 g)
in anhydrous toluene was stirred for 24 hours under nitrogen
atmosphere, and the solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column chromatography
(chloroform) to give the title compound (3.49 g) as yellow
solid.
[0545] .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.70 (m, 1H), 8.16
(d, 2H, J=8.6 Hz), 8.07 (d, 2H, J=8.6 Hz), 7.82 (dt, 1H, J=7.9, 2.0
Hz), 7.68 (m, 1H), 7.37 (m, 1H), 3.97 (s, 3H).
Reference Example 4-2
[0546] (1H-Pyrrol-2-yl)(4-methoxycarbonylphenyl)ketone
[0547] To a solution of pyrrole (1.68 g) in toluene (40 mL) was
added dropwise methyl magnesium bromide in THF (0.93N solution,
27.8 mL) at -20 to -30.degree. C. After the addition, the reaction
solution was further stirred for 30 minutes. A solution of methyl
4-[(2-pyridylsulfanyl)-carbo- nyl]benzoate (8.33 mmol) in toluene
(80 mL) was cooled to -78.degree. C., and thereto was added
dropwise the above toluene solution via a cannula in such a manner
that the temperature of the reaction mixture was not raised over
-65.degree. C. After the addition, the reaction solution was
stirred at -78.degree. C. for 2 hours, and thereto was added a
saturated aqueous ammonium chloride solution (50 mL), and the
mixture was warmed to room temperature. To the reaction solution
was added ethyl acetate (100 mL), and the organic layer was
separated. Further, the aqueous layer was extracted with ethyl
acetate (50 mL.times.2). The organic layers were combined, and
washed successively with 9% hydrochloric acid (100 mL), 10% aqueous
sodium hydrogen carbonate solution (100 mL), water (100 mL) and a
saturated brine (100 mL), dried over magnesium sulfate, filterd and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl
acetate=5/1.fwdarw.4/1) to give the title compound (1.40 g) as
colorless solid.
[0548] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.72 (brs, 1H),
8.15 (d, 2H, J=8.4 Hz), 7.94 (d, 2H, J=8.4 Hz), 7.19 (m, 1H), 6.87
(m, 1H), 6.37 (m, 1H), 3.97 (s, 3H).
Reference Example 4-3
[0549]
[1-(3-Quinolylmethyl)-1H-pyrrol-2-yl](4-methoxycarbonylphenyl)
ketone
[0550] The title compound was obtained from 3-methylquinoline and
the compound of Reference Example 4-2 in a similar manner to
Example 1.
[0551] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.83 (d, 1H, J=2.2
Hz), 8.09 (m, 3H), 7.95 (1H, brd, J=1.35 Hz), 7.78 (m, 3H), 7.69
(ddd, 1H, J=8.4, 6.9, 1.4 Hz), 7.53 (ddd, 1H, J=8.1, 6.9, 1.1 Hz),
7.16 (dd, 1H, J=2.4, 1.8 Hz), 6.81 (dd, 1H, J=4.1, 1.8 Hz), 6.30
(dd, 1H, J=4.1, 2.4 Hz), 5.87 (s, 2H), 3.94 (s, 3H).
Reference Example 4-4
[0552] [1-(3-Quinolylmethyl)-1H-pyrrol-2-yl](4-carboxyphenyl)ketone
hydrochloride
[0553] The compound of Reference Example 4-3 (379.1 mg) was
dissolved in a mixture of THF/MeOH (1:1, 30 mL), and thereto was
added 2N NaOH (1.54 mL). The reaction mixture was stirred at room
temperature for one day, and concentrated under reduced pressure.
The residue was dissolved in a 0.5N NaOH (20 mL), and washed with
ethyl acetate. The aqueous layer was acidified with a 6N
hydrochloric acid, and the precipitated solid was collected by
filtration, and dried to give the title compound (341.8 mg,
85%).
[0554] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.22 (brs, 1H),
8.82 (d, 1H, J=2.2 Hz), 8.00 (m, 4H), 7.94 (dd, 1H, J=8.1, 1.0 Hz),
7.74 (m, 3H), 7.67 (dd, 1H, J=2.3, 1.7 Hz), 7.58 (ddd, 1H, J=8.1,
6.9, 1.0 Hz), 6.81 (dd, 1H, J=4.1, 1.7 Hz), 6.35 (dd, 1H, J=4.1,
2.3 Hz), 5.87 (s, 2H).
Example 74
[0555] 93
[0556] The title compound was obtained from the compound of
Reference Example 4-4 and a 29% aqueous ammonia in a similar manner
to Example 44.
[0557] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.82 (d, 1H,
J=2.2 Hz), 8.10 (brs, 1H), 8.00 (m, 2H), 7.94 (m, 3H), 7.73 (m,
3H), 7.66 (dd, 1H, J=2.3, 1.8 Hz), 7.58 (ddd, 1H, J=8.1, 7.0, 1.1
Hz), 7.51 (brs, 1H), 6.80 (dd, 1H, J=4.1, 1.6 Hz), 6.35 (dd, 1H,
J=4.1, 2.3 Hz), 5.86 (s, 2H).
Example 75
[0558] 94
[0559] The title compound was obtained from the compound of
Reference Example 4-3 and methylamine hydrochloride in a similar
manner to Example 44.
[0560] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.5 Hz), 7.94 (d, 1H, J=1.3 Hz), 7.79 (m, 5H),
7.69 (m, 1H), 7.53 (m, 1H), 7.16 (dd, 1H, J=2.5, 1.7 Hz), 6.80 (dd,
1H, J=4.1, 1.7 Hz), 6.30 (dd, 1H, J=4.1, 2.5 Hz), 6.21 (brs, 1H),
5.86 (s, 2H), 3.03 (s, 3H).
Example 76
[0561] 95
[0562] The title compound was obtained from the compound of
Reference Example 4-3 and dimethylamine hydrochloride in a similar
manner to Example 44.
[0563] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.5 Hz), 7.94 (d, 1H, J=1.3 Hz), 7.77 (m, 3H),
7.69 (m, 1H), 7.53 (m, 1H), 7.46 (d, 2H, J=8.4 Hz), 7.16 (dd, 1H,
J=2.4, 1.7 Hz), 6.83 (dd, 1H, J=4.1, 1.7 Hz), 6.30 (dd, 1H, J=4.1,
2.4 Hz), 5.86 (s, 2H), 3.13 (s, 3H), 2.96 (s, 3H).
Example 77
[0564] 96
[0565] The compound of Example 15 (10.0 mg) was dissolved in THF
(1.0 mL), and thereto was added a solution of diisobutyl aluminium
hydride in THF (1.0 M solution, 241 mL) at 0.degree. C. The
reaction solution was treated with an aqueous hydrochloric acid
solution, and extracted with ethyl acetate. The residue was
purified by silica gel column chromatography to give
2-(4-{hydroxy[1-(3-quinolylmethyl)-1H-pyrrol-2-yl]-
methyl}phenoxy)ethanol (2.00 mg, 22%).
[0566] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.52 (d, 1H, J=2.2
Hz), 8.06 (brd, 1H, J=8.3 Hz), 7.68 (dt, 1H, J=1.3, 8.3 Hz), 7.67
(d, 1H, J=7.6 Hz), 7.52 (ddd, 1H, J=0.9, 7.6, 8.3 Hz), 7.51 (brs,
1H), 7.21 (brd, 2H, J=8.7 Hz), 6.74 (d, 2H, J=8.7 Hz), 6.73 (dd,
1H, J=1.8, 3.1 Hz), 6.17 (dd, 1H, J=3.1, 3.5 Hz), 6.04 (dd, 1H,
J=1.8, 3.5 Hz), 5.81 (brs, 1H), 5.32 (d, 1H, J=16.2 Hz), 5.29 (d,
1H, J=16.2 Hz), 3.89-3.99 (m, 4H).
[0567] (77-2)
[0568] The compound of Example 77-1 (2.00 mg) was dissolved in THF
(1.0 mL), and thereto was added manganese dioxide (50.0 mg), and
the mixture was stirred at room temperature for 15 minutes. The
reaction solution was filtered, and the filtrate was concentrated,
and the residue was purified by silica gel column chromatography to
give the title compound (2.00 mg, 100%).
[0569] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.07 (brd, 1H, J=8.6 Hz), 7.93 (brs, 1H), 7.79 (d, 2H, J=8.8
Hz), 7.76 (brd, 1H, J=7.6 Hz), 7.68 (ddd, 1H, J=1.7, 7.6, 8.6 Hz),
7.52 (dt, 1H, J=0.9, 7.6 Hz), 7.10 (dd, 1H, J=1.5, 2.5 Hz), 6.95
(d, 2H, J=8.8 Hz), 6.82 (dd, 1H, J=1.5, 4.0 Hz), 6.28 (dd, 1H,
J=2.5, 4.0 Hz), 5.84 (brs, 2H), 4.15 (dt, 2H, J=5.0, 1.6 Hz),
3.97-4.02 (m, 2H).
Example 78
[0570] 97
[0571] 3-Hydroxy-4-methylbenzoic acid (7.60 g) was dissolved in
methanol (400 mL), and thereto was added sulfuric acid (15.0 g),
and the mixture was allowed to stand at room temperature for 10
hours. The reaction solution was concentrated to 150 mL, and
diluted with water, and extracted with toluene. The extract was
washed with an aqueous sodium hydrogen carbonate solution, and
concentrated to give methyl 3-hydroxy-4-methylbenzoate (7.76 g,
94%). This product was dissolved in THF (140 mL), and thereto was
added NaH (60% dispersion in oil, 2.22 g), and the mixture was
stirred at 50.degree. C. for one hour. To the mixture was added
allyl bromide (7.00 g), and the mixture was refluxed for 5 hours.
Water was added to the reaction solution, and the mixture was
extracted with toluene, dried, filtered, and concentrated. The
residue was purified by silica gel column chromatography to give
methyl [3-(allyloxy)-4-methyl]benzoate (8.92 g, 93%).
[0572] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.56 (dd, 1H,
J=1.5, 7.7 Hz), 7.47 (d, 1H, J=1.5 Hz), 7.19 (dd, 1H, J=0.5, 7.7
Hz), 6.08 (ddt, 1H, J=10.6, 17.3, 5.0 Hz), 5.45 (ddt, 1H, J=17.3,
1.6, 1.6 Hz), 5.29 (ddt, 1H, J=10.6, 1.6, 1.6 Hz), 4.60 (dt, 2H,
J=5.0, 1.6 Hz), 3.90 (s, 3H), 2.30 (brs, 3H).
[0573] (78-2)
[0574] [3-(Allyloxy)-4-methylphenyl](1H-pyrrol-2-yl)ketone was
obtained from the compound of Example 78-1 in a similar manner to
Example 10-1.
[0575] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.78 (brs, 1H),
7.46 (dd, 1H, J=1.5, 7.2 Hz), 7.36 (d, 1H, J=1.5 Hz), 7.24 (dd, 1H,
J=0.2, 7.2 Hz), 7.13 (dt, 1H, J=1.3, 2.7 Hz), 6.91 (ddd, 1H, J=3.8,
2.4, 1.3 Hz), 6.34 (dt, 1H, J=3.8, 2.7 Hz), 6.09 (ddt, 1H, J=10.6,
17.3, 5.0 Hz), 5.45 (ddt, 1H, J=17.3, 1.6, 1.6 Hz), 5.30 (ddt, 1H,
J=10.6, 1.6, 1.6 Hz), 4.62 (dt, 2H, J=5.0, 1.6 Hz), 2.33 (brs,
3H).
[0576] (78-3)
[0577] The title compound was obtained from 3-methylquinoline and
the compound of Example 78-2 in a similar manner to Example 1.
[0578] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.4 Hz), 7.94 (d, 1H, J=2.0 Hz), 7.76 (brd, 1H,
J=8.1 Hz), 7.69 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.53 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.30 (dd, 1H, J=1.5, 7.2 Hz), 7.23 (d, 1H,
J=1.5 Hz), 7.18 (brd, 1H, J=7.2 Hz), 7.11 (dd, 1H, J=1.7, 2.5 Hz),
6.86 (dd, 1H, J=1.7, 4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 6.06
(ddt, 1H, J=10.6, 17.3, 5.0 Hz), 5.84 (brs, 2H), 5.42 (ddt, 1H,
J=17.3, 1.6, 1.6 Hz), 5.27 (ddt, 1H, J=10.6, 1.6, 1.6 Hz), 4.57
(dt, 2H, J=5.0, 1.6 Hz), 2.30 (brs, 3H).
Example 79
[0579] 98
[0580] The title compound was obtained from the compound of Example
78 in a similar manner to Example 14.
[0581] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.73 (brs, 1H),
8.08 (d, 1H, J=8.4 Hz), 7.94 (brs, 1H), 7.71 (brd, 1H, J=8.1 Hz),
7.65 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.40-7.53 (series of m, 2H),
7.23 (d, 1H, J=1.5 Hz), 7.21 (brd, 1H, J=7.2 Hz), 7.14 (brd, 1H,
J=7.2 Hz), 7.05 (dd, 1H, J=1.7, 2.5 Hz), 6.80 (dd, 1H, J=1.7, 4.0
Hz), 6.18 (dd, 1H, J=2.5, 4.0 Hz), 5.84 (brs, 2H), 2.29 (brs,
3H).
Example 80
[0582] 99
[0583] The title compound was obtained from the compound of Example
79 in a similar manner to Example 15.
[0584] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.76 (brd, 1H,
J=8.1 Hz), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.51 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.34 (dd, 1H, J=1.5, 7.2 Hz), 7.20 (brd, 1H,
J=7.2 Hz), 7.12 (d, 1H, J=1.5 Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz),
6.83 (dd, 1H, J=1.7, 4.0 Hz), 6.27 (dd, 1H, J=2.5, 4.0 Hz), 5.83
(brs, 2H), 4.66 (s, 2H), 4.24 (q, 2H, J=7.1 Hz), 2.34 (brs, 3H),
1.27 (t, 3H, J=7.1 Hz).
Example 81
[0585] 100
[0586] The compound of Example 79 (20.0 mg), dimethylaminoethyl
chloride hydrochloride (168 mg) and potassium carbonate (400 mg)
were refluxed in acetone (3.0 mL) for 3 hours. The reaction
solution was poured into water, and the mixture was extracted with
ethyl acetate. The extract was dried, filtered, and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography to give the title compound (18.1
mg, 75%).
[0587] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.76 (brd, 1H,
J=8.1 Hz), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.52 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.29 (dd, 1H, J=1.5, 7.2 Hz), 7.24 (d, 1H,
J=1.5 Hz), 7.17 (brd, 1H, J=7.2 Hz), 7.11 (dd, 1H, J=1.7, 2.5 Hz),
6.86 (dd, 1H, J=1.7, 4.0 Hz), 6.27 (dd, 1H, J=2.5, 4.0 Hz), 5.83
(brs, 2H), 4.11 (t, 2H, J=5.7 Hz), 2.78 (t, 2H, J=5.7 Hz), 2.36 (s,
6H), 2.27 (brs, 3H).
Example 82
[0588] 101
[0589] The title compound was obtained from the compound of Example
79 and diethylaminoethyl chloride hydrochloride in a similar manner
to Example 81.
[0590] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.82 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.76 (brd, 1H,
J=8.1 Hz), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.52 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.29 (dd, 1H, J=1.5, 7.2 Hz), 7.24 (d, 1H,
J=1.5 Hz), 7.16 (brd, 1H, J=7.2 Hz), 7.11 (dd, 1H, J=1.7, 2.5 Hz),
6.86 (dd, 1H, J=1.7, 4.0 Hz), 6.27 (dd, 1H, J=2.5, 4.0 Hz), 5.84
(brs, 2H), 4.07 (t, 2H, J=5.7 Hz), 2.92 (t, 2H, J=5.7 Hz), 2.64 (q,
4H, J=7.1 Hz), 2.27 (brs, 3H), 1.07 (t, 6H, J=7.1 Hz).
Example 83
[0591] 102
[0592] The title compound was obtained from the compound of Example
78 in a similar manner to Example 13.
[0593] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.77 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.75 (brd, 1H,
J=8.1 Hz), 7.67 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.51 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.31 (dd, 1H, J=1.5, 7.2 Hz), 7.22 (d, 1H,
J=1.5 Hz), 7.16 (brd, 1H, J=7.2 Hz), 7.12 (dd, 1H, J=1.7, 2.5 Hz),
6.84 (dd, 1H, J=1.7, 4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.82
(brs, 2H), 4.04-4.15 (series of m, 3H), 3.83 (dd, 1H, J=11.4, 3.8
Hz), 3.76 (dd, 1H, J=11.4, 5.5 Hz), 2.25 (brs, 3H).
Example 84
[0594] 103
[0595] Methyl [2-(allyloxy)-4-methyl]benzoate was obtained from
2-hydroxy-4-methylbenzoic acid in a similar manner to Example
78-1.
[0596] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.73 (d, 1H, J=7.9
Hz), 6.79 (dd, 1H, J=0.6, 7.9 Hz), 6.76 (brs, 1H), 6.08 (ddt, 1H,
J=10.6, 17.3, 5.0 Hz), 5.53 (ddt, 1H, J=17.3, 1.6, 1.6 Hz), 5.30
(ddt, 1H, J=10.6, 1.6, 1.6 Hz), 4.61 (dt, 2H, J=5.0, 1.6 Hz), 3.88
(s, 3H), 2.37 (brs, 3H).
[0597] (84-2)
[0598] [2-(Allyloxy)-4-methylphenyl](1H-pyrrol-2-yl)ketone was
obtained from the compound of Example 81-1 in a similar manner to
Example 10-1.
[0599] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.69 (brs, 1H),
7.36 (d, 1H, J=7.9 Hz), 7.08 (dt, 1H, J=1.3, 2.7 Hz), 6.82 (brd,
1H, J=7.9 Hz), 6.79 (brs, 1H), 6.67 (ddd, 1H, J=3.8, 2.4, 1.3 Hz),
6.26 (dt, 1H, J=3.8, 2.7 Hz), 5.95 (ddt, 1H, J=10.6, 17.3, 5.0 Hz),
5.30 (ddt, 1H, J=17.3, 1.6, 1.6 Hz), 5.18 (ddt, 1H, J=10.6, 1.6,
1.6 Hz), 4.56 (dt, 2H, J=5.0, 1.6 Hz), 2.39 (brs, 3H).
[0600] (84-3)
[0601] The title compound was obtained from 3-methylquinoline and
the compound of Example 81-2 in a similar manner to Example 1.
[0602] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.84 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.4 Hz), 7.95 (d, 1H, J=2.0 Hz), 7.76 (dd, 1H,
J=1.1, 8.1 Hz), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.51 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.20 (d, 1H, J=7.9 Hz), 7.06 (dd, 1H, J=1.7,
2.5 Hz), 6.77 (brd, 1H, J=7.9 Hz), 6.72 (brs, 1H), 6.64 (dd, 1H,
J=1.7, 4.0 Hz), 6.19 (dd, 1H, J=2.5, 4.0 Hz), 5.89 (brs, 2H), 5.77
(ddt, 1H, J=10.6, 17.3, 5.0 Hz), 5.12 (ddt, 1H, J=17.3, 1.6, 1.6
Hz), 5.02 (ddt, 1H, J=10.6, 1.6, 1.6 Hz), 4.44 (dt, 2H, J=5.0, 1.6
Hz), 2.36 (brs, 3H).
Example 85
[0603] 104
[0604] The title compound was obtained from the compound of Example
84 in a similar manner to Example 14.
[0605] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.89 (d, 1H, J=2.0 Hz), 7.75 (dd, 1H,
J=1.1, 8.1 Hz), 7.74 (d, 1H, J=7.9 Hz), 7.69 (ddd, 1H, J=8.4, 7.0,
1.5 Hz), 7.52 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.10 (dd, 1H, J=1.7,
2.5 Hz), 6.89 (dd, 1H, J=1.7, 4.0 Hz), 6.80 (brs, 1H), 6.68 (brd,
1H, J=7.9 Hz), 6.32 (dd, 1H, J=2.5, 4.0 Hz), 5.75 (brs, 2H), 2.34
(brs, 3H).
Example 86
[0606] 105
[0607] The title compound was obtained from the compound of Example
85 in a similar manner to Example 15.
[0608] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.83 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.4 Hz), 7.96 (d, 1H, J=2.0 Hz), 7.77 (dd, 1H,
J=1.1, 8.1 Hz), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.51 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.21 (d, 1H, J=7.9 Hz), 7.06 (dd, 1H, J=1.7,
2.5 Hz), 6.81 (brd, 1H, J=7.9 Hz), 6.71 (brs, 1H), 6.62 (dd, 1H,
J=1.7, 4.0 Hz), 6.20 (dd, 1H, J=2.5, 4.0 Hz), 5.89 (brs, 2H), 4.53
(s, 2H), 4.17 (q, 2H, J=7.1 Hz), 2.34 (brs, 3H), 1.21 (t, 3H, J=7.1
Hz).
Example 87
[0609] 106
[0610] The title compound was obtained from the compound of Example
86 in a similar manner to Example 16.
[0611] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.83 (brs, 1H),
8.49 (brs, 1H), 8.43 (brd, 1H, J=8.4 Hz), 7.96 (brd, 1H, J=8.1 Hz),
7.83 (brdd, 1H, J=8.4, 7.0 Hz), 7.69 (brdd, 1H, J=8.1, 7.0 Hz),
7.34 (d, 1H, J=7.9 Hz), 7.27 (brs, 1H), 6.87 (brd, 1H, J=7.9 Hz),
6.81 (brd, 1H, J=4.0 Hz), 6.80 (brs, 1H), 6.30 (brd, 1H, J=4.0 Hz),
5.92 (brs, 2H), 4.66 (s, 2H), 2.37 (brs, 3H).
Example 88
[0612] 107
[0613] The title compound was obtained from the compound of Example
85 in a similar manner to Example 81.
[0614] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.84 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=8.4 Hz), 7.97 (d, 1H, J=2.0 Hz), 7.78 (dd, 1H,
J=1.1, 8.1 Hz), 7.69 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.53 (ddd, 1H,
J=8.1, 7.0, 1.1 Hz), 7.19 (d, 1H, J=7.9 Hz), 7.07 (dd, 1H, J=1.7,
2.5 Hz), 6.77 (brd, 1H, J=7.9 Hz), 6.73 (brs, 1H), 6.61 (dd, 1H,
J=1.7, 4.0 Hz), 6.19 (dd, 1H, J=2.5, 4.0 Hz), 5.87 (brs, 2H), 3.98
(t, 2H, J=5.7 Hz), 2.42 (t, 2H, J=5.7 Hz), 2.36 (brs, 3H), 2.08 (s,
6H).
Reference Example 5-1
[0615]
(1-Benzenesulfonyl-1H-pyrrol-2-yl)[4-(methoxy)phenyl]ketone
[0616] The title compound was obtained from 4-methoxybenzoyl
chloride in a similar manner to Reference Example 1-1.
[0617] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.12 (dt, 2H,
J=7.2, 1.5 Hz), 7.84 (d, 2H, J=8.9 Hz), 7.73 (dd, 1H, J=1.7, 3.2
Hz), 7.65 (tt, 1H, J=1.5, 7.2 Hz), 7.58 (tt, 2H, J=1.5, 7.2 Hz),
6.93 (d, 2H, J=8.9 Hz), 6.68 (dd, 1H, J=1.7, 3.6 Hz), 6.34 (dd, 1H,
J=3.2, 3.6 Hz), 3.87 (s, 3H).
Reference Example 5-2
[0618] (1H-Pyrrol-2-yl) [4-(methoxy)phenyl]ketone
[0619] The title compound was obtained from the compound of
Reference Example 5-1 in a similar manner to Reference Example
1-2.
[0620] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.54 (brs, 1H),
7.94 (d, 2H, J=8.9 Hz), 7.12 (dt, 1H, J=1.3, 2.7 Hz), 6.93 (d, 2H,
J=8.9 Hz), 6.89 (ddd, 1H, J=3.8, 2.4, 1.3 Hz), 6.34 (dt, 1H, J=3.8,
2.7 Hz), 3.89 (s, 3H).
Example 89
[0621] 108
[0622] The title compound was obtained from 3-methylquinoline and
the compound of Reference Example 5 in a similar manner to Example
1.
[0623] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.07 (brd, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.79 (dt,
2H, J=8.4, 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0, 1.5 Hz), 7.51 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.09 (dd, 1H,
J=1.7, 2.5 Hz), 6.92 (dt, 2H, J=8.4, 2.0 Hz), 6.82 (dd, 1H, J=1.7,
4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.84 (brs, 2H), 3.86 (s,
3H).
Example 90
[0624] 109
[0625] The title compound was obtained from the compound of
Reference Example 5 and the compound of Example 18-2 in a similar
manner to Example 18-3.
[0626] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.87 (dd, 1H,
J=1.2, 7.7 Hz), 7.86 (d, 2H, J=8.8 Hz), 7.53 (brd, 1H, J=7.7 Hz),
7.43 (dt, 1H, J=1.1, 7.7 Hz), 7.30 (brd, 1H, J=15.7 Hz), 7.29 (dt,
1H, J=1.2, 7.7 Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz), 6.95 (brd, 2H,
J=8.8 Hz), 6.76 (dd, 1H, J=1.7, 4.0 Hz), 6.35 (dt, 1H, J=15.7, 6.2
Hz), 6.21 (dd, 1H, J=2.5, 4.0 Hz), 5.21 (dd, 2H, J=6.2, 1.4 Hz),
4.34 (q, 2H, J=7.2 Hz), 3.88 (s, 3H), 1.37 (t, 3H, J=7.2 Hz).
Example 91
[0627] 110
[0628] The title compound was obtained from 2-methylquinoxaline and
the compound of Reference Example 5 in a similar manner to Example
1.
[0629] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.66 (s, 1H),
8.01-8.10 (m, 2H), 7.83 (d, 2H, J=8.8 Hz), 7.70-7.78 (m, 2H), 7.19
(dd, 1H, J=1.6, 2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 5.95 (brs, 2H), 3.86
(s, 3H).
Example 92
[0630] 111
[0631] To a solution of the compound of Example 91 (530 mg) in
methylene chloride (15 mL) was added dropwise at 0.degree. C. a
solution of boron tribromide in methylene chloride (6.13 mL, 1M
solution). The reaction solution was warmed to room temperature,
and stirred for 2 hours. The reaction solution was basified with an
aqueous sodium hydrogen carbonate solution, and thereto was added
ethyl acetate, and stirred for 4 hours. The aqueous layer was
extracted twice with ethyl acetate, and the organic layers were
combined, dried, and filtered. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel
chromatography to give the title compound (413 mg, 81%).
[0632] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.64 (s, 1H),
8.03-8.11 (m, 2H), 7.76 (d, 2H, J=8.8 Hz), 7.72-7.79 (m, 2H), 7.19
(dd, 1H, J=1.6, 2.5 Hz), 6.86 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 6.04 (brs, 1H), 5.95
(brs, 2H).
Example 93
[0633] 112
[0634] The title compound was obtained from the compound of Example
92 in a similar manner to Example 15.
[0635] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.65 (s, 1H),
8.01-8.10 (m, 2H), 7.82 (d, 2H, J=8.8 Hz), 7.70-7.78 (m, 2H), 7.19
(dd, 1H, J=1.6, 2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 5.94 (brs, 2H), 4.68
(s, 2H), 4.28 (q, 2H, J=7.1 Hz), 1.30 (t, 3H, J=7.1 Hz).
Example 94
[0636] 113
[0637] The title compound was obtained from the compound of Example
93 in a similar manner to Example 16.
[0638] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.65 (s, 1H),
8.03-8.12 (m, 2H), 7.81 (d, 2H, J=8.8 Hz), 7.72-7.79 (m, 2H), 7.19
(dd, 1H, J=1.6, 2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 5.95 (brs, 2H), 4.72
(s, 2H).
Example 95
[0639] 114
[0640] The title compound was obtained from the compound of Example
92 and N-chloroethylmorpholine hydrochloride in a similar manner to
Example 81.
[0641] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.65 (s, 1H),
8.01-8.10 (m, 2H), 7.82 (d, 2H, J=8.8 Hz), 7.70-7.78 (m, 2H), 7.18
(dd, 1H, J=1.6, 2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 5.94 (brs, 2H), 4.17
(t, 2H, J=5.7 Hz), 3.74 (dd, 4H, J=4.6, 4.7 Hz), 2.83 (t, 2H, J=5.7
Hz), 2.59 (dd, 4H, J=4.6, 4.7 Hz).
Example 96
[0642] 115
[0643]
2-[4-(4-{[1-(3-Quinolylmethyl)-1H-pyrrol-2-yl]carbonyl}phenoxy)-but-
yl]-1H-isoindole-1,3(2H)-dione was obtained from the compound of
Example 14 and N-(4-bromobutyl)phthalimide in a similar manner to
Example 81.
[0644] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.82-7.87 (m,
2H), 7.77 (d, 2H, J=8.4 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.69-7.74
(m, 2H), 7.68 (ddd, 1H, J=8.4, 7.0, 1.5 Hz), 7.51 (ddd, 1H, J=8.1,
7.0, 1.1 Hz), 7.09 (dd, 1H, J=1.7, 2.5 Hz), 6.89 (d, 2H, J=8.4 Hz),
6.81 (dd, 1H, J=1.7, 4.0 Hz), 6.27 (dd, 1H, J=2.5, 4.0 Hz), 5.83
(brs, 2H), 4.05 (t, 2H, J=5.9 Hz), 3.78 (t, 2H, J=6.7 Hz),
1.81-1.95 (m, 4H).
[0645] (96-2)
[0646] The compound of Example 96-1 (28.0 mg) was dissolved in THF
(1.0 mL) and methanol (2.0 mL), and thereto was added hydrazine
hydrate (27.0 mg), and the mixture was stirred at room temperature
for 1 hour. The mixture was concentrated, and thereto was added a
3N aqueous hydrochloric acid solution, and the mixture was washed
with ether. The aqueous layer was basified with a 5N aqueous NaOH
solution, and extracted with ethyl acetate. The organic layer was
dried, filtered, and concentrated to give the title compound (18.0
mg, 85%).
[0647] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.91 (d, 1H, J=2.0 Hz), 7.77 (d, 2H,
J=8.4 Hz), 7.75 (brd, 1H, J=8.1 Hz), 7.67 (ddd, 1H, J=8.4, 7.0, 1.5
Hz), 7.51 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.09 (dd, 1H, J=1.7, 2.5
Hz), 6.88 (d, 2H, J=8.4 Hz), 6.81 (dd, 1H, J=1.7, 4.0 Hz), 6.27
(dd, 1H, J=2.5, 4.0 Hz), 5.83 (brs, 2H), 4.05 (t, 2H, J=6.4 Hz),
2.79 (t, 2H, J=7.2 Hz), 1.84 (tt, 2H, J=6.4, 7.3 Hz), 1.64 (tt, 2H,
J=7.2, 7.3 Hz).
Example 97
[0648] 116
[0649] The title compound was obtained from the compound of Example
14 and N-chloroethylmorpholine hydrochloride in a similar manner to
Example 81.
[0650] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.93 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4, 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0, 1.5 Hz), 7.51 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.09 (dd, 1H,
J=1.7, 2.5 Hz), 6.92 (dt, 2H, J=8.4, 2.0 Hz), 6.82 (dd, 1H, J=1.7,
4.0 Hz), 6.27 (dd, 1H, J=2.5, 4.0 Hz), 5.83 (brs, 2H), 4.17 (t, 2H,
J=5.7 Hz), 3.74 (dd, 4H, J=4.6, 4.7 Hz), 2.82 (t, 2H, J=5.7 Hz),
2.59 (dd, 4H, J=4.6, 4.7 Hz).
Example 98
[0651] 117
[0652] The compound of Example 16 (50.0 mg), morpholine (16.2 mg),
1-hydroxybenzotriazole (23.4 mg) and
1-(3-dimethylaminopropyl)-3-ethylcar- bodiimide hydrochloride (34.4
mg) were dissolved in DMF (3.0 mL), and thereto was added
triethylamine (34.6 mg). The mixture was stirred under nitrogen
atmosphere at room temperature for 8 hours. To the reaction mixture
was further added the same amount of the reacting reagents, and the
mixture was further stirred for 2 hours. The reaction was quenched
by adding a saturated aqueous sodium hydrogen carbonate solution to
the mixture. The reaction mixture was extracted with ethyl acetate,
dried, and filtered. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column to give
the title compound (56.0 mg, 100%).
[0653] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4, 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0, 1.5 Hz), 7.52 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.11 (dd, 1H,
J=1.7, 2.5 Hz), 6.97 (dt, 2H, J=8.4, 2.0 Hz), 6.82 (dd, 1H, J=1.7,
4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.84 (brs, 2H), 4.75 (s,
2H), 3.57-3.70 (series of m, 8H).
Example 99
[0654] 118
[0655] The title compound was obtained from methylpiperazine and
the compound of Example 16 in a similar manner to Example 98.
[0656] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.80 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=8.4 Hz), 7.92 (d, 1H, J=2.0 Hz), 7.78 (dt, 2H,
J=8.4, 2.0 Hz), 7.76 (brd, 1H, J=8.1 Hz), 7.68 (ddd, 1H, J=8.4,
7.0, 1.5 Hz), 7.51 (ddd, 1H, J=8.1, 7.0, 1.1 Hz), 7.10 (dd, 1H,
J=1.7, 2.5 Hz), 6.96 (dt, 2H, J=8.4, 2.0 Hz), 6.82 (dd, 1H, J=1.7,
4.0 Hz), 6.28 (dd, 1H, J=2.5, 4.0 Hz), 5.83 (brs, 2H), 4.74 (s,
2H), 3.64 (brt, 2H, J=4.8 Hz), 3.58 (brt, 2H, J=4.8 Hz), 2.41 (brt,
2H, J=5.1 Hz), 2.38 (brt, 2H, J=5.1 Hz), 2.29 (s, 3H).
Example 100
[0657] 119
[0658] The title compound was obtained from the compound of Example
92 and diethylaminoethyl chloride hydrochloride in a similar manner
to Example 81.
[0659] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.65 (s, 1H),
8.01-8.10 (m, 2H), 7.82 (d, 2H, J=8.8 Hz), 7.70-7.78 (m, 2H), 7.17
(dd, 1H, J=1.6, 2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (dd, 1H,
J=1.6, 4.0 Hz), 6.30 (dd, 1H, J=2.5, 4.0 Hz), 5.94 (brs, 2H), 4.11
(t, 2H, J=6.2 Hz), 2.90 (t, 2H, J=6.2 Hz), 2.65 (q, 4H, J=7.1 Hz),
1.08 (t, 6H, J=7.1 Hz).
Example 101
[0660] 120
[0661] The title compound was obtained from the compound of Example
9-2 and the compound of Reference Example 5 in a similar manner to
Example 9-3.
[0662] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 2H, J=8.8
Hz), 7.85 (d, 1H, J=2.2 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=8.5, 2.2 Hz), 7.20 (dt, 1H, J=15.8, 1.4 Hz), 7.07 (dd, 1H, J=1.7,
2.5 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.77 (dd, 1H, J=1.7, 4.0 Hz), 6.35
(dt, 1H, J=15.8, 6.1 Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 5.20 (dd,
2H, J=1.4, 6.1 Hz), 3.88 (s, 3H), 3.86 (s, 3H).
Example 102
[0663] 121
[0664] The compound of Example 101 (100 mg) was dissolved in
methanol (3.0 mL) and THF (3.0 mL), and thereto was added a 1N
aqueous NaOH solution (3.0 mL), and the mixture was stirred at
55.degree. C. for 30 minutes. The reaction solution was
concentrated to about 3 mL, and thereto were added a 1N aqueous
NaOH solution and ether, and the mixture was stirred. The
precipitated crystals were collected by filtration to give the
title compound (100 mg, 98%).
[0665] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.78 (d, 2H,
J=8.8 Hz), 7.44 (brd, 1H, J=15.8 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.37
(brs, 1H), 7.31 (dd, 1H, J=1.7, 2.5 Hz), 7.11 (brd, 1H, J=8.5 Hz),
7.04 (d, 2H, J=8.8 Hz), 6.65 (dd, 1H, J=1.7, 4.0 Hz), 6.23 (dt, 1H,
J=15.8, 6.1 Hz), 6.20 (dd, 1H, J=2.5, 4.0 Hz), 5.20 (dd, 2H, J=1.4,
6.1 Hz), 3.84 (s, 3H).
Examples 103 and 104
[0666] 122
[0667] The title compounds were obtained from the compound of
Example 101 in a similar manner to Example 92.
[0668] .sup.1H NMR (the compound of Example 103: CDCl.sub.3, 400
MHz) .delta. 7.85 (d, 1H, J=2.2 Hz), 7.79 (d, 2H, J=8.7 Hz), 7.47
(d, 1H, J=8.5 Hz), 7.39 (dd, 1H, J=8.5, 2.2 Hz), 7.19 (dt, 1H,
J=15.8, 1.4 Hz), 7.08 (dd, 1H, J=1.7, 2.5 Hz), 6.88 (d, 2H, J=8.7
Hz), 6.77 (dd, 1H, J=1.7, 4.0 Hz), 6.34 (dt, 1H, J=15.8, 6.0 Hz),
6.23 (dd, 1H, J=2.5, 4.0 Hz), 5.20 (dd, 2H, J=1.4, 6.0 Hz), 3.86
(s, 3H)
[0669] .sup.1H NMR (the compound of Example 104: DMSO-d.sub.6, 400
MHz) .delta. 7.68 (d, 2H, J=8.7 Hz), 7.42 (brd, 1H, J=15.8 Hz),
7.38 (d, 1H, J=8.5 Hz), 7.35 (d, 1H, J=2.2 Hz), 7.27 (dd, 1H,
J=1.7, 2.5 Hz), 7.10 (dd, 1H, J=8.5, 2.2 Hz), 6.84 (d, 2H, J=8.7
Hz), 6.63 (dd, 1H, J=1.7, 4.0 Hz), 6.22 (dt, 1H, J=15.8, 6.0 Hz),
6.18 (dd, 1H, J=2.5, 4.0 Hz), 5.06 (brd, 2H, J=6.0 Hz).
Example 105
[0670] 123
[0671] Under nitrogen atmosphere, to a mixture of
7-bromopyrido[2,3-b]pyra- zine (300 mg), methyl boronate (100 mg)
and cesium carbonate (930 mg) were added dioxane (7.0 ml),
bis(dibenzilidenacetone)-palladium (80.0 mg) and triphenylphosphine
(87.0 mg), and the mixture was stirred at 100.degree. C. for 2.5
hours. To the reaction solution was added a saturated aqueous
sodium hydrogen carbonate solution, and the mixture was extracted
three times with ethyl acetate. The extracts were combined, washed
with a saturated brine, dried over magnesium sulfate, and filtered.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.1/1.fwdarw.0/1.fwdarw.- ethyl
acetate/ethanol=10/1) to give 7-methylpyrido[2,3-b]pyrazine (125
mg, 60%).
[0672] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.06 (d, 1H, J=2.3
Hz), 9.02 (d, 1H, J=1.7 Hz), 8.91 (d, 1H, J=1.7 Hz), 8.24 (d, 1H,
J=2.3 Hz), 2.65 (s, 3H).
[0673] (105-2)
[0674] Under nitrogen atmosphere, to a solution of the compound of
Example 105-1 (107 mg) in chlorobenzene (5.0 ml) were added
N-bromosuccinimide (132 mg) and 2,2'-azobis(isobutyronitrile) (10.0
mg), and the mixture was stirred at 90.degree. C. for 2 hours. The
solvent in the reaction solution was evaporated under reduced
pressure to about a half volume thereof, and purified by silica gel
column (ethyl acetate). The fractions containing a bromo compound
were changed to a toluene solution thereof (about 3 ml) while these
fractions should not be concentrated to dryness.
[0675] Under nitrogen atmosphere, a solution of the compound of
Reference Example 1 (100 mg) in THF (2.0 mL) was cooled to
0.degree. C., and thereto was added potassium t-butoxide (60.6 mg).
Further, thereto was added the above toluene solution of the bromo
compound, and the mixture was stirred at 50.degree. C. for 3 hours.
The reaction solution was cooled to room temperature, and thereto
was added a saturated aqueous sodium hydrogen carbonate solution,
and extracted with ethyl acetate. The extract was dried over
magnesium sulfate, filtered, and the solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
to give the title compound (3.6 mg, 0.77%).
[0676] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.09 (d, 1H, J=2.4
Hz), 9.03 (d, 1H, J=1.7 Hz), 8.90 (d, 1H, J=1.7 Hz), 8.10 (d, 1H,
J=2.4 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.14
(dd, 1H, J=1.7, 2.5 Hz), 6.89 (dd, 1H, J=1.7, 4.1 Hz), 6.34 (dd,
1H, J=2.5, 4.1 Hz), 5.94 (s, 2H), 2.41 (s, 3H).
Example 106
[0677] 124
[0678]
(4-Methylphenyl)[5-methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl]ketone
was obtained from p-toluoyl chloride and
1-(phenylsulfonyl)-2-methyl-1H-p- yrrole in a similar manner to
Reference Example 1-1.
[0679] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.23 (d, 2H, J=7.2
Hz), 7.84 (d, 2H, J=8.1 Hz), 7.56-7.68 (m, 3H), 7.26 (d, 2H, J=8.1
Hz), 6.48 (d, 1H, J=3.5 Hz), 6.01 (d, 1H, J=3.5 Hz), 2.53 (s, 3H),
2.43 (s, 3H).
