U.S. patent application number 14/956116 was filed with the patent office on 2016-03-24 for substituted phenylazole derivative.
This patent application is currently assigned to DAIICHI SANKYO COMPANY, LIMITED. The applicant listed for this patent is DAIICHI SANKYO COMPANY, LIMITED. Invention is credited to Madoka HOSHINO, Koji MATSUMOTO, Hidenori NAMIKI, Yuichi OCHIAI, Shigeo YAMANOI.
Application Number | 20160081993 14/956116 |
Document ID | / |
Family ID | 48799224 |
Filed Date | 2016-03-24 |
United States Patent
Application |
20160081993 |
Kind Code |
A1 |
YAMANOI; Shigeo ; et
al. |
March 24, 2016 |
SUBSTITUTED PHENYLAZOLE DERIVATIVE
Abstract
Compounds are provided having an excellent hypoglycemic effect
and .beta. cell- or pancreas-protecting effects, or
pharmaceutically acceptable salts thereof, and a pharmaceutical
composition having an excellent therapeutic effect and/or
prophylactic effect on type 1 diabetes, type 2 diabetes, and the
like, which cause hyperglycemia due to abnormal glucose metabolism.
A compound represented by general formula (I), or a
pharmaceutically acceptable salt thereof, is disclosed.
##STR00001##
Inventors: |
YAMANOI; Shigeo; (Tokyo,
JP) ; NAMIKI; Hidenori; (Tokyo, JP) ; OCHIAI;
Yuichi; (Tokyo, JP) ; HOSHINO; Madoka; (Tokyo,
JP) ; MATSUMOTO; Koji; (Tokyo, JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
DAIICHI SANKYO COMPANY, LIMITED |
Tokyo |
|
JP |
|
|
Assignee: |
DAIICHI SANKYO COMPANY,
LIMITED
Tokyo
JP
|
Family ID: |
48799224 |
Appl. No.: |
14/956116 |
Filed: |
December 1, 2015 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14372832 |
Jul 17, 2014 |
9233958 |
|
|
PCT/JP2013/050710 |
Jan 17, 2013 |
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14956116 |
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Current U.S.
Class: |
514/342 ;
514/374 |
Current CPC
Class: |
A61P 43/00 20180101;
A61K 31/421 20130101; C07D 257/04 20130101; A61P 3/04 20180101;
C07D 249/06 20130101; C07D 263/32 20130101; A61K 31/4439 20130101;
C07D 413/12 20130101; C07D 277/20 20130101; C07D 401/14 20130101;
A61P 1/18 20180101; A61P 3/10 20180101; C07D 417/12 20130101; C07D
401/12 20130101; C07D 271/06 20130101; C07D 277/30 20130101; A61P
3/00 20180101; C07D 403/12 20130101 |
International
Class: |
A61K 31/4439 20060101
A61K031/4439; A61K 31/421 20060101 A61K031/421 |
Foreign Application Data
Date |
Code |
Application Number |
Jan 18, 2012 |
JP |
2012-007840 |
Claims
1. A method of treating obesity, comprising administering to a
mammal a compound of formula (VII): ##STR00190## or a
pharmaceutically acceptable salt thereof, wherein X is CH or N,
R.sup.1 is --C(.dbd.O)--NH--R.sup.5 or
--NH--C(.dbd.O)--NH--R.sup.5, R.sup.3 is --CH.sub.3, and R.sup.5 is
--H, or a C1-C6 alkyl group or a C3-C6 cycloalkyl group, each of
which may be independently substituted with 1 to 3 --OH.
2. The method of claim 1, wherein the mammal is a human.
3. The method of claim 1, wherein the compound is selected from the
group consisting of:
4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-yl]-
-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide;
N-cyclopropyl-4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,-
3-oxazol-2-yl]-2-fluorobenzamide;
1-{4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2--
yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea;
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluoro--
N-[(1R)-2-hydroxy-1-methylethyl]benzamide;
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluoro--
N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide; and
1-[4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluo-
rophenyl]urea; or a pharmaceutically acceptable salt thereof.
4. A method of protecting .beta. cells or the pancreas comprising
administering to a mammal a compound of formula (VII): ##STR00191##
or a pharmaceutically acceptable salt thereof, wherein X is CH or
N, R.sup.1 is --C(.dbd.O)--NH--R.sup.5 or
--NH--C(.dbd.O)--NH--R.sup.5, R.sup.3 is --CH.sub.3, and R.sup.5 is
--H, or a C1-C6 alkyl group or a C3-C6 cycloalkyl group, each of
which may be independently substituted with 1 to 3 --OH.
5. The method of claim 4, wherein the mammal is a human.
6. The method of claim 4, wherein the compound is selected from the
group consisting of:
4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-yl]-
-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide;
N-cyclopropyl-4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,-
3-oxazol-2-yl]-2-fluorobenzamide;
1-{4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2--
yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea;
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluoro--
N-[(1R)-2-hydroxy-1-methylethyl]benzamide;
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluoro--
N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide; and
1-[4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-oxazol-2-yl)-2-fluo-
rophenyl]urea; or a pharmaceutically acceptable salt thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No.
14/372,832, filed Jul. 17, 2014, entitled "Substituted Phenylazole
Derivatives," which is a national stage application under 35 U.S.C.
.sctn.371 of International Application No. PCT/JP2013/050710, filed
Jan. 17, 2013, entitled "Substituted Phenylazole Derivative," which
claims priority to Japanese Patent Application No. 2012-007840,
filed Jan. 18, 2012, the entire contents of each of which are
incorporated herein by reference.
TECHNICAL FIELD
[0002] The present invention relates to novel substituted
phenylazole derivatives which have a hypoglycemic effect and/or a
.beta. cell- or pancreas-protecting effect, or pharmaceutically
acceptable salts thereof, and pharmaceutical compositions
containing those as an active ingredient.
BACKGROUND ART
[0003] Diabetes mellitus is a metabolic disease basically
characterized by a chronic hyperglycemic state due to impaired
insulin action. The treatment of diabetes is generally performed by
drug therapy together with diet and exercise therapies. Oral
hypoglycemic agents, which are one type of anti-diabetic agent,
include biguanides and thiazolidinediones that improve insulin
resistance; sulfonylureas and glinides that promote insulin
secretion from pancreatic .beta. cells; and .alpha.-glucosidase
inhibitors that inhibit sugar absorption.
[0004] However, it is reported that they have side effects:
biguanides produce gastrointestinal symptoms and lactic acidosis;
thiazolidinediones produce weight gain and edema; sulfonylureas and
glinides produce hypoglycemia or secondary failure due to long-term
use; and .alpha.-glucosidase inhibitors produce diarrhea etc.
Therefore, development of an oral hypoglycemic agent which can
address such problems is desired. In recent years, compounds having
new structures have been developed as oral hypoglycemic agents
(see, for example, Patent Literature 1 to 9).
CITATION LIST
Patent Literature
[0005] Patent Literature 1: WO 2007/116229
[0006] Patent Literature 2: WO 2007/003960
[0007] Patent Literature 3: WO 2007/003962
[0008] Patent Literature 4: WO 2005/061489
[0009] Patent Literature 5: WO 2009/051119
[0010] Patent Literature 6: WO 2010/119881
[0011] Patent Literature 7: WO 2011/016469
[0012] Patent Literature 8: WO 2011/016470
[0013] Patent Literature 9: WO 2012/050151
SUMMARY OF THE INVENTION
Problems to be Solved by the Invention
[0014] An object of the present invention is to provide a compound
which has a new structure that is neither described nor suggested
in the above patent literature and has an excellent hypoglycemic
effect or a .beta. cell- or pancreas-protecting effect, or a
pharmaceutically acceptable salt thereof; a pharmaceutical
composition having an excellent therapeutic effect and/or
prophylactic effect on type 1 diabetes, type 2 diabetes and the
like, which cause an increase in blood sugar levels due to abnormal
glucose metabolism; and a pharmaceutical composition having a
.beta. cell- or pancreas-protecting effect.
Means for Solving the Problems
[0015] The present invention provides:
[0016] (1) a compound represented by general formula (I):
##STR00002##
[0017] wherein the ring A represents
##STR00003##
* represents the bonding site with the benzene ring, X represents
CH or N, R.sup.1 represents --C(.dbd.O)--NH--R.sup.5,
--NH--C(.dbd.O)--NH--R.sup.5, or --S(.dbd.O).sub.2--R.sup.5,
R.sup.2 represents --F or --H, R.sup.3 represents --CH.sub.3 or
--C.sub.2H.sub.5, R.sup.4 represents
##STR00004##
and
[0018] R.sup.5 represents --H, or represents a C1-C6 alkyl group, a
C3-C6 cycloalkyl group, or
##STR00005##
each of which may be substituted with 1 to 3 --OH, or a
pharmaceutically acceptable salt thereof;
[0019] (2) the compound as set forth in item (1), wherein the ring
A represents
##STR00006##
R.sup.1 represents --C(.dbd.O)--NH--R.sup.5 or
--NH--C(.dbd.O)--NH--R.sup.5, R.sup.2 represents --F, and R.sup.4
represents
##STR00007##
or a pharmaceutically acceptable salt thereof;
[0020] (3) the compound as set forth in item (1), wherein the ring
A represents
##STR00008##
R.sup.1 represents --C(.dbd.O)--NH--R.sup.5, R.sup.2 represents
--F, R.sup.4 represents
##STR00009##
and R.sup.5 represents a hydroxyisopropyl group or a cyclopropyl
group, or a pharmaceutically acceptable salt thereof;
[0021] (4) the compound as set forth in item (1), wherein the ring
A represents
##STR00010##
R.sup.1 represents --C(.dbd.O)--NH--R.sup.5 or
--S(.dbd.O).sub.2--R.sup.5, R.sup.3 represents --CH.sub.3, R.sup.4