[0680] (106-2)
[0681] (4-Methylphenyl)(5-methyl-1H-pyrrol-2-yl)ketone was obtained
from the compound of Example 106-1 in a similar manner to Reference
Example 1-2.
[0682] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.97 (brs, 1H),
7.80 (d, 2H, J=8.0 Hz), 7.27 (d, 2H, J=8.0 Hz), 6.80 (dd, 1H,
J=2.7, 3.4 Hz), 6.04 (d, 1H, J=3.0, 3.4 Hz), 2.43 (s, 3H), 2.39 (s,
3H).
[0683] (106-3)
[0684] The title compound was obtained from the compound of Example
106-2 in a similar manner to Example 1.
[0685] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.73 (d, 1H, J=2.2
Hz), 8.12 (d, 1H, J=7.8 Hz), 7.67-7.75 (m, 3H), 7.68 (d, 2H, J=8.0
Hz), 7.52 (t, 1H, J=7.8 Hz), 7.23 (d, 2H, J=8.0 Hz), 6.81 (d, 1H,
J=4.0 Hz), 6.10 (d, 1H, J=4.0 Hz), 5.90 (s, 2H), 2.41 (s, 3H), 2.29
(s, 3H).
Example 107
[0686] 125
[0687] Ethyl
4-methyl-1-(3-quinolinylmethyl)-1H-pyrrole-2-carboxylate was
obtained from ethyl 4-methyl-2-pyrrolecarboxylate in a similar
manner to Example 1.
[0688] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.78 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=7.9 Hz), 7.79 (d, 1H, J=2.2 Hz), 7.75 (d, 1H,
J=7.9 Hz), 7.68 (t, 1H, J=7.9 Hz), 7.52 (t, 1H, J=7.9 Hz), 6.86 (d,
1H, J=1.3 Hz), 6.74 (d, 1H, J=1.3 Hz), 5.69 (s, 2H), 4.21 (q, 2H,
J=7.1 Hz), 2.09 (s, 3H), 1.28 (t, 3H, J=7.1 Hz).
[0689] (107-2)
[0690] Under nitrogen atmosphere, to a solution of the compound of
Example 107-1 (346 mg) in toluene (10 mL) that was cooled to
-78.degree. C. was added dropwise a 0.93N solution of diisobutyl
aluminum hydride in toluene (1.3 mL). The mixture was stirred at
-78.degree. C. for 2.5 hours, and thereto was further added a 0.93N
solution of diisobutylaluminum hydride in toluene (1.3 mL). The
reaction solution was warmed gradually to room temperature over a
period of 3.5 hours. To the reaction solution were added water and
ethyl acetate, and the precipitated crystals were removed by
filtration. The organic layer in the filtrate was collected, and
washed twice with a saturated aqueous sodium hydrogen carbonate
solution, and washed with a saturated brine, dried over magnesium
sulfate, and filtered. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=1/1.fwdarw.1/2.fwdarw.0/1) to give
[4-methyl-1-(3-quinolinylmethy- l)-1H-pyrrol-2-yl]methanol (211 mg,
71%).
[0691] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.77 (d, 1H, J=2.2
Hz), 8.09 (d, 1H, J=7.9 Hz), 7.76 (d, 1H, J=7.9 Hz), 7.75 (d, 1H,
J=2.2 Hz), 7.70 (t, 1H, J=7.9 Hz), 7.54 (t, 1H, J=7.9 Hz), 6.51 (d,
1H, J=1.3 Hz), 6.04 (d, 1H, J=1.3 Hz), 5.33 (s, 2H), 4.53 (d, 2H,
J=5.8 Hz), 2.08 (s, 3H), 1.38 (t, 1H, J=5.8 Hz)
[0692] (107-3)
[0693] 4-Methyl-1-(3-quinolinylmethyl)-1H-pyrrole-2-carbaldehyde
was obtained from the compound of Example 107-2 in a similar manner
to Example 28-4.
[0694] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.48 (s, 1H), 8.79
(d, 1H, J=2.2 Hz), 8.08 (d, 1H, J=7.9 Hz), 7.89 (d, 1H, J=2.2 Hz),
7.77 (d, 1H, J=7.9 Hz), 7.69 (t, 1H, J=7.9 Hz), 7.53 (t, 1H, J=7.9
Hz), 6.86 (d, 1H, J=1.3 Hz), 6.80 (d, 1H, J=1.3 Hz), 5.70 (s, 2H),
2.11 (s, 3H).
[0695] (107-4)
[0696]
(4-Methylphenyl)[4-methyl-1-(3-quinolinylmethyl)-1H-pyrrol-2-yl]met-
hanol was obtained from the compound of Example 107-3 in a similar
manner to Example 20-2.
[0697] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.65 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=7.9 Hz), 7.69 (d, 1H, J=7.9 Hz), 7.68 (dd, 1H,
J=7.9, 7.9 Hz), 7.56 (d, 1H, J=2.2 Hz), 7.52 (dd, 1H, J=7.9, 7.9
Hz), 7.21 (d, 2H, J=8.0 Hz), 7.05 (d, 2H, J=8.0 Hz), 6.46 (d, 1H,
J=1.3 Hz), 5.78 (d, 1H, J=1.3 Hz), 5.76 (d, 1H, J=4.5 Hz), 5.30 (d,
1H, J=16.3 Hz), 5.21 (d, 1H, J=16.3 Hz), 2.23 (s, 3H), 2.23 (1H),
2.05 (s, 3H).
[0698] (107-5)
[0699] The title compound was obtained from the compound of Example
107-4 in a similar manner to Example 28-4.
[0700] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.81 (d, 1H, J=2.2
Hz), 8.07 (d, 1H, J=7.9 Hz), 7.95 (d, 1H, J=2.2 Hz), 7.77 (d, 1H,
J=7.9 Hz), 7.67 (t, 1H, J=7.9 Hz), 7.67 (d, 2H, J=7.9 Hz), 7.51 (t,
1H, J=7.9 Hz), 7.22 (d, 2H, J=7.9 Hz), 6.88 (d, 1H, J=1.3 Hz), 6.63
(d, 1H, J=1.3 Hz), 5.79 (s, 2H), 2.41 (s, 3H), 2.09 (s, 3H).
Example 108
[0701] 126
[0702] 3-Methyl-1-(3-quinolinylmethyl)-1H-pyrrole-2-carbaldehyde
was obtained from 3-methyl-1H-pyrrole-2-carbaldehyde in a similar
manner to Example 20-1.
[0703] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.71 (s, 1H), 8.77
(d, 1H, J=2.2 Hz), 8.17 (d, 1H, J=7.9 Hz), 7.98 (d, 1H, J=2.2 Hz),
7.80 (d, 1H, J=7.9 Hz), 7.73 (t, 1H, J=7.9 Hz), 7.57 (t, 1H, J=7.9
Hz), 6.98 (d, 1H, J=2.4 Hz), 6.12 (d, 1H, J=2.4 Hz), 5.72 (s, 2H),
2.39 (s, 3H).
[0704] (108-2)
[0705]
(4-Methylphenyl)[3-methyl-1-(3-quinolinylmethyl)-1H-pyrrol-2-yl]met-
hanol was obtained from the compound of Example 108-1 in a similar
manner to Example 20-2.
[0706] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.44 (d, 1H, J=2.2
Hz), 8.08 (d, 1H, J=7.8 Hz), 7.66 (dd, 1H, J=7.8, 7.8 Hz), 7.61 (d,
1H, J=7.8 Hz), 7.50 (dd, 1H, J=7.8, 7.8 Hz), 7.37 (d, 1H, J=2.2
Hz), 7.11 (d, 2H, J=8.0 Hz), 6.89 (d, 2H, J=8.0 Hz), 6.56 (d, 1H,
J=2.7 Hz), 6.11 (s, 1H), 6.06 (d, 1H, J=2.7 Hz), 5.22 (d, 1H,
J=16.3 Hz), 5.10 (d, 1H, J=16.3 Hz), 2.17 (s, 3H), 2.04 (s,
3H).
[0707] (108-3)
[0708] The title compound was obtained from the compound of Example
108-2 in a similar manner to Example 28-4.
[0709] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.72 (d, 1H, J=2.2
Hz), 8.16 (brd, 1H, J=7.7 Hz), 7.98 (brs, 1H), 7.77 (d, 1H, J=7.7
Hz), 7.71 (t, 1H, J=7.7 Hz), 7.55 (t, 1H, J=7.7 Hz), 7.52 (d, 2H,
J=8.0 Hz), 7.19 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=2.5 Hz), 6.09 (d,
1H, J=2.5 Hz), 5.64 (s, 2H), 2.38 (s, 3H), 1.82 (s, 3H).
Example 109
[0710] 127
[0711] Ethyl 4-methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carboxylate
was obtained from methyl 4-methyl-1H-pyrrole-2-carboxylate in a
similar manner to Example 6-1.
[0712] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.97 (d, 2H, J=7.7
Hz), 7.61 (t, 1H, J=7.7 Hz), 7.53 (dd, 2H, J=7.7, 7.7 Hz), 7.48 (d,
1H, J=2.0 Hz), 6.90 (d, 1H, J=2.0 Hz), 3.70 (s, 3H), 2.10 (s,
3H).
[0713] (109-2)
[0714] Under nitrogen atmosphere, to a solution of the compound of
Example 109-1 (1.58 g) in toluene (30 mL) that was colled to
-78.degree. C. was added dropwise a 0.93N solution of
diisobutylaluminum hydride in toluene (12.5 mL). The mixture was
stirred at -78.degree. C. for 1 hour, and to the reaction solution
was added a 1N aqueous hydrochloric acid solution. The mixture was
extracted with ethyl acetate, and the extract was washed with a
saturated brine, dried over magnesium sulfate, and filtered. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=3/1.fwdarw.2/1)
to give [4-methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl]methanol (1.24
g, 87%).
[0715] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (dd, 2H,
J=1.4, 7.7 Hz), 7.61 (dt, 1H, J=7.7, 1.4 Hz), 7.52 (t, 2H, J=7.7
Hz), 7.00 (d, 1H, J=1.7 Hz), 6.11 (d, 1H, J=1.7 Hz), 4.56 (s, 2H),
2.02 (s, 3H).
[0716] (109-3)
[0717] 4-Methyl-1-(phenylsulfonyl)-1H-pyrrole-2-carbaldehyde was
otained from the compound of Example 109-2 in a similar manner to
Example 28-4.
[0718] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.95 (s, 1H), 7.90
(dd, 2H, J=1.4, 7.7 Hz), 7.64 (dt, 1H, J=7.7, 1.4 Hz), 7.53 (t, 2H,
J=7.7 Hz), 7.37 (d, 1H, J=1.8 Hz), 7.00 (d, 1H, J=1.8 Hz), 2.10 (s,
3H).
[0719] (109-4)
[0720]
[4-Methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl](4-methoxyphenyl)-metha-
nol was obtained from the compound of Example 109-3 and
4-bromoanisole in a similar manner to Example 20-2.
[0721] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.71 (dd, 2H,
J=1.3, 7.8 Hz), 7.60 (dt, 1H, J=7.8, 1.3 Hz), 7.47 (t, 2H, J=7.8
Hz), 7.16 (d, 2H, J=8.6 Hz), 7.04 (d, 1H, J=2.0 Hz), 6.81 (d, 2H,
J=8.6 Hz), 5.97 (s, 1H), 5.67 (d, 1H, J=2.0 Hz), 3.80 (s, 3H), 1.96
(s, 3H).
[0722] (109-5)
[0723]
[4-Methyl-1-(phenylsulfonyl)-1H-pyrrol-2-yl](4-methoxyphenyl)
ketone was obtained from the compound of Example 109-4 in a similar
manner to Example 28-4.
[0724] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.10 (dd, 2H,
J=1.6, 7.4 Hz), 7.82 (d, 2H, J=8.9 Hz), 7.64 (dt, 1H, J=7.4, 1.6
Hz), 7.57 (t, 2H, J=7.4 Hz), 7.47 (d, 1H, J=1.8 Hz), 6.92 (d, 2H,
J=8.9 Hz), 6.51 (d, 1H, J=1.8 Hz), 3.87 (s, 3H), 2.10 (s, 3H).
[0725] (109-6)
[0726] (4-Methyl-1H-pyrrol-2-yl)(4-methoxyphenyl)ketone was
obtained from the compound of Example 109-5 in a similar manner to
Reference Example 1-2.
[0727] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.38 (brs, 1H),
7.92 (d, 2H, J=8.9 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.89-6.90 (m, 1H),
6.70 (dd, 1H, J=1.2, 2.0 Hz), 3.88 (s, 3H), 2.15 (s, 3H).
[0728] (109-7)
[0729] The title compound was obtained from the compound of Example
109-6 in a similar manner to Example 18-3.
[0730] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.83 (d, 2H, J=8.9 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=2.3, 8.5 Hz), 7.21 (dt, 1H, J=15.8, 1.4 Hz), 6.94 (d, 2H, J=8.9
Hz), 6.85 (d, 1H, J=1.1 Hz), 6.57 (d, 1H, J=1.1 Hz), 6.34 (dt, 1H,
J=15.8, 6.1 Hz), 5.14 (dd, 2H, J=1.4, 6.1 Hz), 3.88 (s, 3H), 3.87
(s, 3H), 2.09 (s, 3H).
Example 109
[0731] The compound of Example 109 was also prepared as
follows.
[0732] (109-8)
[0733] 5-Chloroanthranilic acid (15.0 g), (CH.sub.3).sub.2SO.sub.4
(11.6 g) and K.sub.2CO.sub.3 (12.7 g) were refluxed in acetone (150
g) for 30 minutes. The mixture was concentrated to about 90 g, and
thereto was added water (90 g). The mixture was extracted with
toluene (75 g), and the organic layer was concentrated to give
methyl 5-chloroanthranilate (15.6 g, 96%).
[0734] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 1H, J=2.6
Hz), 7.21 (dd, 1H, J=8.5 and 2.6 Hz), 6.61 (d, 1H, J=8.5 Hz), 5.73
(brs, 2H), 3.88 (s, 3H).
[0735] (109-9)
[0736] To conc. sulfuric acid (221 g) was added NaNO.sub.2 (12.3
g), and the mixture was dissovled, during which the reaction
temperature was raised to about 60.degree. C. This solution was
cooled to 10.degree. C., and thereto was added dropwise a solution
of methyl 5-chloro-2-aminobenzoate (30.0 g) in acetic acid (360 g)
at a temperature of from 15 to 25.degree. C. The mixture was warmed
to 45.degree. C., and the mixture was stirred for 40 minutes. The
mixture (suspension) was added dropwise into an aqueous solution of
KI (40.2 g) in water (300 mL) in such a manner that the reaction
temperature was not raised over 10.degree. C. The mixture was
further stirred at 35.degree. C. for 1.5 hour, and thereto was
added water (300 mL). The mixture was extracted twice with toluene
(450 g), and the organic layers were combined, washed twice with
water (450 mL), and washed successively with an aqueous solution of
sodium hydrogen carbonate (450 g), a 10% aqueous sodium thiosulfate
solution (450 g) and water (225 mL). Then, the mixture was
concentrated to give methyl 5-chloro-2-iodobenzoate (44.1 g, yield:
92%).
[0737] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.91 (d, 1H, J=8.5
Hz), 7.80 (d, 1H, J=2.6 Hz), 7.15 (dd, 1H, J=8.5 and 2.6 Hz), 3.94
(s, 3H).
[0738] (109-10)
[0739] Under nitrogen atmosphere, to a solution of the compound of
Reference Example 5-2 (5 g) in THF (15 mL) was added KOtBu (3.07
g). Further, a solution of allyl bromide (4.51 g) in THF (9.0 mL)
was added thereto, and the mixture was stirred at 45.degree. C. for
2 hours. Water was added to the mixture, and the mixture was
extracted twice with toluene. The organic layers were concentrated
to give [1-(2-propenyl)-1H-pyrrol-2-yl][4-methoxyphenyl]ketone
(6.00 g, 98%). To DMF (7.31 g) was added dropwise POCl.sub.3 (11.5
g) at 10.degree. C., and the mixture was stirred for 15 minutes. To
the mixture was added THF (5.41 g), and thereto was added dropise a
solution of [1-(2-propenyl)-1H-pyrrol-2-yl][4-methoxyphenyl]ketone
in toluene (10 mL). The mixture was stirred at room temperature for
5 hours, and thereto was added a solution of sodium acetate (11.2
g) in water (22 g), and the mixture was stirred for 3 hours. The
precipitated crystals were collected by filtration, and dried to
give (4-formyl-1-(2-propenyl)-1H-pyrrol-2-yl)- (4-methoxyphenyl)
ketone (3.31 g). The organic layer of the filtrate was collected,
concentraed, and the precipitated crystals were collected by
filtration, and dried (1.48 g, total 4.79 g, 71%).
[0740] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.81 (s, 1H), 7.86
(d, 2H, J=8.6 Hz), 7.58 (d, 1H, J=1.8 Hz), 7.15 (d, 1H, J=1.8 Hz),
6.97 (d, 2H, J=8.6 Hz), 6.06 (ddt, 1H, J=10.0, 15.0 and 5.8 Hz),
5.26 (dq, 1H, J=10.0 and 1.1 Hz), 5.16 (dq, 1H, J=15.0 and 1.1 Hz),
5.05 (dt, 1H, J=5.8 and 1.1 Hz), 3.89 (s, 3H).
[0741] (109-11)
[0742] The above compound (300 mg) and TFA (4.50 g) were dissolved
in CH.sub.2Cl.sub.2, and thereto was added Et.sub.3SiH (1.30 g).
The mixture was stirred at room temperature for 30 minuts, and the
reaction solution was poured into a 1N aqueous NaOH solution, and
extracted with toluene. The solvent was evaporated under reduced
pressure to give
(4-methyl-1-(2-propenyl)-1H-pyrrol-2-yl)(4-methoxyphenyl)ketone
(280 mg).
[0743] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.82 (d, 2H, J=8.8
Hz), 6.94 (d, 2H, J=8.8 Hz), 6.76 (brs, 1H), 6.54 (brd, 1H, J=1.8
Hz), 6.05 (ddt, 1H, J=10.0, 15.0 and 5.8 Hz), 5.14 (dq, 1H, J=10.0
and 1.1 Hz), 5.07 (dq, 1H, J=15.0 and 1.1 Hz), 4.97 (dt, 1H, J=5.8
and 1.1 Hz), 3.87 (s, 3H), 2.08 (brs, 3H).
[0744] (109-12)
[0745] Methyl 5-chloro-2-iodobenzoate (300 mg),
(4-methyl-1-(2-propenyl)-1- H-pyrrol-2-yl)(4-methoxyphenyl)ketone
(258 mg), NaHCO.sub.3 (170 mg), and Et.sub.3BnNCl (230 mg) were
dissolved in DMF (3.0 g), and thereto was blown nitrogen gas for
nitrogen-substitituion. To the mixture was added Pd(OAc).sub.2
(11.0 mg), and the mixture was warmed to 50.degree. C., and stirred
for 8 hours. Water was added to the reaction solution, and the
mixture was extracted with toluene. The organic layer was
concentrated, and the residue was purified by silica gel column
chromatography to give the compound of Example 109.
Example 110
[0746] 128
[0747] The title compound was obtained from the compound of Example
109-7 in a similar manner to Example 19.
[0748] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.97 (d, 1H, J=2.2
Hz), 7.83 (d, 2H, J=8.9 Hz), 7.50 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H,
J=2.2, 8.5 Hz), 7.28 (dt, 1H, J=15.5, 1.3 Hz), 6.93 (d, 2H, J=8.9
Hz), 6.86 (d, 1H, J=1.1 Hz), 6.58 (d, 1H, J=1.1 Hz), 6.35 (dt, 1H,
J=15.5, 6.0 Hz), 5.15 (dd, 2H, J=1.3, 6.0 Hz), 3.85 (s, 3H), 2.09
(s, 3H).
Example 111
[0749] 129
[0750] The title compound was obtained from the compound of Example
109-7 in a similar manner to Example 92.
[0751] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.78 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=2.3, 8.5 Hz), 7.20 (dt, 1H, J=15.8, 1.4 Hz), 6.87 (d, 2H, J=8.7
Hz), 6.86 (d, 1H, J=1.6 Hz), 6.57 (d, 1H, J=1.6 Hz), 6.33 (dt, 1H,
J=15.8, 6.1 Hz), 5.13 (dd, 2H, J=1.4, 6.1 Hz), 3.87 (s, 3H), 2.09
(s, 3H).
Example 112
[0752] 130
[0753] Under nitrogen atmosphere, to a solution of the compound of
Reference Example 1-2 (2.00 g) in 1,2-dichloroethane (14
mL)-nitromethane (14 ml) was added aluminum chloride (3.17 g), and
the mixture was cooled to about -20.degree. C. To the mixture was
added a solution of dichloromethyl methyl ether (1.05 mL) in
1,2-dichloroethane (3.0 mL), and the mixture was stirred at about
-20.degree. C. for 2 hours, and then allowed to stand overnight.
The reaction solution was poured into ice water, and extracted
three times with chloroform. The extracts were washed with a
saturated brine, dried over magnesium sulfate, and filtered. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl-acetate=3/1.fwdar-
w.1/1) to give [5-(4-methylbenzoyl)-1H-pyrrol-3-yl]carbaldehyde
(1.65 g, 72%).
[0754] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.22 (brs, 1H),
9.90 (s, 1H), 7.86 (d, 2H, J=8.2 Hz), 7.73 (dd, 1H, J=1.4, 3.4 Hz),
7.31-7.34 (m, 3H), 2.46 (s, 3H).
[0755] (112-2)
[0756] The title compound was obtained from the compound of Example
111-2 and the compound of Example 9-2 in a similar manner in
Example 9-3.
[0757] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.81 (s, 1H), 8.00
(d, 1H, J=1.4 Hz), 7.75 (d, 2H, J=8.2 Hz), 7.73 (d, 1H, J=1.7 Hz),
7.48 (m, 2H), 7.34 (dt, 1H, J=15.7, 1.3 Hz), 7.27 (d, 2H, J=8.2
Hz), 7.21 (d, 1H, J=1.7 Hz), 6.33 (dd, 1H, J=15.7, 6.1 Hz), 5.26
(dd, 2H, J=1.3, 6.1 Hz), 2.42 (s, 3H).
Example 113
[0758] 131
[0759] The title compound was obtained from the compound of Example
90 in a similar manner to Example 19.
[0760] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.01 (dd, 1H,
J=1.2, 7.7 Hz), 7.86 (d, 2H, J=8.8 Hz), 7.57 (brd, 1H, J=7.7 Hz),
7.50 (dt, 1H, J=1.1, 7.7 Hz), 7.36 (brd, 1H, J=15.7 Hz), 7.34 (dt,
1H, J=1.2, 7.7 Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz), 6.94 (brd, 2H,
J=8.8 Hz), 6.77 (dd, 1H, J=1.7, 4.0 Hz), 6.37 (dt, 1H, J=15.7, 6.2
Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 5.24 (dd, 2H, J=6.2, 1.4 Hz),
3.86 (s, 3H).
Example 114
[0761] 132
[0762] The compound of Example 113 (560 mg) was dissolved in THF
(2.0 mL), and the mixture was treated with a 1N aqueous NaOH
solution (1.50 mL), and the solvent was evaporated under reduced
pressure. The residue was suspended in ether, and the solid was
collected by filtration, and dried to give the title compound (510
mg, 89%).
[0763] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.78 (d, 2H,
J=8.8 Hz), 7.46 (brd, 1H, J=15.7 Hz), 7.31-7.37 (m, 2H), 7.31 (dd,
1H, J=1.7, 2.5 Hz), 7.04 (d, 2H, J=8.8 Hz), 7.02-7.08 (m, 2H), 6.65
(dd, 1H, J=1.7, 4.0 Hz), 6.20 (dd, 1H, J=2.5, 4.0 Hz), 6.19 (dt,
1H, J=15.7, 6.2 Hz), 5.08 (dd, 2H, J=6.2, 1.4 Hz), 3.84 (s,
3H).
Example 115
[0764] 133
[0765] Under nitrogen atmosphere, to a solution of the compound of
Example 9 (44.6 mg) in DMF (0.7 mL) was added carbonyldiimidazole
(26.0 mg), and the mixture was stirred at room temperature for 2
hours. Subsequently, to the mixture were added methanesulfonamide
(15.5 mg) and DBU (30 .mu.L), and the mixture was stirred at
90.degree. C. for 2 hours. The reaction mixture was cooled to room
temperature, and thereto was added a 5% aqueous potassium hydrogen
sulfate solution, and the mixture was extracted with ethyl
acetate-toluene. The organic layer was washed with a 5% aqueous
potassium hydrogen sulfate solution, dried over magnesium sulfate.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl
acetate=1/1.fwdarw.0/1) to give the title compound (30.5 mg,
57%).
[0766] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.79 (brs, 1H),
7.69 (d, 2H, J=8.0 Hz), 7.52 (d, 1H, J=2.1 Hz), 7.44 (d, 1H, J=8.4
Hz), 7.39 (dd, 1H, J=2.1, 8.4 Hz), 7.23 (d, 2H, J=8.0 Hz), 7.06
(dd, 1H, J=1.6, 2.5 Hz), 6.78 (dd, 1H, J=1.6, 4.0 Hz), 6.70 (d, 1H,
J=15.6 Hz), 6.40 (dt, 1H, J=15.6, 5.4 Hz), 6.23 (dd, 1H, J=2.5, 4.0
Hz), 5.16 (d, 2H, J=5.4 Hz), 3.33 (s, 3H), 2.41 (s, 3H).
Example 116
[0767] 134
[0768] Under nitrogen atmosphere, to the compound of Example 9
(25.3 mg), dimethylamine hydrochloride (13.5 mg) and
1-hydroxybenzotriazole (11.9 mg) were added successively DMF (0.5
ml), WSCI hydrochloride (17.5 mg), triethylamine (40 .mu.L), and
the mixture was stirred at room temperature for 11 hours. Water was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate-toluene, washed with water and a saturated brine, and
dried over magnesium sulfate. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=2/1) to give the title compound (16.1 mg,
59%).
[0769] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.71 (d, 2H, J=8.1
Hz), 7.44 (d, 1H, J=8.4 Hz), 7.27 (dd, 1H, J=2.2, 8.4 Hz), 7.25 (d,
2H, J=8.1 Hz), 7.19 (d, 1H, J=2.2 Hz), 7.00 (dd, 1H, J=1.6, 2.5
Hz), 6.78 (dd, 1H, J=1.6, 4.0 Hz), 6.43 (dt, 1H, J=15.8, 5.7 Hz),
6.29 (d, 1H, J=15.8 Hz), 6.22 (dd, 1H, J=2.5, 4.0 Hz), 5.17 (brs,
2H), 3.02 (s, 3H), 2.66 (s, 3H), 2.43 (s, 3H).
Example 117
[0770] 135
[0771] The title compound (24.6 mg, 95%) was obtained from the
compound of Example 9 (25.0 mg) and methylamine hydrochloride in a
similar manner to Example 116.
[0772] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.72 (d, 2H, J=8.0
Hz), 7.53 (d, 1H, J=2.2 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.31 (dd, 1H,
J=2.2, 8.4 Hz), 7.26(d, 2H, J=8.0 Hz), 7.04 (dd, 1H, J=1.6, 2.5
Hz), 6.79 (dd, 1H, J=1.6, 4.0 Hz), 6.72(d, 1H, J=15.7 Hz), 6.30
(dt, 1H, J=15.7, 5.7 Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 6.04 (brs,
1H), 5.14 (d, 2H, J=5.7 Hz), 2.94 (d, 3H, J=4.8 Hz), 2.43 (s,
3H).
Example 118
[0773] 136
[0774] The title compound (15.4 mg, 64%) was obtained from the
compound of Example 9 (24.3 mg) and ammonium chloride in a similar
manner to Example 116.
[0775] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.70 (d, 2H, J=8.0
Hz), 7.60 (d, 1H, J=2.2 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.34 (dd, 1H,
J=2.2, 8.4 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.04 (dd, 1H, J=1.7, 2.5
Hz), 6.81 (dd, 1H, J=1.7, 4.0 Hz), 6.76 (d, 1H, J=15.8 Hz), 6.32
(dt, 1H, J=15.8, 5.6 Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 6.09 (br,
1H), 5.78 (br, 1H), 5.16 (d, 2H, J=5.6 Hz), 2.43 (s, 3H).
[0776] The structures of the compounds of Examples 119 to 226 are
shown in the following Tables. In Tables, the compounds having the
indications in the columns of the starting compounds and Reference
Examples were prepared by using said starting compounds in a
similar manner to said Reference Examples. Following to Tables,
processes for the compounds having no indication in these columns
and the spectrum data of the compounds of Examples 119 to 226 are
shown.
1 137 Comp. Ex. R.sup.a R.sup.b R.sup.c R.sup.d (Ex) Ref. Ex. 119
CO.sub.2CH.sub.3 CH.sub.3 H 2-morpholinoethoxy 120 CO.sub.2Na
CH.sub.3 H 2-morpholinoethoxy 119-2 16 121 CONHCH.sub.3 CH.sub.3 H
2-morpholinoethoxy 119-2 116 hydrochloride 122 CO.sub.2CH.sub.3 H H
morpholinomethyl 123 CO.sub.2H H H morpholinomethyl 122 16
hydrochloride 124 CONHCH.sub.3 H H morpholinomethyl 123 116 125
CO.sub.2H H H 2-morpholinoethyl 126 CO.sub.2H CH.sub.3 H
morpholinomethyl 127 CO.sub.2H H H morpholino 128 CN H H CH.sub.3
129 5-tetrazolyl H H CH.sub.3 130 CONHCH.sub.3 H H OCH.sub.3 102
116 131 CONHSO.sub.2CH.sub.3 H H OCH.sub.3 102 115 132
CONHSO.sub.2CH.sub.3 H H OH 131 119-1 133 CONHCH.sub.3 H H OH 130
119-1 134 1-sodio-5-tetrazolyl H H OCH.sub.3 135 5-tetrazolyl
CH.sub.3 H OCH.sub.3 109 128, 129 136 CONNaSO.sub.2CH.sub.3
CH.sub.3 H OCH.sub.3 137 OCH.sub.3 CH.sub.3 H OCH.sub.3 138
CO.sub.2CH.sub.3 CH.sub.3 H CH.sub.3 139 CO.sub.2Na CH.sub.3 H
CH.sub.3 140 CONaSO.sub.2CH.sub.3 CH.sub.3 H CH.sub.3 139-1 115 141
OCH.sub.3 CH.sub.3 H CH.sub.3 137-5 18-3 138-1 142
NHSO.sub.2CH.sub.3 CH.sub.3 H OCH.sub.3 143 OCH.sub.3 CH.sub.3 H OH
144 OCH.sub.3 CH.sub.3 H 2-morpholinoethoxy 143 119-2 145
CONHSO.sub.2CH.sub.3 CH.sub.3 H OH 136 119-1 146 CO.sub.2H CHO H
OCH.sub.3 147 CONHSO.sub.2Et CH.sub.3 H OCH.sub.3 148
CONHSO.sub.2Ph CH.sub.3 H OCH.sub.3 149 CO.sub.2CH.sub.3 H H H 9-2
18-3 150 CO.sub.2H H H H 149 16 151 CO.sub.2CH.sub.3 H Cl CH.sub.3
152 CO.sub.2H H Cl CH.sub.3 151 16 153 CO.sub.2CH.sub.3 H H
OCH.sub.2CH.sub.2OH 154 CO.sub.2H H H OCH.sub.2CH.sub.2OH 153 16
155 CONHCH.sub.3 H H OCH.sub.2CH.sub.2OH 156 CONHSO.sub.2CH.sub.3 H
H OCH.sub.2CH.sub.2OH 157 CO.sub.2CH.sub.3 CH.sub.3 H
OCH.sub.2CH.sub.2OH 158 CO.sub.2R CH.sub.3 H OCH.sub.2CH.sub.2OH
157 16 159 CO.sub.2CH.sub.3 H H OCH.sub.2CH.sub.2Cl 160
CO.sub.2CH.sub.3 H H OCH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OEt).sub.2
159-1 81 161 CO.sub.2H H H
OCH.sub.2CH.sub.2N(CH.sub.2CH.sub.2OEt).sub.2 160 16 162 CO.sub.2H
CH.sub.3 H O(CH.sub.2).sub.8N.sub.3 163 CO.sub.2CH.sub.3 H H
CH(OCH.sub.2).sub.2CH.sub.2 164 CO.sub.2H H H CH.sub.2OH 165
CO.sub.2CH.sub.3 H H CH.sub.2N(CH.sub.2CH.sub.2).su- b.2CHOH 166
CO.sub.2CH.sub.3 H H pyrazolylmethyl 167 CO.sub.2H H H
pyrazolylmethyl 166 16 168 CO.sub.2H H H 2-thiazolyl 169
CO.sub.2CH.sub.3 H H CH.sub.2OCH.sub.3 170 CO.sub.2H H H
CH.sub.2OCH.sub.3 169 16 171 CO.sub.2CH.sub.3 H H pyrazolyl 172
CO.sub.2H H H pyrazolyl 171 16 173 CO.sub.2CH.sub.3 H H
triazolylmethyl 220 CO.sub.2CH.sub.3 H H Cl 221 CO.sub.2H H H Cl
220 16 222 CO.sub.2CH.sub.3 H H CF.sub.3 223 CO.sub.2H H H CF.sub.3
222 16
[0777]
2 138 Starting Comp. Ex. R.sup.e R.sup.f R.sup.g R.sup.h (Ex) Ref.
Ex. 174 H CO.sub.2CH.sub.3 CH.sub.3 OCH.sub.3 109-6, 18-2 18-3 175
H CO.sub.2Na CH.sub.3 OCH.sub.3 174 16 176 CO.sub.2Et H H CH.sub.3
177 CO.sub.2Et H H OCH.sub.3 176-1, 18-3 Ref. Ex. 5
[0778]
3 139 Starting Comp. Ex. R.sup.i Ring R.sup.j (Ex) Ref. Ex. 178
CO.sub.2H 140 CH.sub.3 179 CO.sub.2CH.sub.3 141 OCH.sub.3 180
CO.sub.2CH.sub.3 142 CH.sub.3 181 CO.sub.2CH.sub.3 143 CH.sub.3 182
CO.sub.2H 144 CH.sub.3 183 CO.sub.2CH.sub.3 145 CH.sub.3 184
CO.sub.2H 146 CH.sub.3 183 16 185 CO.sub.2H 147 CH.sub.3 148
Starting Comp. Ex. R.sup.k Chain Ring R.sup.l (Ex) Ref. Ex. 186
CO.sub.2H 149 CH.sub.3 187 CO.sub.2CH.sub.3 150 CH.sub.3 188
CO.sub.2CH.sub.3 151 CH.sub.3 189 CO.sub.2CH.sub.3 152 CH.sub.3
[0779]
4 153 Starting Comp. Ex. R.sup.m Ar.sup.a (Ex.) Ref. Ex. 190
CO.sub.2CH.sub.3 5-methylthienyl 191 CO.sub.2H 5-methylthienyl 190
16 192 CO.sub.2CH.sub.3 1-methyl-5-indolyl 193 CO.sub.2H
1-methyl-5-indolyl 192 16 194 CO.sub.2H 2-methyl-5-thiazolyl 195
CO.sub.2H 6-benzothiazolyl 196 CO.sub.2CH.sub.3 6-methyl-2-pyridyl
197 CO.sub.2H 6-methyl-2-pyridyl 196 16 198 CO.sub.2CH.sub.3
3,4-dimethoxyphenyl 199 CO.sub.2Na 3,4-dimethoxyphenyl 198 16 200
CO.sub.2CH.sub.3 1,3-benzodioxol-5-yl 201 CO.sub.2Na
1,3-benzodioxol-5-yl 200 16
[0780]
5 154 Starting Comp. Ex. R.sup.n L R.sup.o R.sup.d (Ex) Ref. Ex.
202 CO.sub.2H 155 CH.sub.3 OCH.sub.3 203 CO.sub.2H 156 CH.sub.3
OCH.sub.3 204 CO.sub.2CH.sub.3 --C.ident.CCH.sub.2-- H CH.sub.3 205
CO.sub.2CH.sub.3 --OCH.sub.2CH.sub.2-- CH.sub.3 OCH.sub.3 206
CO.sub.2H --OCH.sub.2CH.sub.2-- CH.sub.3 OCH.sub.3 205 16 207
CO.sub.2CH.sub.3 157 CH.sub.3 OCH.sub.3 208 CO.sub.2H 158 CH.sub.3
OCH.sub.3 207 16 209 CO.sub.2CH.sub.3 159 CH.sub.3 OCH.sub.3 210
CO.sub.2H 160 CH.sub.3 OCH.sub.3 209 16 211 CO.sub.2H
--C.ident.CCH.sub.2-- H CH.sub.3 212 CO.sub.2CH.sub.3 161 CH.sub.3
OCH.sub.3 213 CO.sub.2H 162 CH.sub.3 OCH.sub.3 212 16 214 CO.sub.2H
--OCH.sub.2C.ident.CCH.sub.2-- H CH.sub.3 215 CO.sub.2CH.sub.3 163
CH.sub.3 OCH.sub.3 216 CO.sub.2H 164 CH.sub.3 OCH.sub.3 215 16
[0781]
6 165 Starting Comp. Ex. Ar.sup.b (Ex) Ref. Ex. 217 166 218 167 219
168 218 16
[0782]
7 169 Starting Comp. Ex. R.sup.q L R.sup.r (Ex) Ref. Ex. 224
CO.sub.2H --CONH-- OCH.sub.3 225 CO.sub.2CH.sub.3 --CONCH.sub.3--
CH.sub.3 226 CO.sub.2H --CONCH.sub.3-- CH.sub.3 225 16
Example 119
[0783] (119-1)
[0784] Under nitrogen atmosphere, a solution of AiCl.sub.3 (180 mg)
and EtSH (300 .mu.l) in CH.sub.2Cl.sub.2 (1.0 mL) was cooled to
0.degree. C., and thereto was added the compound of Example 109
(150 mg), and the mixture was stirred for 2.5 hours. The reaction
solution was poured into an aqueous hydrochloric acid solution, and
the mixture was extracted twice with ethyl acetate. The extract was
washed with a saturated brine, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=3/1.fwdarw.2/1)
to give methyl 5-chloro-2-{(1E)-3-[2-(4-hydroxybe-
nzoyl)-4-methyl-1H-pyrrol-1-yl]-1-propenyl}benzoate (94.8 mg,
65%).
[0785] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.78 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=2.3, 8.5 Hz), 7.20 (dt, 1H, J=15.8, 1.4 Hz), 6.87 (d, 2H, J=8.7
Hz), 6.86 (d, 1H, J=1.6 Hz), 6.57 (d, 1H, J=1.6 Hz), 6.33 (dt, 1H,
J=15.8, 6.1 Hz), 5.13 (dd, 2H, J=1.4, 6.1 Hz), 3.87 (s, 3H), 2.09
(s, 3H).
[0786] (119-2)
[0787] The title compound was obtained from the compound of Example
119-1 and N-(2-chloroethyl)morpholine hydrochloride in a similar
manner to Example 81.
[0788] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.82 (d, 2H, J=8.8 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H,
J=2.3, 8.4 Hz), 7.20 (d, 1H, J=15.8 Hz), 6.95 (d, 2H, J=8.8 Hz),
6.86 (d, 1H, J=1.1 Hz), 6.56 (d, 1H, J=1.1 Hz), 6.34 (dt, 1H,
J=15.8, 6.1 Hz), 5.14 (d, 2H, J=6.1 Hz), 4.20-4.23 (m, 2H), 3.87
(s, 3H), 3.76-3.79 (m, 4H), 2.87 (m, 2H), 2.64 (m, 4H), 2.09 (s,
3H).
Example 120
[0789] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.74 (d, 2H,
J=8.7 Hz), 7.46 (d, 1H, J=16.1 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.38
(d, 1H, J=2.4 Hz), 7.11 (dd, 1H, J=2.4, 8.3 Hz), 7.08 (s, 1H), 7.03
(d, 2H, J=8.7 Hz), 6.47 (s, 1H), 6.21 (dt, 1H, J=16.1, 6.4 Hz),
5.01 (d, 2H, J=6.4 Hz), 4.16-4.19 (m, 2H), 3.57-3.59 (m, 4H),
2.71-2.73 (m, 2H), 2.48-2.51 (m, 4H), 2.03 (s, 3H).
Example 121
[0790] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 10.92 (brs, 1H),
8.31 (br, 1H), 7.77 (d, 2H, J=8.6 Hz), 7.63 (d, 1H, J=8.5 Hz), 7.41
(dd, 1H, J=2.2, 8.5 Hz), 7.34 (d, 1H, J=2.2 Hz), 7.10 (d, 2H, J=8.6
Hz), 7.09 (s, 1H), 6.46-6.52 (m, 3H), 5.09 (d, 2H, J=3.7 Hz), 4.50
(m, 2H), 3.96-3.99 (m, 2H), 3.77-3.83 (m, 2H), 3.50-3.63 (m, 4H),
3.20-3.23 (m, 2H), 2.70 (d, 3H, J=4.6 Hz), 2.04 (s, 3H).