represents
##STR00011##
and R.sup.5 represents a C1-C6 alkyl group which may be substituted
with 1 to 3 --OH, or a pharmaceutically acceptable salt
thereof;
[0022] (5) the compound as set forth in item (1), wherein the ring
A represents
##STR00012##
R.sup.1 represents --C(.dbd.O)--NH--R.sup.5 or
--NH--C(.dbd.O)--NH--R.sup.5, R.sup.2 represents --F, R.sup.3
represents --CH.sub.3, R.sup.4 represents
##STR00013##
and R.sup.5 represents --H, or represents a C1-C6 alkyl group or a
C3-C6 cycloalkyl group, each of which may be substituted with 1 to
3 --OH, or a pharmaceutically acceptable salt thereof;
[0023] (6) the compound as set forth in item (1), wherein the ring
A represents
##STR00014##
R.sup.1 represents --C(.dbd.O)--NH--R.sup.5 or
--NH--C(.dbd.O)--NH--R.sup.5, R.sup.2 represents --F, R.sup.4
represents
##STR00015##
and R.sup.5 represents --H, or represents a C1-C6 alkyl group or a
C3-C6 cycloalkyl group, each of which may be substituted with 1 to
3 --OH, or a pharmaceutically acceptable salt thereof;
[0024] (7) a compound represented by general formula (II):
##STR00016##
[0025] wherein R.sup.3 represents --CH.sub.3 or --C.sub.2H.sub.5,
R.sup.6 represents a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
each of which may be substituted with 1 to 3 --OH, R.sup.7
represents
##STR00017##
or a pharmaceutically acceptable salt thereof;
[0026] (8) a compound represented by general formula (III):
##STR00018##
wherein X represents CH or N, R.sup.3 represents --CH.sub.3 or
--C.sub.2H.sub.5, R.sup.8 represents --H, or represents a C1-C6
alkyl group which may be substituted with 1 to 3 substituents
selected from substituent subgroup .alpha., R.sup.9 represents
##STR00019##
and substituent subgroup .alpha. is --OH,
--O--C(.dbd.O)--O--CH.sub.3, or --O--C(.dbd.O)--NH--C.sub.2H.sub.5.
or a pharmaceutically acceptable salt thereof.
[0027] (9) a compound selected from the group consisting of the
following compounds: [0028]
1-[4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2-yl)-
-2-fluorophenyl]-3-(2-hydroxyethyl)urea; [0029]
4-{4-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3-tr-
iazol-2-yl}-N-[(1R,2R)-2,3-dihydroxy-1-methylpropyl]-2-fluorobenzamide;
[0030]
1-(4-{4-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2-
H-1,2,3-triazol-2-yl}-2-fluorophenyl)-3-(2-hydroxyethyl)urea;
[0031]
4-(5-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-tetrazol-2-yl)-2-fluor-
o-N-[(1R)-2-hydroxy-1-methylethyl]benzamide; [0032]
4-(5-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)-2-fluoro-
-N-[(1R)-2-hydroxy-1-methylethyl]benzamide; [0033]
4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-yl]-
-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide; [0034]
N-cyclopropyl-4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,-
3-oxazol-2-yl]-2-fluorobenzamide; [0035]
1-{4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2--
yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea; [0036]
4-{5-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-1,2,4-oxadi-
azol-3-yl}-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide;
[0037]
1-{4-[5-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiaz-
ol-3-yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea; [0038]
4-[3-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiazol--
5-yl]-2-fluoro-N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide; and
[0039]
1-{4-[3-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiaz-
ol-5-yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea; or a
pharmaceutically acceptable salt thereof;
[0040] (10) a pharmaceutical composition containing, as an active
ingredient, the compound as set forth in any one of items (1) to
(9),
or a pharmaceutically acceptable salt thereof;
[0041] (11) the pharmaceutical composition as set forth in item
(10), for treating type 1 diabetes, type 2 diabetes, or
obesity;
[0042] (12) the pharmaceutical composition as set forth in item
(10), for protecting .beta. cells or the pancreas;
[0043] (13) use of the compound as set forth in any one of items
(1) to (9), or a pharmaceutically acceptable salt thereof, for
producing a pharmaceutical composition;
[0044] (14) a method for treating a disease, the method including
administering to a mammal the compound as set forth in any one of
items (1) to (9),
or a pharmaceutically acceptable salt thereof; and
[0045] (15) the method as set forth in item (14), wherein the
mammal is a human being.