Example 122
[0791] (122-1)
[0792] Under nitrogen atmosphere, a solution of
2,2,6,6-tetramethylpiperid- ine (1.87 g) in THF (30 mL) was cooled
to -78.degree. C., and thereto was added dropwise a 1.5N solution
of n-BuLi in n-hexane (8.85 mL), and the mixture was stirred at
-78.degree. C. for 5 minutes, and stirred at -30.degree. C. for 5
minutes. Then, the mixture was cooled to -78.degree. C., and
thereto was added dropwise a solution of 1-(phenylsulfonyl)pyrrol-
e (2.50 g) in THF (20 mL). The mixture was stirred at -78.degree.
C. for 45 minutes, and thereto was added dropwise a solution of
methyl telephthalaldehyde (2.38 g) in THF (20 mL), and the mixture
was further stirred at -78.degree. C. for 1.5 hour. To the mixture
was added drowpise aqueous NH.sub.4Cl solution, and the mixture was
warmed to room temperature. The mixture was extracted with ethyl
acetate, and the organic layer was washed with a 2.5N aqueous
hydrochloric acid solution and NaHCO.sub.3, and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=4/1.fwdarw.3/1) to give methyl
4-{hydroxy[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}-benzoate (3.67
g, 82%).
[0793] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.94 (d, 2H, J=8.4
Hz), 7.73 (d, 2H, J=8.4 Hz), 7.63 (m, 1H), 7.49 (m, 2H), 7.34 (dd,
1H, J=3.3, 1.8 Hz), 7.31 (d, 2H, J=8.4 Hz), 6.21 (dd, 1H, J=3.3,
3.3 Hz), 6.11 (d, 1H, J=4.6 Hz), 5.77 (m, 1H), 3.92 (s, 3H), 3.33
(d, 1H, J=4.6 Hz).
[0794] (122-2)
[0795] Under nitrogen atmosphere, a solution of the compound of
Example 122-1 (3.64 g) in toluene (100 mL) was cooled to
-78.degree. C., and thereto was added dropwise a 1.01 N solution of
diisobutylaluminum hydride in toluene (29.2 mL), and the mixture
was stirred at -78.degree. C. for 2 hours. To the mixture was added
dropwise an aqueous NH.sub.4Cl solution, and the mixture was warmed
to room temperature. The mixture was extracted five times with
ethyl acetate, and the extract was dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=1/1) to give
4-{hydroxy[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}benzoic acid
(2.82 g, 84%).
[0796] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.73 (d, 2H, J=8.4
Hz), 7.61 (m, 1H), 7.49 (m, 2H), 7.33 (dd, 1H, J=3.3, 1.8 Hz), 7.28
(d, 2H, J=8.4 Hz), 7.23 (d, 2H, J=8.4 Hz), 6.20 (dd, 1H, J=3.3, 3.3
Hz), 6.07 (d, 1H, J=4.7 Hz), 5.82 (m, 1H), 4.68 (d, 2H, J=5.7 Hz),
3.21 (d, 1H, J=4.7 Hz), 1.73 (t, 1H, J=5.7 Hz).
[0797] (122-3)
[0798] The compound of Example 122-2 was treated in a similar
manner to Example 28-4 to give
4-{hydroxy[1-(phenylsulfonyl)-1H-pyrrol-2-yl]methyl}-
benzaldehyde.
[0799] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.11 (s, 1H,),
8.13 (m, 2H), 7.96 (d, 2H, J=8.5 Hz), 7.92 (d, 2H, J=8.5 Hz),
7.85(dd, 1H, J=3.1, 1.7 Hz), 7.67 (m, 1H), 7.60 (m, 2H), 6.75 (dd,
1H, J=3.7, 1.7 Hz), 6.39 (dd, 1H, J=3.7, 3.1 Hz).
[0800] (122-4)
[0801] Under nitrogen atmosphere, to a solution of the compound of
Example 122-3 (726 mg) in 1,2-dichloroethane (50 mL) were added
successively morpholine (933.9 mg) and NaBH(OAc).sub.3 (908 mg),
and the mixture was stirred at room temperature for 7 hours. In
addition, NaBH(OAc).sub.3 (908 mg) was added to the reaction
mixture, and stirred at room temperature for 2 hours. To the
mixture was added NaHCO.sub.3, and the mixture was extracted twice
with ethyl acetate, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure to give crude
[4-(morpholin-4-ylmethyl)phenyl][1-(phenylsulfonyl)-1H-pyrrol-2-yl]-
methanol, which was dissolved in MeOH (50 mL), and thereto was
added a 5N aqueous NaOH solutin (20 mL). The mixture was stirred at
65.degree. C. for 4 hours. Water was added to the mixture, and the
mixture was extracted twice with ethyl acetate, and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column
(CHCl.sub.3/MeOH=100/1) to give
[4-(morpholin-4-yl-methyl)phenyl](1H-pyrrol-2-yl)methanol (559 mg,
97%).
[0802] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.65 (brs, 1H),
7.87 (d, 2H, J=8.2 Hz), 7.46 (d, 2H, J=8.2 Hz), 7.14 (m, 1H), 6.90
(m, 1H), 6.35 (m, 1H), 3.73 (t, 4H, J=4.7 Hz), 3.58 (s, 2H), 2.48
(t, 4H, J=4.7 Hz).
[0803] (122-5)
[0804] The title compound was obtained from the compound of Example
122-4 in a similar manner to Example 18-3.
[0805] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.78 (d, 2H, J=8.1 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.42 (d, 2H,
J=8.1 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.21 (d, 1H, J=15.8 Hz),
7.10 (dd, 1H, J=2.6, 1.6 Hz), 6.79 (dd, 1H, J=4.0, 1.6 Hz), 6.35
(dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd, 1H, J=4.0, 2.6 Hz), 5.23 (dd,
2H, J=6.0, 1.3 Hz), 3.87 (s, 3H), 3.73 (t, 4H, J=4.6 Hz), 3.56 (s,
2H), 2.47 (t, 4H, J=4.6 Hz).
Example 123
[0806] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.71 (m, 3H),
7.66 (d, 1H, J=8.6 Hz), 7.52 (dd, 1H, J=8.6, 2.2 Hz), 7.43 (d, 2H,
J=8.1 Hz), 7.36 (m, 1H), 7.00 (d, 1H, J=15.8 Hz), 6.70 (m, 1H),
6.48 (dt, 1H, J=15.8, 5.5 Hz), 6.23 (dd, 1H, J=3.9, 2.6 Hz), 5.20
(d, 2H, J=5.5 Hz), 3.58 (t, 4H, J=4.3 Hz), 3.54 (s, 2H), 2.37 (t,
4H, J=4.3 Hz).
Example 124
[0807] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.76 (d, 2H, J=8.1
Hz), 7.53 (d, 1H, J=2.2 Hz), 7.41 (m, 3H), 7.31 (dd, 1H, J=8.4, 2.2
Hz), 7.05 (dd, 1H, J=2.5, 1.6 Hz), 6.80 (dd, 1H, J=4.0, 1.6 Hz),
6.73 (d, 1H, J=15.8 Hz), 6.31 (dt, 1H, J=15.8, 5.8 Hz), 6.23 (dd,
1H, J=4.0, 2.5 Hz), 6.01 (brs, 1H), 5.15 (dd, 2H, J=5.8, 1.4 Hz),
3.73 (t, 4H, J=4.6 Hz), 3.56 (s, 2H), 2.95 (m, 3H), 2.47 (t, 4H,
J=4.6 Hz).
Example 125
[0808] (125-1)
[0809] Under nitrogen atmosphere, a solution of
methoxymethyl-triphenylpho- sphonium oxide (10.8 g) in Et.sub.2O
(60 mL) was cooled to 0.degree. C., and thereto was added dropwise
a 1.7N solution of t-BuLi in pentane (18.6 mL). After the addition,
the mixture was stirred at room temperature for 30 minutes, and
cooled to 0.degree. C. To the mixture was added a solution of
methyl terephthalaldehyde (5.20 g) in Et.sub.2O (80 mL), and the
mixture was stirred at 0.degree. C. for 30 minutes, and stirred at
room temperature for 80 minuts. To the mixture was added an aqueous
NH.sub.4Cl solution, and the mixture was extracted twice with
Et.sub.2O. The organic layer was washed twice with an aqueous
NaHSO.sub.3 solution, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure to give crude methyl
4-[(E)-2-methoxyethenyl]benzoate (3.71 g). This product was
dissolved in a mixture of THF (60 mL)-MeOH (20 mL)-water (20 mL),
and thereto was added LiOH hydrate (2.04 g). The mixture was
stirred at room temperature for 24 hours, and the solvent was
evaporated under reduced pressure. Water was added to the
resultant, and the aqueous mixture was washed with ethyl acetate,
and cooled to 0.degree. C. The pH value of the mixture was adjusted
to pH=3 with a 5% aqueous KHSO.sub.4 solution, and the mixture was
extracted twice with ethyl acetate, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (CHCl.sub.3/MeOH=50/1) to give
4-[(E)-2-methoxyethenyl]benzoic acid (1.37 g, 20%).
[0810] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.73 (brs, 2H),
7.84 (d, 2H, J=8.4 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.60 (d, 2H, J=8.4
Hz), 7.44 (d, 1H, J=13.0 Hz), 7.40 (d, 2H, J=8.4 Hz), 6.45 (d, 1H,
J=7.0 Hz), 5.90 (d, 1H, J=13.0 Hz), 5.31 (d, 1H, J=7.0 Hz), 3.80
(s, 3H), 3.67 (s, 3H).
[0811] (125-2)
[0812] Under nitrogen atmosphere, to a solution of the compound of
Example 125-1 (1.37 g) in toluene (150 mL) were added
2,2'-dipyridyl disulfide (2.82 g) and PPh.sub.3 (3.36 g), and the
mixture was stirred at room temperature for 16 hours. Then, the
reaction mixture was cooled to -78.degree. C., and thereto was
added a 0.93N solution of pyrrolemagnesium bromide, which was
prepared from pyrrole (1.37 g) and a 0.93N solution of
methylmagnesium bromide in Et.sub.2O (23.4 mL), in toluene. The
mixture was stirred at -78.degree. C. for 3 hours, and thereto was
added an aqueous NH.sub.4Cl solution, and the mixture was warmed to
room temperature. Water was added to the mixture, and the mixture
was extracted with ethyl acetate, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=4/1) to give
{4-[(E)-2-methoxyethenyl]phenyl}(1H-pyrrol-2-yl)methanone (1.49 g,
100%).
[0813] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.76 (brs, 2H),
7.86 (d, 2H, J=8.4 Hz), 7.84 (d, 2H, J=8.4 Hz), 7.67 (d, 2H, J=8.4
Hz), 7.32 (d, 2H, J=8.4 Hz), 7.19 (d, 1H, J=13.0 Hz), 7.13 (m, 2H),
6.91 (m, 2H), 6.34 (m, 2H), 6.26 (d, 1H, J=7.0 Hz), 5.86 (d, 1H,
J=13.0 Hz), 5.29 (d, 1H, J=7.0 Hz), 3.84 (s, 3H), 3.73 (s, 3H).
[0814] (125-3)
[0815] To a solution of the compound of Example 125-2 (1.02 g) in
1,4-dioxane (60 mL) were added water (15 mL) and p-toluenesulfonic
acid monohydrate (220 mg), and the mixture was stirred at
101.degree. C. for 2 hours. The solvent was evaporated under
reduced pressure, and thereto was added an aqueous sodium carbonate
solution, and the mixture was extracted twice with ethyl
acetate-toluene. The extracts were dried over MgSO.sub.4, and the
solvent was evaporated under reduced pressure to give crude
{4-[2-oxoethyl]phenyl}(1H-pyrrol-2-yl)methanone. Under nitrogen
atmosphere, to a solution of this compound in 1,2-dichloroethane
(50 mL) were added successively morpholine (1.61 g) and
NaBH(OAc).sub.3 (1.57 g), and the mixture was stirred at room
temperature for 50 hours. To the mixture was added NaBH(OAc).sub.3
(785 mg), and the mixture was stirred at room temperature for 4
hours. To the mixture was added NaHCO.sub.3, and extracted twice
with ethyl acetate. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column (ethyl
acetate) to give [4-(2-morpholin-4-ylethyl)-phenyl](1H-pyrrol-2-yl-
)methanone (328 mg, 31%).
[0816] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.59 (brs, 1H),
7.85 (d, 2H, J=8.3 Hz), 7.32 (d, 2H, J=8.3 Hz), 7.13 (m, 1H), 6.89
(m, 1H), 6.34 (m, 1H), 3.75 (t, 4H, J=4.6 Hz), 2.89 (m, 2H), 2.64
(m, 2H), 2.54 (t, 4H, J=4.6 Hz).
[0817] (125-4)
[0818] Methyl
5-chloro-2-((1E)-3-{2-[4-(2-morpholin-4-ylethyl)benzoyl]-1H--
pyrrol-1-yl}prop-1-enyl)benzoate was obtained from the compound of
Example 125-3 in a similar manner to Example 18-3.
[0819] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.76 (d, 2H, J=8.2 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H,
J=8.4, 2.2 Hz), 7.29 (d, 2H, J=8.2 Hz), 7.20 (d, 1H, J=15.8 Hz),
7.09 (dd, 1H, J=2.5, 1.8 Hz), 6.78 (dd, 1H, J=4.0, 1.8 Hz), 6.35
(dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd, 1H, J=4.0, 2.5 Hz), 5.22 (dd,
2H, J=6.0, 1.4 Hz), 3.87 (s, 3H), 3.75 (t, 4H, J=4.6 Hz), 2.88 (m,
2H), 2.63 (m, 2H), 2.54 (t, 4H, J=4.6 Hz).
[0820] (125-5)
[0821] To a solution of the compound of Example 125-4 (117.8 g) in
THF (5 mL)-MeOH (5 mL) was added a 2N aqueous NaOH solution (0.6
mL), and the mixture was stirred at room temperature for 20 hours.
The solvent was evaporated under reduced pressure, and the residue
was washed with ethyl acetate, and thereto was added a 5% aqueous
KHSO.sub.4 solution until the pH value of the mixture became
pH=5-6. The precipitated solid was collected by filtration to give
the title compound (45.2 mg, 39%).
[0822] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.71 (d, 1H,
J=2.3 Hz), 7.67 (m, 3H), 7.53 (dd, 1H, J=8.5, 2.3 Hz), 7.35 (m,
3H), 7.00 (d, 1H, J=16.0 Hz), 6.69 (dd, 1H, J=4.0, 1.6 Hz), 6.48
(dt, 1H, J=16.0, 5.5 Hz), 6.23 (dd, 1H, J=4.0, 2.5 Hz), 5.20 (d,
2H, J=5.5 Hz), 3.58 (t, 4H, J=4.5 Hz), 2.82 (t, 2H, J=8.2 Hz), 2.57
(t, 2H, J=8.2 Hz), 2.45 (t, 4H, J=4.5 Hz).
Example 126
[0823] (126-1)
[0824] 4-Iodophenylmethoxy-t-butyldimethylsilane (1.48 g) was
dissolved in THF (50 mL), and the mixture was cooled in a dry
ice-acetone bath, and thereto was added dropwise t-BuLi (2.68 mL,
1.7M hexane solution). The mixture was stirred for 40 minuts, and
thereto was added a solution of the compound of Example 109-3 (709
mg) in THF (15 mL). The mixture was stirred at the same temperature
for 3 hours, and then warmed to room temperature over a period of
90 minutes. To the mixture was added an aqueous NH.sub.4Cl
solution, and the mixture was extracted with ethyl acetate. The
organic layer was concentrated, and purified by silica gel column
chromatography to give (4-t-butyldimethylsiloxymethylphenyl)
(1-phenylsulfonyl-4-methyl-1H-pyrrol-2-yl)methanol (452 mg,
34%).
[0825] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.71 (m, 2H), 7.60
(m, 1H), 7.48 (m, 2H), 7.24 (d, 2H, J=8.4 Hz), 7.20 (d, 2H, J=8.4
Hz), 7.05 (m, 1H), 6.01 (d, 1H, J=4.6 Hz), 5.64 (d, 1H, J=1.8 Hz),
4.73 (s, 2H), 3.22 (d, 1H, J=4.7 Hz), 1.95 (d, 3H, J=1.0 Hz), 0.94
(s, 9H), 0.10 (s, 6H).
[0826] (126-2)
[0827] The compound of Example 126-1 was treated with acetic acid
in THF-water to give
(4-hydroxymethylphenyl)(1-phenylsulfonyl-4-methyl-1H-py-
rrol-2-yl)methanol.
[0828] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.75 (m, 2H), 7.61
(m, 1H), 7.49 (m, 2H), 7.29 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.1
Hz), 7.09 (m, 1H), 6.02 (s, 1H), 5.87 (d, 1H, J=1.7 Hz), 4.68 (s,
2H), 1.98 (d, 3H, J=0.9 Hz).
[0829] (126-3)
[0830]
(4-Oxomethylphenyl)(1-phenylsulfonyl-4-methyl-1H-pyrrol-2-yl)methan-
one was obtained from the compound of Example 126-2 in a similar
manner to Example 28-4.
[0831] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.10 (s, 1H),
8.11 (m, 2H), 7.95 (d, 2H, J=8.4 Hz), 7.91 (d, 2H, J=8.4 Hz), 7.66
(m, 1H), 7.58 (m, 3H), 6.58 (d, 1H, J=1.9 Hz), 2.12 (s, 3H).
[0832] (126-4)
[0833]
[4-(Morpholin-4-ylmethyl)phenyl](1-phenylsulfonyl-4-methyl-1H-pyrro-
l-2-yl)methanone was obtained from the compound of Example 126-3 in
a similar manner to Example 122-4.
[0834] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.11 (m, 2H), 7.76
(d, 2H, J=8.3 Hz), 7.64 (m, 1H), 7.57 (m, 2H), 7.53 (m, 1H), 7.40
(d, 2H, J=8.3 Hz), 6.56 (d, 1H, J=1.7 Hz), 3.72 (t, 4H, J=4.6 Hz),
3.55 (s, 2H), 2.45 (t, 4H, J=4.6 Hz), 2.10 (d, 3H, J=0.6 Hz).
[0835] (126-5)
[0836]
[4-(Morpholin-4-ylmethyl)phenyl](4-methyl-1H-pyrrol-2-yl)-methanone
was obtained from the compound of Example 126-4 in a similar manner
to Reference Example 1-2.
[0837] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.34 (brs, 1H),
7.84 (d, 2H, J=8.3 Hz), 7.44 (d, 2H, J=8.3 Hz), 6.92 (m, 1H), 6.71
(m, 1H), 3.73 (t, 4H, J=4.7 Hz), 3.57 (s, 2H), 2.48 (t, 4H, J=4.7
Hz), 2.14 (s, 3H).
[0838] (126-6)
[0839] Methyl
5-chloro-2-((1E)-3-{4-methyl-2-[4-(morpholin-4-yl-methyl)ben-
zoyl]-1H-pyrrol-1-yl}prop-1-enyl)benzoate was obtained from the
compound of Example 9-2 and the compound of Example 126-5 in a
similar manner to Example 18-3.
[0840] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.76 (d, 2H, J=8.2 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.41 (d, 2H,
J=8.2 Hz), 7.40 (dd, 1H, J=8.5, 2.2 Hz), 7.21 (d, 1H, J=15.7 Hz),
6.88 (m, 1H), 6.58 (m, 1H), 6.34 (dt, 1H, J=15.7, 6.1 Hz), 5.16
(dd, 2H, J=6.1, 1.4 Hz), 3.87 (s, 3H), 3.73 (t, 4H, J=4.6 Hz), 3.56
(s, 2H), 2.47 (t, 4H, J=4.6 Hz), 2.09 (s, 3H).
[0841] (126-7)
[0842] The title compound was obtained from the compound of Example
126-6 in a similar manner to Example 16.
[0843] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.70 (d, 2H,
J=8.0 Hz), 7.43 (m, 5H), 7.12 (m, 2H), 6.48 (s, 1H), 6.23 (dt, 1H,
J=15.7, 6.3 Hz), 5.04 (d, 2H, J=6.3 Hz), 3.58 (t, 4H, J=4.3 Hz),
3.53 (s, 2H), 2.38 (t, 4H, J=4.3 Hz), 2.02 (s, 3H).
Example 127
[0844] (127-1)
[0845] Under nitrogen atmosphere, to a solution of
4-fluorobenzonitrile (24.9 g) in CH.sub.3CN (500 mL) was added
morpholine (53.8 g), and the mixture was stirred at 82.degree. C.
for 50 hours. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column (hexane/ethyl
acetate=10/1.fwdarw.4/1) to give 4-morpholin-4-yl-benzonitrile
(25.3 g, 65%).
[0846] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.52 (d, 2H, J=9.1
Hz), 6.87 (d, 2H, J=9.1 Hz), 3.85 (t, 4H, J=4.9 Hz), 3.28 (t, 4H,
J=4.9 Hz).
[0847] (127-2)
[0848] To a solution of the compound of Example 127-1 (5.00 g) in
ethylene glycol (40 mL) were added water (0.5 mL) and NaOH (4.26
g), and the mixture was stirred at 120.degree. C. for 30 minutes.
The mixture was cooled to room temperature, and thereto was added
water. The mixture was washed with ethyl acetate, and the pH value
thereof was adjusted to pH=6 with a 6N aqueous hydrochloric acid
solution. The precipitated solid was collected by filtration to
give 4-morpholin-4-ylbenzoic acid (1.69 g, 31%).
[0849] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.32 (brs, 1H),
7.78 (d, 2H, J=9.0 Hz), 6.97 (d, 2H, J=9.0 Hz), 3.73 (t, 4H, J=4.8
Hz), 3.24 (t, 4H, J=4.8 Hz).
[0850] (127-3)
[0851] (4-Morpholin-4-ylphenyl)(1H-pyrrol-2-yl)methanone was
obtained from the compound of Example 127-2 in a similar manner to
Example 125-2.
[0852] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.58 (brs, 1H),
7.93 (d, 2H, J=8.9 Hz), 7.10 (m, 1H), 6.93 (d, 2H, J=8.9 Hz), 6.90
(m, 1H), 6.34 (m, 1H), 3.88 (t, 4H, J=4.9 Hz), 3.32 (t, 4H, J=4.9
Hz).
[0853] (127-4)
[0854] Methyl
5-chloro-2-{(1E)-3-[2-(4-morpholin-4-ylbenzoyl)-1H-pyrrol-1--
yl]prop-1-enyl}benzoate was obtained from the compound of Example
127-3 in a similar manner to Example 18-3.
[0855] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.84 (d, 2H, J=8.9 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=8.5, 2.3 Hz), 7.20 (d, 1H, J=15.8 Hz), 7.06 (dd, 1H, J=2.6, 1.7
Hz), 6.90 (d, 2H, J=8.9 Hz), 6.77 (dd, 1H, J=4.0, 1.7 Hz), 6.35
(dt, 1H, J=15.8, 6.1 Hz), 6.22 (dd, 1H, J=4.0, 2.6 Hz), 5.19 (dd,
2H, J=6.1, 1.4 Hz), 3.87 (t, 4H, J=5.0 Hz), 3.87 (s, 3H), 3.30 (t,
4H, J=5.0 Hz).
[0856] (127-5)
[0857] The title compound was obtained from the compound of Example
127-4 in a similar manner to Example 16.
[0858] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.72 (d, 2H,
J=8.9 Hz), 7.44 (d, 1H, J=16.1 Hz), 7.39 (d, 1H, J=8.4 Hz), 7.38
(d, 1H, J=2.3 Hz), 7.26 (dd, 1H, J=2.6, 1.7 Hz), 7.12 (dd, 1H,
J=8.4, 2.3 Hz), 7.00 (d, 2H, J=8.9 Hz), 6.64 (dd, 1H, J=3.9, 1.7
Hz), 6.23 (dt, 1H, J=16.1, 6.4 Hz), 6.18 (dd, 1H, J=3.9, 2.6 Hz),
5.06 (d, 2H, J=6.4 Hz), 3.74 (t, 4H, J=5.1 Hz), 3.27 (t, 4H, J=5.1
Hz).
Example 128
[0859] (128-1)
[0860]
5-Chloro-2-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]-1-propenyl}-
benzamide was obtained from the compound of Example 9 and
NH.sub.4Cl in a similar manner to Example 116.
[0861] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.70 (d, 2H, J=8.0
Hz), 7.60 (d, 1H, J=2.2 Hz), 7.40 (d, 1H, J=8.4 Hz), 7.34 (dd, 1H,
J=2.2, 8.4 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.04 (dd, 1H, J=1.7, 2.5
Hz), 6.81 (dd, 1H, J=1.7, 4.0 Hz), 6.76 (d, 1H, J=15.8 Hz), 6.32
(dt, 1H, J=15.8, 5.6 Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 6.09 (br,
1H), 5.78 (br, 1H), 5.16 (d, 2H, J=5.6 Hz), 2.43 (s, 3H).
[0862] (128-2)
[0863] Under nitrogen atmosphere, to a solution of
2-hydroxypyridine (2.66 g) and NEt.sub.3 (4.05 mL) in THF (80 mL)
was added dropwise SOCl.sub.2 (1.05 mL) under ice-cooling, and the
mixture was stirred for one hour. The mixture was filtered, and the
solvent was evaporated under reduced pressure to give di-2-pyridyl
sulfite (3.02 g, 91%).
[0864] (128-3)
[0865] Under nitrogen atmosphere, to a solution of the compound of
Example 128-1 (40.0 mg) in toluene (1.5 mL) was added the compound
of Example 128-2 (53.0 mg), and the mixture was refluxed for one
hour. Water was added to the mixture, and the mixture was extracted
with ethyl acetate. The exract was washed with a saturated brine
and dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1) to give the title compound (28.6 mg,
75%).
[0866] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.75 (d, 2H, J=8.0
Hz), 7.57 (d, 1H, J=8.7 Hz), 7.56 (d, 1H, J=2.1 Hz), 7.47 (dd, 1H,
J=2.1, 8.7 Hz), 7.26 (d, 2H, J=8.0 Hz), 7.04 (dd, 1H, J=1.7, 2.6
Hz), 6.81 (dd, 1H, J=1.7, 4.0 Hz), 6.68-6.69 (m, 2H), 6.25 (dd, 1H,
J=2.6, 4.0 Hz), 5.25 (d, 2H, J=3.8 Hz), 2.43 (s, 3H).
Example 129
[0867] Under nitrogen atmosphere, to a solution of the compound of
Example 128 (25.7 mg) in DMF (0.3 mL) were added NaN.sub.3 (5.8 mg)
and NH.sub.4Cl (4.6 mg), and the mixture was stirred at 100.degree.
C. for 6 hours. Further, thereto were added NaN.sub.3 (10.6 mg) and
NH.sub.4Cl (9.1 mg), and the mixture was stirred at 110.degree. C.
for 9 hours. The mixture was cooled to room temperature, and
thereto was added a 1N aqueous hydrochloric acid solution. The
mixture was extracted with ethyl acetate-toluene, and the extract
was washed twice with a 1N aqueous hydrochloric acid solution,
washed with a saturated brine, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.acetic acid/ethyl acetate=1/100) to give the
title compound (1.6 mg, 5.6%).
[0868] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.22 (d, 1H, J=2.2
Hz), 7.88 (d, 2H, J=8.1 Hz), 7.43 (dd, 1H, J=2.2, 8.3 Hz), 7.38 (d,
1H, J=8.3 Hz), 7.28 (d, 2H, J=8.1 Hz), 7.14 (dd, 1H, J=1.7, 2.5
Hz), 6.94 (dd, 1H, J=1.7, 4.1 Hz), 6.84 (d, 1H, J=15.5 Hz), 6.30
(dd, 1H, J=2.5, 4.1 Hz), 6.15 (dt, 1H, J=15.5, 5.9 Hz), 5.12 (d,
2H, J=5.9 Hz), 2.42 (s, 3H).
Example 130
[0869] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 2H, J=8.7
Hz), 7.54 (d, 1H, J=2.2 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.31 (dd, 1H,
J=8.5 and 2.2 Hz), 7.03 (dd, 1H, J=1.7 and 2.5 Hz), 6.95 (d, 2H,
J=8.7 Hz), 6.78 (dd, 1H, J=1.7 and 4.0 Hz), 6.69 (brd, 1H, J=15.8
Hz), 6.30 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 6.01 (brq, 1H, J=4.9 Hz), 5.12 (dd, 2H, J=1.4 and 6.0 Hz),
3.88 (s, 3H), 2.94 (d, 3H, J=4.9 Hz).
Example 131
[0870] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 2H, J=8.7
Hz), 7.51 (d, 1H, J=2.2 Hz), 7.43 (d, 1H, J=8.5 Hz), 7.34 (dd, 1H,
J=8.5 and 2.2 Hz), 7.0 (dd, 1H, J=1.7 and 2.5 Hz), 6.93 (d, 2H,
J=8.7 Hz), 6.75 (dd, 1H, J=1.7 and 4.0 Hz), 6.73 (brd, 1H, J=15.8
Hz), 6.38 (dt, 1H, J=15.8 and 6.0 Hz), 6.22 (dd, 1H, J=2.5 and 4.0
Hz), 5.13 (dd, 2H, J=1.4 and 6.0 Hz), 3.86 (s, 3H), 3.30 (brs,
3H).
Example 132
[0871] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.73 (d, 2H, J=8.7
Hz), 7.60 (d, 1H, J=2.2 Hz), 7.53 (d, 1H, J=8.5 Hz), 7.35 (dd, 1H,
J=8.5 and 2.2 Hz), 7.24 (dd, 1H, J=1.7 and 2.5 Hz), 7.04 (brd, 1H,
J=15.8 Hz), 6.88 (d, 2H, J=8.7 Hz), 6.77 (dd, 1H, J=1.7 and 4.0
Hz), 6.39 (dt, 1H, J=15.8 and 6.0 Hz), 6.25 (dd, 1H, J=2.5 and 4.0
Hz), 5.17 (dd, 2H, J=1.4 and 6.0 Hz), 3.13 (brs, 3H).
Example 133
[0872] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.78 (d, 2H, J=8.7
Hz), 7.53 (d, 1H, J=2.2 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.31 (dd, 1H,
J=8.5 and 2.2 Hz), 7.03 (dd, 1H, J=1.7 and 2.5 Hz), 6.88 (d, 2H,
J=8.7 Hz), 6.78 (dd, 1H, J=1.7 and 4.0 Hz), 6.69 (brd, 1H, J=15.8
Hz), 6.30 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 6.01 (brs, 1H), 5.12 (dd, 2H, J=1.4 and 6.0 Hz), 2.94 (d, 3H,
J=4.9 Hz).
Example 134
[0873] The compound of Example 102 was treated with an acid, and
further treated in a similar manner to Examples 128 and 129 to give
a tetrazole compound. To this tetrazole compound (91 mg) were added
MeOH (1.0 mL), THF (1.0 mL), and a 1N aqueous NaOH solution (210
.mu.l), and the mixture was allowed to stand at room temperature
for 10 minutes. The solvent was evaporated under reduced pressure,
and thereto was added toluene. This procedure was repeated five
times, and the precipitated solid was suspended in Et.sub.2O, and
collected by filtration to give the title compound (98.5 mg,
35%).
[0874] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.86(d, 1H,
J=2.4 Hz), 7.78(d, 2H, J=8.7 Hz), 7.75(d, 1H, J=15.8 Hz), 7.60(d,
1H, J=8.5 Hz), 7.33(dd, 1H, J=1.6, 2.6 Hz), 7.25(dd, 1H, J=2.4, 8.5
Hz), 7.03(d, 2H, J=8.7 Hz), 6.65(dd, 1H, J=1.6, 3.9 Hz), 6.37(dt,
1H, J=15.8, 6.2 Hz), 6.19(dd, 1H, J=2.6, 3.9 Hz), 5.14(d, 2H, J=6.2
Hz), 3.84(s, 3H)
Example 135
[0875] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.23 (d, 1H, J=2.2
Hz), 7.99 (d, 2H, J=8.9 Hz), 7.43 (dd, 1H, J=2.2, 8.3 Hz), 7.37 (d,
1H, J=8.3 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.91(d, 1H, J=1.1 Hz), 6.79
(d, 1H, J=15.5 Hz), 6.72 (d, 1H, J=1.1 Hz), 6.14 (dt, 1H, J=15.5,
5.8 Hz), 5.04 (d, 2H, J=5.8 Hz), 3.87 (s, 3H), 2.12 (s, 3H).
Example 136
[0876] A methanesulfonylamide compound was obtained from the
compound of Example 110 in a similar manner to Example 115. To this
methanesulfonylamide compound (74.5 mg) were added MeOH (1.0 mL),
THF (1.0 mL), and a 1N aqueous NaOH solution (150 .mu.l), and the
mixture was allowed to stand at room temperature for 10 minutes.
The solvent was evaporated under reduced pressure, and thereto was
added toluene. This procedure was repeated three times. The
precipitated solid was suspended in Et.sub.2O, and collected by
filtration to give the title compound (66.0 mg, 43%).
[0877] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.76 (d, 2H,
J=8.8 Hz), 7.47-7.49 (m, 2H), 7.25 (dd, 1H, J=2.4, 8.4 Hz), 7.11
(d, 1H, J=15.9 Hz), 7.10 (d, 1H, J=1.3 Hz), 7.02 (d, 2H, J=8.8 Hz),
6.46 (d, 1H, J=1.3 Hz), 6.29 (dt, 1H, J=15.9, 5.8 Hz), 5.05 (d, 2H,
J=5.8 Hz), 3.83 (s, 3H), 2.82 (s, 3H), 2.02 (s, 3H).
Example 137
[0878] (137-1)
[0879] Methyl 4-chloro-2-methoxybenzoate was obtained from
4-chlorosalicylic acid in a similar manner to Example 109-8.
[0880] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.76 (d, 1H, J=8.8
Hz), 6.96-6.98 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H).
[0881] (137-2)
[0882] Under nitrogen atmosphere, a solution of the compound of
Example 137-1 (4.50 g) in THF (75 mL) was cooled to 0.degree. C.,
and thereto was added LiAlH.sub.4 (984 mg) in portions. The mixture
was stirred at room temperature for 2 hours, and cooled to
0.degree. C. Water (1.0 mL), a 2N aqueous NaOH solution (2.0 mL)
and water (1.0 mL) were added successively to the mixture, and the
mixture was stirred at room temperature for 1 hour. The solid was
collected by filtration, and washed with ethyl acetate. The
filtrate and the washing were combined, washed with a saturated
brine, and dried over MgSO.sub.4. The solvent was evaporated under
reduced pressure to give (4-chloro-2-methoxy-phenyl)methanol (3.88
g, 100%).
[0883] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.21(d, 1H, J=8.0
Hz), 6.93 (dd, 1H, J=1.9, 8.0 Hz), 6.87 (d, 1H, J=1.9 Hz), 4.64 (s,
2H), 3.86 (s, 3H).
[0884] (137-3)
[0885] 4-Chloro-2-methoxybenzaldehyde was obtained from the
compound of Example 137-2 in a similar manner to Example 28-4.
[0886] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.39 (s, 1H),
7.77 (d, 1H, J=8.3 Hz), 7.02 (dd, 1H, J=1.7, 8.3 Hz), 6.99 (d, 1H,
J=1.7 Hz), 3.94 (s, 3H).
[0887] (137-4)
[0888] Under nitrogen atmosphere, a suspension of 60% NaH (570 mg)
in THF (35 mL) was cooled to 0.degree. C., and thereto was added
dropwise triethyl 2-phosphonopropionate (2.80 mL). Then, the
mixture was stirred for 10 minutes, and thereto was added the
compound of Example 137-3 (2.00 g). The mixture was stirred at
60.degree. C. for 1 hour, and thereto was added water. The mixture
was extracted with ethyl acetate, washed with water and a saturated
brine, and dried over MgSO.sub.4. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(toluene/ethyl acetate=10/1) to give ethyl
3-(4-chloro-2-methoxyphenyl)acrylate (2.56 g, 91%).
[0889] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.89 (d, 1H,
J=16.2 Hz), 7.42 (d, 1H, J=8.3 Hz), 6.95 (dd, 1H, J=1.9, 8.3 Hz),
6.90 (d, 1H, J=1.9 Hz), 6.50 (d, 1H, J=16.2 Hz), 4.26 (q, 2H, J=7.1
Hz), 3.89 (s, 3H), 1.33 (t, 3H, J=7.1 Hz).
[0890] (137-5)
[0891] Under nitrogen atmosphere, to a solution of the compound of
Example 137-4 (1.78 g) in toluene (30 mL) that was cooled to
-78.degree. C. was added dropwise a 1.0N solution of (iBu).sub.2AlH
in toluene (16.5 mL). The mixture was stirred at -78.degree. C. for
30 minutes, and thereto was added a 1 N aqueous hydrochloric acid
solution, and the mixture was extracted with ethyl acetate. The
extract was washed with a 1N aqueous hydrochloric acid solution and
a saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=3/1.fwdarw.1/1) to give
3-(4-chloro-2-methoxyphenyl)propenol (1.36 g, 92%).
[0892] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.34 (d, 1H, J=8.2
Hz), 6.91 (dd, 1H, J=2.0, 8.2 Hz), 6.85 (d, 1H, J=2.0 Hz), 6.85 (d,
1H, J=16.0 Hz), 6.36 (dt, 1H, J=16.0, 5.8 Hz), 4.32 (d, 2H, J=5.8
Hz), 3.84 (s, 3H).
[0893] (137-6)
[0894] Under nitrogen atmosphere, the title compound was obtained
from the compound of Example 137-5 and the compound of Example
109-6 in a similar manner to Example 18-3.
[0895] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 2H, J=8.9
Hz), 7.32 (d, 1H, J=8.2 Hz), 6.94 (d, 2H, J=8.9 Hz), 6.87 (dd, 1H,
J=1.9, 8.2 Hz), 6.83 (d, 1H, J=1.3 Hz), 6.82 (d, 1H, J=1.9 Hz),
6.76 (d, 1H, J=16.0 Hz), 6.42 (dt, 1H, J=16.0, 6.4 Hz), 6.21 (d,
1H, J=1.3 Hz), 5.11 (d, 2H, J=6.4 Hz), 3.88 (s, 3H), 3.81 (s, 3H),
2.08 (s, 3H).
Example 138
[0896] (138-1)
[0897] Under nitrogen atmosphere, a solution of the compound of
Example 109-3 (3.68 g) in THF (45 mL) was cooled to -78.degree. C.,
and thereto was added dropwise a 0.759 N solution of
4-methylphenylmagnesium bromide in THF (20 mL), which was prepared
when used, and the mixture was stirred at the same temperature for
30 minutes. To the reaction solution were added water and a 1N
aqueous hydrochloric acid solution, and the mixture was extracted
three times with ethyl acetate. The organic layers were washed with
a 1N aqueous hydrochloric acid solution and a saturated brine, and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1) to give a crude alcohol compound. Under
nitrogen atmosphere, to a solution of the crude alcohol in
CHCl.sub.3 (100 mL) was added MnO.sub.2 (30 g), and the mixture was
stirred at 50.degree. C. for 3 hours, and stirred at room
temperature overnight and filtered. The solvent was evaporated
under reduced pressure, and the residue was purified by silica gel
column (hexane/ethyl acetate=6/1) to give a crude ketone compound.
Under nitrogen atmosphere, to a solution of the crude ketone
compound in dioxane (10 mL) was added a 2N aqueous NaOH solution
(20 mL), and the mixture was stirred at 80.degree. C. for 3 hours.
The mixture was acidified with a 1N aqueous hydrochloric acid
solution, and the mixture was extracted twice with ethyl acetate,
washed with a saturated brine, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (toluene/ethyl acetate=10/1) to give
(4-methyl-1H-pyrrol-2-yl)- (4-methylphenyl)ketone (993 mg, 34%, 3
steps).
[0898] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.38 (br, 1H),
7.80 (d, 2H, J=8.0 Hz), 7.28 (d, 2H, J=8.0 Hz), 6.91 (m, 1H),
6.70-6.71 (m, 1H), 2.43 (s, 3H), 2.14 (s, 3H).
[0899] (138-2)
[0900] The title compound was obtained from the compound of Example
9-2 and the compound of Example 138-1 in a similar manner to
Example 18-3.
[0901] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.72 (d, 2H, J=8.0 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H,
J=2.3, 8.4 Hz), 7.24 (d, 2H, J=8.0 Hz), 7.21 (d, 1H, J=15.8 Hz),
6.86 (d, 1H, J=1.3 Hz), 6.57 (d, 1H, J=1.3 Hz), 6.34 (dt, 1H,
J=15.8, 6.1 Hz), 5.15 (d, 2H, J=6.1 Hz), 3.87 (s, 3H), 2.42 (s,
3H), 2.08 (s, 3H).
Example 139
[0902] (139-1)
[0903]
5-Chloro-2-{(1E)-3-[2-(4-methylbenzoyl)-4-methyl-1H-pyrrol-1-yl]-1--
propenyl}benzoic acid was obtained from the compound of Example 138
in a similar manner in Example 16.
[0904] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d, 1H, J=2.2
Hz), 7.71 (d, 2H, J=8.0 Hz), 7.51 (d, 1H, J=8.5 Hz), 7.45 (dd, 1H,
J=2.2, 8.5 Hz), 7.27 (d, 1H, J=15.9 Hz), 7.24 (d, 2H, J=8.0 Hz),
6.86 (d, 1H, J=1.3 Hz), 6.58 (d, 1H, J=1.3 Hz), 6.36 (dt, 1H,
J=15.9, 6.0 Hz), 5.17 (d, 2H, J=6.0 Hz), 2.40 (s, 3H), 2.09 (s,
3H).