Effects of the Invention
[0046] The present invention provides a substituted phenylazole
derivative having an excellent hypoglycemic effect, or a .beta.
cell- or pancreas-protecting effect, or a pharmaceutically
acceptable salt thereof; a pharmaceutical composition having an
excellent therapeutic effect and/or prophylactic effect on type 1
diabetes, type 2 diabetes and the like, which cause an increase in
blood sugar levels; and a pharmaceutical composition having a
.beta. cell- or pancreas-protecting effect.
BEST MODES FOR CARRYING OUT THE INVENTION
[0047] One embodiment of the present invention is a compound
represented by general formula (II):
##STR00020##
[0048] wherein R.sup.3 represents --CH.sub.3 or --C.sub.2H.sub.5,
R.sup.6 represents a C1-C6 alkyl group or a C3-C6 cycloalkyl group,
each of which may be substituted with 1 to 3 --OH, and R.sup.7
represents
##STR00021##
or a pharmaceutically acceptable salt thereof.
[0049] One embodiment of the present invention is a compound
represented by general formula (III):
##STR00022##
[0050] wherein X represents CH or N, R.sup.3 represents --CH.sub.3
or --C.sub.2H.sub.5, R.sup.8 represents --H, or represents a C1-C6
alkyl group which may be substituted with 1 to 3 substituents
selected from substituent subgroup .alpha., R.sup.9 represents
##STR00023##
and substituent subgroup .alpha. is --OH,
--O--C(.dbd.O)--O--CH.sub.3, or --O--C(.dbd.O)--NH--C.sub.2H.sub.5;
or a pharmaceutically acceptable salt thereof.
[0051] One embodiment of the present invention is a compound
represented by general formula (IV):
##STR00024##
[0052] wherein X, R.sup.1, and R.sup.3 have the same meanings as
defined above; or a pharmaceutically acceptable salt thereof.
[0053] One embodiment of the present invention is a compound
represented by general formula (V):
##STR00025##
[0054] wherein X, R.sup.3, and R.sup.5 have the same meanings as
defined above; or a pharmaceutically acceptable salt thereof.
[0055] One embodiment of the present invention is a compound
represented by general formula (VI):
##STR00026##
[0056] wherein X, R.sup.1, R.sup.2, R.sup.3 and R.sup.4 have the
same meanings as defined above; or a pharmaceutically acceptable
salt thereof.
[0057] One embodiment of the present invention is a compound
represented by general formula (VII):
##STR00027##
[0058] wherein X, R.sup.1, and R.sup.3 have the same meanings as
defined above; or a pharmaceutically acceptable salt thereof.
[0059] One embodiment of the present invention is a compound
represented by general formula (VIII):
##STR00028##
[0060] wherein X, R.sup.1, R.sup.3, and R.sup.4 have the same
meanings as defined above; or a pharmaceutically acceptable salt
thereof.
[0061] A "C1-C6 alkyl group" as used in the present specification
means a linear or branched alkyl group having 1 to 6 carbon atoms.
Specific examples include a methyl group, an ethyl group, a propyl
group, an isopropyl group, a butyl group, an isobutyl group, a
sec-butyl group, and a tert-butyl group.
[0062] A "C3-C6 cycloalkyl group" as used in the present
specification means a saturated cyclic hydrocarbon group having 3
to 6 carbon atoms, and examples include a cyclopropyl group, a
cyclobutyl group, a cyclopentyl group, and a cyclohexyl group.
[0063] A "pharmaceutically acceptable salt" as used in the present
specification means a salt formed by allowing the compound of the
present invention to react with an acid or a base.
[0064] Examples of the salt include hydrohalogenic acid salts such
as hydrofluorides, hydrochlorides, hydrobromides, and hydroiodides;
inorganic acid salts such as nitrates, perchlorates, sulfates and
phosphates; lower alkanesulfonic acid salts such as
methanesulfonates, trifluoromethanesulfonates, and
ethanesulfonates; arylsulfonic acid salts such as
benzenesulfonates, and p-toluenesulfonates; organic acid salts such
as acetates, malates, fumarates, succinates, citrates, ascorbates,
tartrates, oxalates, and maleates; alkali metal salts such as
sodium salts, potassium salts, and lithium salts; alkaline earth
metal salts such as calcium salts and magnesium salts; metal salts
such as aluminum salts and iron salts; inorganic salts such as
ammonium salts; amine salts including organic salts such as
t-octylamine salts, dibenzylamine salts, morpholine salts,
glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine
salts, N-methylglucamine salts, guanidine salts, diethylamine
salts, triethylamine salts, dicyclohexylamine salts,
N,N'-dibenzylethylenediamine salts, chloroprocaine salts, procaine
salts, diethanolamine salts, N-benzylphenethylamine salts,
piperazine salts, tetramethylammonium salts, and
tris(hydroxymethyl)aminomethane salts; and amino acid salts such as
glycine salts, lysine salts, arginine salts, ornithine salts,
glutamates, and aspartates.