[0905] (139-2)
[0906] To the compound of Example 139-1 (336 mg) were added MeOH
(3.0 mL), THF (3.0 mL), and a 1N aqueous NaOH solution (850 .mu.l),
and the mixture was allowed to stand at room temperature for 10
minutes. The solvent was evaporated under reduced pressure, and
Et.sub.2O was added thereto. The precipitated solid was collected
by filtration to give the title compound (330 mg, 93%).
[0907] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.65 (d, 2H,
J=8.0 Hz), 7.48 (d, 1H, J=16.0 Hz), 7.41 (d, 1H, J=8.4 Hz), 7.39
(d, 1H, J=2.4 Hz), 7.30 (d, 2H, J=8.0 Hz), 7.12 (dd, 1H, J=2.4, 8.4
Hz), 7.11 (d, 1H, J=1.3 Hz), 6.47 (d, 1H, J=1.3 Hz), 6.22 (dt, 1H,
J=16.0, 5.8 Hz), 5.03 (d, 2H, J=5.8 Hz), 2.39 (s, 3H), 2.02 (s,
3H).
Example 140
[0908] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.65 (d, 2H,
J=8.1 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.48 (d, 1H, J=2.5 Hz), 7.29 (d,
2H, J=8.1 Hz), 7.26 (dd, 1H, J=2.5, 8.5 Hz), 7.13 (d, 1H, J=1.4
Hz), 7.10 (d, 1H, J=15.9 Hz), 6.46 (d, 1H, J=1.4 Hz), 6.30 (dt, 1H,
J=15.9, 5.8 Hz), 5.07 (d, 2H, J=5.8 Hz), 2.83 (s, 3H), 2.38 (s,
3H), 2.01 (s, 3H).
Example 141
[0909] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.72 (d, 2H, J=8.1
Hz), 7.33 (d, 1H, J=8.2 Hz), 7.25 (d, 2H, J=8.1 Hz), 6.82-6.88 (m,
3H), 6.77 (d, 1H, J=16.0 Hz), 6.55 (s, 1H), 6.42 (dt, 1H, J=16.0,
6.3 Hz), 5.13 (d, 2H, J=6.3 Hz), 3.82 (s, 3H), 2.42 (s, 3H), 2.07
(s, 3H).
Example 142
[0910] (142-1)
[0911] Under nitrogen atmosphere, a solution of
4-chloro-2-nitrobenzoic acid (4.00 g) in THF (15 mL) was cooled to
0.degree. C., and thereto was added dropwise dimethylsulfideborane
(2.51 mL), and the mixture was stirred at room temperature for 16
hours. To the reaction solution were added water and a saturated
aqueous sodium hydrogen carbonate solution, and the mixture was
extracted with ethyl acetate. The organic layer was washed with a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=2/1) to give
(4-chloro-2-nitrophenyl)met- hanol (1.32 g, 36%).
[0912] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.11 (d, 1H, J=2.1
Hz), 7.74 (d, 1H, J=8.3 Hz), 7.65 (dd, 1H, J=2.1, 8.3 Hz), 4.98 (s,
1H).
[0913] (142-2)
[0914] 4-Chloro-2-nitrobenzaldehyde was obtained from the compound
of Example 142-1 in a similar manner to Example 28-4.
[0915] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.39 (brs, 1H),
8.11 (d, 1H, J=1.9 Hz), 7.95 (d, 1H, J=8.3 Hz), 7.77 (dd, 1H,
J=1.9, 8.3 Hz).
[0916] (142-3)
[0917] Ethyl 3-(4-chloro-2-nitrophenyl)acrylate (1.08 g, 98%) was
obtained from the compound of Example 142-2 (800 mg) in a similar
manner to Example 137-4.
[0918] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.04 (d, 1H,
J=15.8 Hz), 8.04 (d, 1H, J=2.0 Hz), 7.63 (dd, 1H, J=2.0, 8.4 Hz),
7.59 (d, 1H, J=8.4 Hz), 6.36 (d, 1H, J=15.8 Hz), 4.29 (q, 2H, J=7.1
Hz), 1.35 (t, 3H, J=7.1 Hz).
[0919] (142-4)
[0920] Under nitrogen atmosphere, to a solution of the compound of
Example 142-3 (500 mg) in EtOH (12 mL) was added tin (II) chloride
dihydrate (1.40 g), and the mixture was refluxed for 30 minutes.
The reaction solution was poured into a saturated aqueous sodium
hydrogen carbonate solution to made it basic, and extracted three
times with ethyl acetate. The organic layers were washed with water
and a saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=5/1) to give an amino
compound (201 mg). Under nitrogen atmosphere, the resulting amino
compound was dissolved in THF (5.0 mL), and thereto were added
NEt.sub.3 (300 .mu.l) and methanesulfonylchloride (120 .mu.l) at
0.degree. C., and the mixture was stirred at room temperature for 2
hours. Water was added to the mixture, and the mixture was
extracted with ethyl acetate, washed with a saturated brine, and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=3/1) to give ethyl
3-{2-[bis(methanesulfonyl)-amino]-4-chlorophen- yl}acrylate (229
mg, 31%, 2 steps).
[0921] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.91 (d, 1H,
J=16.0 Hz), 7.70 (d, 1H, J=8.5 Hz), 7.50 (dd, 1H, J=1.9, 8.5 Hz),
7.36 (d, 1H, J=1.9 Hz), 6.47 (d, 1H, J=16.0 Hz), 4.27 (q, 2H, J=7.1
Hz), 3.47 (s, 6H), 1.33 (t, 3H, J=7.1 Hz).
[0922] (142-5)
[0923]
N-{5-Chloro-2-[(1E)-3-hydroxy-1-propenyl]phenyl}-N-(methanesulfonyl-
)methanesulfonamide was obtained from the compound of Example 142-4
in a similar manner to Example 137-5.
[0924] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.76 (d, 1H,
J=8.6 Hz), 7.67 (d, 1H, J=2.2 Hz), 7.55 (dd, 1H, J=2.2, 8.6 Hz),
7.79 (d, 1H, J=15.9 Hz), 6.54 (dt, 1H, J=15.9, 4.3 Hz), 5.04 (t,
1H, J=5.4 Hz), 4.15-4.18 (m, 2H), 3.54 (s, 6H)
[0925] (142-6)
[0926] The title compound was obtained from the compound of Example
142-5 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[0927] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.15 (brs, 1H),
7.87(d, 2H, J=8.8 Hz), 7.56 (d, 1H, J=2.1 Hz), 7.20 (dd, 1H, J=2.1,
8.4 Hz), 7.07(d, 1H, J=8.4 Hz), 6.97 (d, 2H, J=8.8 Hz), 6.73 (d,
1H, J=2.5 Hz), 6.40 (d, 1H, J=2.5 Hz), 6.22 (ddd, 1H, J=5.8, 10.2,
17.1 Hz), 5.44 (d, 1H, J=10.2 Hz), 5.03 (d, 1H, J=5.8 Hz), 4.99 (d,
1H, J=17.1 Hz), 3.88 (s, 3H), 2.92 (s, 3H), 2.00 (s, 3H).
Example 143
[0928] (143-1)
[0929] (4-Methyl-1H-pyrrol-2-yl)(4-hydroxyphenyl)ketone was
obtained from the compound of Example 109-6 in a similar manner to
Example 119-1.
[0930] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.40 (br, 1H),
7.86 (d, 2H, J=8.7 Hz), 6.90-6.93 (m, 3H), 6.72 (m, 1H), 2.15 (s,
3H).
[0931] (143-2)
[0932] Under nitrogen atmosphere, to a solution of the compound of
Example 143-1 (174 mg) in DMF (4.0 mL) were added imidazole (89.7
mg) and t-butyldimethylsilyl chloride (147 mg), and the mixture was
stirred at room temperature for 1.5 hours. Water was added thereto,
and the mixture was extracted with ethyl acetate-toluene, washed
with water and a saturated brine, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=5/1) to give
(4-methyl-1H-pyrrol-2-yl)
{4-[(t-butyldimethylsilyl)oxy]phenyl}ketone (199 mg, 73%).
[0933] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.39 (br, 1H),
7.84 (d, 2H, J=8.7 Hz), 6.89-6.92 (m, 3H), 6.71 (m, 1H), 2.15 (s,
3H), 1.00 (s, 9H), 0.25 (s, 6H).
[0934] (143-3)
[0935] A coupling compound (38.4 mg) was obtained from the compound
of Example 137-5 (61.7 mg) and the compound of Example 143-2 (89.6
mg) in a similar manner to Example 18-3. Subsequently, the resuling
compound was dissolvd in THF (3.0 mL), and thereto was added a 1N
solution of Bu.sub.4NF in THF (100 .mu.L), and the mixture was
stirred at room temperature for 1 hour. To the mixture was added a
5% aqueous KHSO.sub.4 solution, and the mixture was extracted with
ethyl acetate, washed with a saturated brine, and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=3/1) to give the title compound (22.7 mg, 21%).
[0936] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.77 (d, 2H, J=8.7
Hz), 7.32 (d, 1H, J=8.2 Hz), 6.84-6.89 (m, 2H), 6.87 (d, 2H, J=8.7
Hz), 6.82 (d, 1H, J=1.9 Hz), 6.75 (d, 1H, J=16.0 Hz), 6.55 (d, 1H,
J=1.9 Hz), 6.41 (dt, 1H, J=16.0, 6.3 Hz), 5.11 (d, 2H, J=6.3 Hz),
3.81 (s, 3H), 2.08 (s, 3H).
Example 144
[0937] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.82 (d, 2H, J=8.8
Hz), 7.32 (d, 1H, J=8.3 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.86 (dd, 1H,
J=1.9, 8.3 Hz), 6.84 (d, 1H, J=1.3 Hz), 6.82 (d, 1H, J=1.9 Hz),
6.76 (d, 1H, J=16.0 Hz), 6.54 (d, 1H, J=1.3 Hz), 6.41 (dt, 1H,
J=16.0, 6.4 Hz), 5.11 (d, 2H, J=6.4 Hz), 4.22 (br, 2H), 3.81 (s,
3H), 3.78 (br, 4H), 2.88 (br, 2H), 2.64 (br, 4H), 2.08 (s, 3H).
Example 145
[0938] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.31 (brs, 1H),
10.14 (s, 1H), 7.64-7.67 (m, 3H), 7.54 (d, 1H, J=2.2 Hz), 7.47 (dd,
1H, J=2.2, 8.4 Hz), 7.05 (d, 1H, J=1.4 Hz), 6.83 (d, 2H, J=8.6 Hz),
6.48 (d, 1H, J=1.4 Hz), 6.48-6.51 (m, 2H), 5.08 (d, 2H, J=3.0 Hz),
3.27 (s, 3H), 2.03 (s, 3H).
Example 146
[0939] (146-1)
[0940] Methyl
5-chloro-2-{(1E)-3-[2-(4-methoxybenzoyl)-4-formyl-1H-pyrrol--
1-yl]-1-propenyl}benzoate was obtained by treating the compound of
Example 101 with a Vilsmeier reagent.
[0941] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.82 (s, 1H), 7.89
(d, 1H, J=2.2 Hz), 7.88 (d, 2H, J=8.9 Hz), 7.68 (d, 1H, J=1.7 Hz),
7.47 (d, 1H, J=8.4 Hz), 7.42 (dd, 1H, J=2.2, 8.4 Hz), 7.33 (d, 1H,
J=15.8 Hz), 7.18 (d, 1H, J=1.7 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.31
(dt, 1H, J=15.8, 6.3 Hz), 5.22 (d, 2H, J=6.3 Hz), 3.90 (s, 3H),
3.88 (s, 3H).
[0942] (146-2)
[0943] The title compound was obtained from the compound of Example
146-1 in a similar manner to Example 16.
[0944] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.78 (s, 1H),
8.13 (d, 1H, J=1.6 Hz), 7.82 (d, 2H, J=8.8 Hz), 7.70 (d, 1H, J=2.2
Hz), 7.65 (d, 1H, J=8.5 Hz), 7.50 (dd, 1H, J=2.2, 8.5 Hz), 7.12 (d,
1H, J=15.8 Hz), 7.05 (d, 1H, J=1.6 Hz), 7.07 (d, 2H, J=8.8 Hz),
6.49 (dt, 1H, J=15.8, 5.4 Hz), 5.23 (d, 2H, J=5.4 Hz), 3.85 (s,
3H).
Example 147
[0945] The title compound was obtained from the compound of Example
110 and ethanesulfonamide in a similar manner to Example 136.
[0946] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.39 (brs, 1H),
7.80 (d, 2H, J=7.7 Hz), 7.55 (s, 1H), 7.36-7.44 (m, 2H), 6.93 (d,
2H, J=7.7 Hz), 6.85 (s, 1H), 6.70-6.74 (m, 1H), 6.57 (s, 1H),
6.40-6.43 (m, 1H), 5.08 (br, 2H), 3.86 (s, 3H), 3.53 (br, 2H), 2.09
(s, 3H), 1.41 (t, 3H, J=7.4 Hz).
Example 148
[0947] The title compound was obtained from the compound of Example
110 and benzenesulfonamide in a similar manner to Example 136.
[0948] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.73 (brs, 1H),
7.95-7.97 (m, 2H), 7.75 (d, 2H, J=8.8 Hz), 7.55-7.60 (m, 5H), 7.48
(d, 1H, J=2.3 Hz), 7.39-7.41 (m, 1H), 7.03 (d, 2H, J=8.8 Hz), 6.99
(d, 1H, J=1.3 Hz), 6.48 (d, 1H, J=1.3 Hz), 6.32-6.36 (m, 1H), 4.94
(d, 2H, J=4.7 Hz), 3.84 (s, 3H), 2.03 (s, 3H).
Example 149
[0949] The title compound was obtained from 2-benzoylpyrrole and
the compound of Example 9-2 in a similar manner to Example
18-3.
[0950] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.2
Hz), 7.81 (dd, 2H, J=1.4, 7.0 Hz), 7.43-7.56 (m, 4H), 7.40 (dd, 1H,
J=2.2, 8.4 Hz), 7.21 (d, 1H, J=15.8 Hz), 7.10 (dd, 1H, J=1.7, 2.5
Hz), 6.78 (dd, 1H, J=1.7, 4.0 Hz), 6.35 (dt, 1H, J=15.8, 6.0 Hz),
6.23 (dd, 1H, J=2.5, 4.0 Hz), 5.24 (d, 2H, J=6.0 Hz), 3.87 (s,
3H).
Example 150
[0951] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.97(d, 1H, J=2.2
Hz), 7.81 (d, 2H, J=7.0 Hz), 7.42-7.55 (m, 5H), 7.27 (d, 1H, J=15.8
Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz), 6.79 (dd, 1H, J=1.7, 4.0 Hz),
6.37 (dt, 1H, J=15.8, 5.9 Hz), 6.23 (dd, 1H, J=2.5, 4.0 Hz), 5.25
(d, 2H, J=5.9 Hz).
Example 151
[0952] (151-1)
[0953] Under nitrogen atmosphere, a solutin of
N-triisopropylsilyl-pyrrole (2.00 g) in acetone (40 mL) was cooled
at 0.degree. C., and thereto was added N-chlorosuccinimide (1.27
g), and the mixture was allowed to stand overnight. The solvent was
evaporated under reduced pressure, and thereto was added hexane.
The insoluble materials were removed by filtration. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane) to give 3-chloro-1-triisopropylsil-
yl-1H-pyrrole (403 mg, 18%).
[0954] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.65-6.68 (m, 2H),
6.23 (dd, 1H, J=1.4, 2.8 Hz), 1.41 (sep, 3H, J=7.5 Hz), 1.09 (d,
18H, J=7.5 Hz).
[0955] (151-2)
[0956] The compound of Example 151-1 (1.38 g) was treated with
acetic acid and Bu.sub.4NF in THF to give a de-silyl compound (520
mg). Under nitrogen atmosphere, to a solution of DMF (400 .mu.L) in
1,2-dichloroethane (2.0 mL) was added dropwise phosphorus
oxychloride (470 .mu.L) under ice-cooling, and the mixture was
stirred at room temperature for 15 minutes. The mixture was cooled
again under ice-cooling, and a solution of the de-sily compound in
1,2-dichloroethane (3.0 mL) was added dropwise thereto, and the
mixture was stirred at room temperature for 16 hours. The reaction
solution was poured into a saturated aqueous sodium hydrogen
carbonate solution to neutralize the mixture, and the mixtuer was
extracted twice with ethyl acetate. The organic layers were washed
with a saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=3/1) to give
3-chloro-1H-pyrrole-2-carbaldehyde (252 mg, 36%, 2 steps).
[0957] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.67 (s, 1H), 9.66
(br, 1H), 7.03-7.05 (m, 1H), 6.29-6.30 (m, 1H).
[0958] (151-3)
[0959] Under nitrogen atmosphere, to a solution of the compound of
Example 151-2 (200 mg) in THF (8.0 mL) was added 60% NaH (73.4 mg),
and the mixture was stirred at room temperature for 10 minutes.
Subsequently, benzenesulfonylchloride (230 .mu.L) was added to the
mixture, and the mixture was stirred at room temperature for 4
hours. Water was added to the mixture, and the mixture was
extracted with ethyl acetate, washed with a saturated brine, and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=6/1.fwdarw.3/1) to give
1-benzenesulfonyl-3-chloro-1H-pyrrole-2-carbaldehyde (407 mg,
98%).
[0960] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.87 (s, 1H), 7.99
(dd, 2H, J=1.3, 8.3 Hz), 7.71 (d, 1H, J=3.4 Hz), 7.67 (tt, 1H,
J=1.3, 7.5 Hz), 7.56 (dd, 2H, J=7.5, 8.3 Hz), 6.41 (d, 1H, J=3.4
Hz).
[0961] (151-4)
[0962]
(1-Benzenesulfonyl-3-chloro-1H-pyrrol-2-yl)(4-methylphenyl)-methano-
ne was obtained from the compound of Example 151-3 in a similar
manner to Example 138-1.
[0963] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.36 (br, 1H),
7.70 (d, 2H, J=8.2 Hz), 7.27 (d, 2H, J=8.2 Hz), 6.99-7.00 (m, 1H),
6.28-6.30 (m, 1H), 2.44 (s, 3H).
[0964] (151-5)
[0965] The title compound was obtained from the compound of Example
9-2 and the compound of Example 151-4 in a similar manner to
Example 18-3.
[0966] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.4
Hz), 7.71 (d, 2H, J=8.1 Hz), 7.39 (m, 2H), 7.24 (d, 2H, J=8.1 Hz),
7.20(d, 1H, J=15.8 Hz), 6.95 (d, 1H, J=2.8 Hz), 6.22 (dt, 1H,
J=15.8, 6.1 Hz), 6.19 (d, 1H, J=2.8 Hz), 4.96 (d, 2H, J=6.1 Hz),
3.87 (s, 3H), 2.42 (s, 3H).
Example 152
[0967] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.99 (d, 1H, J=1.9
Hz), 7.71 (d, 2H, J=8.0 Hz), 7.41-7.46 (m, 2H), 7.28 (d, 1H, J=15.8
Hz), 7.24 (d, 2H, J=8.0 Hz), 6.95 (d, 1H, J=2.8 Hz), 6.24 (dt, 1H,
J=15.8, 6.1 Hz), 6.20 (d, 1H, J=2.8 Hz), 4.98 (d, 2H, J=6.1 Hz),
2.41 (s, 3H).
Example 153
[0968] From the compound of Example 103 and
(2-bromoethoxy)tert-butyldimet- hylsilane, there were obtained the
title compound (15%) and the siliy compound (methyl
5-chloro-N-methyl-2-[(1E)-3-{2-[4-{2-(t-butyldimethylsil-
yloxy)ethoxy}benzoyl]-1H-pyrrol-1-yl}-1-propenyl]-benzoate)
(83%).
[0969] Silyl compound: .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta.
7.85 (d, 1H, J=2.2 Hz), 7.83 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5
Hz), 7.39 (dd, 1H, J=8.5 and 2.2 Hz), 7.20 (brd, 1H, J=15.8 Hz),
7.07 (dd, 1H, J=1.7 and 2.5 Hz), 6.95 (d, 2H, J=8.7 Hz), 6.76 (dd,
1H, J=1.7 and 4.0 Hz), 6.35 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd,
1H, J=2.5 and 4.0 Hz), 5.20 (dd, 2H, J=1.4 and 6.0 Hz), 4.11 (brt,
2H, J=5.0 Hz), 4.00 (brt, 2H, J=5.0 Hz), 3.86 (s, 3H), 0.91 (s,
9H), 0.1 (s, 6H).
[0970] The compound of Example 153: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.85 (d, 1H, J=2.2 Hz), 7.84 (d, 2H, J=8.7 Hz), 7.47
(d, 1H, J=8.5 Hz), 7.39 (dd, 1H, J=8.5 and 2.2 Hz), 7.19 (brd, 1H,
J=15.8 Hz), 7.08 (dd, 1H, J=1.7 and 2.5 Hz), 6.96 (d, 2H, J=8.7
Hz), 6.76 (dd, 1H, J=1.7 and 4.0 Hz), 6.34 (dt, 1H, J=15.8 and 6.0
Hz), 6.23 (dd, 1H, J=2.5 and 4.0 Hz), 5.20 (dd, 2H, J=1.4 and 6.0
Hz), 4.15 (brt, 2H, J=5.0 Hz), 4.00 (brt, 2H, J=5.0 Hz), 3.86 (s,
3H).
Example 154
[0971] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 7.84 (d, 2H, J=8.7
Hz), 7.78-7.83 (m, 1H), 7.59 (d, 1H, J=8.5 Hz), 7.46 (brd, 1H,
J=8.5 Hz), 7.27 (dd, 1H, J=1.7 and 2.5 Hz), 7.18 (brd, 1H, J=15.8
Hz), 7.08 (d, 2H, J=8.7 Hz), 6.81 (dd, 1H, J=1.7 and 4.0 Hz), 6.42
(dt, 1H, J=15.8 and 6.0 Hz), 6.29 (dd, 1H, J=2.5 and 4.0 Hz), 5.24
(dd, 2H, J=1.4 and 6.0 Hz), 4.17 (brt, 2H, J=4.9 Hz), 3.94 (brt,
2H, J=4.9 Hz).
Example 155
[0972] (155-1)
[0973]
5-Chloro-N-methyl-2-[(1E)-3-{2-[4-{2-(t-butyldimethylsilyloxy)-etho-
xy}benzoyl]-1H-pyrrol-1-yl}-1-propenyl]benzamide (100%) was
obtained by subjecting the silyl compound of Example 153 to alkali
hydrolysis, and treating the product with monomethylamine in a
similar manner to Example 116.
[0974] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (d, 2H, J=8.7
Hz), 7.52 (d, 1H, J=2.2 Hz), 7.38 (d, 1H, J=8.5 Hz), 7.30 (dd, 1H,
J=8.5 and 2.2 Hz), 7.03 (dd, 1H, J=1.7 and 2.5 Hz), 6.95 (d, 2H,
J=8.7 Hz), 6.78 (dd, 1H, J=1.7 and 4.0 Hz), 6.69 (brd, 1H, J=15.8
Hz), 6.30 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 6.10 (brq, 1H, J=4.9 Hz), 5.12 (dd, 2H, J=1.4 and 6.0 Hz),
4.11 (brt, 2H, J=5.0 Hz), 4.00 (brt, 2H, J=5.0 Hz), 2.93 (d, 3H,
J=4.9 Hz), 0.91 (s, 9H), 0.11 (s, 6H).
[0975] (155-2)
[0976] The title compound was obtained by treating the compound of
Example 155-1 with p-toluenesulfonic acid monohydrate in MeOH-THF
to remove the silyl group.
[0977] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 2H, J=8.7
Hz), 7.53 (d, 1H, J=2.2 Hz), 7.39 (d, 1H, J=8.5 Hz), 7.31 (dd, 1H,
J=8.5 and 2.2 Hz), 7.03 (dd, 1H, J=1.7 and 2.5 Hz), 6.97(d, 2H,
J=8.7 Hz), 6.78(dd, 1H, J=1.7 and 4.0 Hz), 6.70 (brdt, 1H, J=15.8
and 1.4 Hz), 6.31 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5
and 4.0 Hz), 6.20 (brq, 1H, J=4.9 Hz), 5.13 (dd, 2H, J=1.4 and 6.0
Hz), 4.16 (brt, 2H, J=5.0 Hz), 4.01 (brt, 2H, J=5.0 Hz), 2.94 (d,
3H, J=4.9 Hz).
Example 156
[0978] (156-1)
[0979] The silyl compound of Example 153 was subjected to alkali
hydrolysis, and treated in a similar manner to Example 115 to give
N-(5-chloro-2-[(1E)-3-{2-[4-{2-(t-butyldimethylsilyloxy)ethoxy}benzoyl]-1-
H-pyrrol-1-yl}-1-propenyl]benzoyl)methanesulfonamide.
[0980] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.88 (d, 2H, J=8.7
Hz), 7.49 (d, 1H, J=2.2 Hz), 7.42 (d, 1H, J=8.5 Hz), 7.36 (dd, 1H,
J=8.5 and 2.2 Hz), 7.04 (dd, 1H, J=1.7 and 2.5 Hz), 6.93 (d, 2H,
J=8.7 Hz), 6.76 (dd, 1H, J=1.7 and 4.0 Hz), 6.67 (brd, 1H, J=15.8
Hz), 6.39 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 5.12 (dd, 2H, J=1.4 and 6.0 Hz), 4.10 (brt, 2H, J=5.0 Hz),
3.99 (brt, 2H, J=5.0 Hz), 3.31 (brs, 3H), 0.91 (s, 9H), 0.11 (s,
6H).
[0981] (156-2)
[0982] The title compound was obtained from the compound of Example
156-1 in a similar manner to Example 155-2.
[0983] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.78 (d, 2H, J=8.7
Hz), 7.48 (brs, 1H), 7.42 (d, 1H, J=8.5 Hz), 7.35 (brd, 1H, J=8.5
Hz), 7.05 (dd, 1H, J=1.7 and 2.5 Hz), 6.92 (d, 2H, J=8.7 Hz), 6.76
(dd, 1H, J=1.7 and 4.0 Hz), 6.64 (brd, 1H, J=15.8 Hz), 6.39 (dt,
1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0 Hz), 5.13 (brd,
2H, J=6.0 Hz), 4.10 (brt, 2H, J=5.0 Hz), 3.96 (brt, 2H, J=5.0 Hz),
3.30 (brs, 3H).
Example 157
[0984] (157-1)
[0985] Methyl
5-chloro-2-[(1E)-3-{2-[4-{2-(t-butyldimethylsilyloxy)-ethoxy-
}benzoyl]-4-methyl-1H-pyrrol-1-yl}-1-propenyl]benzoate was obtained
from the compound of Example 119-1 in a similar manner to Example
153.
[0986] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.81 (d, 2H, J=8.8 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H,
J=2.3, 8.4 Hz), 7.20 (d, 1H, J=15.7 Hz), 6.95 (d, 2H, J=8.8 Hz),
6.85 (d, 1H, J=1.2 Hz), 6.56 (d, 1H, J=1.2 Hz), 6.34 (dt, 1H,
J=15.7, 6.1 Hz), 5.13 (d, 2H, J=6.1 Hz), 4.11 (t, 2H, J=5.0 Hz),
4.00 (t, 2H, J=5.0 Hz), 3.87 (s, 3H), 2.09 (s, 3H), 0.92 (s, 9H),
0.11 (s, 6H).
[0987] (157-2)
[0988] Under nitrogen atmosphere, the title compound was obtained
from the compound of Example 157-1 in a similar manner to Example
155-2.
[0989] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.83 (d, 2H, J=8.8 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=2.3, 8.5 Hz), 7.20 (d, 1H, J=15.8 Hz), 6.96 (d, 2H, J=8.8 Hz),
6.86 (d, 1H, J=1.3 Hz), 6.56 (d, 1H, J=1.3 Hz), 6.33 (dt, 1H,
J=15.8, 6.1 Hz), 5.14 (d, 2H, J=6.1 Hz), 4.16 (t, 2H, J=4.5 Hz),
4.00 (t, 2H, J=4.5 Hz), 3.87 (s, 3H), 2.09 (s, 3H).
Example 158
[0990] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.35 (brs, 1H),
7.73 (d, 2H, J=8.7 Hz), 7.72 (d, 1H, J=2.3 Hz), 7.66 (d, 1H, J=8.5
Hz), 7.53 (dd, 1H, J=2.3, 8.5 Hz), 7.10 (d, 1H, J=1.6 Hz), 7.04 (d,
1H, J=16.0 Hz), 7.02 (d, 2H, J=8.7 Hz), 6.50 (d, 1H, J=1.6 Hz),
6.45 (dt, 1H, J=16.0, 5.4 Hz), 5.11 (d, 2H, J=5.4 Hz), 4.91 (t, 1H,
J=5.0 Hz), 4.07 (t, 2H, J=5.0 Hz), 3.74 (dt, 2H, J=5.0, 5.0 Hz),
2.04 (s, 3H).
Example 159
[0991] (159-1)
[0992] Under nitrogen atmosphere, to a solution of the compound of
Example 153 (290 mg) and NEt.sub.3 (467 mg) in CH.sub.2Cl.sub.2
(7.0 mL) was added a solultion of methanesulfonylchloride (227 mg)
in CH.sub.2Cl.sub.2 (1.0 mL) at 0.degree. C. The mixture was
stirred at the same temperature for 20 minutes, and the mixture was
partially concentrated. The resultant was diluted with ethyl
acetate, washed with water, and concentrated. The residue was
purified by silica gel column chromatography to give methyl
5-chloro-N-methyl-2-[(1E)-3-{2-[4-{2-(methanesulfonyloxy)ethoxy}-benzoyl]-
-1H-pyrrol-1-yl}-1-propenyl]benzoate (355 mg, 100%).
[0993] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (d, 1H, J=2.2
Hz), 7.84 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=8.5 and 2.2 Hz), 7.19 (brd, 1H, J=15.8 Hz), 7.09 (dd, 1H, J=1.7
and 2.5 Hz), 6.95 (d, 2H, J=8.7 Hz), 6.76 (dd, 1H, J=1.7 and 4.0
Hz), 6.34 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 5.20 (dd, 2H, J=1.4 and 6.0 Hz), 4.61 (brt, 2H, J=4.5 Hz),
4.32 (brt, 2H, J=4.5 Hz), 3.87 (s, 3H), 3.11 (s, 3H).
[0994] (159-2)
[0995] The title compound was obtained by treating the compound of
Example 159-1 with LiCl.
[0996] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (d, 1H, J=2.2
Hz), 7.83 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=8.5 and 2.2 Hz), 7.19 (brd, 1H, J=15.8 Hz), 7.08 (dd, 1H, J=1.7
and 2.5 Hz), 6.96 (d, 2H, J=8.7 Hz), 6.76 (dd, 1H, J=1.7 and 4.0
Hz), 6.34 (dt, 1H, J=15.8 and 6.0 Hz), 6.23 (dd, 1H, J=2.5 and 4.0
Hz), 5.20 (dd, 2H, J=1.4 and 6.0 Hz), 4.30 (t, 2H, J=5.8 Hz), 3.87
(s, 3H), 3.85 (t, 2H, J=5.8 Hz).
Example 160
[0997] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.83 (d, 2H, J=8.7 Hz), 7.47 (d, 1H, J=8.5 Hz), 7.40 (dd, 1H,
J=8.5 and 2.2 Hz), 7.20 (brd, 1H, J=15.8 Hz), 7.07 (dd, 1H, J=1.7
and 2.5 Hz), 6.94 (d, 2H, J=8.7 Hz), 6.76 (dd, 1H, J=1.7 and 4.0
Hz), 6.34 (dt, 1H, J=15.8 and 6.0 Hz), 6.22 (dd, 1H, J=2.5 and 4.0
Hz), 5.20 (dd, 2H, J=1.4 and 6.0 Hz), 4.13 (t, 2H, J=6.1 Hz), 3.87
(s, 3H), 3.16-3.21 (m, 4H), 3.54 (t, 4H, J=6.2 Hz), 3.48 (q, 4H,
J=7.0 Hz), 3.36 (t, 2H, J=6.1 Hz), 2.87 (t, 4H, J=6.2 Hz), 1.19 (t,
6H, J=7.0 Hz).
Example 161
[0998] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 7.85 (d, 2H, J=8.7
Hz), 7.62 (d, 1H, J=2.2 Hz), 7.54 (d, 1H, J=8.5 Hz), 7.34 (dd, 1H,
J=8.5 and 2.2 Hz), 7.28 (dd, 1H, J=1.7 and 2.5 Hz), 7.14 (brd, 1H,
J=15.8 Hz), 7.11 (d, 2H, J=8.7 Hz), 6.76 (dd, 1H, J=1.7 and 4.0
Hz), 6.42 (dt, 1H, J=15.8 and 6.0 Hz), 6.27 (dd, 1H, J=2.5 and 4.0
Hz), 5.22 (dd, 2H, J=1.4 and 6.0 Hz), 4.47 (t, 2H, J=6.1 Hz), 3.82
(t, 4H, J=6.2 Hz), 3.74 (t, 2H, J=6.1 Hz), 3.50-3.62 (m, 8H), 1.20
(t, 6H, J=7.0 Hz).
Example 162
[0999] The compound of Example 111 and 8-bromoctan-1-ol were
reacted in a similar manner to Example 81, and the resulting
alcohol compound was converted into a iodo compound, and reacted
with NaN.sub.3 to give an azide compound. This azide compound was
converted into the title compound by the method of Example 16.
[1000] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (brs, 1H),
7.75 (d, 1H, J=2.3 Hz), 7.68 (d, 2H, J=8.8 Hz), 7.33 (d, 1H, J=8.5
Hz), 7.24 (dd, 1H, J=2.3, 8.5 Hz), 7.20 (d, 1H, J=15.8 Hz), 6.77
(d, 2H, J=8.8 Hz), 6.73 (d, 1H, J=1.3 Hz), 6.46 (d, 1H, J=1.3 Hz),
6.17 (dt, 1H, J=15.8, 6.1 Hz), 3.86 (d, 2H, J=6.4 Hz), 3.19 (t, 2H,
J=6.9 Hz), 1.97 (brs, 3H), 1.69 (brquintet, 2H, J=6.4 Hz), 1.53
(brquintet, 2H, J=6.9 Hz), 1.01-1.42 (series of m, 8H).
Example 163
[1001] (163-1)
[1002] Under nitrogen atmosphere, to a solution of methyl
terephthalaldehydate (10.0 g) in toluene (200 mL) were added
p-toluenesulfonic acid monohydrate (130 mg) and 1,3-propanediol
(5.56 g), and the mixture was stirred at 111.degree. C. for 3.5
hours. The mixture was cooled to room temperature, washed twice
with a NaHCO.sub.3 solution, and dried over MgSO.sub.4. The solvent
was evaporated under reduced pressure to give crude methyl
4-(1,3-dioxan-2-yl)benzoate (14.2 g). To a solution of this
compound (14.2 g) in THF (150 mL)-MeOH (150 mL) was added a 6N NaOH
solution (50.8 mL), and the mixture was stirred at room temperature
for 78 hours. The solvent was evaporated under reduced pressure,
and the residue was washed with ethyl acetate, and thereto was
added a 6N aqueous hydrochloric acid to adjust the pH value thereof
to pH=2. The precipitated solid was collected by filtration to give
4-(1,3-dioxan-2-yl)benzoic acid (11.725 g, 93%).
[1003] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.93 (d, 2H,
J=8.2 Hz), 7.51 (d, 2H, J=8.2 Hz), 5.58 (s, 1H), 4.15 (m, 2H), 3.95
(m, 2H), 2.00 (m, 1H), 1.45 (m, 1H).
[1004] (163-2)
[1005] [4-(1,3-Dioxan-2-yl)phenyl](1H-pyrrol-2-yl)methanone was
obtained from the compound of Example 163-1 in a similar manner to
Example 125-2.
[1006] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.68 (s, 1H), 7.90
(d, 2H, J=8.4 Hz), 7.61 (d, 2H, J=8.4 Hz), 7.13 (m, 1H), 6.85 (m,
1H), 6.33 (m, 1H), 5.58 (s, 1H), 4.31 (m, 2H), 4.03 (m, 2H), 2.26
(m, 1H), 1.48 (m, 1H).
[1007] (163-3)
[1008] The title compound was obtained from the compound of Example
163-2 in a similar manner to Example 18-3.
[1009] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.81 (d, 2H, J=8.3 Hz), 7.57 (d, 2H, J=8.3 Hz), 7.47 (d, 1H,
J=8.5 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.20 (d, 1H, J=15.8 Hz),
7.09 (dd, 1H, J=2.3, 1.8 Hz), 6.74 (dd, 1H, J=4.0, 1.8 Hz), 6.34
(dt, 1H, J=15.8, 6.0 Hz), 6.22 (dd, 1H, J=4.0, 2.3 Hz), 5.57 (s,
1H), 5.22 (dd, 2H, J=6.0, 1.4 Hz), 4.30 (m, 2H), 4.03 (m, 2H), 3.86
(s, 3H), 2.26 (m, 1H), 1.48 (m, 1H).
Example 164
[1010] (164-1)
[1011] To a solution of the compound of Example 163 (63.6 mg) in
acetone (15 mL) were added water (1.5 mL) and pyridinium
p-toluenesulfonate (10.3 mg), and the mixture was stirred at
56.degree. C. for 12 hours. The solvent was evaporated under
reduced pressure, and to the resultant was added a NaHCO.sub.3
solution. The mixture was extracted twice with ethyl
acetate-toluene, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=4/1) to give methyl
5-chloro-2-{(1E)-3-[2-(4-formyl-
benzoyl)-1H-pyrrol-1-yl]prop-1-enyl}benzoate (36.8 mg).
[1012] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.11 (s, 1H),
7.97 (d, 2H, J=8.4 Hz), 7.94 (d, 2H, J=8.4 Hz), 7.87 (d, 1H, J=2.2
Hz), 7.48 (d, 1H, J=8.4 Hz), 7.41 (dd, 1H, J=8.4, 2.2 Hz), 7.21 (d,
1H, J=15.8 Hz), 7.15 (dd, 1H, J=2.5, 1.6 Hz), 6.76 (dd, 1H, J=4.1,
1.6 Hz), 6.34 (dt, 1H, J=15.8, 6.0 Hz), 6.26 (dd, 1H, J=4.1, 2.5
Hz), 5.25 (dd, 2H, J=6.0, 1.5 Hz), 3.87 (s, 3H).
[1013] (164-2)
[1014] Under nitrogen atmosphere, a solution of the compound of
Example 164-1 (34.4 mg) in THF (5.0 mL)-MeOH (5.0 mL) was cooled to
0.degree. C., and thereto was added NaBH.sub.4 (3.20 mg), and the
mixture was stirred at 0.degree. C. for 1 hour. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (CHCl.sub.3/MeOH=10/1) to give methyl
5-chloro-2-((1E)-3-{2-[4-(hydroxyme-
thyl)benzoyl]-1H-pyrrol-1-yl}prop-1-enyl)benzoate (32.5 mg,
94%).
[1015] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.82 (d, 2H, J=8.2 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.45 (d, 2H,
J=8.2 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.21 (d, 1H, J=15.8 Hz),
7.10 (dd, 1H, J=2.6, 1.7 Hz), 6.77 (dd, 1H, J=4.0, 1.7 Hz), 6.35
(dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd, 1H, J=4.0, 2.6 Hz), 5.23 (dd,
2H, J=6.0, 1.4 Hz), 4.79 (d, 2H, J=4.8 Hz), 3.87 (s, 3H), 1.76 (t,
1H, J=4.8 Hz).
[1016] (164-3)
[1017] The title compound was obtained from the compound of Example
164-2 in a similar manner to Example 16.
[1018] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.96 (d, 1H, J=2.2
Hz), 7.77 (d, 2H, J=8.2 Hz), 7.50 (d, 1H, J=8.5 Hz), 7.45 (dd, 1H,
J=8.5, 2.2 Hz), 7.38 (d, 2H, J=8.2 Hz), 7.22 (d, 1H, J=15.8 Hz),
7.09 (dd, 1H, J=2.5, 1.6 Hz), 6.77 (dd, 1H, J=4.0, 1.6 Hz), 6.36
(dt, 1H, J=15.8, 5.7 Hz), 6.23 (dd, 1H, J=4.0, 2.5 Hz), 5.24 (dd,
2H, J=5.7, 1.4 Hz), 4.73 (s, 2H).
Example 165
[1019] (165-1)
[1020] To a solution of the compound of Example 163-2 (300 mg) in
acetone (30 mL) were added water (3 mL) and p-toluenesulfonic acid
monohydrate (66 mg), and the mixture was stirred at 56.degree. C.
for 1.5 hour. The solvent was evaporated under reduced pressure,
and thereto was added a NaHCO.sub.3 solution, and the mixture was
extracted twice with ethyl acetate-toluene, and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure to
give crude (4-formylphenyl)(1H-pyrrol-2-yl)meth- anone (258 mg). To
a solution of this compound (170 mg) in 1,2-dichloroethane (20 mL)
were added successively 4-piperidone monohydrate hydrochloride (263
mg), triethylamine (261 mg) and NaBH(OAc).sub.3 (546 mg), and the
mixture was stirred at room temperature for 71 hours. To the
mixture was added NaHCO.sub.3, and the mixture was extracted twice
with ethyl acetate, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=2/1.fwdarw.1/1) to give
1-[4-(1H-pyrrol-2-ylcarbonyl)benzyl]piperidin-4-one (80.1 mg,
33%).
[1021] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.73 (brs, 1H),
7.89 (d, 2H, J=8.2 Hz), 7.49 (d, 2H, J=8.2 Hz), 7.16 (m, 1H), 6.91
(m, 1H), 6.35 (m, 1H), 3.70 (s, 2H), 2.79 (t, 4H, J=6.1 Hz), 2.49
(t, 4H, J=6.1 Hz).
[1022] (165-2)
[1023] Methyl
5-chloro-2-[(1E)-3-(2-{4-[(4-oxopiperidin-1-yl)methyl]-benzo-
yl}-1H-pyrrol-1-yl)prop-1-enyl]benzoate was obtained from the
compound of Example 165-1 in a similar manner to Example 18-3.
[1024] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.80 (d, 2H, J=8.2 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.45 (d, 2H,
J=8.2 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.21(d, 1H, J=15.8 Hz),
7.11 (dd, 1H, J=2.4, 1.8 Hz), 6.80 (dd, 1H, J=4.0, 1.8 Hz), 6.35
(dt, 1H, J=15.8, 6.0 Hz), 6.24 (dd, 1H, J=4.0, 2.4 Hz), 5.23 (dd,
2H, J=6.0, 1.4 Hz), 3.87 (s, 3H), 3.69 (s, 2H), 2.78 (t, 4H, J=6.1
Hz), 2.48 (t, 4H, J=6.1 Hz).
[1025] (165-3)
[1026] Under nitrogen atmosphere, a solution of the compound of
Example 165-2 (76.4 mg) in THF (10 mL)-MeOH (10 mL) was cooled to
0.degree. C., and thereto was added NaBH.sub.4 (5.90 mg), and the
mixture was stirred at 0.degree. C. for 1 hour. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (CHCl.sub.3/MeOH=10/1) to give the title compound
(67.5 mg, 88%).
[1027] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.78 (d, 2H, J=8.1 Hz), 7.48 (d, 1H, J=8.4 Hz), 7.40 (m, 3H),
7.21 (d, 1H, J=15.8 Hz), 7.09 (dd, 1H, J=2.6, 1.6 Hz), 6.79 (dd,
1H, J=4.0, 1.6 Hz), 6.35 (dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd, 1H,
J=4.0, 2.6 Hz), 5.23 (dd, 2H, J=6.0, 1.3 Hz), 3.87 (s, 3H), 3.72
(m, 1H), 3.56 (s, 2H), 2.77 (m, 2H), 2.18 (m, 2H), 1.90 (m, 2H),
1.62 (m, 2H).
Example 166
[1028] (166-1)
[1029] Under nitrogen atmosphere, a solution of pyrazole (743 mg)
in DMF (10 mL) was cooled to 0.degree. C., and thereto was added
NaH (480 mg, 60%). The mixture was stirred at 0.degree. C. for 10
minutes, and stirred at room temperature for one hour. Methyl
4-(bromomethyl)benzoate (2.50 g) was added to the mixture, and the
mixture was stirred at room temperature for 2 hours. To the mixture
was added ice water (50 mL), and extracted three times with ethyl
acetate-toluene, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=10/1=3/1) to give methyl
4-(1H-pyrazol-1-ylmethyl)benzoate (2.17 g, 92%).
[1030] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.00 (d, 2H, J=8.3
Hz), 7.57 (d, 1H, J=2.2 Hz), 7.42 (d, 1H, J=2.2 Hz), 7.23 (d, 2H,
J=8.3 Hz), 6.31 (dd, 1H, J=2.2, 2.2 Hz), 5.38 (s, 2H), 3.90 (s,
3H).
[1031] (166-2)
[1032] 4-(1H-Pyrazol-1-ylmethyl)benzoic acid was obtained from the
compound of Example 166-1 in a similar manner to Example 16.
[1033] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.98 (brs, 1H),
7.90 (d, 2H, J=8.2 Hz), 7.86 (d, 1H, J=2.2 Hz), 7.49 (d, 1H, J=2.2
Hz), 7.26 (d, 2H, J=8.2 Hz), 6.29 (dd, 1H, J=2.2, 2.2 Hz), 5.42 (s,
2H).
[1034] (166-3)
[1035] [4-(1H-Pyrazol-1-ylmethyl)phenyl](1H-pyrrol-2-yl)methanone
was obtained from the compound of Example 166-2 in a similar manner
to Example 125-2.
[1036] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.00 (brs, 1H),
7.87 (d, 2H, J=8.3 Hz), 7.59 (d, 1H, J=2.2 Hz), 7.45 (d, 1H, J=2.2
Hz), 7.28 (d, 2H, J=8.3 Hz), 7.14 (m, 1H), 6.86 (m, 1H), 6.33 (m,
2H), 5.42 (s, 2H).
[1037] (166-4)
[1038] The title compound was obtained from the compound of Example
166-3 in a similar manner to Example 18-3.
[1039] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.79 (d, 2H, J=8.2 Hz), 7.58 (d, 1H, J=2.2 Hz), 7.47 (d, 1H,
J=8.4 Hz), 7.44 (d, 1H, J=2.2 Hz), 7.40 (dd, 1H, J=8.4, 2.3 Hz),
7.25 (d, 2H, J=8.2 Hz), 7.19 (d, 1H, J=15.7 Hz), 7.09 (dd, 1H,
J=2.6, 1.7 Hz), 6.75 (dd, 1H, J=4.0, 1.7 Hz), 6.33 (dt, 1H, J=15.7,
6.0 Hz), 6.32 (dd, 1H, J=2.2, 2.2 Hz), 6.22 (dd, 1H, J=4.0, 2.6
Hz), 5.40 (s, 2H), 5.22 (dd, 2H, J=6.0, 1.4 Hz), 3.86 (s, 3H).
Example 167
[1040] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=1.8
Hz), 7.77 (d, 2H, J=8.1 Hz), 7.59 (d, 1H, J=1.2 Hz), 7.44 (m, 3H),
7.23 (m, 3H), 7.07 (s, 1H), 6.73 (dd, 1H, J=4.0, 1.4 Hz), 6.31 (m,
2H), 6.19 (dd, 1H, J=4.0, 2.6 Hz), 5.39 (s, 2H), 5.20 (d, 2H, J=5.7
Hz).
Example 168
[1041] (168-1)
[1042] Under nitrogen atmosphere, a solution of 2-bromothiazole
(2.00 g) in Et.sub.2O (38 mL) was cooled to -78.degree. C., and
thereto was added a 1.5N solution of n-BuLi in hexane (8.5 mL), and
the mixture was stirred at -78.degree. C. for 30 minutes. To the
mixture was added a 1.0N solution of ZnCl.sub.2 in Et.sub.2O (12.2
mL), and the mixture was stirred at -78.degree. C. for 10 minutes,
and stirred at room temperature for 30 minutes. To the mixture were
added successively Pd(PPh.sub.3).sub.4 (704 mg) and ethyl
4-iodobenzoate (2.26 g), and the mixture was stirred at 66.degree.
C. for 1 hour. To the mixture was added a 1.0N solution of
ZnCl.sub.2 in Et.sub.2O (12.2 mL), and the mixture was stirred at
66.degree. C. for 2 hours. To the mixture was added THF (60 mL),
and the mixture was stirred at 66.degree. C. for 2.5 hours. To the
mixture were added a 0.18N aqueous solution of
ethylenediaminetetraacetic acid disodium salt dihydrate (300 mL),
and sodium hydrogen carbonate until the pH value of the mixture
became pH=8. The mixture was extracted with ethyl acetate, washed
with an aqueous NaHSO.sub.3 solution, and dried over MgSO.sub.4.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl acetate=12.5/1) to
give ethyl 4-(1,3-thiazol-2-yl)benzoate (1.35 g, 71%).
[1043] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.12 (d, 2H, J=8.5
Hz), 8.04 (d, 2H, J=8.5 Hz), 7.93 (d, 1H, J=3.2 Hz), 7.42 (d, 1H,
J=3.2 Hz), 4.41 (q, 2H, J=7.1 Hz), 1.42 (3H, t, J=7.1 Hz).
[1044] (168-2)
[1045] 4-(1,3-Thiazol-2-yl)benzoic acid was obtained from the
compound of Example 168-1 in a similar manner to Example 16.
[1046] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.16 (brs, 1H),
8.08 (d, 2H, J=8.7 Hz), 8.05 (d, 2H, J=8.7 Hz), 8.01 (d, 1H, J=3.2
Hz), 7.90 (d, 1H, J=3.2 Hz).
[1047] (168-3)
[1048] 1H-Pyrrol-2-yl[4-(1,3-thiazol-2-yl)phenyl]methanone was
obtained from the compound of Example 168-2 in a similar manner to
Example 125-2.
[1049] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.67 (brs, 1H),
8.10 (d, 2H, J=8.5 Hz), 7.99 (d, 2H, J=8.5 Hz), 7.94 (d, 1H, J=3.2
Hz), 7.42 (d, 1H, J=3.2 Hz), 7.17 (m, 1H), 6.93 (m, 1H), 6.37 (m,
1H).
[1050] (168-4)
[1051] Methyl
5-chloro-2-((1E)-3-{2-[4-(1,3-thiazol-2-yl)benzoyl]-1H-pyrro-
l-1-yl}prop-1-enyl)benzoate was obtained from the compound of
Example 168-3 in a similar manner to Example 18-3.
[1052] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.06 (d, 2H, J=8.4
Hz), 7.93 (d, 1H, J=3.3 Hz), 7.91 (d, 2H, J=8.4 Hz), 7.86 (d, 1H,
J=3.3 Hz), 7.49 (d, 1H, J=8.3 Hz), 7.41 (dd, 1H, J=8.3, 2.4 Hz),
7.41 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=15.8 Hz), 7.13 (dd, 1H,
J=2.3, 1.8 Hz), 6.82 (dd, 1H, J=4.0, 1.8 Hz), 6.36 (dt, 1H, J=15.8,
6.0 Hz), 6.26 (dd, 1H, J=4.0, 2.3 Hz), 5.25 (dd, 2H, J=6.0, 1.4
Hz), 3.87 (s, 3H).
[1053] (168-5)
[1054] The title compound was obtained from the compound of Example
168-4 in a similar manner to Example 16.
[1055] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.32 (brs, 1H),
8.08 (d, 2H, J=8.4 Hz), 8.01 (d, 1H, J=3.2 Hz), 7.89 (d, 1H, J=3.2
Hz), 7.87 (d, 2H, J=8.4 Hz), 7.72 (d, 1H, J=2.3 Hz), 7.68 (d, 1H,
J=8.5 Hz), 7.54 (dd, 1H, J=8.5, 2.3 Hz), 7.41 (dd, 1H, J=2.5, 1.6
Hz), 7.01 (d, 1H, J=15.9 Hz), 6.78 (dd, 1H, J=4.0, 1.6 Hz), 6.50
(dt, 1H, J=15.9, 5.4 Hz), 6.27 (dd, 1H, J=4.0, 2.5 Hz), 5.23 (d,
2H, J=5.4 Hz).
Example 169
[1056] (169-1)
[1057] Under nitrogen atmosphere, a solution of
4-(hydroxymethyl)-benzoic acid (5.00 g) in DMF (200 mL) was cooled
to 0.degree. C., and thereto was added NaH (2.76 g, 60%). The
mixture was stirred at the same temperature for 10 minutes, and
stirred at room temperature for 20 minutes. The mixture was cooled
to 0.degree. C., and thereto were added DMF (100 mL) and
iodomethane (18.7 g), and the mixuture was stirred at room
temperature for 48 hours. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=15/1) to give methyl
4-(methoxymethyl)benzoate (4.27 g, 72%).
[1058] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (d, 2H, J=8.3
Hz), 7.40 (d, 2H, J=8.3 Hz), 4.51 (s, 2H), 3.91 (s, 3H), 3.42 (s,
3H).
[1059] (169-2)
[1060] 4-(Methoxymethyl)benzoic acid was obtained from the compound
of Example 169-1 in a similar manner to Example 16.
[1061] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.91 (brs, 1H),
7.92 (d, 2H, J=8.2 Hz), 7.42 (d, 2H, J=8.2 Hz), 4.48 (s, 2H), 3.31
(s, 3H).
[1062] (169-3)
[1063] [4-(Methoxymethyl)phenyl](1H-pyrrol-2-yl)methanone was
obtained from the compound of Example 169-2 in a similar manner to
Example 125-2.
[1064] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.78 (brs, 1H),
7.90 (d, 2H, J=8.3 Hz), 7.46 (d, 2H, J=8.3 Hz), 7.15 (m, 1H), 6.89
(m, 1H), 6.34 (m, 1H), 4.55 (s, 2H), 3.44 (s, 3H).
[1065] (169-4)
[1066] The title compound was obtained from the compound of Example
169-3 in a similar manner to Example 18-3.
[1067] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.81 (d, 2H, J=8.2 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.42 (d, 2H,
J=8.2 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.21 (d, 1H, J=15.8 Hz),
7.10 (dd, 1H, J=2.6, 1.7 Hz), 6.78 (dd, 1H, J=4.0, 1.7 Hz), 6.35
(dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd, 1H, J=4.0, 2.6 Hz), 5.23 (dd,
2H, J=6.0, 1.4 Hz), 4.53 (s, 2H), 3.87 (s, 3H), 3.43 (s, 3H).
Example 170
[1068] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (brs, 1H),
7.71 (d, 2H, J=7.9 Hz), 7.37 (m, 3H), 7.28 (d, 2H, J=7.9 Hz), 6.97
(brs, 1H), 6.68 (m, 1H), 6.17 (m, 1H), 6.09 (brs, 1H), 5.03 (brs,
2H), 4.42 (s, 2H), 3.38 (s, 3H).
Example 171
[1069] (171-1)
[1070] Under nitrogen atmosphere, a solution of pyrazole (2.43 g)
in DMSO (90 mL) was cooled to 0.degree. C., and thereto was added
successively NaH (1.57 g, 60%), and the mixture was stirred at room
temperature for 30 minutes. To the mixture was added ethyl
4-fluorobenzoate (6.00 g) and the mixture was stirred at
110-120.degree. C. for 20 hours. The mixture was cooled to room
temperature, and thereto was added ice water (150 mL). The mixture
was extracted twice with ethyl acetate, and dried over MgSO.sub.4.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl
acetate=50/3.fwdarw.50/4) to give ethyl 4-(1H-pyrazol-1-yl)benzoate
(6.12 g, 79%).
[1071] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.14 (d, 2H, J=8.9
Hz), 8.01 (d, 1H, J=2.5 Hz), 7.79 (d, 2H, J=8.9 Hz), 7.76 (d, 1H,
J=2.5 Hz), 6.51 (dd, 1H, J=2.5, 2.5 Hz), 4.40 (q, 2H, J=7.1 Hz),
1.41 (t, 3H, J=7.1 Hz).
[1072] (171-2)
[1073] 4-(1H-Pyrazol-1-yl)benzoic acid was obtained from the
compound of Example 171-1 in a similar manner to Example 16.
[1074] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.03 (brs, 1H),
8.63 (d, 1H, J=2.5 Hz), 8.05 (d, 2H, J=8.9 Hz), 7.98 (d, 2H, J=8.9
Hz), 7.82 (d, 1H, J=2.5 Hz), 6.60 (dd, 1H, J=2.5, 2.5 Hz).
[1075] (171-3)
[1076] [4-(1H-Pyrazol-1-yl)phenyl](1H-pyrrol-2-yl)methanone was
obtained from the compound of Example 171-2 in a similar manner to
Example 125-2.
[1077] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.65 (brs, 1H),
8.04 (d, 2H, J=8.8 Hz), 8.03 (d, 1H, J=2.4 Hz), 7.84 (d, 2H, J=8.8
Hz), 7.78 (d, 1H, J=2.4 Hz), 7.17 (m, 1H), 6.92 (m, 1H), 6.53 (dd,
1H, J=2.4, 2.4 Hz), 6.37 (m, 1H).
[1078] (171-4)
[1079] The title compound was obtained from the compound of Example
171-3 in a similar manner to Example 18-3.
[1080] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (dd, 1H,
J=2.5, 0.4 Hz), 7.95 (d, 2H, J=8.8 Hz), 7.86 (d, 1H, J=2.5 Hz),
7.80 (d, 2H, J=8.8 Hz), 7.77 (d, 1H, J=2.5 Hz), 7.49 (d, 1H, J=8.5
Hz), 7.41 (ddd, 1H, J=8.5, 2.5, 0.4 Hz), 7.21 (d, 1H, J=15.8 Hz),
7.12 (dd, 1H, J=2.5, 1.8 Hz), 6.81 (dd, 1H, J=4.0, 1.8 Hz), 6.52
(dd, 1H, J=2.5, 2.5 Hz), 6.35 (dt, 1H, J=15.8, 6.0 Hz), 6.26 (dd,
1H, J=4.0, 2.5 Hz), 5.24 (dd, 2H, J=6.0, 1.5 Hz), 3.87 (s, 3H).
Example 172
[1081] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.32 (brs, 1H),
8.63 (d, 1H, J=2.4 Hz), 7.98 (d, 2H, J=8.7 Hz), 7.88 (d, 2H, J=8.7
Hz), 7.82 (d, 1H, J=2.4 Hz), 7.72 (d, 1H, J=2.5 Hz), 7.67 (d, 1H,
J=8.6 Hz), 7.53 (dd, 1H, J=8.6, 2.5 Hz), 7.39 (dd, 1H, J=2.5, 1.6
Hz), 7.01 (d, 1H, J=15.9 Hz), 6.77 (dd, 1H, J=4.0, 1.6 Hz), 6.61
(dd, 1H, J=2.4, 2.4 Hz), 6.50 (dt, 1H, J=15.9, 5.5 Hz), 6.26 (dd,
1H, J=4.0, 2.5 Hz), 5.22 (d, 2H, J=5.5 Hz).
Example 173
[1082] (173-1)
[1083] Methyl 4-(1H-1,2,4-triazol-1-ylmethyl)benzoate was obtained
from 1,2,4-triazole in a similar manner to Example 166-1.
[1084] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.12 (s, 1H), 8.05
(d, 2H, J=8.4 Hz), 8.00 (s, 1H), 7.31 (d, 2H, J=8.4 Hz), 5.42 (s,
2H), 3.92 (s, 3H).
[1085] (173-2) 4-(1H-1,2,4-Triazol-1-ylmethyl)benzoic acid was
obtained from the compound of Example 173-1 in a similar manner to
Example 16.
[1086] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.95 (brs, 1H),
8.69 (s, 1H), 8.01 (s, 1H), 7.92 (d, 2H, J=8.3 Hz), 7.34 (d, 2H,
J=8.3 Hz), 5.51 (s, 2H).
[1087] (173-3)
[1088]
1H-Pyrrol-2-yl[4-(1H-1,2,4-triazol-1-ylmethyl)phenyl]methanone was
obtained from the compound of Example 173-2 in a similar manner to
Example 125-2.
[1089] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.59 (bs, 1H),
8.15 (s, 1H), 8.02 (s, 1H), 7.90 (d, 2H, J=8.3 Hz), 7.36 (d, 2H,
J=8.3 Hz), 7.15 (m, 1H), 6.86 (m, 1H), 6.35 (m, 1H), 5.44 (s,
2H).
[1090] (173-4)
[1091] The title compound was obtained from the compound of Example
173-3 in a similar manner to Example 18-3.
[1092] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.13 (s, 1H), 8.01
(s, 1H), 7.86 (d, 1H, J=2.2 Hz), 7.82 (d, 2H, J=8.3 Hz), 7.47 (d,
1H, J=8.3 Hz), 7.40 (dd, 1H, J=8.3, 2.2 Hz), 7.32 (d, 2H, J=8.3
Hz), 7.20 (d, 1H, J=15.8 Hz), 7.11 (dd, 1H, J=2.4, 1.7 Hz), 6.75
(dd, 1H, J=4.1, 1.7 Hz), 6.33 (dt, 1H, J=15.8, 6.0 Hz), 6.23 (dd,
1H, J=4.1, 2.4 Hz), 5.43 (s, 2H), 5.22 (dd, 2H, J=6.0, 1.5 Hz),
3.86 (s, 3H).
Example 174
[1093] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (dd, 1H,
J=1.3 and 7.8 Hz), 7.83 (d, 2H, J=8.8 Hz), 7.54 (brd, 1H, J=7.6
Hz), 7.43 (dt, 1H, J=1.1 and 7.8 Hz), 7.29 (dt, 1H, J=1.3 and 7.6
Hz), 7.27 (brd, 1H, J=15.7 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.88 (brd,
1H, J=0.9 Hz), 6.56 (brd, 1H, J=1.4 Hz), 6.34 (dt, 1H, J=15.7 and
6.5 Hz), 5.15 (dd, 2H, J=1.4 and 6.5 Hz), 3.88 (s, 3H), 3.87 (s,
3H), 2.09 (brs, 3H).
Example 175
[1094] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 7.82 (d, 2H, J=8.8
Hz), 7.53 (brd, 1H, J=7.6 Hz), 7.47 (dd, 1H, J=1.3 and 7.8 Hz),
7.26 (dt, 1H, J=1.3 and 7.6 Hz), 7.22 (dt, 1H, J=1.1 and 7.8 Hz),
7.15 (brd, 1H, J=15.7 Hz), 7.10 (brs, 1H), 7.05 (d, 2H, J=8.8 Hz),
6.58 (brd, 1H, J=1.4 Hz), 6.41 (dt, 1H, J=15.7 and 6.5 Hz), 5.13
(dd, 2H, J=1.4 and 6.5 Hz), 3.92 (s, 3H), 2.11 (brs, 3H).
Example 176
[1095] (176-1)
[1096] Ethyl 3-(3-bromo-1-propen-1-yl)benzoate was obtained from
ethyl 3-iodobenzoate in a similar manner to Example 9-1,9-2.
[1097] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.06 (t, 1H, J=1.4
Hz), 7.95 (dt, 1H, J=7.8 and 1.4 Hz), 7.56 (dt, 1H, J=7.8 and 1.4
Hz), 7.41 (t, 1H, J=7.8 Hz), 6.68 (brd, 1H, J=15.6 Hz), 6.49 (dt,
1H, J=15.6 and 7.7 Hz), 4.39 (q, 2H, J=7.1 Hz), 4.16 (dd, 2H, J=7.7
and 0.8 Hz), 1.41 (t, 3H, J=7.1 Hz).
[1098] (176-2)
[1099] The title compound was obtained from the compound of Example
176-1 and the compound of Reference Example 1.
[1100] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (t, 1H, J=1.4
Hz), 7.90 (dt, 1H, J=7.8 and 1.4 Hz), 7.74 (brd, 2H, J=8.1 Hz),
7.54 (dt, 1H, J=7.8 and 1.4 Hz), 7.36 (t, 1H, J=7.8 Hz), 7.25 (brd,
2H, J=8.1 Hz), 7.05 (dd, 1H, J=2.6 and 1.6 Hz), 6.78 (dd, 1H, J=4.0
and 1.6 Hz), 6.46-6.57 (m, 2H), 6.23 (dd, 1H, J=4.0 and 2.6 Hz),
5.21-5.25 (m, 2H), 4.37 (q, 2H, J=7.1 Hz), 2.43 (brs, 3H), 1.39 (t,
3H, J=7.1 Hz).
Example 177
[1101] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (t, 1H, J=1.4
Hz), 7.89 (dt, 1H, J=7.8 and 1.4 Hz), 7.85 (brd, 2H, J=8.1 Hz),
7.54 (dt, 1H, J=7.8 and 1.4 Hz), 7.36 (t, 1H, J=7.8 Hz), 7.04 (dd,
1H, J=2.6 and 1.6 Hz), 6.95 (brd, 2H, J=8.1 Hz), 6.77 (dd, 1H,
J=4.0 and 1.6 Hz), 6.46-6.57 (m, 2H), 6.23 (dd, 1H, J=4.0 and 2.6
Hz), 5.19-5.24 (m, 2H), 4.37 (q, 2H, J=7.1 Hz), 3.88 (s, 3H), 1.39
(t, 3H, J=7.1 Hz).
Example 178
[1102] (178-1)
[1103] Under nitrogen atmosphere, to a solution of
5-methoxyindole-2-carbo- xylic acid (1.00 g) in Et.sub.2O (40 mL)
was added LiAiH.sub.4 (280 mg) at 0.degree. C., and the mixture was
stirred under reflux for 3 hours. The mixture was treated with
ethyl acetate, diluted with an aqueous hydrochloric acid solution,
and extracted with ethyl acetate. The mixture was concentrated to
give a crude alcohol compound (840 mg, 91%), which was dissolved in
THF (10 mL), and stirred with MnO.sub.2 (4.20 g) at room
temperature for 5 hours. The mixture was filtered on celite, and
the filtrate was concentrated, and the residue was purified by
silica gel column chromatography to give
5-methoxyindole-2-carbaldehyde (300 mg, 36%).
[1104] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.80 (s, 1H), 8.90
(brs, 1H), 7.34 (brd, 1H, J=8.9 Hz), 7.19 (dd, 1H, J=2.1 and 0.8
Hz), 7.11 (brs, 1H), 7.08 (dd, 1H, J=8.9 and 2.1 Hz), 3.86 (s,
3H).
[1105] (178-2)
[1106] 1-Benzenesulfonyl-5-methoxy-1H-indole-2-carbaldehyde was
obtained from the compound of Example 178-1 and benzenesulfonyl
chloride in a similar manner to Example 6-1.
[1107] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.51 (s, 1H),
8.13 (brd, 1H, J=8.9 Hz), 7.74 (dq, 2H, J=8.3 and 1.0 Hz), 7.54
(tt, 1H, J=8.3 and 1.0 Hz), 7.41 (tt, 2H, J=8.3 and 1.0 Hz), 7.40
(brs, 1H), 7.15 (dd, 1H, J=8.9 and 2.1 Hz), 6.99 (brd, 1H, J=2.1
Hz), 3.82 (s, 3H).
[1108] (178-3)
[1109] To Mg (72.0 mg) was added THF (0.50 mL), and the mixture was
warmed at 40.degree. C. under nitrogen atmosphere. A drop of
bromotoluene was added thereto, and the mixture was stirred for 10
minutes. To the mixture was added dropwise a solution of
bromotoluene (513 mg) in THF (5.5 mL), and the mixture was further
stirred for 2 hours to give a 0.5 M Grignard solution. To a
solution of the compound of Example 178-2 (50.0 mg) in THF (1.0 mL)
was added the above 0.5 M Grignard solution (0.320 mL) at
-75.degree. C. under nitrogen atmosphere, and the mixture was
stirred for 10 minutes, and further added thereto the Grignard
solution (0.160 mL). The mixture was stirred for 10 minutes, and
thereto was added a 5% aqueous KHSO.sub.4 solution, and the mixture
was warmed to room temperature. The mixture was extracted with
ethyl acetate, and concentrated to give a crude alcohol (70 mg).
This compound was dissolved in CHCl.sub.3 (4.0 mL), and the mixture
was stirred with MnO.sub.2 (350 mg) at room temperature for 8
hours. The mixture was filtered on celite, and the filtrate was
concentrated, and the residue was purified by silica gel column
chromatography to give (1-benzenesulfonyl-5-methoxy-1H-indol-2-
-yl)(4-methylphenyl)methanone (17.0 mg, 24%). The starting alcohol
(22.0 mg, 31%) and the unreacted reagent in the Grignard reaction
(10 mg) were recovered.
[1110] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.02 (brd, 1H,
J=8.9 Hz), 7.98 (dq, 2H, J=8.3 and 1.0 Hz), 7.87 (brd, 2H, J=8.2
Hz), 7.55 (tt, 1H, J=8.3 and 1.0 Hz), 7.46 (tt, 2H, J=8.3 and 1.0
Hz), 7.29 (brd, 2H, J=8.2 Hz), 7.06 (dd, 1H, J=8.9 and 2.1 Hz),
6.97 (brd, 1H, J=2.1 Hz), 6.86 (d, 1H, J=0.8 Hz), 3.82 (s, 3H),
2.44 (brs, 3H).
[1111] (178-4)
[1112] To a solution of the compound of Example 178-3 (17.0 mg) in
dioxane (3.0 mL) was added a 5N NaOH (3.0 mL) under nitrogen
atmosphere and the mixture was stirred at 90.degree. C. for 6
hours. The mixture was concentrated, and the resultant was diluted
with water, and extracted with ethyl acetate. The extract was
concentrated, and the residue was purified by silica gel column
chromatography to give
(5-methoxy-1H-indol-2-yl)(4-methylphenyl)methanone (12.0 mg,
100%).
[1113] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.19 (brs, 1H),
7.90 (brd, 2H, J=8.2 Hz), 7.37 (brd, 1H, J=8.9 Hz), 7.33 (brd, 2H,
J=8.2 Hz), 7.09 (brs, 1H), 7.08 (brd, 1H, J=2.1 Hz), 7.06 (dd, 1H,
J=8.9 and 2.1 Hz), 3.86 (s, 3H), 2.47 (brs, 3H).
[1114] (178-5)
[1115] Methyl
5-chloro-2-{(1E)-3-[5-methoxy-2-(4-methylbenzoyl)-1H-indol-1-
-yl]prop-1-enyl}benzoate was obtained from the compound of Example
178-4 and the compound of Example 9-2 in a similar manner to
Example 18-3.
[1116] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (brd, 2H,
J=8.2 Hz), 7.82 (d, 1H, J=2.2 Hz), 7.45 (brd, 1H, J=8.9 Hz), 7.43
(d, 1H, J=8.5 Hz), 7.36 (dd, 1H, J=8.5 and 2.2 Hz), 7.30 (brd, 2H,
J=8.2 Hz), 7.21 (dt, 1H, J=15.8 and 1.7 Hz), 7.08 (dd, 1H, J=8.9
and 2.1 Hz), 7.07 (brs, 1H, J=2.1 Hz), 6.96 (d, 1H, J=0.6 Hz), 6.32
(dt, 1H, J=15.8 and 5.8 Hz), 5.36 (dd, 2H, J=1.7 and 5.8 Hz), 3.84
(s, 3H), 3.77 (s, 3H), 2.46 (brs, 3H).
[1117] (178-6)
[1118] The title compound was obtained from the compound of Example
178-5 in a similar manner to Example 16.
[1119] .sup.1H NMR (CD.sub.3OD, 400 MHz) .delta. 7.85 (brd, 2H,
J=8.2 Hz), 7.70 (d, 1H, J=2.2 Hz), 7.55 (brd, 1H, J=9.1 Hz), 7.53
(d, 1H, J=8.6 Hz), 7.39 (brd, 2H, J=8.2 Hz), 7.36 (dd, 1H, J=8.6
and 2.2 Hz), 7.26 (dt, 1H, J=15.8 and 1.7 Hz), 7.17 (brs, 1H, J=2.4
Hz), 7.08 (dd, 1H, J=9.1 and 2.4 Hz), 7.00 (d, 1H, J=0.6 Hz), 6.40
(dt, 1H, J=15.8 and 5.8 Hz), 5.39 (dd, 2H, J=1.7 and 5.8 Hz), 3.85
(s, 3H), 2.49 (brs, 3H).
Example 179
[1120] The title compound was obtained as a by-product when
preparing the compound of Example 109.
[1121] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.43 (brs, 1H),
7.89 (d, 1H, J=2.2 Hz), 7.88 (d, 2H, J=8.9 Hz), 7.44 (d, 1H, J=8.3
Hz), 7.41 (dd, 1H, J=2.2 and 8.3 Hz), 7.24 (brd, 1H, J=15.7 Hz),
6.96 (d, 2H, J=8.9 Hz), 6.67 (brd, 1H, J=2.4 Hz), 6.11 (dt, 1H,
J=15.7 and 6.7 Hz), 3.92 (s, 3H), 3.88 (s, 3H), 3.58 (dd, 2H, J=1.4
and 6.7 Hz), 2.10 (brs, 3H).
Example 180
[1122] (180-1)
[1123] Under nitrogen atmosphere, to a solution of
3-thiophene-carboxyalde- hyde (9.81 g) in toluene (200 mL) were
added p-toluenesulfonic acid monohydrate (190 mg) and ethylene
glycol (6.52 g), and the mixture was stirred at 111.degree. C. for
5 hours. The mixture was cooled to room temperature, washed twice
with an aqueous NaHCO.sub.3 solution, dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure to give
3-(1,3-dioxolan-2-yl)thiophene (10.4 g).
[1124] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.42 (m, 1H), 7.32
(dd, 1H, J=5.0, 3.0 Hz), 7.16 (dd, 1H, J=5.0, 1.2 Hz), 5.91 (s,
1H), 4.11 (m, 2H), 4.03 (m, 2H).
[1125] (180-2)
[1126] Under nitrogen atmosphere, a solution of the compound of
Example 180-1 (12.0 g) in Et.sub.2O (100 mL) was cooled to
0.degree. C., and thereto was added a 2.46N solution of n-BuLi in
hexane (30.1 mL), and the mixture was stirred at 0.degree. C. for 5
minutes, and further stirred at 35.degree. C. for 1 hour. The
mixture was cooled to -78.degree. C., and thereto was added
dropwise a solution of 12 (18.8 g) in Et.sub.2O (150 mL), and the
mixture was stirred at -78.degree. C. for 20 minutes. The mixture
was warmed to room temperature, and thereto was added an aqueous
NH.sub.4Cl solution, and the mixture was extracted twice with ethyl
acetate. The organic layer was washed with NaHSO.sub.3, dried over
MgSO.sub.4, and the solvent was evaporated under reduced pressure
to give 3-(1,3-dioxolan-2-yl)-2-iodothiophene (20.11 g, 100%).
[1127] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.44 (d, 1H, J=5.6
Hz), 6.98 (d, 1H, J=5.6 Hz), 5.75 (s, 1H), 4.13 (m, 2H).
[1128] (180-3)
[1129] (2E)-3-[3-(1,3-Dioxolan-2-yl)thien-2-yl]prop-2-enal was
obtained from the compound of Example 180-2 in a similar manner to
Example 109-12.
[1130] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.19 (s, 1H),
9.75 (d, 1H, J=7.6 Hz), 8.39 (dd, 1H, J=15.8, 0.5 Hz), 7.54 (d, 1H,
J=5.3 Hz), 7.48 (d, 1H, J=5.3 Hz), 6.67 (dd, 1H, J=15.8, 7.6).
[1131] (180-4)
[1132] Under hydrogen atmosphere, to a solution of the compound of
Example 180-3 (1.00 g) in ethyl acetate (150 mL) was added a 5%
Pd/BaSO.sub.4 (4.00 g), and the mixture was stirred for 13.5 hours.
The solvent was evaporated under reduced pressure to give
3-[3-(1,3-dioxolan-2-yl)thien-2- -yl]propanal (1.00 g, 99%).
[1133] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.82 (t, 1H, J=1.0
Hz), 7.09 (d, 1H, J=5.3 Hz), 7.05 (d, 1H, J=5.3 Hz), 5.87 (s, 1H),
4.12 (m, 2H), 4.01 (m, 2H), 3.22 (t, 2H, J=7.3 Hz), 2.86 (dt, 2H,
J=7.3, 1.0).
[1134] (180-5)
[1135] Under nitrogen atmosphere, a 2.46N solution of
LiN(iPr).sub.2 in THF (1.91 mL) was cooled to 0.degree. C., and
thereto was added dropwise nBu.sub.3SnH (1.37 g), and the mixture
was stirred at 0.degree. C. for 20 minutes. The mixture was cooled
to -78.degree. C., and thereto was added dropwise a solution of the
compound of Example 180-4 (996 mg) in THF (4.0 mL), and the mixture
was stirred at -78.degree. C. for 20 minutes. To the mixture was
added dropwise an aqueous NH.sub.4Cl solution, and the mixture was
warmed to room temperature. The mixture was extracted twice with
ethyl acetate, and the organic layer was washed with water, and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure to give a crude tin-addition compound. Under nitrogen
atmosphere, to a solution of PPh.sub.3 (1.85 g) in CH.sub.2Cl.sub.2
(7 mL) were added successively imidazole (480.0 mg) and I.sub.2
(1.79 g), and the mixture was stirred at room temperature for 10
minutes. The mixture was cooled to 0.degree. C., and thereto was
added dropwise a solution of the above tin-addition compound in
CH.sub.2Cl.sub.2 (6 mL). The mixture was stirred at 0.degree. C.
for 5 minutes, and stirred at room temperature for 30 minutes. To
the mixture were added hexane (150 mL) and CH.sub.3CN (20 mL), and
the hexane layer was evaporated under reduced pressure to give a
crude iodo compound. Under nitrogen atmosphere, to a solution of
this iodo compound in THF (47 mL) was added
1,8-diazabicyclo[5.4.0]undec-7-ene (2.15 g), and the mixture was
stirred at room temperature for 93 hours. To the mixture was added
hexane, and the mixture was washed with an aqueous 5% KHSO.sub.4
solution and water, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=100/1) to give
tributyl{(1E)-3-[3-(1,3-dioxolan-2-yl)thien-2-yl]prop-1-enyl}tin
(365 mg, 16%).
[1136] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.09 (d, 1H, J=5.3
Hz), 7.07 (d, 1H, J=5.3 Hz), 6.06 (m, 2H), 5.86 (s, 1H), 4.08 (m,
2H), 3.99 (m, 2H), 3.72 (d, 2H, J=4.2 Hz), 1.51 (m, 6H), 1.30 (m,
6H), 0.90 (m, 15H).
[1137] (180-6)
[1138] To the compound of Example 180-5 (365 mg) were added methyl
5-chloro-2-iodobenzoate (223 mg), Pd.sub.2(dba).sub.3 CHCl.sub.3
(39.0 mg), PPh.sub.3 (35.0 mg) and THF (5.0 mL), and the mixture
was stirred for 10 hours under nitrogen atmosphere. The mixture was
cooled to room temperature, and the solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate=8/1.fwdarw.6/1) to give methyl
5-chloro-2-{(1Z)-3-[3-(1,3-dioxolan-2-yl)thien-2-yl]prop-1-enyl}benzoate
(168 mg, 61%).
[1139] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.48 (d, 1H, J=8.5 Hz), 7.40 (dd, 1H, J=8.5, 2.3 Hz), 7.21 (d,
1H, J=15.6 Hz), 7.12 (d, 1H, J=5.3 Hz), 7.09 (d, 1H, J=5.3 Hz),
6.22 (dt, 1H, J=15.6, 6.8 Hz), 5.92 (s, 1H), 4.14 (m, 2H), 4.03 (m,
2H), 3.89 (s, 3H), 3.84 (dd, 2H, J=6.8, 1.5).
[1140] (180-7)
[1141] Methyl
5-chloro-2-[(1Z)-3-(3-formylthien-2-yl)prop-1-enyl]-benzoate was
obtained from the compound of Example 180-6 in a similar manner to
Example 155-2.
[1142] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.10 (s, 1H),
7.88 (d, 1H, J=2.2 Hz), 7.47 (d, 1H, J=8.4 Hz), 7.44 (d, 1H, J=5.4
Hz), 7.42 (dd, 1H, J=8.4, 2.2 Hz), 7.27 (d, 1H, J=15.7 Hz), 7.16
(d, 1H, J=5.4 Hz), 6.24 (dt, 1H, J=15.7, 6.7 Hz), 4.15 (dd, 2H,
J=6.7, 1.5 Hz), 3.90 (s, 3H).
[1143] (180-8)
[1144] Methyl
5-chloro-2-((1Z)-3-{3-[hydroxy-(4-methylphenyl)methyl]-thien-
-2-yl}prop-1-enyl)benzoate was obtained from the compound of
Example 180-7 in a similar manner to Example 138-1, which was
further treated in a similar manner to Example 28-4 to give the
title compound.
[1145] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.72 (d, 2H, J=8.1 Hz), 7.47 (d, 1H, J=8.4 Hz), 7.39 (dd, 1H,
J=8.4, 2.2 Hz), 7.27 (d, 2H, J=8.1 Hz), 7.22 (d, 1H, J=15.7 Hz),
7.17 (d, 1H, J=5.3 Hz), 7.14 (d, 1H, J=5.3 Hz), 6.29 (dt, 1H,
J=15.7, 7.0 Hz), 3.82 (d, 2H, J=7.0 Hz), 3.89 (s, 3H), 2.43 (s,
3H).
Example 181
[1146] (181-1)
[1147] 2-Bromobenzaldehyde (11.4 g) was dissolved in toluene (150
mL), and thereto were added ethyleneglycol (4.58 g) and
p-toluenesulfonic acid monohydrate (135 mg), and the mixture was
refluxed for 6 hours with azeotropic distillation. The reaction
solution was washed with an aqueous sodium hydrogen carbonate
solution, and the solvent was evaporated under reduced pressure to
give 2-(2-bromophenyl)-1,3-dioxolane (13.4 g, 95%).
[1148] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.60 (dd, 1H,
J=7.6, 1.8 Hz), 7.57 (dd, 1H, J=7.6, 1.8 Hz), 7.34 (ddd, 1H, J=7.6,
7.6, 1.8 Hz), 7.22 (ddd, 1H, J=7.6, 7.6, 1.8 Hz), 6.10 (s, 1H),
4.15 (m, 2H), 4.09 (m, 2H).