[0065] The compound of the present invention absorbs water when,
for example, left to stand in the atmosphere, and a hydrate may be
formed. Therefore, such a hydrate is also included in the concept
of the salt of the present invention.
[0066] Since the compound of the present invention may have
asymmetric carbon atoms in the molecule, the compound has optical
isomers. These isomers and mixtures of these isomers are all
represented by a single formula, that is, the general formula (I)
to (VIII). Therefore, the present invention encompasses all of the
optical isomers of the compound represented by the general formula
(I) to (VIII), and mixtures of these optical isomers at any ratios.
Such an optical isomer can be produced by, for example, using raw
materials having optical activity instead of the raw materials
shown in the Reference Examples and Examples that will be described
below. Such an optical isomer can also be obtained by subjecting a
compound that has been produced by making reference to the
Reference Examples, Examples and the like that will be described
below, to an optical resolution method that is known in the
pertinent art, for example, a diastereomer method, an enzymatic
reaction method, an optical resolution method based on
chromatography or the like.
[0067] The present invention may also encompass compounds in which
one or more of the atoms constituting the compound represented by
the general formula (I) to (VIII) have been substituted with
isotopes of the atoms. Isotopes include the two classes of
radioactive isotopes and stable isotopes, and examples of the
isotopes include, for example, isotopes of hydrogen (.sup.2H and
.sup.3H), isotopes of carbon (.sup.11C, .sup.13C and .sup.14C),
isotopes of nitrogen (.sup.13N and .sup.15N), isotopes of oxygen
(.sup.15O, .sup.17O and .sup.18O), and isotopes of fluorine
(.sup.18F). A composition containing a compound labeled with an
isotope is useful as, for example, a therapeutic agent, a
prophylactic agent, a research reagent, an assay reagent, a
diagnostic agent, or an in vivo diagnostic imaging agent. Compounds
labeled with isotopes and mixtures of compounds labeled with
isotopes at any ratios are all included in the present invention. A
compound labeled with an isotope can be produced by a method that
is known in the pertinent art, for example, using raw materials
labeled with isotopes instead of the raw materials used in the
production methods that will be described below.
[0068] The present invention may also encompass prodrugs of the
compound represented by the general formula (I) to (VIII). A
prodrug is a derivative of the compound represented by the general
formula (I) to (VIII), and means a compound which is enzymatically
or chemically converted to the compound of the present invention in
the living body.
[0069] Examples of a prodrug include compounds in which an amino
group in the molecule has been acylated, alkylated or
phosphorylated; and compounds in which a hydroxyl group in the
molecule has been acylated, alkylated or phosphorylated (see, for
example, Povl Krogsgaard-Larsen, et al., "A Textbook of Drug Design
and Development", Second Edition, Harwood Academic Publishers,
1996, pp. 351-385). Such a prodrug can be produced from the
compound represented by the general formula (I) to (VIII) by a
method known in the pertinent art.
[0070] The compound of the present invention can be easily produced
from known compounds according to the Reference Examples and
Examples that will be described below.
[0071] The compound of the present invention or a pharmaceutically
acceptable salt thereof has an excellent hypoglycemic effect, and
can therefore be used as an active ingredient of a pharmaceutical
composition that can be used in the treatment and/or prevention of
type 1 diabetes, type 2 diabetes, gestational diabetes,
hyperglycemia due to other factors, impaired glucose tolerance
(IGT), obesity, diabetes-associated diseases (for example,
hyperlipidemia, hypercholesterolemia, abnormal lipid metabolism,
hypertension, fatty liver, metabolic syndrome, edema, heart
failure, angina pectoris, myocardial infarction, arteriosclerosis,
hyperuricemia, and gout), or diabetic complications (for example,
retinosis, kidney failure, neuropathy, cataract, gangrenous leg,
infections, and ketosis).
[0072] The compound of the present invention or a pharmaceutically
acceptable salt thereof has an excellent .beta. cell- or
pancreas-protecting effect, and can therefore be used as an active
ingredient of a pharmaceutical composition that can be used for
protecting .beta. cells or the pancreas.
[0073] The compound of the present invention or a pharmaceutically
acceptable salt thereof can also be used in combination with other
therapeutic drugs for diabetes, diabetic complications,
hyperlipidemia, hypertension, and the like.
[0074] When a pharmaceutical composition containing the compound of
the present invention or a pharmaceutically acceptable salt thereof
is administered to a mammal (for example, human, horse, cow or pig;
preferably a human being), the pharmaceutical composition can be
administered systemically or topically, and orally or
parenterally.
[0075] Appropriate dosage forms of the pharmaceutical composition
of the present invention can be selected in accordance with the
administration mode. The pharmaceutical composition of the present
invention can be prepared according to the preparation methods for
various conventionally used formulations.
[0076] Examples of the dosage form of the pharmaceutical
composition for oral use include tablets, pills, powders, granules,
capsules, liquids, suspensions, emulsions, syrups, and elixirs.