[1149] (181-2)
[1150] A solution of the compound of Example 181-1 (6.00 g) in THF
(60 mL) was cooled to -78.degree. C., and thereto was added
dropwise nBuLi (11.7 mL, 2.46 M hexane solution). The mixture was
stirred for 20 minutes, and thereto was added ZnCl.sub.2 (28.8 mL,
1.0 M Et.sub.2O solution), and the mixture was further stirred for
30 minutes. To the mixture were added a solution of propargyl
bromide (3.12 g) in THF (40 mL) and CuI (499 mg). The reaction
solution was gradually warmed to room temperature, and thereto was
added an aqueous NH.sub.4Cl solution, and the mixture was extracted
twice with ethyl acetate. The organic layers were combined, dried,
filtered, and concentrated. The residue was purified by silica gel
column chromatography to give a crude acetylene compound (810 mg).
To a solution of this compound in CH.sub.2Cl.sub.2 (60 mL) was
added Pd(PPh.sub.3).sub.2Cl.sub.2 (60.5 mg). Under ice-cooling,
n-Bu.sub.3SnH (1.88 g) was added dropwise to the mixture, and the
mixture was stirred at the same temperature for 30 minutes. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column chromatography to give
tributyl{(1E)-3-[2-(1,3-dioxolan-2-yl)phenyl]prop-- 1-enyl}tin (944
mg, 46%).
[1151] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.57 (m, 2H), 7.25
(m, 2H), 6.10 (td, 1H, J=18.9, 5.8 Hz), 5.93 (ddd, 1H, J=18.8, 1.4,
1.4 Hz), 4.14 (m, 2H), 4.02 (m, 2H), 3.63 (dd, 2H, J=5.8, 1.4 Hz),
1.46 (m, 6H), 1.31 (m, 6H), 0.83 (m, 15H).
[1152] (181-3)
[1153] Methyl
5-chloro-2-{(1E)-3-[2-(1,3-dioxolan-2-yl)phenyl]prop-1-enyl}-
benzoate was obtained from the compound of Example 181-2 in a
similar manner to Example 180-3.
[1154] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.82 (d, 1H, J=2.3
Hz), 7.60 (dd, 1H, J=8.5, 2.3 Hz), 7.46 (d, 1H, J=8.5 Hz), 7.38
(dd, 1H, J=8.5, 2.3 Hz), 7.32 (dd, 1H, J=8.5, 2.3 Hz), 7.27 (m,
2H), 7.12 (d, 1H, J=15.7 Hz), 6.25 (dt, 1H, J=15.7, 6.7 Hz), 6.05
(s, 1H), 4.14 (m, 2H), 4.06 (m, 2H), 3.87 (s, 3H), 3.74 (dd, 2H,
J=6.7, 1.4).
[1155] (181-4)
[1156] Methyl
5-chloro-2-[(1E)-3-(2-formylphenyl)prop-1-enyl]benzoate was
obtained from the compound of Example 181-3 in a similar manner to
Example 155-2, which was further treated in a similar manner to
Example 138-1 to give methyl
5-chloro-2-((1E)-3-{2-[hydroxy(4-methylphenyl)methyl-
]phenyl}prop-1-enyl)benzoate. This compound was treated in a
similar manner to Example 28-4 to give the title compound.
[1157] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 1H, J=1.6
Hz), 7.70 (d, 2H, J=8.2 Hz), 7.44 (dd, 1H, J=7.3, 1.6 Hz), 7.40 (d,
1H, J=7.3 Hz), 7.30 (m, 4H), 7.22 (d, 2H, J=8.2 Hz), 7.05 (d, 1H,
J=15.7 Hz), 6.15 (dt, 1H, J=15.7, 6.9 Hz), 3.87 (s, 3H), 3.60 (dd,
2H, J=6.9, 1.3 Hz), 2.41 (s, 3H).
Example 182
[1158] (182-1)
[1159] Under nitrogen atmosphere, to a solution of
3-pyrazolcarboxyaldehyd- e (500 mg) in THF (50 mL) were added KOtBu
(643 mg) and 18-crown-6 (138 mg), and the mixture was stirred at
room temperature for 15 minutes. To the mixture was added allyl
bromide (630 mg), and the mixture was stirred at room temperature
for 1 hour. To the reaction mixture was added an aqueous NH.sub.4Cl
solution, and the mixture was extracted twice with ethyl acetate,
and dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=8/1) to give
1-allyl-1H-pyrazole-5-carbaldehyde (23.1 mg, 3%) and
1-allyl-1H-pyrazole-3-carbaldehyde (413.1 mg, 58%).
1-Allyl-1H-pyrazole-5-carbaldehyde: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 9.87 (s, 1H), 7.60 (d, 1H, J=2.0 Hz), 6.93 (d, 1H,
J=2.0 Hz), 6.00 (dddd, 1H, J=17.1, 10.3, 5.7, 5.7 Hz), 5.20 (dd,
1H, J=10.3, 1.2 Hz), 5.17 (ddd, 2H, J=5.7, 1.5, 1.5 Hz), 5.10 (dd,
1H, J=17.1, 1.2). 1-allyl-1H-pyrazole-3-carbaldehyde: .sup.1H NMR
(CDCl.sub.3, 400 MHz) .delta. 9.98 (s, 1H), 7.47 (d, 1H, J=2.4 Hz),
6.84 (d, 1H, J=2.4 Hz), 6.05 (dddd, 1H, J=16.3, 10.2, 6.0, 6.0 Hz),
5.35 (dd, 1H, J=10.2, 1.1 Hz), 5.28 (dd, 1H, J=16.3, 1.1 Hz), 4.85
(ddd, 2H, J=6.0, 1.4 and 1.4).
[1160] (182-2)
[1161] In a similar manner to Example 138-1,
(1-allyl-1H-pyrazol-3-yl)(4-m- ethylphenyl)methanol was obtained
from 1-allyl-1H-pyrazol-3-carbaldehyde, and
(1-allyl-1H-pyrazol-3-yl)(4-methylphenyl)methanone was obtained in
a similar manner to Example 28-4.
[1162] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.15 (d, 2H, J=8.2
Hz), 7.47 (d, 1H, J=2.4 Hz), 7.28 (d, 2H, J=8.2 Hz), 6.95 (d, 1H,
J=2.4 Hz), 6.07 (dddd, 1H, J=16.3, 10.2, 6.0, 6.0 Hz), 5.33 (dd,
1H, J=10.2, 1.1 Hz), 5.27 (dd, 1H, J=16.3, 1.1 Hz), 4.85 (ddd, 1H,
J=6.0, 1.3, 1.3 Hz), 2.42 (s, 3H).
[1163] (182-3)
[1164] Methyl
5-chloro-2-{(1E)-3-[3-(4-methylbenzoyl)-1H-pyrazol-1-yl]prop-
-1-enyl}benzoate was obtained from the compound of Example 182-2 in
a similar manner to Example 109-12.
[1165] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.17 (d, 2H, J=8.2
Hz), 7.91 (d, 1H, J=2.0 Hz), 7.57 (d, 1H, J=2.4 Hz), 7.48 (d, 1H,
J=8.4 Hz), 7.45 (dd, 1H, J=8.4, 2.0 Hz), 7.39 (d, 1H, J=15.7 Hz),
7.28 (d, 2H, J=8.2 Hz), 6.98 (d, 1H, J=2.4 Hz), 6.27 (dt, 1H,
J=15.7, 6.4 Hz), 5.04 (dd, 2H, J=6.4, 1.4 Hz), 3.90 (s, 3H), 2.43
(s, 3H).
[1166] (182-4)
[1167] The title compound was obtained from the compound of Example
182-3 in a similar manner to Example 16.
[1168] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.10 (d, 2H,
J=8.1 Hz), 7.94 (brs, 1H), 7.62 (brs, 1H), 7.57 (m, 2H), 7.31 (m,
3H), 6.87 (d, 1H, J=1.7 Hz), 6.35 (dt, 1H, J=15.9, 6.6 Hz), 5.01
(d, 2H, J=6.6 Hz), 2.38 (s, 3H).
Example 183
[1169] (183-1)
[1170] (1-Allyl-1H-pyrazol-5-yl)(4-methylphenyl)methanol was
obtained from 1-allyl-1H-pyrazole-5-carbaldehyde (Example 182-1) in
a similar manner to Example 138-1, and
(1-allyl-1H-pyrazol-5-yl)(4-methylphenyl)methanone was obtained in
a similar manner to Example 28-4.
[1171] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 2H, J=8.2
Hz), 7.56 (d, 1H, J=2.0 Hz), 7.30 (d, 2H, J=8.2 Hz), 6.66 (d, 1H,
J=2.0 Hz), 6.07 (m, 1H), 5.15 (m, 3H), 2.45 (s, 3H).
[1172] (183-2)
[1173] The title compound was obtained from the compound of Example
183-1 in a similar manner to Example 109-12.
[1174] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 1H, J=2.3
Hz), 7.82 (d, 2H, J=8.5 Hz), 7.59 (d, 1H, J=2.0 Hz), 7.45 (d, 1H,
J=8.5 Hz), 7.38 (dd, 1H, J=8.5, 2.3 Hz), 7.30 (d, 2H, J=8.5 Hz),
7.26 (d, 1H, J=15.8 Hz), 6.69 (d, 1H, J=2.0 Hz), 6.34 (dt, 1H,
J=15.8, 6.1 Hz), 5.37 (dd, 2H, J=6.1, 1.3 Hz), 3.85 (s, 3H), 2.45
(s, 3H).
Example 184
[1175] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.79 (d, 2H,
J=8.1 Hz), 7.64 (d, 1H, J=2.0 Hz), 7.57 (brs, 1H), 7.49 (d, 1H,
J=8.5 Hz), 7.43 (d, 1H, J=16.0 Hz), 7.37 (d, 2H, J=8.1 Hz), 7.25
(d, 1H, J=8.5 Hz), 6.75 (d, 1H, J=2.0 Hz), 6.32 (dt, 1H, J=16.0,
5.7 Hz), 5.22 (d, 2H, J=5.7 Hz), 2.40 (s, 3H).
Example 185
[1176] (185-1)
[1177] A suspension of N,N-dimethyl-1H-imidazole-1-sulfonamide
(2.02 g) in THF (50 mL) was cooled to -78.degree. C., and thereto
was added dropwise n-BuLi (4.77 mL, 2.66 M hexane solution), and
the mixture was stirred for 30 minutes. To the mixture was added
p-tolyl benzaldehyde (2.08 g), and the mixture was warmed to room
temperature over a period of 1 hour, and then stirred for 16 hours.
The mixture was extracted with aqueous hydrochloric acid solution,
washed with Et.sub.2O, and basified with an aqueous NaOH solution.
This solution was extracted with Et.sub.2O, and the organic layer
was dried and filtered. The solvent was evaporated under reduced
pressure to give 2-[hydroxy(4-methylphenyl)methyl]-N,N-dime-
thyl-1H-imidazole-1-sulfonamide.
[1178] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.26 (d, 2H, J=8.1
Hz), 7.24 (d, 1H, J=1.6 Hz), 7.14 (d, 2H, J=8.1 Hz), 7.07 (d, 1H,
J=1.6 Hz), 6.15 (s, 1H), 2.70 (s, 6H), 2.32 (s, 3H).
[1179] (185-2)
[1180] N,N-Dimethyl-2-(4-methylbenzoyl)-1H-imidazole-1-sulfonamide
was obtained from the compound of Example 185-1 in a similar manner
to Example 28-4.
[1181] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.95 (d, 2H, J=8.3
Hz), 7.52 (d, 1H, J=1.4 Hz), 7.29 (d, 2H, J=8.3 Hz), 7.16 (d, 1H,
J=1.4 Hz), 3.10 (s, 6H), 2.43 (s, 3H).
[1182] (185-3)
[1183] The compound of Example 185-2 was treated with hydrochloric
acid in THF to give 1H-imidazol-2-yl(4-methylphenyl)methanone.
[1184] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.72 (brs, 1H),
8.52 (d, 2H, J=8.3 Hz), 7.39 (s, 0.5H), 7.32 (d, 2H, J=8.3 Hz),
7.32 (s, 0.5H), 2.44 (s, 3H).
[1185] (185-4)
[1186] (1-Allyl-1H-imidazol-2-yl)(4-methylphenyl)methanone was
obtained from the compound of Example 185-3 in a similar manner to
Example 109-10.
[1187] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.17 (d, 2H, J=8.2
Hz), 7.28 (d, 2H, J=8.2 Hz), 7.25 (m, 1H), 7.16 (m, 1H), 6.07
(dddd, 1H, J=17.0, 10.2, 5.7, 5.7 Hz), 5.24 (dd, 1H, J=10.2, 1.2
Hz), 5.14 (dd, 1H, J=17.0, 1.2 Hz), 5.09 (ddd, 2H, J=5.7, 1.4, 1.4
Hz), 2.42 (s, 3H).
[1188] (185-5)
[1189] Methyl
5-chloro-2-{(1E)-3-[2-(4-methylbenzoyl)-1H-imidazol-1-yl]pro-
p-1-enyl}benzoate was obtained from the compound of Example 185-4
in a similar manner to Example 109-12.
[1190] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.19 (d, 2H, J=8.3
Hz), 7.88 (d, 1H, J=2.2 Hz), 7.47 (d, 1H, J=8.4 Hz), 7.42 (dd, 1H,
J=8.4, 2.2 Hz), 7.31 (d, 1H, J=15.8 Hz), 7.29 (m, 2H), 7.27 (d, 2H,
J=8.3 Hz), 6.31 (dt, 1H, J=15.8, 6.3 Hz), 5.26 (dd, 2H, J=6.3, 1.4
Hz), 3.88 (s, 3H), 2.42 (s, 3H).
[1191] (185-6)
[1192] The title compound was obtained from the compound of Example
185-5 in a similar manner to Example 16.
[1193] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.16 (d, 2H,
J=8.2 Hz), 7.66 (d, 1H, J=0.8 Hz), 7.56 (d, 1H, J=16.1 Hz), 7.44
(d, 1H, J=2.4 Hz), 7.44 (d, 1H, J=8.4 Hz), 7.33 (d, 2H, J=8.2 Hz),
7.22 (d, 1H, J=0.8 Hz), 7.15 (dd, 1H, J=8.4, 2.4 Hz), 6.27 (dt, 1H,
J=16.1, 6.5 Hz), 5.16 (dd, 2H, J=6.5, 0.8 Hz), 2.39 (s, 3H).
Example 186
[1194] (186-1)
[1195] To a suspension of NaH (6.12 g, 60% dispersion in oil) in
DMF (70 mL) was added dropwise a mixture of MeI (21.7 g) and methyl
thien-3-ylacetate (11.0 g) under ice-cooling. The reaction solution
was stirred at room temperature for 5 hours, and cooled again with
ice. To the mixture was added dropwise an aquoues hydrochloric acid
solution, and the mixture was diluted with water. The mixture was
extracted with ethyl acetate-toluene, and the organic layer was
dried, filtered and concentrated. The residue was purified by
silica gel chromatography (hexane/ethyl acetate=100:3) to give
methyl 2-methyl-2-thien-3-yl-propion- ate (11.2 g, 91%).
[1196] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.26 (dd, 1H,
J=5.0 and 3.0 Hz), 7.10 (dd, 1H, J=1.4 and 3.0 Hz), 7.08 (dd, 1H,
J=5.0 and 1.4 Hz), 3.65 (s, 3H), 1.58 (s, 6H).
[1197] (186-2)
[1198] The compound of Example 186-1 was formylated using
Cl.sub.2CHOCH.sub.3 and SnCl.sub.4, and protected with
ethyleneglycol, and the ester group was converted into a formyl
group to give 2-[2-(1,3-dioxolan-2-yl)
thien-3-yl]-2-methylpropanal.
[1199] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.59(s, 1H), 7.31
(d, 1H, J=5.3 Hz), 7.00 (d, 1H, J=5.3 Hz), 5.98 (s, 1H), 4.11 (m,
2H), 4.01 (m, 2H), 1.44 (s, 6H).
[1200] (186-3)
[1201] The compound of Example 186-2 was treated with CBr.sub.4 and
PPh.sub.3, and the resulting dibromoolefin was treated with n-BuLi
to give
2-[3-(1,1-dimethylprop-2-ynyl)thien-2-yl]-1,3-dioxolane.
[1202] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.16 (d, 1H, J=5.3
Hz), 7.03 (d, 1H, J=5.3 Hz), 6.06 (s, 1H), 4.14 (m, 2H), 4.03 (m,
2H), 2.31 (s, 1H), 1.56 (s, 6H).
[1203] (186-4)
[1204] The compound of Example 186-3 was treated with n-Bu.sub.3SnH
and Pd(PPh.sub.3).sub.2Cl.sub.2 to give
tributyl{3-[2-(1,3-dioxolan-2-yl)thie-
n-3-yl]-3-methylbut-1-enyl}tin.
[1205] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.21 (d, 1H, J=5.3
Hz), 6.97 (d, 1H, J=5.3 Hz), 6.33 (s, 1H), 6.22 (d, 1H, J=19.3 Hz),
5.98 (d, 1H, J=19.3 Hz), 4.12 (m, 2H), 3.95 (m, 2H), 1.48 (m, 6H),
1.43 (s, 6H), 1.29 (m, 6H), 0.88 (m, 15H).
[1206] (186-5)
[1207] Methyl
5-chloro-2-{(1E)-3-[2-(1,3-dioxolan-2-yl)thien-3-yl]-3-methy-
lbut-1-enyl}benzoate was obtained from the compound of Example
186-4 in a similar manner to Example 180-3.
[1208] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.87 (d, 1H, J=2.3
Hz), 7.54 (d, 1H, J=8.5 Hz), 7.41 (dd, 1H, J=8.5 and 2.3 Hz), 7.24
(d, 1H, J=5.3 Hz), 7.18 (d, 1H, J=16.1 Hz), 7.03 (d, 1H, J=5.3 Hz),
6.36 (d, 1H, J=16.1 Hz), 6.33 (s, 1H), 4.12 (m, 2H), 3.90 (s, 3H),
3.89 (s, 3H), 1.57 (s, 6H).
[1209] (186-6)
[1210] Methyl
5-chloro-2-[(1E)-3-(2-formylthien-3-yl)-3-methylbut-1-enyl]b-
enzoate was obtained from the compound of Example 186-5 in a
similar manner to Example 155-2.
[1211] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.33 (d, 1H,
J=1.2 Hz), 7.90 (d, 1H, J=2.3 Hz), 7.42 (m, 4H), 7.22 (d, 1H,
J=16.1 Hz), 7.19 (d, 1H, J=5.1 Hz), 6.37 (d, 1H, J=16.1 Hz), 3.89
(s, 3H), 1.67 (s, 6H).
[1212] (186-7)
[1213] Methyl
5-chloro-2-((1E)-3-{2-[hydroxy-(4-methylphenyl)methyl]-thien-
-3-yl}-3-methylbut-1-enyl)benzoate was obtained from the compound
of Example 186-6 in a similar manner Example 138-1.
[1214] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=1.8
Hz), 7.40 (m, 2H), 7.24 (d, 2H, J=8.1 Hz), 7.23 (d, 1H, J=5.0 Hz),
7.07 (d, 2H, J=8.1 Hz), 7.04 (d, 1H, J=5.0 Hz), 7.03 (d, 1H, J=15.9
Hz), 6.38 (d, 1H, J=3.6 Hz), 6.36 (d, 1H, J=15.9 Hz), 3.85 (s, 3H),
3.45 (d, 1H, J=3.6 Hz), 2.31 (s, 3H), 1.57 (s, 6H).
[1215] (186-8)
[1216] Methyl
5-chloro-2-{(1E)-3-methyl-3-[2-(4-methylbenzoyl)thien-3-yl]b-
ut-1-enyl}benzoate was obtained from the compound of Example 186-7
in a similar manner to Example 28-4.
[1217] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.79 (d, 1H, J=2.2
Hz), 7.66 (d, 2H, J=8.2 Hz), 7.37 (d, 1H, J=5.1 Hz), 7.25 (dd, 1H,
J=8.5 and 2.2 Hz), 7.20 (d, 1H, J=8.5 Hz), 7.17 (d, 1H, J=5.1 Hz),
7.14 (d, 2H, J=8.2 Hz), 7.02 (d, 1H, J=16.2 Hz), 6.34 (d, 1H,
J=16.2 Hz), 3.87 (s, 3H), 2.38 (s, 3H), 1.57 (s, 6H).
[1218] (186-9)
[1219] The title compound was obtained from the compound of Example
186-8 in a similar manner to Example 16.
[1220] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.62 (d, 2H, J=8.2 Hz), 7.34 (d, 1H, J=5.1 Hz), 7.24 (dd, 1H,
J=8.5 and 2.3 Hz), 7.17 (d, 1H, J=8.5 Hz), 7.14 (d, 1H, J=5.1 Hz),
7.09 (d, 2H, J=8.2 Hz), 7.08 (d, 1H, J=16.2 Hz), 6.25 (d, 1H,
J=16.2 Hz), 2.35 (s, 3H), 1.53 (s, 6H).
Example 187
[1221] (187-1)
[1222] Methyl 4-allylisothiazole-3-carboxylate was obtained from
methyl 4-iodoisothiazole-3-carboxylate in a similar manner to
Example 180-3.
[1223] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.40 (s, 1H), 6.01
(dddd, 1H, J=16.8, 10.2, 6.6, 6.6 Hz), 5.12 (m, 2H), 3.98 (s, 3H),
3.76 (dd, 2H, J=6.6, 1.0).
[1224] (187-2)
[1225] 4-Allylisothiazole-3-carbaldehyde was obtained from the
compound of Example 187-1 in a similar manner to Example 137-5.
[1226] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.14 (s, 1H),
8.37 (s, 1H), 5.99 (dddd, 1H, J=16.9, 10.2, 6.6, 6.6 Hz), 5.11 (m,
2H), 3.76 (dd, 2H, J=6.6, 1.1).
[1227] (187-3)
[1228] (4-Allylisothiazol-3-yl)(4-methylphenyl)methanol was
obtained from the compound of Example 187-2 in a similar manner to
Example 138-1, and
(4-allylisothiazol-3-yl)(4-methylphenyl)methanone was obtained in a
similar manner to Example 28-4.
[1229] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.40 (s, 1H), 7.98
(d, 2H, J=8.3 Hz), 7.29 (d, 2H, J=8.3 Hz), 6.00 (dddd, 1H, J=16.3,
9.7, 6.6, 6.6 Hz), 5.11 (m, 2H), 3.69 (dd, 2H, J=6.6, 1.0 Hz), 2.44
(s, 3H).
[1230] (187-4)
[1231] The title compound was obtained from the compound of Example
187-3 in a similar manner to Example 109-12.
[1232] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.62 (s, 1H), 8.51
(s, 1H), 7.99 (d, 2H, J=8.2 Hz), 7.94 (d, 2H, J=8.2 Hz), 7.88 (d,
1H, J=2.3 Hz), 7.84 (d, 1H, J=2.3 Hz), 7.40 (m, 3H), 7.27 (m, 5H),
7.19 (d, 1H, J=15.7 Hz), 6.82 (d, 1H, J=15.9 Hz), 6.28 (m, 2H),
3.90 (s, 3H), 3.88 (s, 3H), 3.84 (m, 2H), 2.43 (s, 6H).
Example 188 and Example 189
[1233] (188-1)
[1234] Under nitrogen atmosphere, to a solution of 60% NaH (285 mg)
in DMF (10 mL) was added the compound of Reference Example 3 (1.20
g) under ice-cooling, and the mixture was stirred for 20 minutes.
Subsequently, triisopropylsilyl chloride (1.40 g) was added
dropwise thereto, and the mixture was stirred at 0.degree. C. for 4
hours. The reaction solution was poured into water, and the mixture
was etxtracted with ethyl acetate-toluene. The organic layer was
washed with water and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (ethyl acetate) to give
(1H-pyrrole-1-triisopropylsilyl-3-yl)(4-methylphenyl)ketone (2.08
g, 94%).
[1235] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.77 (d, 2H, J=8.0
Hz), 7.33 (dd, 1H, J=1.7, 1.7 Hz), 7.26 (d, 2H, J=8.0 Hz),
6.78-6.80 (m, 2H), 2.43 (s, 3H), 1.47 (sep, 3H, J=7.5 Hz), 1.11 (d,
18H, J=7.5 Hz).
[1236] (188-2)
[1237] Under nitrogen atmosphere, to a solution of the compound of
Example 188-1 (1.00 g) in CH.sub.3CN (20 mL) were added I.sub.2
(185 mg) and ammonium cerium (IV) nitrate (963 mg), and the mixture
was stirred at room temperature for 3 hours. The solvent was
evaporated under reduced pressure, and thereto was added an aqueous
sodium sulfite solution, and the mixture was extracted with ethyl
acetate. The organic layer was washed with water and a saturated
brine, and dried over MgSO.sub.4. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=15/1.fwdarw.8/1) to give
(4-iodo-1H-pyrrole-1-triisopropylsilyl-3-yl)(4-methylphenyl)ketone
(870 mg).
[1238] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.73 (d, 2H, J=8.1
Hz), 7.25 (d, 2H, J=8.1 Hz), 7.06 (d, 1H, J=2.2 Hz), 6.91 (d, 1H,
J=2.2 Hz), 2.43 (s, 3H), 1.43 (sep, 3H, J=7.5 Hz), 1.10 (d, 18H,
J=7.5 Hz).
[1239] (188-3)
[1240] Under nitrogen atmosphere, to a solution of the compound of
Example 188-2 (750 mg) in THF (7.0 mL) was added a solution of
Bu.sub.4NF (420 mg) in THF (3.0 mL), and the mixture was stirred at
room temperature for 1 hour. To the mixture was added a 5% aqueous
KHSO.sub.4 solution, and the mixture was extracted with ethyl
acetate, washed with a saturated brine, and dried over MgSO.sub.4.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl
acetate=3/1.fwdarw.1/1) to give (4-iodo-1H-pyrrol-3-yl)(4-m-
ethylphenyl)ketone (364 mg).
[1241] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.87 (br, 1H),
7.73 (d, 2H, J=8.1 Hz), 7.25 (d, 2H, J=8.1 Hz), 7.15 (dd, 1H,
J=2.2, 3.1 Hz), 7.00 (dd, 1H, J=2.2, 2.2 Hz), 2.42 (s, 3H).
[1242] (188-4)
[1243] Under nitrogen atmosphere, to a solution of the compound of
Example 188-3 (250 mg) in THF (5.0 mL) were added successively
KOt-Bu (108 mg) and MeI (100 .mu.l), and the mixture was stirred at
room temperature for 30 minutes. Water was added to the mixture,
and the mixture was extracted with ethyl acetate, washed with a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=3/1) to give
(4-iodo-1-methyl-1H-pyrrol-3-yl)(4-methylphenyl)ketone (219 mg,
39%, 3 steps).
[1244] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.70 (d, 2H, J=8.0
Hz), 7.24 (d, 2H, J=8.0 Hz), 6.97 (d, 1H, J=2.3 Hz), 6.81 (d, 1H,
J=2.3 Hz), 3.69 (s, 3H), 2.42 (s, 3H).
[1245] (188-5)
[1246] Under nitrogen atmosphere, to a solution of the compound of
Example 188-4 (200 mg) and allyltributyltin (314 mg) in THF (5.0
mL) were added successivly Pd(PPh.sub.3).sub.4 (101 mg) and LiCl
(41.2 mg), and the mixture was refluxed for 10 hours. The solvent
was evaporated under reduced pressure, and the residue was purified
by silica gel column (hexane/ethyl acetate=5/1) to give
(4-allyl-1-methyl-1H-pyrrol-3-yl) (4-methylphenyl)ketone (52.0 mg,
35%).
[1247] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.67 (d, 2H, J=8.0
Hz), 7.23 (d, 2H, J=8.0 Hz), 6.93 (d, 1H, J=2.2 Hz), 6.45 (d, 1H,
J=2.2 Hz), 6.06 (ddt, 1H, J=10.1, 17.0, 6.8 Hz), 5.11 (dd, 1H,
J=17.0, 2.0 Hz), 5.02 (dd, 1H, J=10.1, 2.0 Hz), 3.62 (s, 3H),
3.59(d, 2H, J=6.8 Hz), 2.41(s, 3H).
[1248] (188-6)
[1249] Under nitrogen atmosphere, to a suspension of methyl
5-chloro-2-iodobenzoate (Example 109-9) (63.6 mg), the compound of
Example 188-5 (45.0 mg), sodium hydrogen carbonate (33.3 mg), and
BnEt.sub.3NCl (47.5 mg) in DMF (3.0 mL) was added Pd(OAc).sub.2
(10.5 mg), and the mixture was stirred at 80.degree. C. for 6
hours. Water was added to the mixture, and the mixture was
extracted with ethyl acetate-toluene, and the organic layer was
washed with water and a saturated brine, and dried over MgSO.sub.4.
The solvent was evaporated under reduced pressure, and the residue
was purified by silica gel column (hexane/ethyl
acetate=5/1.fwdarw.3/1) to give the compound of Example 188 (10.2
mg, 13%) and the compound of Example 189 (9.5 mg, 12%).
[1250] The compound of Example 188: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.81 (d, 1H, J=2.2 Hz), 7.69 (d, 2H, J=7.9 Hz), 7.52
(d, 1H, J=8.5 Hz), 7.37 (d, 1H, J=2.2, 8.5 Hz), 7.24 (d, 2H, J=7.9
Hz), 7.17 (d, 1H, J=15.7 Hz), 6.94 (d, 1H, J=2.2 Hz), 6.52 (d, 1H,
J=2.2 Hz), 6.41 (dt, 1H, J=15.7, 7.0 Hz), 3.88 (s, 3H), 3.76 (d,
2H, J=7.0 Hz), 3.63 (s, 3H), 2.42 (s, 3H).
[1251] The compound of Example 189: .sup.1H NMR (CDCl.sub.3, 400
MHz) .delta. 7.84 (d, 1H, J=2.3 Hz), 7.67 (d, 2H, J=8.0 Hz), 7.38
(dd, 1H, J=2.3, 8.3 Hz), 7.29 (d, 1H, J=8.3 Hz), 7.22 (d, 2H, J=8.0
Hz), 6.95 (d, 1H, J=16.0 Hz), 6.87 (d, 1H, J=2.2 Hz), 6.76 (d, 1H,
J=2.2 Hz), 6.07 (dt, 1H, J=16.0, 7.2 Hz), 3.91. (s, 3H), 3.80 (d,
2H, J=7.2 Hz), 3.62 (s, 3H), 2.42 (s, 3H).
Example 190
[1252] (190-1)
[1253] (5-Methylthien-2-yl)(1H-pyrrol-2-yl)methanone was obtained
from 5-methyl-2-thiophenecarboxylic acid in a similar manner to
Example 125-2.
[1254] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.60 (brs, 1H),
7.75 (d, 1H, J=3.7 Hz), 7.13 (m, 1H), 7.11 (m, 1H), 6.84 (m, 1H),
6.35 (m, 1H), 2.57 (d, 3H, J=0.4 Hz).
[1255] (190-2)
[1256] The title compound was obtained from the compound of Example
190-1 in a similar manner to Example 18-3.
[1257] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.59 (d, 1H, J=3.7 Hz), 7.46 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=8.5, 2.3 Hz), 7.18 (d, 1H, J=15.8 Hz), 7.07 (dd, 1H, J=2.6, 1.6
Hz), 7.04 (dd, 1H, J=4.0, 1.6 Hz), 6.81 (m, 1H), 6.33 (dt, 1H,
J=15.8, 6.1 Hz), 6.24 (dd, 1H, J=4.0, 2.6 Hz), 5.14 (dd, 2H, J=6.1,
1.4 Hz), 3.87 (s, 3H), 2.56 (d, 3H, J=0.6 Hz).
Example 191
[1258] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.88 (d, 1H,
J=1.5 Hz), 7.55 (d, 1H, J=3.7 Hz), 7.38 (d, 1H, J=8.3 Hz), 7.32 (m,
2H), 7.00 (m, 2H), 6.73 (d, 1H, J=3.7 Hz), 6.22 (dt, 1H, J=15.7,
5.8 Hz), 6.14 (m, 1H), 5.01 (d, 2H, J=5.8 Hz), 2.48 (s, 3H).
Example 192
[1259] (192-1)
[1260] Under nitrogen atmosphere, a solution of indole-5-carboxylic
acid (1.05 g) in DMF (40 mL) was cooled to 0.degree. C., and
thereto was added NaH (544 mg, 60%), and the mixture was stirred at
the same temperature for 10 minutes, and stirred at room
temperature for 30 minutes. The mixture was cooled to 0.degree. C.,
and thereto was added iodomethane (3.68 g), and the mixture was
stirred at room temperature for 48 hours. Water was added to the
mixture, and the mixture was extracted three times with ethyl
acetate-toluene, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure to give a crude methyl
1-methylindole-5-carboxylate. To a solution of the crude methyl
1-methylindole-5-carboxylate in THF (50 mL)-MeOH (50 mL) was added
a 6N NaOH solution (5.4 mL), and the mixture was stirred at room
temperature for 144 hours. The solvent was evaporated under reduced
pressure. The residue was washed with ethyl acetate, and thereto
was added a 6N aqueous hydrochloric acid solution to adjust the pH
value thereof to pH=5-6. The mixture was extracted twice with ethyl
acetate, and dried over MgSO.sub.4. The solvent was evaporated
under reduced pressure to give 1-methyl-1H-indol-5-carboxylic acid
(1.08 g, 96%).
[1261] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.42 (brs,
1H,), 8.23 (d, 1H, J=1.2 Hz), 7.76 (dd, 1H, J=8.6, 1.2 Hz), 7.50
(d, 1H, J=8.6 Hz), 7.43 (d, 1H, J=3.1 Hz), 6.57 (dd, 1H, J=3.1, 0.7
Hz), 3.82 (s, 3H).
[1262] (192-2)
[1263] (1-Methyl-1H-indol-5-yl)(1H-pyrrol-2-yl)methanone was
obtained from the compound of Example 125-2 in a similar manner to
Example 192-1.
[1264] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.62 (brs, 1H),
8.30 (d, 1H, J=1.6 Hz), 7.86 (dd, 1H, J=8.6, 1.6 Hz), 7.40 (d, 1H,
J=8.6 Hz), 7.14 (d, 1H, J=3.1 Hz), 7.12 (m, 1H), 6.96 (m, 1H), 6.62
(dd, 1H, J=3.1, 0.9 Hz), 6.36 (m, 1H), 3.85 (s, 3H).
[1265] (192-3)
[1266] The title compound was obtained from the compound of the
compound of Example 192-2 in a similar manner to Example 18-3.
[1267] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.21 (d, 1H, J=1.6
Hz), 7.85 (d, 1H, J=2.3 Hz), 7.80 (dd, 1H, J=8.6, 1.6 Hz), 7.48 (d,
1H, J=8.5 Hz), 7.39 (dd, 1H, J=8.5, 2.3 Hz), 7.37 (d, 1H, J=8.6
Hz), 7.22 (d, 1H, J=15.8 Hz), 7.13 (d, 1H, J=3.1 Hz), 7.08 (dd, 1H,
J=2.4, 1.8 Hz), 6.81 (dd, 1H, J=4.0, 1.8 Hz), 6.59 (dd, 1H, J=3.1,
0.6 Hz), 6.38 (dt, 1H, J=15.8, 6.1 Hz), 6.24 (dd, 1H, J=4.0, 2.4
Hz), 5.23 (dd, 2H, J=6.1, 1.4 Hz), 3.87 (s, 3H).
Example 193
[1268] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.06 (d, 1H,
J=1.6 Hz), 7.65 (d, 1H, J=2.3 Hz), 7.63 (dd, 1H, J=8.6, 1.6 Hz),
7.60 (d, 1H, J=8.5 Hz), 7.52 (d, 1H, J=8.6 Hz), 7.44 (d, 1H, J=3.1
Hz), 7.42 (dd, 1H, J=8.5, 2.3 Hz), 7.31 (dd, 1H, J=2.6, 1.6 Hz),
7.20 (d, 1H, J=16.2 Hz), 6.67 (dd, 1H, J=3.9, 1.6 Hz), 6.58 (dd,
1H, J=3.1, 0.5 Hz), 6.43 (dt, 1H, J=16.2, 5.9 Hz), 6.22 (dd, 1H,
J=3.9, 2.6 Hz), 5.18 (d, 2H, J=5.9 Hz), 3.84 (s, 3H).
Example 194
[1269] (194-1)
[1270] Under nitrogen atmosphere, a solution of KOtBu (11.5 g) in
THF (203 mL) was cooled to 0.degree. C., and thereto were added
dropwise ethyl chloroacetate (12.5 g) and ethyl formate (7.60 g) in
THF (40 mL). After the addition, the mixture was stirred at
0.degree. C. for 3 hours, and further stirred at room temperature
for 16 hours. Water and a 6N aqueous hydrochloric acid solution
were added to the mixture, and the mixture was extracted with
Et.sub.2O, and dried over MgSO.sub.4. The solvent was evaporated
under reduced pressure to give ethyl 2-chloroformylpropionate.
Under nitrogen atmosphere, to a solution of ethyl
2-chloroformylpropionat- e in acetone (250 mL) was added
thioacetamide (7.74 g), and the mixture was stirred at 56.degree.
C. for 6 hours, and stirred at room temperature for 16 hours. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl
acetate=12.5/1.fwdarw.10/1) to give ethyl
2-methyl-1,3-thiazole-5-carboxy- late (5.74 g, 32%).
[1271] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.24 (s, 1H), 4.35
(q, 2H, J=7.1 Hz), 2.75 (s, 3H), 1.37 (t, 3H, J=7.1 Hz).
[1272] (194-2)
[1273] To a solution of the compound of Example 194-1 (5.74 g) in
THF (100 mL)-MeOH (100 mL) was added a 6N NaOH solution (27 mL),
and the mixture was stirred at room temperature for 16 hours. The
solvent was evaporated under reduced pressure, and thereto was
added a 6N aqueous hydrochloric acid solution, and the mixture was
extracted with ethyl acetate, and dried over MgSO.sub.4' The
solvent was evaporated under reduced pressure to give
2-methyl-1,3-thiazole-5-carboxylic acid (4.02 g, 86%).
[1274] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.31 (brs, 1H),
8.17 (s, 1H), 2.70 (s, 3H).
[1275] (194-3)
[1276] Under nitrogen atmosphere, to a solution of the compound of
Example 194-2 (1.35 g) in toluene (150 mL) were added
2,2'-dipyridyldisulfide (4.15 g) and PPh.sub.3 (4.94 g), and the
mixture was stirred at room temperature for 16 hours. Then, the
mixture was cooled to -78.degree. C., and thereto was added a 1N
pyrrolemagnesium bromide, which was prepared from pyrrole (2.02 g)
and a 0.93N solution of methylmagnesium bromide in Et.sub.2O (34.4
mL), in toluene, and the mixture was stirred at -78.degree. C. for
3 hours. To the mixture was added an aqueous NH.sub.4Cl solution,
and the mixture was warmed to room temperature. To the mixture was
added water, and the mixure was extracted with ethyl acetate, and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=4/1) to give
(2-methyl-1,3-thiazol-5-yl)(1H-pyrrol-- 2-yl)methanone (1.12 g,
62%).
[1277] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.67 (brs, 1H),
8.36 (s, 1H), 7.16 (m, 1H), 7.13 (m, 1H), 6.38 (m, 1H), 2.79 (s,
3H). (194-4)
[1278] Under nitrogen atmosphere, to a solution of the compound of
Example 9-2 (443 mg) in CH.sub.2Cl.sub.2 (20 mL) were added
N-bromosuccinimide (348 mg) and PPh.sub.3 (513 mg), and the mixture
was stirred at room temperature for 2 hours. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=20/1) to give a bromo
compound (462 mg, 82%). Under nitrogen atmosphere, to a solution of
the compound of Example 194-3 (195 mg) in THF (10 mL) was added
KOtBu (125 mg). Further, a solution of the bromo compound (294 mg)
in THF (10 mL) was added thereto, and the mixture was stirred at
room temperature for 1 hour. To the mixture was added an aqueous
NH.sub.4Cl solution, and the mixture was extracted with ethyl
acetate, and dried over MgSO.sub.4. The solvent was evaporated
under reduced pressure, and the residue was purified by silica gel
column (hexane/ethyl acetate=8/1.fwdarw.6/1) to give methyl
5-chloro-2-((1E)-3-{2-[(2-methyl-1,3-thiazol-5-yl)carbonyl]-1H-pyrrol-1-y-
l}prop-1-enyl)benzoate (248 mg, 61%).
[1279] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.20 (s, 1H), 7.86
(d, 1H, J=2.2 Hz), 7.46 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H, J=8.4, 2.2
Hz), 7.18 (d, 1H, J=15.7 Hz), 7.12 (m, 1H), 7.08 (m, 1H), 6.30 (m,
2H), 5.15 (dd, 2H, J=6.0, 1.3 Hz), 3.87 (s, 3H), 2.77 (s, 3H).
[1280] (194-5)
[1281] To a solution of the compound of Example 194-4 (248 mg) in
THF (7.5 mL)-MeOH (7.5 mL) was added a 2N NaOH solution (1.6 mL),
and the mixture was stirred at room temperature for 48 hours. The
solvent was evaporated under reduced pressure, and thereto was
added a 2N aqueous hydrochloric acid solution, and the mixture was
extracted with ethyl acetate, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (CHCl.sub.3/MeOH=34/1.f- wdarw.10/1)
to give the title compound (181 mg, 76%).
[1282] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.26 (s, 1H),
7.67 (d, 1H, J=2.3 Hz), 7.61 (d, 1H, J=8.5 Hz), 7.46 (dd, 1H,
J=8.5, 2.3 Hz), 7.40 (dd, 1H, J=2.5, 1.6 Hz), 7.15 (dd, 1H, J=4.1,
1.6 Hz), 7.09 (d, 1H, J=15.7 Hz), 6.40 (dt, 1H, J=15.7, 5.7 Hz),
6.28 (dd, 1H, J=4.1, 2.5 Hz), 5.12 (dd, 2H, J=5.7, 1.1 Hz), 2.71
(s, 3H).
Example 195
[1283] (195-1)
[1284] A solution of ethyl p-aminobenzoate (23.2 g) and potassium
thiocyanate (40.9 g) in acetic acid (280 mL) was cooled to
0.degree. C., and thereto was added dropwise bromine (22.4 g), and
the mixture was stirred at 0.degree. C. for 20 minuts, and stirred
at room temperature for 135 minutes, and stirred for 5 hours. The
precipitated solid was collected by filtration to give ethyl
2-amino-1,3-benzothiazole-6-carboxy- late (9.62 g, 31%).
[1285] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.65 (brs, 2H),
8.38 (d, 1H, J=1.7 Hz), 7.89 (dd, 1H, J=8.5, 1.7 Hz), 7.44 (d, 1H,
J=8.5 Hz), 4.30 (q, 2H, J=7.1 Hz), 1.32 (t, 3H, J=7.1 Hz).
[1286] (195-2)
[1287] Under nitrogen atmosphere, a solution of the compound of
Example 195-1 (3.09 g) and copper (II) bromide (10.8 g) in
CH.sub.3CN (200 mL) was cooled to 0.degree. C., and thereto was
added dropwise isobutyl nitrite (6.27 g), and the mixture was
stirred at 0.degree. C. for 10 minutes, and stirred at room
temperature for 2 hours. Water was added to the mixture, and the
mixture was extracted twice with Et.sub.2O. The organic layer was
washed with water, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure to give a crude ethyl
2-bromo-1,3-benzothiazole-6-carboxylate (8.16 g). Under nitrogen
atmosphere, to a solution of this compound (4.00 g) in DMSO (100
mL)-CH.sub.3CN (100 mL) were added successively Pd(PPh.sub.3).sub.4
(485 mg) and sodium formate (4.76 g), and the mixture was stirred
at 100.degree. C. for 75 minutes. The solvent was evaporated under
reduced pressure, and thereto was added water, and the mixture was
extracted four times with Et.sub.2O, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (hexane/ethyl acetate=10/1) to give
ethyl 1,3-benzothiazole-6-carboxylate (1.21 g, 42%).
[1288] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.15 (s, 1H), 8.71
(dd, 1H, J=1.6, 0.5 Hz), 8.21 (dd, 1H, J=8.6, 1.6 Hz), 8.17 (dd,
1H, J=8.6, 0.5 Hz), 4.44 (q, 2H, J=7.1 Hz), 1.44 (t, 3H, J=7.1
Hz).
[1289] (195-3)
[1290] To a solution of the compound of Example 195-2 (1.21 g) in
THF (50 mL)-EtOH (50 mL) was added a 2N NaOH solution (14.6 mL),
and the mixture was stirred at room temperature for 64 hours. The
solvent was evaporated under reduced pressure, and thereto was
added water, and washed with ethyl acetate. The mixture was cooled
to 0.degree. C., and thereto was added a 2.5N aqueous hydrochloric
acid to adjust the pH value thereof to pH=3. The mixtuer was
extracted five times with ethyl acetate, and dried over MgSO.sub.4.
The solvent was evaporated under reduced pressure to give
1,3-benzothiazole-6-carboxylic acid (983.1 mg, 94%).
[1291] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.10 (brs, 1H),
9.58 (s, 1H), 8.81 (d, 1H, J=1.3 Hz), 8.17 (d, 1H, J=8.5 Hz), 8.08
(dd, 1H, J=8.5, 1.3 Hz).
[1292] (195-4)
[1293] Ethyl 2-bromo-1,3-benzothiazole-6-carboxylate was obtained
from the compound of Example 195-3 in a similar manner to Example
125-2.
[1294] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.71 (brs, 1H),
9.16 (s, 1H), 8.56 (d, 1H, J=1.2 Hz), 8.24 (d, 1H, J=8.5 Hz), 8.09
(dd, 1H, J=8.5, 1.2 Hz), 7.19 (m, 1H), 6.95 (m, 1H), 6.39 (m,
1H).
[1295] (195-5)
[1296] Methyl
2-{(1E)-3-[2-(1,3-benzothiazol-6-ylcarbonyl)-1H-pyrrol-1-yl]-
prop-1-enyl}-5-chlorobenzoate was obtained from the compound of
Example 195-4 in a similar manner to Example 18-3.
[1297] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.14 (s, 1H), 8.48
(d, 1H, J=1.3 Hz), 8.20 (d, 1H, J=8.5 Hz), 8.01 (dd, 1H, J=8.5, 1.3
Hz), 7.86 (d, 1H, J=2.2 Hz), 7.49 (d, 1H, J=8.5 Hz), 7.41 (dd, 1H,
J=8.5, 2.2 Hz), 7.22 (d, 1H, J=15.8 Hz), 7.14 (dd, 1H, J=2.4, 1.8
Hz), 6.81 (dd, 1H, J=4.0, 1.8 Hz), 6.36 (dt, 1H, J=15.8, 5.9 Hz),
6.27 (dd, 1H, J=4.0, 2.4 Hz), 5.26 (dd, 2H, J=5.9, 1.5 Hz), 3.87
(s, 3H).
[1298] (195-6)
[1299] The title compound was obtained from the compound of Example
195-5 in a similar manner to Example 16.
[1300] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 9.56 (s, 1H),
8.62 (d, 1H, J=1.5 Hz), 8.17 (d, 1H, J=8.5 Hz), 7.90 (dd, 1H,
J=8.5, 1.5 Hz), 7.64 (d, 1H, J=2.2 Hz), 7.59 (d, 1H, J=8.5 Hz),
7.39 (m, 2H), 7.26 (d, 1H, J=15.3 Hz), 6.76 (dd, 1H, J=4.0, 1.6
Hz), 6.42 (dt, 1H, J=15.3, 5.9 Hz), 6.25 (dd, 1H, J=4.0, 2.5 Hz),
5.20 (d, 2H, J=5.9 Hz).
Example 196
[1301] (196-1)
[1302] Under nitrogen atmosphere, a solution of
2,2,6,6-tetramethylpiperid- ine (5.00 mL) in THF (120 mL) was
cooled to -78.degree. C., and thereto was added dropwise a 1.6N
solution of BuLi in hexane (18.5 mL), and the mixture was stirred
at room temperature for 30 minutes. The mixture was cooled again to
-78.degree. C., and thereto was added a solution of
N-benzenesulfonylpyrrole (5.58 g) in THF (25 mL). The mixture was
stirred for 30 minutes, and thereto was added a solution of
6-methylpyridine-2-aldehyde (3.94 g) in THF (20 mL), and the
mixture was stirred at -78.degree. C. for 2 hours. Water was added
to the mixture, and the mixture was extracted twice with ethyl
acetate. The organic layer was washed with a saturated brine and
dried over MgSO.sub.4. The solvent was evaporated under reduced
pressure, and the precipitated solid was suspended in a mixed
solvent of hexane/ethyl acetate=5/1, and collected by filtration to
give [1-(phenylsulfonyl)-1H-pyrrol-2-yl](6-methylpyridin-
-2-yl)methanol (6.78 g, 77%).
[1303] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.99 (dd, 2H,
J=1.3, 8.4 Hz), 7.61 (tt, 1H, J=1.3, 7.4 Hz), 7.49-7.56 (m, 3H),
7.30 (dd, 1H, J=1.7, 3.3 Hz), 7.08 (d, 1H, J=7.6 Hz), 7.04 (d, 1H,
J=7.7 Hz), 6.25 (d, 1H, J=5.3 Hz), 6.16 (dd, 1H, J=3.3, 3.3 Hz),
5.76 (dd, 1H, J=1.7, 3.3 Hz), 5.14 (d, 1H, J=5.3 Hz), 2.55 (s,
3H).
[1304] (196-2)
[1305] Under nitrogen atmosphere, to a solution of the compound of
Example 196-1 (5.83 g) in CHCl.sub.3 (90 mL) was added MnO.sub.2
(31.2 g), and the mixture was stirred at room temperature for 1
hour, and filtered. The solvent was evaporated under reduced
pressure to give a crude ketone compound (5.94 g). Under nitrogen
atmosphere, to a solution of the crude ketone compound (4.62 g) in
dioxane (30 mL) was added a 2N aqueous NaOH solution (27 mL), and
the mixture was stirred at 80.degree. C. for 1 hour. The reaction
solution was cooled to room temperature, and the pH value of the
mixture was adjusted to pH=8 with conc. hydrochloric acid and a
saturated aqueous sodium hydrogen carbonate solution, and the
mixture was extracted twice with ethyl acetate. The extract was
washed with a saturated brine, and dried over MgSO.sub.4. The
solvent was evaporated under reduced pressure, and the residue was
purified by silica gel column (toluene/ethyl acetate=3/2) to give
(1H-pyrrol-2-yl) (6-methylpyridin-2-yl)ketone (2.68 g, 100%).
[1306] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 11.7 (br, 1H),
8.08 (d, 1H, J=7.7 Hz), 7.78 (dd, 1H, J=7.7, 7.7 Hz), 7.48 (br,
1H), 7.33 (d, 1H, J=7.7 Hz), 7.11-7.12 (m, 1H), 6.36-6.38 (m, 1H),
2.70 (s, 3H).
[1307] (196-3)
[1308] The title compound was obtained from the compound of Example
196-2 and the compound of Example 9-2 in a similar manner to
Example 18-3.
[1309] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.71-7.72 (m, 2H), 7.49 (d, 1H, J=8.4 Hz), 7.40 (dd, 1H,
J=2.3, 8.4 Hz), 7.36 (dd, 1H, J=1.7, 4.1 Hz), 7.28-7.30 (m, 1H),
7.23 (d, 1H, J=15.8 Hz), 7.10 (dd, 1H, J=1.7, 2.5 Hz), 6.38 (dt,
1H, J=15.8, 6.1 Hz), 6.25 (dd, 1H, J=2.5, 4.1 Hz), 5.25 (d, 2H,
J=6.1 Hz), 3.87 (s, 3H), 2.65 (s, 3H).
Example 197
[1310] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.78-7.82 (m, 2H),
7.49 (d, 1H, J=7.6 Hz), 7.35-7.38 (m, 2H), 7.26 (d, 1H, J=8.3 Hz),
7.07 (dd, 1H, J=1.6, 2.5 Hz), 6.77 (dd, 1H, J=1.6, 4.1 Hz), 6.42
(d, 1H, J=15.8 Hz), 6.23 (dd, 1H, J=2.5, 4.1 Hz), 6.05 (dt, 1H,
J=15.8, 4.2 Hz), 5.27 (d, 2H, J=4.2 Hz), 2.79 (s, 3H).
Example 198
[1311] (198-1)
[1312] (1-Phenylsulfonyl-1H-pyrrol-2-yl)(3,4-dimethoxyphenyl)ketone
was obtained from veratroyl chloride and pyrrolesulfonamide.
[1313] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.55 (brs, 1H),
7.62 (dd, 1H, J=8.3 and 2.0 Hz), 7.48 (d, 1H, J=2.0 Hz), 7.13 (dt,
1H, J=1.3 and 2.6 Hz), 6.94 (d, 1H, J=8.3 Hz), 6.92 (ddd, 1H,
J=3.8, 2.4 and 1.3 Hz), 6.35 (dt, 1H, J=3.8 and 2.6 Hz), 3.97 (s,
3H), 3.96 (s, 3H).
[1314] (198-2)
[1315] The title compound was obtained from the compound of Example
198-1 and the compound of Example 9-2 in a similar manner to
Example 18-3.
[1316] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.52 (dd, 1H, J=8.3 and 2.0 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.44
(d, 1H, J=2.0 Hz), 7.40 (dd, 1H, J=8.5 and 2.2 Hz), 7.21 (dt, 1H,
J=15.8 and 1.4 Hz), 7.09 (dd, 1H, J=1.7 and 2.5 Hz), 6.91 (d, 1H,
J=8.3 Hz), 6.80 (dd, 1H, J=1.7 and 4.0 Hz), 6.36 (dt, 1H, J=15.8
and 6.1 Hz), 6.23 (dd, 1H, J=2.5 and 4.0 Hz), 5.20 (dd, 2H, J=1.4
and 6.1 Hz), 3.96 (s, 3H), 3.94 (s, 3H), 3.87 (s, 3H).
Example 199
[1317] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.43 (dd, 1H,
J=8.3 and 2.0 Hz), 7.42 (brd, 1H, J=15.8 Hz), 7.38 (d, 1H, J=8.5
Hz), 7.37 (brs, 1 Hz), 7.34 (brs, 1H), 7.31 (dd, 1H, J=1.7 and 2.5
Hz), 7.09 (dd, 1H, J=8.5 and 2.2 Hz), 7.05 (d, 1H, J=8.3 Hz), 6.70
(dd, 1H, J=1.7 and 4.0 Hz), 6.23 (dt, 1H, J=15.8 and 6.1 Hz), 6.20
(dd, 1H, J=2.5 and 4.0 Hz), 5.08 (brd, 2H, J=6.1 Hz), 3.84 (s, 3H),
3.82 (s, 3H).
Example 200
[1318] (200-1)
[1319] 1,3-Benzodioxol-5-yl(1H-pyrrol-2-yl)methanone was obtained
from piperonyl chloride and pyrrolesulfonamide.
[1320] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.50 (brs, 1H),
7.55 (dd, 1H, J=8.1 and 1.7 Hz), 7.48 (d, 1H, J=1.7 Hz), 7.12 (dt,
1H, J=1.3 and 2.7 Hz), 6.89 (d, 1H, J=8.1 Hz), 6.88 (ddd, 1H,
J=3.8, 2.4 and 1.3 Hz), 6.34 (dt, 1H, J=3.8 and 2.7 Hz), 6.06 (s,
2H).
[1321] (200-2)
[1322] The title compound was obtained from the compound of Example
200-1 and the compound of Example 9-2 in a similar manner to
Example 18-3.
[1323] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.2
Hz), 7.48 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H, J=8.1 and 1.7 Hz), 7.40
(dd, 1H, J=8.5 and 2.2 Hz), 7.35 (d, 1H, J=1.7 Hz), 7.18 (dt, 1H,
J=15.8 and 1.4 Hz), 7.08 (dd, 1H, J=1.7 and 2.5 Hz), 6.86 (d, 1H,
J=8.1 Hz), 6.78 (dd, 1H, J=1.7 and 4.0 Hz), 6.33 (dt, 1H, J=15.8
and 6.1 Hz), 6.23 (dd, 1H, J=2.5 and 4.0 Hz), 6.04 (s, 2H), 5.19
(dd, 2H, J=1.4 and 6.1 Hz), 3.87 (s, 3H).
Example 201
[1324] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.40 (brd, 1H,
J=15.8 Hz), 7.38 (dd, 1H, J=8.1 and 1.7 Hz), 7.38-7.32 (m, 2H),
7.31 (dd, 1H, J=1.7 and 2.5 Hz), 7.28 (d, 1H, J=1.7 Hz), 7.10 (m,
1H), 7.01 (d, 1H, J=8.1 Hz), 6.67 (dd, 1H, J=1.7 and 4.0 Hz), 6.22
(brdt, 1H, J=15.8 and 6.1 Hz), 6.19 (dd, 1H, J=2.5 and 4.0 Hz),
6.13 (s, 2H), 5.07 (brd, 2H, J=6.1 Hz).
Example 202
[1325] (202-1)
[1326] Under nitrogen atmosphere, to a solution of the compound of
Example 109-6 (300 mg) in DMF (4.0 mL) were added successively 60%
NaH (69.8 mg) and 4-bromo-1-butene (170 .mu.L), and the mixture was
stirred at 80.degree. C., during which 60% NaH (45.0 mg) and
4-bromo-1-butene (200 .mu.L) were added thereto, and the mixture
was stirred for total 9 hours. Water was added to the reaction
solution, and the mixture was extracted with ethyl acetate-toluene.
The organic layer was washed twice with water, and washed with a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=6/1.fwdarw.2/1) to give
[1-(4-buten-1-yl)-4-methyl-1H-pyrrol-2-yl](4-methoxyphenyl)methanone
(242 mg, 65%).
[1327] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 2H, J=8.8
Hz), 6.94 (d, 2H, J=8.8 Hz), 6.74 (d, 1H, J=1.3 Hz), 6.52 (d, 1H,
J=1.3 Hz), 5.79 (ddt, 1H, J=10.4, 17.1, 7.1 Hz), 5.06 (dd, 1H,
J=17.1, 1.7 Hz), 5.02 (dd, 1H, J=10.4, 1.7 Hz), 4.38 (t, 2H, J=7.1
Hz), 3.88 (s, 3H), 2.54 (dt, 2H, J=7.1, 7.1 Hz), 2.07 (s, 3H).
[1328] (202-2)
[1329] Under nitrogen atmosphere, a suspension of methyl
5-chloro-2-iodobenzoate (Example 109-9) (220 mg), the compound of
Example 202-1 (200 mg), Pd(OAc).sub.2 (22.9 mg), BnEt.sub.3NCl (171
mg), sodium hydrogen carbonate (130 mg), tri-o-tolylphosphine (68.4
mg) in DMF (4.0 mL) was stirred at 80.degree. C. for 4 hours, and
stirred at 100.degree. C. for 11 hours, during which silver (I)
carbonate (207 mg) was added thereto. The mixture was cooled to
room temperature, and the mixture was filtered. Water was added to
the filtrate, and the mixture was extracted with ethyl
acetate/toluene. The organic layer was washed with water and a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=7/1.fwdarw.5/1) to give
methyl
5-chloro-2-{(1E)-4-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrrol-1-yl]-1-buten-
yl}benzoate (55.0 mg, 17%).
[1330] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (d, 1H, J=2.2
Hz), 7.77 (d, 2H, J=8.8 Hz), 7.36 (d, 1H, J=8.5 Hz), 7.32 (dd, 1H,
J=2.2, 8.5 Hz), 7.10 (d, 1H, J=15.7 Hz), 6.90 (d, 2H, J=8.8 Hz),
6.77 (d, 1H, J=1.4 Hz), 6.51 (d, 1H, J=1.4 Hz), 6.08 (dt, 1H,
J=15.7, 7.1 Hz), 4.49 (t, 2H, J=7.1 Hz), 3.89 (s, 3H), 3.87 (s,
3H), 2.72 (dt, 2H, J=7.1, 7.1 Hz), 2.07 (s, 3H).
[1331] (202-3)
[1332] The title compound was obtained from the compound of Example
202-2 in a similar manner to Example 16.
[1333] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=1.7
Hz), 7.76 (d, 2H, J=8.8 Hz), 7.37 (m, 2H), 7.16 (d, 1H, J=15.6 Hz),
6.90 (d, 2H, J=8.8 Hz), 6.78 (d, 1H, J=1.3 Hz), 6.52 (d, 1H, J=1.3
Hz), 6.09 (dt, 1H, J=15.6, 6.9 Hz), 4.50 (t, 2H, J=6.9 Hz), 3.86
(s, 3H), 2.72 (dt, 2H, J=6.9, 6.9 Hz), 2.07 (s, 3H).
Example 203
[1334] (203-1)
[1335]
(2E,4E)-5-(4-Chloro-2-methoxycarbonylphenyl)-2,4-pentadienoic acid
was obtained from methyl 5-chloro-2-iodobenzoate (Example 109-9)
(600 mg) and 1,3-butadiene-1-carboxylic acid (240 mg) in a similar
manner to Example 202-2.
[1336] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 12.38 (brs, 1H),
7.85 (d, 1H, J=8.6 Hz), 7.82 (d, 1H, J=2.3 Hz), 7.68 (dd, 1H,
J=2.3, 8.6 Hz), 7.53 (d, 1H, J=15.5 Hz), 7.34 (dd, 1H, J=11.0, 15.1
Hz), 7.10 (dd, 1H, J=11.0, 15.5 Hz), 6.07 (d, 1H, J=15.1 Hz), 3.87
(s, 3H).
[1337] (203-2)
[1338] Methyl
5-chloro-2-[(1E,3E)-5-hydroxy-1,3-pentadienyl]benzoate was obtained
from the compound of Example 203-1 (173 mg) in a similar manner to
Example 9-2.
[1339] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.3
Hz), 7.55 (d, 1H, J=8.5 Hz), 7.43 (dd, 1H, J=2.3, 8.5 Hz), 7.34 (d,
1H, J=15.5 Hz), 6.70 (dd, 1H, J=10.6, 15.5 Hz), 6.49 (dd, 1H,
J=10.6, 15.1 Hz), 6.01 (dd, 1H, J=15.1, 5.7 Hz), 4.27 (d, 2H, J=5.7
Hz), 3.91 (s, 3H).
[1340] (203-3)
[1341] Methyl
5-chloro-2-{(1E,3E)-5-[2-(4-methoxybenzoyl)-4-methyl-1H-pyrr-
ol-1-yl]-1,3-pentadienyl}benzoate was obtained from the compound of
Example 203-2 and Example 109-6 in a similar manner to Example
18-3.
[1342] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (d, 1H, J=2.2
Hz), 7.82 (d, 2H, J=8.8 Hz), 7.51 (d, 1H, J=8.5 Hz), 7.40 (dd, 1H,
J=2.2, 8.5 Hz), 7.30 (d, 1H, J=15.6 Hz), 6.95 (d, 2H, J=8.8 Hz),
6.79 (d, 1H, J=1.3 Hz), 6.67 (dd, 1H, J=10.5, 15.6 Hz), 6.56 (d,
1H, J=1.3 Hz), 6.30 (dd, 1H, J=10.5, 15.0 Hz), 6.09 (dt, 1H,
J=15.0, 6.0 Hz), 5.05 (d, 2H, J=6.0 Hz), 3.90 (s, 3H), 3.88 (s,
3H), 2.10 (s, 3H).
[1343] (203-4)
[1344] The title compound was obtained from the compound of Example
203-3 in a similar manner to Example 16.
[1345] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.97 (d, 1H, J=2.3
Hz), 7.82 (d, 2H, J=8.8 Hz), 7.53 (d, 1H, J=8.5 Hz), 7.45 (dd, 1H,
J=2.3, 8.5 Hz), 7.37 (d, 1H, J=15.6 Hz), 6.95 (d, 2H, J=8.8 Hz),
6.80 (d, 1H, J=1.5 Hz), 6.68 (dd, 1H, J=10.4, 15.6 Hz), 6.57 (d,
1H, J=1.5 Hz), 6.33 (dd, 1H, J=10.4, 15.0 Hz), 6.10 (dt, 1H,
J=15.0, 6.0 Hz), 5.06 (d, 2H, J=6.0 Hz), 3.87 (s, 3H), 2.10 (s,
3H).
Example 204
[1346] (204-1)
[1347] [1-(2-propin-1-yl)-1H-pyrrol-2-yl](4-methylphenyl)methanone
was obtained from the compound of Reference Example 1 and propargyl
chloride in a similar manner to Example 202-1.
[1348] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.73 (d, 2H, J=8.1
Hz), 7.29 (dd, 1H, J=1.6, 2.6 Hz), 7.26 (d, 2H, J=8.1 Hz), 6.78
(dd, 1H, J=1.6, 4.0 Hz), 6.22 (dd, 1H, J=2.6, 4.0 Hz), 5.30 (d, 2H,
J=2.6 Hz), 2.45 (t, 1H, J=2.6 Hz), 2.43 (s, 3H).
[1349] (204-2)
[1350] The title compound was obtained from methyl
5-chloro-2-iodobenzoate (Example 109-9) and the compound of Example
204-1 in a similar manner to Example 48.
[1351] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=2.2
Hz), 7.74 (d, 2H, J=8.0 Hz), 7.56 (dd, 1H, J=1.7, 2.7 Hz), 7.49 (d,
1H, J=8.3 Hz), 7.43 (dd, 1H, J=2.2, 8.3 Hz), 7.26 (d, 2H, J=8.0
Hz), 6.80 (dd, 1H, J=1.7, 4.0 Hz), 6.26 (dd, 1H, J=2.7, 4.0 Hz),
5.58 (s, 2H), 3.89 (s, 3H), 2.43 (s, 3H).
Example 205
[1352] (205-1)
[1353] Under nitrogen atmosphere, a solution of 5-chlorosalicylic
acid (5.00 g) in MeOH (100 mL) was cooled to 0.degree. C., and
thereto was added dropwise SOCl.sub.2 (3.20 mL). After the
addition, the mixture was stirred at 60.degree. C. for 10 hours.
The solvent was evaporated under reduced pressure, and the residue
was dissolved in ethyl acetate, washed twice with water, washed
with a saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=5/1) to give methyl
5-chloro-2-hydroxybenzoate (4.03 g, 74%).
[1354] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 10.68 (s, 1H),
7.81 (d, 1H, J=2.7 Hz), 7.40 (dd, 1H, J=2.7, 8.9 Hz), 6.94 (d, 1H,
J=8.9 Hz), 3.96 (s, 3H).
[1355] (205-2)
[1356] Under nitrogen atmosphere, a solution of the compound of
Example 205-1 (500 mg) in DMF (10 mL) was cooled to 0.degree. C.,
and thereto were added successively 60% NaH (122 mg) and
(2-bromoethoxy)tert-butyldim- ethylsilane (960 mg), and the mixture
was stirred at 50.degree. C. for 2 hours, and stirred at 80.degree.
C. for 4 hours. The reaction solution was poured into a 5% aqueous
KHSO.sub.4 solution, and the mixture was extracted with ethyl
acetate-toluene. The organic layer was washed with water and a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=12/1.fwdarw.8/1) to give
methyl 2-[2-(t-butyldimethylsilyl)oxy]ethoxy-5-chlorobenzoate (553
mg, 60%).
[1357] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.72 (d, 1H, J=2.7
Hz), 7.38 (dd, 1H, J=2.7, 8.9 Hz), 6.97 (d, 1H, J=8.9 Hz), 4.11 (t,
2H, J=5.4 Hz), 3.98 (t, 2H, J=5.4 Hz), 3.88 (s, 3H), 0.89 (s, 9H),
0.08 (s, 6H).
[1358] (205-3)
[1359] Under nitrogen atmosphere, to a solution of the compound of
Example 205-2 (350 mg) in THF (6.0 mL) were added successively
acetic acid (200 .mu.L) and Bu.sub.4NF (400 mg), and the mixture
was stirred at room temperature for 2 hours. To the mixture was
added a 5% aqueous KHSO.sub.4 solution, and the mixture was
extracted with ethyl acetate. The extract was washed with water and
a saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=3/1.fwdarw.1/3) to give
methyl 5-chloro-2-(2-hydroxyethoxy)benzoate (187 mg, 80%).
[1360] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 1H, J=2.7
Hz), 7.44 (dd, 1H, J=2.7, 8.8 Hz), 6.96 (d, 1H, J=8.8 Hz), 4.21 (t,
2H, J=4.5 Hz), 3.90-3.92 (m, 2H), 3.90 (s, 3H), 3.59 (brs, 1H).
[1361] (205-4)
[1362] The title compound was obtained from the compound of Example
205-3 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[1363] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.79 (d, 2H, J=8.8
Hz), 7.75 (d, 1H, J=2.7 Hz), 7.36 (dd, 1H, J=2.7, 8.9 Hz), 7.05 (d,
1H, J=1.4 Hz), 6.95 (d, 2H, J=8.8 Hz), 6.88 (d, 1H, J=8.9 Hz), 6.57
(d, 1H, J=1.4 Hz), 4.72 (t, 2H, J=4.8 Hz), 4.40 (t, 2H, J=4.8 Hz),
3.91 (s, 3H), 3.88 (s, 3H), 2.08 (s, 3H).
Example 206
[1364] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.0 (brs, 1H),
7.72 (d, 2H, J=8.5 Hz), 7.62 (d, 1H, J=2.6 Hz), 7.50 (dd, 1H,
J=2.6, 8.9 Hz), 7.14-7.17 (m, 2H), 7.03 (d, 2H, J=8.5 Hz), 6.48 (s,
1H), 4.64 (t, 2H, J=4.8 Hz), 4.33 (t, 2H, J=4.8 Hz), 3.84 (s, 3H),
2.01 (s, 3H).
Example 207
[1365] (207-1)
[1366] Under nitrogen atmosphere, to a solution of methyl
5-chloro-2-iodobenzoate (Example 109-9) (202 mg) and
(2E)-2-methyl-3-tributyl-stannylprop-2-en-1-ol (230 mg) in THF (5.0
mL) were added successively bis(dibenzylideneacetone)palladium
(26.8 mg) and tri-(2-furyl)-phosphine (31.4 mg), and the mixture
was refluxed for 22 hours. The solvent was evaporated under reduced
pressure, and the residue was purified by silica gel column
(hexane/ethyl acetate=8/1.fwdarw.3/1.fw- darw.1/1) to give
(2E)-3-(4-chloro-2-methoxycarbonylphenyl)-2-methylpropen- ol (72.0
mg, 47%).
[1367] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.94 (d, 1H, J=2.3
Hz), 7.45 (dd, 1H, J=2.3, 8.3 Hz), 7.23 (d, 1H, J=8.3 Hz), 6.88 (q,
1H, J=1.3 Hz), 4.22 (d, 2H, J=6.0 Hz), 3.87 (s, 3H), 1.72 (d, 3H,
J=1.3 Hz), 1.64 (t, 1H, J=6.0 Hz).
[1368] (207-2)
[1369] The title compound was obtained from the compound of Example
207-1 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[1370] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.89 (d, 1H, J=2.3
Hz), 7.82 (d, 2H, J=8.8 Hz), 7.40 (dd, 1H, J=2.3, 8.3 Hz), 7.15 (d,
1H, J=8.3 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.90 (d, 1H, J=1.4 Hz), 6.55
(d, 1H, J=1.4 Hz), 6.47 (s, 1H), 5.10 (s, 2H), 3.87 (s, 3H), 3.81
(s, 3H), 2.11 (s, 3H), 1.65 (s, 3H).
Example 208
[1371] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.99 (d, 1H, J=2.3
Hz), 7.80 (d, 2H, J=8.8 Hz), 7.45 (dd, 1H, J=2.3, 8.3 Hz), 7.18 (d,
1H, J=8.3 Hz), 6.91 (d, 2H, J=8.8 Hz), 6.89 (d, 1H, J=1.3 Hz), 6.55
(d, 1H, J=1.3 Hz), 6.49 (s, 1H), 5.08 (s, 2H), 3.84 (s, 3H), 2.09
(s, 3H), 1.66 (s, 3H).
Example 209
[1372] (209-1)
[1373] Under nitrogen atmosphere, a solution of the compound of
Example 9-2 (250 mg) in CH.sub.2Cl.sub.2 (5.0 mL) was cooled to
0.degree. C., and thereto was added dropwise a 1.02N solution of
Et.sub.2Zn in hexane (3.50 mL), and the mixture was stirred at the
same temperature for 30 minutes. To the mixture was added dropwise
CH.sub.2I.sub.2 (500 .mu.L), and the mixture was stirred at
0.degree. C. for 1 hour, and stirred at room temperature for 3
hours. To the mixture was added a 1N aqueous hydrochloric acid
solution, and the mixture was extracted with ethyl acetate. The
extract was washed with a saturated brine, and dried over
MgSO.sub.4. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=3/2) to give methyl
5-chloro-2-[2-(hydroxymethyl)cyclopropyl]benzoate (189 mg,
71%).
[1374] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.92 (d, 1H, J=2.3
Hz), 7.40 (dd, 1H, J=2.3, 8.4 Hz), 7.08 (d, 1H, J=8.4 Hz), 3.94 (s,
3H), 3.95-4.01 (m, 1H), 3.16-3.21 (m, 2H), 2.31-2.35 (m, 1H),
1.13-1.23 (m, 2H), 0.83-0.87 (m, 1H).
[1375] (209-2)
[1376] The title compound was obtained from the compound of Example
209-1 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[1377] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.80 (d, 2H, J=8.8
Hz), 7.80 (d, 1H, J=2.3 Hz), 7.31 (dd, 1H, J=2.3, 8.4 Hz), 6.94 (d,
2H, J=8.8 Hz), 6.90 (d, 1H, J=8.4 Hz), 6.85 (d, 1H, J=1.4 Hz), 6.53
(d, 1H, J=1.4 Hz), 4.53 (dd, 1H, J=6.3, 14.0 Hz), 4.29 (dd, 1H,
J=7.2, 14.0 Hz), 3.92 (s, 3H), 3.88 (s, 3H), 2.69-2.73 (m, 1H),
2.08 (s, 3H), 1.63-1.70 (m, 1H), 1.05-1.10 (m, 1H), 0.93-0.98 (m,
1H).
Example 210
[1378] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.91 (d, 1H, J=2.4
Hz), 7.80 (d, 2H, J=8.8 Hz), 7.36 (dd, 1H, J=2.4, 8.4 Hz), 6.96 (d,
1H, J=8.4 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.85 (d, 1H, J=1.3 Hz), 6.54
(d, 1H, J=1.3 Hz), 4.63 (dd, 1H, J=6.1, 14.0 Hz), 4.23 (dd, 1H,
J=7.4, 14.0 Hz), 3.87 (s, 3H), 2.72-2.77 (m, 1H), 2.07 (s, 3H),
1.65-1.70 (m, 1H), 1.08-1.13 (m, 1H), 0.96-1.01 (m, 1H).
Example 211
[1379] (211-1)
[1380] A carboxylic acid (969 mg) was obtained from methyl
5-chloro-2-iodobenzoate (Example 109-9) (1.00 g) in a similar
manner to Example 16. Under nitrogen atmosphere, to the carboxylic
acid (969 mg) were added successively toluene (3.0 mL), SOCl.sub.2
(500 .mu.l) and a drop of DMF, and the mixture was stirred
70.degree. C. for 1 hour. The solvent was subjected three times to
azeotropic distillation with toluene, and thereto were added
successively toluene (3.0 mL), t-butanol (3.0 mL) and
N,N'-dimethylaminopyridine (500 mg). The mixture was stirred at
50.degree. C. for 8 hours, and water was added thereto. The mixture
was extracted with ethyl acetate, and the extract was washed with a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=10/1) to give t-butyl
5-chloro-2-iodobenzoate (536 mg, 47%).
[1381] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=8.4
Hz), 7.65 (d, 1H, J=2.6 Hz), 7.10 (dd, 1H, J=2.6, 8.4 Hz), 1.62 (s,
9H).
[1382] (211-2)
[1383] The title compound was obtained from the compound of Example
204-1 and the compound of Example 211-1 in a similar manner to
Example 48.
[1384] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.83 (d, 1H, J=2.2
Hz), 7.73 (d, 2H, J=8.1 Hz), 7.57 (dd, 1H, J=1.6, 2.6 Hz), 7.46 (d,
1H, J=8.3 Hz), 7.39 (dd, 1H, J=2.2, 8.3 Hz), 7.26 (d, 2H, J=8.1
Hz), 6.79 (dd, 1H, J=1.6, 4.0 Hz), 6.23 (dd, 1H, J=2.6, 4.0 Hz),
5.57 (s, 2H), 2.43 (s, 3H), 1.58 (s, 9H).
[1385] (211-3)
[1386] Under nitrogen atmosphere, to a solution of the compound of
Example 211-2 (21.0 mg) in dioxane (1.0 mL) were added water (1.0
mL) and a 4N solution of hydrochloric acid in dioxane (1.0 mL), and
the mixture was stirred at room temperature for 6 hours. A 4N
hydrochloric acid in dioxane (1.0 ml) was added thereto, and the
mxiture was stirred at room temperature for 30 minutes, and then
thereto was added acetic acid (2.0 mL), and the mixture was stirred
at 50.degree. C. for 1 hour. The solvent was evaporated under
reduced pressure, and thereto was added a 1N aqueous hydrochloric
acid solution. The mixture was extracted with ethyl acetate, and
dried over MgSO.sub.4. The solvent was purified by silica gel
column (hexane/ethyl acetate=1/1.fwdarw.ethyl acetate/acetic
acid=100/1) to give the title compound (6.8 mg, 37%).
[1387] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 13.54 (brs, 1H),
7.86 (d, 1H, J=2.3 Hz), 7.68 (d, 2H, J=8.0 Hz), 7.67 (dd, 1H,
J=1.6, 2.6 Hz), 7.63 (dd, 1H, J=2.3, 8.3 Hz), 7.55 (d, 1H, J=8.3
Hz), 7.33 (d, 2H, J=8.0 Hz), 6.72 (dd, 1H, J=1.6, 3.9 Hz), 6.26
(dd, 1H, J=2.6, 3.9 Hz), 5.55 (s, 2H), 2.40 (s, 3H).
Example 212
[1388] (212-1)
[1389] (2E)-3-(4-Chloro-2-methoxycarbonylphenyl)-3-methylpropenol
was obtained from (2E)-3-methyl-3-tributylstannylprop-2-en-1-ol and
methyl 5-chloro-2-iodobenzoate (Example 109-9) in a similar manner
to Example 207-1.
[1390] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (d, 1H, J=2.3
Hz), 7.42 (dd, 1H, J=2.3, 8.2 Hz), 7.16 (d, 1H, J=8.2 Hz), 5.11
(tq, 1H, J=6.3, 1.3 Hz), 4.30 (d, 2H, J=6.3 Hz), 3.86 (s, 3H), 1.98
(d, 3H, J=1.3 Hz).
[1391] (212-2)
[1392] The title compound was obtained from the compound of Example
212-1 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[1393] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (d, 2H, J=8.8
Hz), 7.78 (d, 1H, J=2.3 Hz), 7.38 (dd, 1H, J=2.3, 8.2 Hz), 7.13 (d,
1H, J=8.2 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.89 (d, 1H, J=1.3 Hz), 6.53
(d, 1H, J=1.3 Hz), 5.50 (t, 1H, J=6.9 Hz), 5.13 (d, 2H, J=6.9 Hz),
3.88 (s, 3H), 3.81 (s, 3H), 2.08 (s, 3H), 2.08 (s, 3H).
Example 213
[1394] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.90 (d, 1H, J=2.3
Hz), 7.80 (d, 2H, J=8.8 Hz), 7.43 (dd, 1H, J=2.3, 8.2 Hz), 7.15 (d,
1H, J=8.2 Hz), 6.93 (d, 2H, J=8.8 Hz), 6.90 (d, 1H, J=1.2 Hz), 6.53
(d, 1H, J=1.2 Hz), 5.52 (t, 1H, J=6.7 Hz), 5.12 (d, 2H, J=6.7 Hz),
3.87 (s, 3H), 2.10 (s, 3H), 2.06 (s, 3H).
Example 214
[1395] (214-1)
[1396]
[1-(4-Chloro-2-butynyl)-1H-pyrrol-2-yl](4-methylphenyl)ketone was
obtained from the compound of Reference Example 1 and
1,4-dichloro-2-butyne in a similar manner to Example 202-1.
[1397] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.72 (d, 2H, J=7.9
Hz), 7.26 (d, 2H, J=7.9 Hz), 7.25-7.26 (m, 1H), 6.77 (dd, 1H,
J=1.7, 4.0 Hz), 6.22 (dd, 1H, J=2.6, 4.0 Hz), 5.35 (t, 2H, J=2.1
Hz), 4.18 (t, 2H, J=2.1 Hz), 2.43 (s, 3H).
[1398] (214-2)
[1399] Under nitrogen atmosphere, to a solution of the compound of
Example 205-1 (52.0 mg) in DMF (1.5 mL) was added 60% NaH (11.2
mg), and the mixture was stirred at room temperature for 20
minutes. Then, thereto was added a solution of the compound of
Example 214-1 (77.0 mg) in DMF (1.5 mL), and the mixture was
stirred at room temperature for 4 hours, and stirred at 60.degree.
C. for 6 hours. To the mixture was added a 1N aqueous hydrochloric
acid solution, and the mixture was extracted with ethyl
acetate-toluene. The organic layer was washed with water and a
saturated brine, and dried over MgSO.sub.4. The solvent was
evaporated under reduced pressure, and the residue was purified by
silica gel column (hexane/ethyl acetate=5/1.fwdarw.3/1) to give
methyl
5-chloro-2-{[4-{2-(4-methylbenzoyl)-1H-pyrrol-1-yl}-2-butynyl]oxy}benzoat-
e (57.3 mg, 49%).
[1400] .sup.1H NMR (CDCl.sub.3; 400 MHz) .delta. 7.77 (d, 1H, J=2.7
Hz), 7.70 (d, 2H, J=8.1 Hz), 7.30 (dd, 1H, J=2.7, 8.9 Hz), 7.25 (d,
2H, J=8.1 Hz), 7.13 (dd, 1H, J=1.7, 2.6 Hz), 7.02 (d, 1H, J=8.9
Hz), 6.75 (dd, 1H, J=1.7, 4.0 Hz), 6.19 (dd, 1H, J=2.6, 4.0 Hz),
5.30 (t, 2H, J=1.9 Hz), 4.81 (t, 2H, J=1.9 Hz), 3.88 (s, 3H), 2.43
(s, 3H).
[1401] (214-3)
[1402] The title compound was obtained from the compound of Example
214-2 in a similar manner to Example 16.