Pharmaceutical compositions of such dosage forms can be prepared
according to conventional methods, by appropriately selecting, as
necessary, excipients, binders, disintegrants, lubricating agents,
swelling agents, swelling aids, coating agents, plasticizers,
stabilizers, antiseptics, antioxidants, colorants, dissolution
aids, suspending agents, emulsifiers, sweeteners, preservatives,
buffers, diluents, wetting agents and the like, which are
conventionally used as additives.
[0077] Examples of the dosage forms of a pharmaceutical composition
for parenteral use include injections, ointments, gels, creams,
poultices, patches, aerosols, inhalants, sprays, eye drops, nose
drops, and suppositories. Pharmaceutical compositions of such
dosage forms can be prepared according to conventional methods, by
appropriately selecting as necessary, stabilizers, antiseptics,
dissolution aids, moisturizers, preservatives, antioxidants,
fragrances, gelling agents, neutralizing agents, buffers, isotonic
agents, surfactants, colorants, buffering agents, thickeners,
wetting agents, fillers, absorption promoting agents, suspending
agents, binders, and the like, which are conventionally used as
additives.
[0078] The administration amount of the compound of the present
invention or a pharmaceutically acceptable salt thereof may vary
with the symptoms, age, body weight or the like. However, in the
case of oral administration, the compound or the salt is
administered once to several times a day, in an amount of 1 to 2000
mg, and preferably 1 to 400 mg, in terms of the compound, per dose
for an adult; and in the case of parenteral administration, the
compound or the salt is administered once to several times a day,
in an amount of 0.01 to 500 mg, and preferably 0.1 to 300 mg, in
terms of the compound, per dose for an adult.
[0079] Hereinafter, the present invention will be described in more
detail by way of Reference Examples, Examples, a Formulation
Example and Test Examples, but the scope of the present invention
is not intended to be limited to these.
EXAMPLES
Reference Example 1
Ethyl
2-[3-fluoro-4-(methoxycarbonyl)phenyl]-2H-1,2,3-triazol-4-carboxylat-
e
##STR00029##
[0081] Methyl 4-amino-2-fluorobenzoate (Bioorg. Med. Chem. 2009,
17, 7042-7051.) (13.0 g, 76.9 mmol) was suspended in a 3 N aqueous
hydrochloric acid solution (108 mL), and an aqueous (25 mL)
solution of sodium nitrite (5.57 g, 80.7 mmol) was added to the
resulting suspension over 10 minutes under ice cooling. The
resulting mixture was stirred at the same temperature for 30
minutes, and then the obtained reaction mixture was added to a
mixed water (412 mL) and ethanol (52 mL) suspension of sodium
acetate (82.0 g) and 3-dimethylamino ethyl acrylate (14.3 mL) over
5 minutes under ice cooling. The resulting mixture was stirred at
the same temperature for 90 minutes. Subsequently, water was added
to the reaction mixture, and the resulting mixture was extracted
twice with dichloromethane. The organic layer thus obtained was
dried over anhydrous sodium sulfate. The resulting mixture was
filtered, and then the solvent was distilled off under reduced
pressure. The resulting residue was diluted with ethanol (228 mL)
and water (114 mL), and then hydroxylamine hydrochloride (6.06 g,
84.5 mmol) and sodium acetate (13.9 g, 169 mmol) were added to the
resulting mixture. The mixture was stirred at room temperature for
2.5 hours. Subsequently, water was added to the reaction mixture,
and the resulting mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, then the solvent was
distilled off under reduced pressure, and the resulting residue was
diluted with acetic acid (120 mL) and acetic anhydride (179 mL).
The resulting mixture was stirred at 60.degree. C. for 1 hour, and
then the solvent in the reaction mixture was distilled off under
reduced pressure. The resulting residue was diluted with
tetrahydrofuran (239 mL), and then potassium carbonate (106 g,
0.769 mol) was added to the resulting mixture. The mixture was
stirred at room temperature for 1 hour. Subsequently, water was
added to the reaction mixture, and the resulting mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, then the solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (dichloromethane) to give the title
compound (15.9 g, yield: 71%).
[0082] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0083] 8.27 (1H, s), 8.13-7.98 (3H, m), 4.49 (2H, q, J=7 Hz), 3.97
(3H, s), 1.45 (3H, t, J=7 Hz).
Reference Example 2
2-[3-Fluoro-4-(methoxycarbonyl)phenyl]-2H-1,2,3-triazol-4-carboxylic
acid
##STR00030##
[0085] 1 N Aqueous sodium hydroxide solution (59.6 mL) was added
dropwise to a methanol (159 mL) and tetrahydrofuran (159 mL) mixed
solution of the compound obtained in Reference Example 1 (15.9 g,
54.2 mmol) at room temperature over 5 minutes, and the mixture was
stirred at the same temperature for 1.5 hours. Subsequently, water
and diethyl ether were added to the reaction mixture, and the
mixture was separated into two layers. 1 N Aqueous hydrochloric
acid solution (59.6 mL) was added to the aqueous layer thus
obtained, and the mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, and then the solvent
was distilled off under reduced pressure to give the title compound
(12.6 g, yield: 88%).