[1403] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.08 (d, 1H, J=2.7
Hz), 7.69 (d, 2H, J=8.0 Hz), 7.37 (dd, 1H, J=2.7, 8.9 Hz), 7.26 (d,
2H, J=8.0 Hz), 7.06 (dd, 1H, J=1.7, 2.6 Hz), 7.05 (d, 1H, J=8.9
Hz), 6.77 (dd, 1H, J=1.7, 4.0 Hz), 6.21 (dd, 1H, J=2.6, 4.0 Hz),
5.31 (t, 2H, J=1.8 Hz), 4.94 (t, 2H, J=1.8 Hz), 2.44 (s, 3H).
Example 215
[1404] (215-1)
[1405] Methyl 5-chloro-2-(3-hydroxy-1-propyn-1-yl)benzoate was
obtained from methyl 5-chloro-2-iodobenzoate (Example 109-9) and
propargyl alcohol in a similar manner to Example 48.
[1406] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=2.1
Hz), 7.49 (d, 1H, J=8.3 Hz), 7.44 (dd, 1H, J=2.1, 8.3 Hz), 4.54 (d,
2H, J=4.9 Hz), 3.93 (s, 3H), 2.01 (br, 1H).
[1407] (215-2)
[1408] Under nitrogen atmosphere, to a solution of the compound of
Example 215-1 (100 mg) in MeOH (2.5 mL) was added a Lindler
catalyst (35.2 mg), and the mixture was subjected to hydrogenolysis
at room temperature for 5 hours. The mixture was filtered on
cerite, and the solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column (hexane/ethyl
acetate=2/1) to give methyl 5-chloro-2-[(1Z)-3-hydroxy-1-pr-
open-1-yl]benzoate (43.7 mg, 43%).
[1409] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.95 (d, 1H, J=2.3
Hz), 7.46 (dd, 1H, J=2.3, 8.3 Hz), 7.18 (d, 1H, J=8.3 Hz), 6.98 (d,
1H, J=11.6 Hz), 5.97 (dt, 1H, J=11.6, 5.8 Hz), 4.54 (d, 1H, J=5.7
Hz), 4.19 (dd, 2H, J=5.7, 5.8 Hz), 3.89 (s, 3H).
[1410] (215-3)
[1411] The title compound was obtained from the compound of Example
215-2 and the compound of Example 109-6 in a similar manner to
Example 18-3.
[1412] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.98 (d, 1H, J=2.3
Hz), 7.79 (d, 2H, J=8.8 Hz), 7.47 (dd, 1H, J=2.3, 8.2 Hz), 7.26 (d,
1H, J=8.2 Hz), 7.01 (d, 1H, J=11.5 Hz), 6.94 (d, 2H, J=8.8 Hz),
6.69 (d, 1H, J=1.3 Hz), 6.51 (d, 1H, J=1.3 Hz), 5.95 (dt, 1H,
J=11.5, 6.6 Hz), 5.03 (d, 2H, J=6.6 Hz), 3.88 (s, 3H), 3.86 (s,
3H), 2.04 (s, 3H).
Example 216
[1413] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.00 (d, 1H, J=2.2
Hz), 7.77 (d, 2H, J=8.8 Hz), 7.50 (dd, 1H, J=2.2, 8.2 Hz), 7.23 (d,
1H, J=8.2 Hz), 6.91-6.95 (m, 3H), 6.74 (s, 1H), 6.55 (s, 1H), 5.90
(dt, 1H, J=11.4, 5.9 Hz), 5.01 (d, 2H, J=5.9 Hz), 3.85 (s, 3H),
2.05 (s, 3H).
Example 217
[1414] (217-1) 4-Aminoisothiazole-3-carboxylic acid hydrochloride
was treated with MeOH and hydrochloric acid, and further treated in
a similar manner to Example 109-9 to give methyl
4-iodoisothiazole-3-carboxylate. This compound and acrolein are
treated in a similar manner to Example 109-12 to give methyl
4-[(1E)-3-oxoprop-1-enyl]isothiazole-3-carboxylate.
[1415] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.76 (d, 1H, J=7.7
Hz), 9.00 (d, 1H, J=0.3 Hz), 8.27 (dd, 1H, J=16.1, 0.3 Hz), 6.62
(dd, 1H, J=16.1, 7.7 Hz), 4.04 (s, 3H).
[1416] (217-2)
[1417] Methyl
4-[(1E)-3-hydroxyprop-1-enyl]isothiazole-3-carboxylate was obtained
from the compound of Example 217-1 in a similar manner to Example
164-2.
[1418] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.70 (s, 1H), 7.27
(d, 1H, J=16.0 Hz), 6.31 (dt, 1H, J=16.0, 5.6 Hz), 4.36 (dd, 2H,
J=5.6, 1.6 Hz), 1.59 (brs, 1H).
[1419] (217-3)
[1420] Methyl
4-{(1E)-3-[2-(4-methylbenzoyl)-1H-pyrrol-1-yl]prop-1-enyl}is-
othiazole-3-carboxylate was obtained from the compound of Example
217-2 in a similar manner to Example 18-3.
[1421] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.69 (s, 1H), 7.74
(d, 2H, J=8.1 Hz), 7.26 (d, 2H, J=8.1 Hz), 7.14 (d, 1H, J=16.0 Hz),
7.06 (dd, 1H, J=2.6, 1.6 Hz), 6.79 (dd, 1H, J=4.0, 1.6 Hz), 6.43
(dt, 1H, J=16.0, 6.0 Hz), 6.23 (dd, 1H, J=4.0, 2.6 Hz), 5.20 (dd,
2H, J=6.0, 1.4 Hz), 3.96 (s, 3H), 2.43 (s, 3H).
[1422] (217-4)
[1423] The title compound was obtained from the compound of Example
217-3 in a similar manner to Example 16.
[1424] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 8.90 (s, 1H),
7.67 (d, 2H, J=8.0 Hz), 7.33 (dd, 1H, J=2.5, 1.6 Hz), 7.31 (d, 2H,
J=8.0 Hz), 6.99 (d, 1H, J=15.6 Hz), 6.66 (dd, 1H, J=4.0, 1.6 Hz),
6.34 (dt, 1H, J=15.6, 5.9 Hz), 6.21 (dd, 1H, J=4.0, 2.5 Hz), 5.12
(d, 2H, J=5.9 Hz), 2.38 (s, 3H).
Example 218
[1425] (218-1)
[1426] Thiophene-3-caboxylic acid was treated with lithium
diisopropylamide and iodine, and the resultant was reacted with
(CH.sub.3).sub.2SO.sub.4 in the presence of K.sub.2CO.sub.3 to give
methyl 4-iodothiophene-3-carboxylate.
[1427] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.41 (d, 1H, J=5.6
Hz), 7.33 (d, 1H, J=5.6 Hz), 3.89 (s, 3H).
[1428] (218-2)
[1429] Methyl 4-[(1E)-3-oxoprop-1-enyl]thiophene-3-carboxylate was
obtained from the compound of Example 218-1 in a similar manner to
Example 109-12.
[1430] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.73 (d, 1H, J=7.7
Hz), 8.58 (d, 1H, J=15.9 Hz), 7.53 (d, 1H, J=5.3 Hz), 7.39 (d, 1H,
J=5.3 Hz), 6.60 (dd, 1H, J=15.9, 7.7 Hz), 3.93 (s, 3H).
[1431] (218-3)
[1432] Methyl 4-[(1E)-3-hydroxyprop-1-enyl]thiophene-3-carboxylate
was obtained from the compound of Example 218-2 in a similar manner
to Example 164-2.
[1433] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.63 (d, 1H,
J=15.9 Hz), 7.38 (d, 1H, J=5.4 Hz), 7.06 (d, 1H, J=5.4 Hz), 6.38
(dt, 1H, J=15.9, 5.6 Hz), 4.34 (d, 2H, J=5.6 Hz), 3.86 (s, 3H),
1.67 (brs, 1H).
[1434] (218-4)
[1435] The title compound was obtained from the compound of Example
218-3 in a similar manner to Example 18-3.
[1436] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.75 (d, 2H, J=8.1
Hz), 7.48 (d, 1H, J=15.9 Hz), 7.36 (d, 1H, J=5.4 Hz), 7.25 (d, 2H,
J=8.1 Hz), 7.05 (dd, 1H, J=2.4, 1.7 Hz), 7.03 (d, 1H, J=5.4 Hz),
6.78 (dd, 1H, J=4.0, 1.7 Hz), 6.47 (dt, 1H, J=15.9, 6.0 Hz), 6.23
(dd, 1H, J=4.0, 2.4 Hz), 5.22 (dd, 2H, J=6.0, 1.5 Hz), 3.83 (s,
3H), 2.43 (s, 3H).
Example 219
[1437] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.74 (d, 2H, J=8.1
Hz), 7.53 (d, 1H, J=16.0 Hz), 7.43 (d, 1H, J=5.4 Hz), 7.25 (d, 2H,
J=8.1 Hz), 7.07 (d, 1H, J=5.4 Hz), 7.05 (dd, 1H, J=2.6, 1.7 Hz),
6.79 (dd, 1H, J=4.0, 1.7 Hz), 6.50 (dt, 1H, J=16.0, 6.1 Hz), 6.23
(dd, 1H, J=4.0, 2.6 Hz), 5.23 (dd, 2H, J=6.1, 1.4 Hz), 2.41 (s,
3H).
Example 220
[1438] The title compound was obtained from the compound of Example
9-2 and (1H-pyrrol-2-yl)(4-chlorophenyl)methanone in a similar
manner to Example 18-3.
[1439] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.86 (d, 1H, J=2.2
Hz), 7.77 (d, 2H, J=8.5 Hz), 7.47 (d, 1H, J=8.4 Hz), 7.43 (d, 2H,
J=8.5 Hz), 7.40 (dd, 1H, J=2.2, 8.4 Hz), 7.20 (d, 1H, J=15.8 Hz),
7.11 (dd, 1H, J=1.6, 2.6 Hz), 6.75 (dd, 1H, J=1.6, 4.0 Hz),
6.33(dt, 1H, J=15.8, 6.0 Hz), 6.24(dd, 1H, J=2.6, 4.0 Hz), 5.22(d,
2H, J=6.0 Hz), 3.86 (s, 3H).
Example 221
[1440] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.76 (d, 2H,
J=8.5 Hz), 7.72 (d, 1H, J=2.3 Hz), 7.67 (d, 1H, J=8.6 Hz), 7.56 (d,
2H, J=8.5 Hz), 7.54 (dd, 1H, J=2.3, 8.6 Hz), 7.39 (dd, 1H, J=1.6,
2.5 Hz), 6.98 (d, 1H, J=16.0 Hz), 6.72 (dd, 1H, J=1.6, 4.0 Hz),
6.48 (dt, 1H, J=16.0, 5.4 Hz), 6.25 (dd, 1H, J=2.5, 4.0 Hz), 5.21
(d, 2H; J=5.4 Hz).
Example 222
[1441] The title compound was obtained from the compound of Example
9-2 and (1H-pyrrol-2-yl)(4-trifluoromethylphenyl)methanone in a
similar manner to Example 18-3.
[1442] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.90 (d, 2H, J=8.1
Hz), 7.86 (d, 1H, J=2.2 Hz), 7.71 (d, 2H, J=8.1 Hz), 7.48 (d, 1H,
J=8.4 Hz), 7.41 (dd, 1H, J=2.2, 8.4 Hz), 7.21 (d, 1H, J=15.8 Hz),
7.14 (dd, 1H, J=1.6, 2.5 Hz), 6.75 (dd, 1H, J=1.6, 4.1 Hz), 6.33
(dt, 1H, J=15.8, 5.9 Hz), 6.25 (dd, 1H, J=2.5, 4.1 Hz), 5.24 (d,
2H, J=5.9 Hz), 3.86 (s, 3H).
Example 223
[1443] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.98 (d, 1H, J=2.1
Hz), 7.89 (d, 2H, J=8.1 Hz), 7.70 (d, 2H, J=8.1 Hz), 7.51 (d, 1H,
J=8.5 Hz), 7.47 (dd, 1H, J=2.1, 8.5 Hz), 7.26 (d, 1H, J=15.3 Hz),
7.13 (dd, 1H, J=1.6, 2.5 Hz), 6.76 (dd, 1H, J=1.6, 4.1 Hz), 6.36
(dt, 1H, J=15.3, 5.9 Hz), 6.25 (dd, 1H, J=2.5, 4.1 Hz), 5.26 (d,
2H, J=5.9 Hz).
Example 224
[1444] (224-1)
[1445] Methyl 1-allyl-4-methyl-1H-pyrrole-2-carboxylate was
obtained from methyl 4-methyl-1H-pyrrole-2-carboxylate in a similar
manner to Example 109-10.
[1446] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.77 (d, 1H, J=1.3
Hz), 6.63 (d, 1H, J=1.3 Hz), 5.99 (ddt, 1H, J=10.2, 17.1, 5.4 Hz),
5.13 (d, 1H, J=10.2 Hz), 4.98 (d, 1H, J=17.1 Hz), 4.89 (d, 2H,
J=5.4 Hz), 3.78 (s, 3H), 2.07 (s, 3H).
[1447] (224-2)
[1448] 1-Allyl-4-methyl-1H-pyrrole-2-carboxylic acid was obtained
from the compound of Example 224-1 in a similar manner to Example
16.
[1449] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 6.91 (d, 1H, J=1.4
Hz), 6.69 (d, 1H, J=1.4 Hz), 5.99 (ddt, 1H, J=10.2, 17.0, 5.5 Hz),
5.14 (d, 1H, J=10.2 Hz), 5.00 (d, 1H, J=17.0 Hz), 4.88 (d, 2H,
J=5.5 Hz), 2.08 (s, 3H).
[1450] (224-3)
[1451] Under nitrogen atmosphere, to a solution of the compound of
Example 224-2 (152 mg) and p-anisidine (123 mg) in CH.sub.2Cl.sub.2
(5.0 mL) was added NEt.sub.3 (400 .mu.L). The mixture was cooled to
0.degree. C., and thereto was added
N,N-bis(2-oxo-3-oxazolidinyl)phosphinic chloride (332 mg), and the
mixture was stirred at room temperature for 13 hours. Water was
added to the mixture, and the mixture was extracted with ethyl
acetate. The extract was washed with a saturated brine and dried
over MgSO.sub.4. The solvent was evaporated under reduced pressure,
and the residue was purified by silica gel column (hexane/ethyl
acetate=10/1.fwdarw.5/1.fwdarw.3/1) to give
1-allyl-N-(4-methoxyphenyl)-4- -methyl-1H-pyrrole-2-carboxamide
(181 mg, 73%).
[1452] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.43 (br, 1H),
7.43 (d, 2H, J=9.0 Hz), 6.87 (d, 2H, J=9.0 Hz), 6.62 (d, 1H, J=1.2
Hz), 6.50 (d, 1H, J=1.2 Hz), 6.03 (ddt, 1H, J=10.2, 17.0, 5.5 Hz),
5.13 (d, 1H, J=10.2 Hz), 5.02 (d, 1H, J=17.0 Hz), 4.95 (d, 2H,
J=5.5 Hz), 3.80 (s, 3H), 2.10 (s, 3H).
[1453] (224-4)
[1454] Methyl
5-chloro-2-[(1E)-3-(2-{[(4-methoxyphenyl)amino]-carbonyl}-4--
methyl-1H-pyrrol-1-yl)prop-1-enyl]benzoate was obtained from the
compound of Example 224-3 in a similar manner to Example
109-12.
[1455] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.84 (d, 1H, J=2.3
Hz), 7.51 (brs, 1H), 7.47. (d, 1H, J=8.4 Hz), 7.44 (d, 2H, J=9.0
Hz), 7.38 (dd, 1H, J=2.3, 8.4 Hz), 7.10 (d, 1H, J=15.8 Hz), 6.88
(d, 2H, J=9.0 Hz), 6.70 (d, 1H, J=1.2 Hz), 6.53 (d, 1H, J=1.2 Hz),
6.31 (dt, 1H, J=15.8, 5.9 Hz), 5.12 (d, 2H, J=5.9 Hz), 3.86 (s,
3H), 3.80 (s, 3H), 2.11 (s, 3H).
[1456] (224-5)
[1457] The title compound was obtained from the compound of Example
224-4 in a similar manner to Example 16.
[1458] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=2.4
Hz), 7.56 (brs, 1H), 7.48 (d, 1H, J=8.5 Hz), 7.42 (dd, 1H, J=2.4,
8.5 Hz), 7.42 (d, 2H, J=9.0 Hz), 7.13 (d, 1H, J=15.8 Hz), 6.85 (d,
2H, J=9.0 Hz), 6.70 (d, 1H, J=1.5 Hz), 6.54 (d, 1H, J=1.5 Hz), 6.31
(dt, 1H, J=15.8, 5.7 Hz), 5.13 (d, 2H, J=5.7 Hz), 3.78 (s, 3H),
2.10 (s, 3H).
Example 225
[1459] An amide comound
1-allyl-N,4-dimethyl-N-(4-methylphenyl)-1H-pyrrole- -2-carboxamide
was obtained from the compound of Example 224-2 and
N-methyl-p-toluidine in a similar manner to Example 224-3.
Subsequently, this compound was converted into the title compound
in a similar manner to Example 109-12.
[1460] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.51 (d, 1H, J=8.5 Hz), 7.41 (dd, 1H, J=2.3, 8.5 Hz), 7.12 (d,
1H, J=15.7 Hz), 7.09 (d, 2H, J=8.1 Hz), 6.99 (d, 2H, J=8.1 Hz),
6.50 (d, 1H, J=1.2 Hz), 6.31 (dt, 1H, J=15.7, 6.0 Hz), 5.45 (d, 1H,
J=1.2 Hz), 5.00 (d, 2H, J=6.0 Hz), 3.85 (s, 3H), 3.38 (s, 3H), 2.34
(s, 3H), 1.85 (s, 3H).
Example 226
[1461] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.94 (d, 1H, J=2.2
Hz), 7.52 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H, J=2.2, 8.5 Hz), 7.26 (d,
1H, J=15.8 Hz), 7.09 (d, 2H, J=8.2 Hz), 7.00 (d, 2H, J=8.2 Hz),
6.50 (d, 1H, J=1.4 Hz), 6.29 (dt, 1H, J=15.8, 6.1 Hz), 5.47 (d, 1H,
J=1.4 Hz), 5.00 (d, 2H, J=6.1 Hz), 3.38 (s, 3H), 2.33 (s, 3H), 1.85
(s, 3H).
Example 227
[1462] Compound G (the free compound of the compound of Example
136) was obtained by the following reaction scheme. 170
[1463] Preparation of Compound A
[1464] A mixture of magnesium (4.12 g, 170 mmol) and THF (20 ml)
was cooled to 10.degree. C., and thereto was added dropwise a
solution of ethyl bromide (20.1 g, 185 mmol) in THF (60 ml) at an
inner temperature of from 20 to 25.degree. C. The mixture was
warmed to 30.degree. C., and stirred for 1 hour, and thereto was
added dropwise a solution of pyrrole (10.3 g, 154 mmol) in toluene
(80 ml) at 30-35.degree. C. The solution was stirred for 0.5 hour,
and warmed to 40.degree. C. To the mixture was added dropwise a
solution of p-anisoyl choride (13.2 g, 77.1 mmol) in toluene (20
ml) at 40-45.degree. C., and the mixture was further stirred for
0.5 hour. To the mixture were added an aqueous ammonium chloride
solution and toluene, and the mixture was stirred. The organic
layer was separated and concentrated. The residue was
recrystallized from 2-propanol/water (1:2) to give Compound A (13.7
g, 88%).
[1465] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 9.54 (brs, 1H),
7.94 (d, 2H, J=8.9 Hz), 7.12 (dt, 1H, J=1.3, 2.7 Hz), 6.93 (d, 2H,
J=8.9 Hz), 6.89 (ddd, 1H, J=3.8, 2.4, 1.3 Hz), 6.34 (dt, 1H, J=3.8,
2.7 Hz), 3.89 (s, 3H).
[1466] Preparation of Compound C
[1467] Under nitrogen atmosphere, to a solution of potassium
t-butoxide (61.3 g, 546 mmol) in THF (400 g) was added dropwise a
solution of Compound A (100 g, 497 mmol) in THF (200 g), and the
mixture was warmed to 45.degree. C. The mixture was stirred for 15
minutes, and thereto was added dropwise a solution of allyl bromide
(90.2 g, 746 mmol) in THF (200 g). The mixture was stirred at the
same temperature for 2 hours, diluted with toluene (800 g), and
washed with water (800 g). The toluene layer was concentrated to
give a solution of Compound B in toluene.
[1468] Separately, DMF (84.8 g, 1.16 mol) was cooled to 15.degree.
C., and thereto was added dropwise phosphorus oxychloride (133.6 g,
871 mmol) in such a manner that the inner temperature was not
raised to over 20.degree. C. The mixture was stirred for 20
minutes, and thereto was added THF (62.7 g, 871 mmol), and thereto
was added a solution of Compound B (70 g, 260 mmol) in toluene (140
g) in such a manner that the inner temperature was not raised to
over 20.degree. C. The mixture was stirred at room temperature for
5 hours, and thereto was added an aqueous solution of sodium
acetate (357 g, 4.35 mol) in water (714 g) during which the inner
temperature was raised. After the addition, the mixture was stirred
at room temperature overnight. Seed crystals of Compound C (100 mg,
371 .mu.mol) were added to the mixture, and the mixture was stirred
for 3 hours. The precipitated crystals were collected by
filtration, washed with water and toluene, and dried. The organic
layer of the filtrate was washed with water, and concentrated. The
precipitated crystals were collected by filtration, washed with
cold toluene, and dried. The resulting crystals were combined with
the above crystals to give Compound C (50.6 g, 67%).
[1469] .sup.1H NMR (Compound B: CDCl.sub.3, 400 MHz) .delta. 7.84
(d, 2H, J=8.9 Hz), 6.98 (dd, 1H, J=2.5 and 1.7 Hz), 6.94 (d, 2H,
J=8.9 Hz), 6.73 (dd, 1H, J=4.0 and 1.7 Hz), 6.19 (dd, 1H, J=4.0 and
2.5 Hz), 6.07 (ddt, 1H, J=17.1, 10.2 and 5.7 Hz), 5.16 (dq, 1H,
J=10.2 and 1.1 Hz), 5.06 (dq, 1H, J=17.1 and 1.1 Hz), 5.03 (dt, 2H,
J=5.7 and 1.1 Hz), 3.88 (s, 3H).
[1470] .sup.1H NMR (Compound C: CDCl.sub.3, 400 MHz) .delta. 9.81
(s, 1H), 7.85 (d, 2H, J=8.9 Hz), 7.58 (d, 1H, J=2.3 Hz), 7.16 (d,
1H, J=2.3 Hz), 6.97 (d, 2H, J=8.9 Hz), 6.06 (ddt, 1H, J=17.1, 10.2
and 5.7 Hz), 5.26 (dq, 1H, J=10.2 and 1.1 Hz), 5.16 (dq, 1H, J=17.1
and 1.1 Hz), 5.05 (dt, 2H, J=5.7 and 1.1 Hz), 3.89 (s, 3H).
[1471] Preparation of Compound D
[1472] Compound C (10.0 g, 37.1 mmol) was dissolved in methylene
chloride (212 g) and trifluoroacetic acid (212 g, 1.86 mol), and
the mixture was cooled to 0.degree. C. To the mixture was added
t-butyldimethylsilane (21.6 g, 186 mmol), and the mixture was
stirred at the same temperature for 6 hours. The reaction solution
was diluted with toluene (470 g), and the mixture was poured into a
3N aqueous sodium hydroxide solution. The organic layer was
separated and treated with an activated carbon, and filtered. The
filtrate was concentrated to give Compound D (8.42 g, 89%).
[1473] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.81 (d, 2H, J=8.9
Hz), 6.94 (d, 2H, J=8.9 Hz), 6.77 (br, 1H), 6.54 (brd, 1H, J=1.4
Hz), 6.05 (ddt, 1H, J=10.0, 15.0 and 5.8 Hz), 5.14 (dq, 1H, J=10.0
and 1.1 Hz), 5.07 (dq, 1H, J=15.0 and 1.1 Hz), 4.97 (dt, 2H, J=5.8
and 1.1 Hz), 3.87 (s, 3H), 2.08 (brs, 3H).
[1474] Preparation of Compound E
[1475] Under nitrogen atmosphere, to a mixture of methyl
5-chloro-2-iodobenzoate (146 mg, 0.492 mmol), Compound D (128 mg,
0.501 mmol), sodium hydrogen carbonate (86.0 mg, 1.01 mmol) and
benzyltriethylammonium chloride (120 mg, 0.527 mmol) were added
acetonitrile (1.0 ml) and palladium acetate (5.7 mg, 0.0254 mmol),
and the mixture was warmed to 50.degree. C., and stirred for 16
hours. Water was added to the reaction solution, and the mixture
was extracted with toluene. The extract was washed with a 10%
aqueous sodium thiosulfate solution, and dried over magnesium
sulfate. The resultant was filtered and the solvent was evaporated
under reduced pressure to give Compound E (207 mg).
[1476] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.85 (d, 1H, J=2.3
Hz), 7.83 (d, 2H, J=8.9 Hz), 7.48 (d, 1H, J=8.5 Hz), 7.39 (dd, 1H,
J=2.3, 8.5 Hz), 7.21 (d, 1H, J=15.8 Hz), 6.94 (d, 2H, J=8.9 Hz),
6.85 (d, 1H, J=1.1 Hz), 6.57 (d, 1H, J=1.1 Hz), 6.34 (dt, 1H,
J=15.8, 6.1 Hz), 5.14 (d, 2H, J=6.1 Hz), 3.88 (s, 3H), 3.87 (s,
3H), 2.09 (s, 3H).
[1477] Preparation of Compound F
[1478] Under nitrogen atmosphere, to a mixture of Compound E (400
mg, 0.944 mmol) in a mixed solvent of THF (2.0 ml) and methanol
(2.0 ml) was added a 1N aqueous sodium hydroxide solution (1.0 ml,
1.0 mmol), and the mixture was stirred at 50.degree. C. for 1 hour.
The solvent was evaporated under reduced pressure, and thereto were
added toluene (3.5 ml) and water (2.5 ml). The mixture was stirred
at 0.degree. C. for 4 hours to give a sodium salt of Compoun F (258
mg).
[1479] .sup.1H NMR (DMSO-d.sub.6, 400 MHz) .delta. 7.76 (d, 2H,
J=8.8 Hz), 7.47 (d, 1H, J=16.0 Hz), 7.40 (d, 1H, J=8.3 Hz), 7.39
(d, 1H, J=2.4 Hz), 7.12 (dd, 1H, J=2.4, 8.3 Hz), 7.08 (d, 1H, J=1.2
Hz), 7.03 (d, 2H, J=8.8 Hz), 6.47 (d, 1H, J=1.2 Hz), 6.22 (dt, 1H,
J=16.0, 6.4 Hz), 5.01 (d, 2H, J=6.4 Hz), 3.84 (s, 3H), 2.03 (s,
3H).
[1480] To a sodium salt of Compound F was added 1N hydrochloric
acid, and the mixture was extrated with ethyl acetate. The solvent
was evaporated under reduced pressure to give the residue (226 mg),
which was further recrystallized from acetonitrile (5.0 ml) to give
Compound F (122 mg).
[1481] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.97 (d, 1H, J=2.2
Hz), 7.83 (d, 2H, J=8.9 Hz), 7.50 (d, 1H, J=8.5 Hz), 7.44 (dd, 1H,
J=2.2, 8.5 Hz), 7.28 (d, 1H, J=15.5 Hz), 6.93 (d, 2H, J=8.9 Hz),
6.86 (d, 1H, J=1.1 Hz), 6.58 (d, 1H, J=1.1 Hz), 6.35 (dt, 1H,
J=15.5, 6.0 Hz), 5.15 (d, 2H, J=6.0 Hz), 3.85 (s, 3H), 2.09 (s,
3H).
[1482] Preparation of Compound G
[1483] Under nitrogen atmosphere, to a solution of isopropyl
chloroformate (920 .mu.l, 8.08 mmol) in THF (3.0 ml), which was
cooled at 0.degree. C., was added dropwise a solution of Compound F
(3.00 g, 7.32 mmol) and N-methylmorpholine (845 .mu.l, 7.69 mmol)
in THF (8.0 ml), and the mixture was stirred at 0.degree. C. for 30
minutes. The insoluble materials were removed by filtration, and
washed with THF (5.0 ml) to give a solution of a mixed acid
anhydride of Compound F in THF.
[1484] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 7.93 (d, 1H, J=2.2
Hz), 7.83 (d, 2H, J=8.8 Hz), 7.53 (d, 1H, J=8.5 Hz), 7.47 (dd, 1H,
J=2.2, 8.5 Hz), 7.27 (d, 1H, J=15.8 Hz), 6.94 (d, 2H, J=8.8 Hz),
6.85 (d, 1H, J=1.2 Hz), 6.56 (d, 1H, J=1.2 Hz), 6.40 (dt, 1H,
J=15.8, 6.2 Hz), 5.12 (d, 2H, J=6.2 Hz), 5.08 (sep, 1H, J=6.3 Hz),
3.87 (s, 3H), 2.08 (s, 3H), 1.41 (d, 6H, J=6.3 Hz).
[1485] Under nitrogen atmosphere, to a solution of potassium
t-butoxide (1.07 g, 9.54 mmol) in THF (11 ml) was added
methanesulfonamide (910 mg, 9.57 mmol), and the mixture was stirred
at room temperature for 1 hour. Then, the mixture was cooled to
-10.degree. C., and thereto was slowly added dropwise the above
solution of the mixed acid anhydride of Compound F in THF, and the
mixture was stirred at -10.degree. C. for 8 hours. To the mixture
was added 1N hydrochloric acid (32.9 g), and the mixture was
extracted with ethyl acetate (30 ml), and dried over magnesium
suflate. The solvent was evaporated under reduced pressure, and the
precipitated solid (3.65 g) was recrystallized from isopropyl
alcohol (70 ml) to give Compound G (3.00 g, 84%).
[1486] .sup.1H NMR (CDCl.sub.3, 400 MHz) .delta. 8.67 (brs, 1H),
7.80 (d, 2H, J=8.8 Hz), 7.54 (d, 1H, J=2.1 Hz), 7.46 (d, 1H, J=8.4
Hz), 7.41 (dd, 1H, J=2.1, 8.4 Hz), 6.94 (d, 2H, J=8.8 Hz), 6.85 (d,
1H, J=1.5 Hz), 6.67 (d, 1H, J=15.8 Hz), 6.58 (d, 1H, J=1.5 Hz),
6.41 (dt, 1H, J=15.8, 5.5 Hz), 5.09 (d, 2H, J=5.5 Hz), 3.87 (s,
3H), 3.35 (s, 3H), 2.09 (s, 3H).
[1487] The compounds of other Examples can also be prepared in a
similar manner to the process shown in the above reaction
scheme.
[1488] Experiment 1
[1489] Effects on the Extracellular Matrix Production by
TGF-.beta.
[1490] The effect of the compounds of Examples on the production of
proteoglycan when TGF-.beta. was added to fibroblast was
evaluated.
[1491] NRK-49F cells (rat fibroblast) were cultured in Dulbecco's
Modified Eagle Medium (DMEM: manufactured by GIBCO) containing 10%
bovine serum, and used in this experiment. The cells were put into
a 96-well plate in an amount of 2.5.times.10.sup.4 cells/100
.mu.l/well. On the next day, the medium in the plate was exchanged
to the DMEM medium containing 3 ng/ml of TGF-.beta. (manufactured
by Nacalai Tesque, Inc.), 0.5 .mu.Ci/well of
[.sup.35S]--Na.sub.2SO.sub.4, and a test compound. Twenty-four
hours thereafter, the supernatant was collected, and subjected to
SDS-polyacrylamide gel electrophoresis (SDS-PAGE) in a conventional
manner. The gel after electrophoresis was dried with a gel drier,
and exposed to an imaging plate, which was analyzed with BSA2000
(manufactured by Fuji Photo Film). The radioactivity of
proteoglycan to be electrophoresed was measured, and the TGF-.beta.
inhibitory rate was calculated by the following equation.
TGF-.beta. Inhibitory rate (%)=(A-B).times.100/(A-C)
[1492] A: Radioactivity in the presence of TGF-.beta. without a
test compound
[1493] B: Radioactivity in the presence of TGF-.beta. and a test
compound
[1494] C: Radioactivity in the absence of TGF-.beta. and a test
compound
[1495] The TGF-.beta. inhibitory rates (%) of the test compound at
concentrations of 3 .mu.M and 10 .mu.M are shown in Table 1. From
the results, the pyrrole derivatives of the present invention
inhibit the activity of TGF-.beta. and inhibit the production of
proteoglycan in fibroblast.
8 TABLE 1 Compound 3 .mu.M 10 .mu.M Comp. of Ex. 2 33 61 Comp. of
Ex. 3 25 38 Comp. of Ex. 5 6 51 Comp. of Ex. 6 66 88 Comp. of Ex. 7
44 78 Comp. of Ex. 8 16 46 Comp. of Ex. 9 88 91 Comp. of Ex. 10 63
86 Comp. of Ex. 14 40 56 Comp. of Ex. 19 51 72 Comp. of Ex. 20 61
90 Comp. of Ex. 25 6 74 Comp. of Ex. 31 34 38 Comp. of Ex. 33 74 91
Comp. of Ex. 38 51 40 Comp. of Ex. 43 31 66 Comp. of Ex. 61 15 86
Comp. of Ex. 64 43 75 Comp. of Ex. 66 88 94 Comp. of Ex. 67 55 75
Comp. of Ex. 73 70 85 Comp. of Ex. 76 56 58 Comp. of Ex. 83 42 47
Comp. of Ex. 85 29 75 Comp. of Ex. 91 66 73 Comp. of Ex. 97 58 75
Comp. of Ex. 103 55 90 Comp. of Ex. 105 14 48 Comp. of Ex. 107 90
95 Comp. of Ex. 108 42 56 Comp. of Ex. 111 90 118 Comp. of Ex. 112
23 73 Comp. of Ex. 115 46 56 Comp. of Ex. 117 71 83 Comp. of Ex.
120 99 117 Comp. of Ex. 128 14 80 Comp. of Ex. 134 59 80 Comp. of
Ex. 136 87 88 Comp. of Ex. 137 74 85 Comp. of Ex. 167 67 96 Comp.
of Ex. 178 83 97 Comp. of Ex. 180 80 83 Comp. of Ex. 188 84 Comp.
of Ex. 190 65 85 Comp. of Ex. 193 86 98 Comp. of Ex. 195 52 103
[1496] Experiment 2
[1497] Evaluation Using rat Thy-1 Nephritis Model
[1498] The anti-fibrosis activity was evaluated on the compounds of
Examples 9, 14, 110, 120 and 136 by using a rat Thy-1 nephritis
model, which is an animal model for kidney fibrosis (cf, "Kidney
and Dialysis", vol. 31, p. 343-347 (1991)). Thy-1 is one of the
surface antigens of thymocyte.
[1499] Male Wister rats were purchased from Charles River Japan,
Inc. at an age of 3-weeks old. After pre-feeding, the animals were
used in this experiment when their body weights became about 100 g.
The animals were kept in a room being controlled at a temperature
of 24.+-.2.degree. C. under a humidity of 55.+-.10%, with an
illumination cycle of light on (8:00 to 20:00). The animals were
given food (CRF-1, Oriental Yeast Co. Ltd.) and sterilized tap
water ad libitum.
[1500] Anti-Thy-1 monoclonal antibody (OX-7, Biosource
International Inc.) was administered to the rats at a dose of 50
.mu.g/100 g of body weight at the tail vein. Then, the animals were
grouped into the vehicle-treated group (n=8) and the test
compound-treated group (n=8) with respect to the body weight. From
the day of administration of anti-Thy-1 monoclonal antibody, a test
compound, which was suspended in a 0.5% carboxymethylcellulose
(vehicle), was orally administered to the animals once a day at a
dose of 15 or 150 mg/kg/day by using an oral sonde. To the
vehicle-treated group, a vehicle was administered likewise.
[1501] After the administration for 7 days, the right kidney of the
rats was taken out, and the content of hydroxyproline therein,
which was an index for organ fibrosis, was measured according to
the method of J. F. Woessner, et al. (Arch. Biochem. Biophys.
Vol.93 p440 (1961)). That is, the kidney was homogenized, and 500
.mu.L of the suspension was dried, and thereto was added a 4N
aqueous sodium hydroxide solution (225 .mu.L). The mixture was
heated on a heat block at 100.degree. C. for 15 minutes to
hydrolyze proteins, and the mixture was neutralized with a 1.4 M
aqueous citric acid solution (275 .mu.L). The mixture was
centrifuged at 3000 rpm for 10 minutes at room temperature, and the
supernatant was collected as a kidney extract. To the extract were
added Chloramine T solution and an Ehrlich solution (which was
prepared by adding n-propanol (31 ml) to
p-dimethylaminobenzaldehyde (7.5 g), and further slowly adding
thereto a 60% perchloric acid (13 mL), and followed by adjusting
the volume to 50 ml by distilled water), and the mixture was
reacted at 65.degree. C. for 15 minutes. The OD 550 (absorbance at
550 nm) was measured, and the concentration of hydroxyproline was
calcurated from the analytical curve of hydroxyproline. The content
of hydroxyproline thus obtained was adjusted with respect to the
protein amount in the kidney extract.
[1502] The results are shown in Tables 2 to 5. Each value was
expressed in average value.+-.standard deviation of 8 animals in
each group. As compared with the values of normal rats, the
hydroxyproline content in the kideny of rats treated with
anti-Thy-1 antibody was increased, and it was found that the
extracellular matrix was accumulated in the kidney. In the group
treated with the pyrrole derivative of the present invention, the
hydroxyproline content was decreased as compared to the
vehicle-treated group, and it was found that the pyrrole
derivatives of the present invention inhibit the accumulation of
extracellular matrix in the kidney.
9 TABLE 2 Hydroxyproline content Groups (.mu.g/mg protein) Normal
Rat 6.7 .+-. 1.6 Anti-Thy-1 antibody + the vehicle 8.7 .+-. 2.0#
Anti-Thy-1 antibody + the 7.2 .+-. 2.1 compound of Example 9 (15
mg/kg) Anti-Thy-1 antibody + the 6.3 .+-. 1.3* compound of Example
14 (150 mg/kg) #P < 0.05 in Student's t-test as compared with
the normal rat group *P < 0.05 in Student's t-test as compared
with the group treated with the anti-Thy-1 antibody and the
vehicle
[1503]
10 TABLE 3 Hydroxyproline content Groups (.mu.g/mg protein) Normal
Rat 8.2 .+-. 0.8 Anti-Thy-1 antibody + the vehicle 11.8 .+-. 0.6##
Anti-Thy-1 antibody + the 10.1 .+-. 0.8** compound of Example 110
(1.5 mg/kg) Anti-Thy-1 antibody + the compound of 9.5 .+-. 0.8**
Example 110 (5 mg/kg) Anti-Thy-1 antibody + the compound of 9.7
.+-. 0.7** Example 110 (15 mg/kg) Anti-Thy-1 antibody + the
compound of 9.5 .+-. 0.6** Example 110 (50 mg/kg) ##P < 0.01 in
Student's t-test as compared with the normal rat group. **P <
0.01 in Williams test as compared with the group treated with the
anti-Thy-1 antibody and the vehicle.
[1504]
11 TABLE 4 Hydroxyproline content Groups (.mu.g/mg protein) Normal
Rat 8.0 .+-. 0.5 Anti-Thy-1 antibody + the vehicle 10.8 .+-. 1.8##
Anti-Thy-1 antibody + the 9.7 .+-. 1.0* compound of Example 120
(1.5 mg/kg) Anti-Thy-1 antibody + the compound of 9.3 .+-. 0.9**
Example 120 (5 mg/kg) Anti-Thy-1 antibody + the compound of 7.9
.+-. 1.0** Example 120 (15 mg/kg) Anti-Thy-1 antibody + the
compound of 8.1 .+-. 1.5** Example 120 (50 mg/kg) ##P < 0.01 in
Student's t-test as compared with the normal rat group. *, **P <
0.05, P < 0.01, respectively, in Williams test as compared with
the group treated with the anti-Thy-1 antibody and the vehicle.
[1505]
12 TABLE 5 Hydroxyproline content Groups (.mu.g/mg protein) Normal
Rat 11.3 .+-. 0.7 Anti-Thy-1 antibody + the vehicle 16.1 .+-. 1.6##
Anti-Thy-1 antibody + the 17.2 .+-. 2.2 compound of Example 136
(1.5 mg/kg) Anti-Thy-1 antibody + the compound of 13.4 .+-. 1.0**
Example 136 (5 mg/kg) Anti-Thy-1 antibody + the compound of 12.2
.+-. 1.6** Example 136 (15 mg/kg) Anti-Thy-1 antibody + the
compound of 11.2 .+-. 1.4** Example 136 (50 mg/kg) ##P < 0.01 in
Student's t-test as compared with the normal rat group. **P <
0.01 in Williams test as compared with the group treated with the
anti-Thy-1 antibody and the vehicle.
INDUSTRIAL APPLICABILITY
[1506] According to the present invention, the pyrrole derivatives
being useful as medicaments such as fibrosis inhibitors for organs
and tissues are provided.
* * * * *