[0086] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0087] 13.80 (1H, m), 8.63 (1H, s), 8.16-7.92 (3H, m), 3.90 (3H,
s).
Reference Example 3
Methyl
2-fluoro-4-{4-[methoxy(methyl)carbamoyl]-2H-1,2,3-triazol-2-yl}benz-
oate
##STR00031##
[0089] Triethylamine (15.9 mL, 0.114 mol) was added to a
dichloromethane (189 mL) suspension of the compound obtained in
Reference Example 2 (12.6 g, 47.5 mmol), N,O-dimethylhydroxylamine
hydrochloride (5.56 g, 57.0 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (10.9
g, 57.0 mmol), and 1-hydroxybenzotriazole monohydrate (8.73 g, 57.0
mmol) under ice cooling. The mixture was stirred at the same
temperature for 15 minutes, and at room temperature for 18 hours.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted with dichloromethane. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (10% ethyl
acetate/dichloromethane) to give the title compound (9.65 g, yield:
66%).
[0090] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0091] 8.25 (1H, s), 8.13-7.95 (3H, m), 3.97 (3H, s), 3.85 (3H, s),
3.46 (3H, br s).
Reference Example 4
Methyl 2-fluoro-4-(4-propionyl-2H-1,2,3-triazol-2-yl)benzoate
##STR00032##
[0093] Ethylmagnesium chloride (containing 10 mol % zinc chloride
as an activator, 1.0 mol/L tetrahydrofuran solution, 7.04 mL, 7.04
mmol) was added dropwise to a tetrahydrofuran (33 mL) suspension of
the compound obtained in Reference Example 3 (1.67 g, 5.42 mmol)
under ice cooling. The mixture was stirred at the same temperature
for 35 minutes, and then ethylmagnesium chloride (the same as the
above, 3.52 mL, 3.52 mmol) was further added. The mixture was
stirred at the same temperature for 20 minutes, and then
ethylmagnesium chloride (the same as the above, 3.52 mL, 3.52 mmol)
was further added. The mixture was stirred at the same temperature
for 10 minutes. Subsequently, water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was dried over anhydrous
sodium sulfate. The resulting mixture was filtered, then the
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(dichloromethane) to give the title compound (0.921 g, yield:
61%).
[0094] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0095] 8.27 (1H, s), 8.14-8.10 (1H, m), 8.02-7.95 (2H, m), 3.98
(3H, s), 3.16-3.11 (2H, m), 1.29-1.25 (3H, m).
Reference Example 5
Methyl
2-fluoro-4-[4-(1-hydroxypropyl)-2H-1,2,3-triazol-2-yl]benzoate
##STR00033##
[0097] Sodium borohydride (49.8 mg) was added to a mixed methanol
(5 mL) and tetrahydrofuran (5 mL) suspension of the compound
obtained in Reference Example 4 (0.231 g, 0.833 mmol) under ice
cooling. The mixture was stirred at the same temperature for 2
hours. Subsequently, water was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (25% ethyl acetate/hexane) to give
the title compound (0.213 g, yield: 92%).
[0098] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0099] 8.09-8.05 (1H, m), 7.93-7.85 (2H, m), 7.81 (1H, s),
4.94-4.89 (1H, m), 3.96 (3H, s), 2.20-2.19 (1H, m), 2.01-1.88 (2H,
m), 1.05-1.02 (3H, m).
Reference Example 6
Methyl
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2--
yl)-2-fluorobenzoate
##STR00034##
[0101] Di-tert-butyl azodicarboxylate (0.187 g, 0.811 mmol) was
added to a tetrahydrofuran (5 mL) solution of the compound obtained
in Reference Example 5 (0.206 g, 0.738 mmol),
cyclopropyl(4-hydroxyphenyl)methanone (0.132 g, 0.811 mmol), and
triphenylphosphine (0.213 g, 0.811 mmol) at room temperature. The
mixture was stirred at room temperature for 5.5 hours.
Subsequently, the solvent in the reaction mixture was distilled off
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (20% ethyl acetate/hexane) to give
the title compound (0.295 g, yield: 94%).
[0102] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0103] 8.10-8.06 (1H, m), 7.98-7.86 (4H, m), 7.76 (1H, s),
7.01-6.99 (2H, m), 5.52-5.49 (1H, m), 3.96 (3H, s), 2.62-2.56 (1H,
m), 2.21-2.07 (2H, m), 1.20-1.17 (2H, m), 1.10-1.06 (3H, m),
1.00-0.97 (2H, m).
Reference Example 7
4-(4-{1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2-yl)-2-f-
luorobenzoic acid
##STR00035##
[0105] 1 N Aqueous sodium hydroxide solution (0.73 mL) was added to
a tetrahydrofuran (5.6 mL) solution of the compound obtained in
Reference Example 6 (0.282 g, 0.666 mmol) at room temperature. The
mixture was stirred at 60.degree. C. for 1 hour, and then 1 N
aqueous sodium hydroxide solution (0.73 mL) was further added. The
mixture was stirred at 60.degree. C. for 1 hour, and then returned
to room temperature. Subsequently, water and diethyl ether were
added to the reaction mixture, and the mixture was separated into
two layers. 1 N Aqueous hydrochloric acid solution (1.46 mL) was
added to the aqueous layer thus obtained, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (0.243 g, yield:
89%).
[0106] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0107] 8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s),
7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06
(2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H,
m).
Reference Example 8
Methyl 4-(4-acetyl-2H-1,2,3-triazol-2-yl)-2-fluorobenzoate
##STR00036##
[0109] Methylmagnesium bromide (0.99 mol/L tetrahydrofuran
solution, 34.6 mL, 34.3 mmol) was added dropwise to a
tetrahydrofuran (132 mL) suspension of the compound obtained in
Reference Example 3 (6.60 g, 21.4 mmol) under ice cooling. The
mixture was stirred at the same temperature for 1 hour.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (dichloromethane) to give the
title compound (4.63 g, yield: 82%).
[0110] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0111] 8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98
(3H, s), 2.71 (3H, s).
Reference Example 9
Methyl
2-fluoro-4-[4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl]benzoate
##STR00037##
[0113] Sodium borohydride (42.0 mg) was added to a methanol (4 mL)
suspension of the compound obtained in Reference Example 8 (0.185
g, 0.703 mmol) under ice cooling. The mixture was stirred at the
same temperature for 5 hours. Subsequently, water was added to the
reaction mixture, and the resulting mixture was extracted with
ethyl acetate. The organic layer thus obtained was dried over
anhydrous sodium sulfate. The resulting mixture was filtered, then
the solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(15% ethyl acetate/dichloromethane) to give the title compound
(0.174 g, yield: 93%).
[0114] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0115] 8.10-8.05 (1H, m), 7.93-7.86 (2H, m), 7.83 (1H, s),
5.19-5.12 (1H, m), 3.96 (3H, s), 1.65 (3H, d, J=7 Hz).
Reference Example 10
Methyl
4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-2H-1,2,3-triazol-2-y-
l)-2-fluorobenzoate
##STR00038##
[0117] Di-tert-butyl azodicarboxylate (0.165 g, 0.717 mmol) was
added to a tetrahydrofuran (4 mL) solution of the compound obtained
in Reference Example 9 (0.173 g, 0.652 mmol),
cyclopropyl(4-hydroxyphenyl)methanone (0.116 g, 0.717 mmol), and
triphenylphosphine (0.188 g, 0.717 mmol) at room temperature. The
mixture was stirred at room temperature for 1 hour. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (20% ethyl acetate/hexane) to give the title
compound (0.293 g, quantitative).
[0118] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0119] 8.10-8.06 (1H, m), 7.99-7.97 (2H, m), 7.93-7.86 (2H, m),
7.80 (1H, s), 7.04-7.00 (2H, m), 5.77-5.73 (1H, m), 3.96 (3H, s),
2.63-2.57 (1H, m), 1.80 (3H, d, J=7 Hz), 1.21-1.18 (2H, m),
1.01-0.96 (2H, m).
Reference Example 11
4-(4-{1-[4-(Cyclopropylcarbonyl)phenoxy]ethyl}-2H-1,2,3-triazol-2-yl)-2-fl-
uorobenzoic acid
##STR00039##
[0121] 1 N Aqueous sodium hydroxide solution (1.43 mL) was added to
a tetrahydrofuran (5.8 mL) solution of the compound obtained in
Reference Example 10 (0.290 g) at room temperature. The mixture was
stirred at 60.degree. C. for 1 hour, and then returned to room
temperature. Subsequently, water and diethyl ether were added to
the reaction mixture, and the mixture was separated into two
layers. 1 N Aqueous hydrochloric acid solution (1.43 mL) was added
to the aqueous layer thus obtained, and the mixture was extracted
twice with dichloromethane. The organic layer thus obtained was
dried over anhydrous sodium sulfate. The resulting mixture was
filtered, and then the solvent was distilled off under reduced
pressure to give the title compound (0.226 g, yield: 88%).
[0122] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0123] 8.32 (1H, s), 8.12-8.01 (3H, m), 7.94-7.85 (2H, m),
7.18-7.16 (2H, m), 6.02-5.97 (1H, m), 2.87-2.80 (1H, m), 1.75 (3H,
d, J=6 Hz), 0.98-0.96 (4H, m).
Reference Example 12
2-Fluoro-4-(4-propionyl-2H-1,2,3-triazol-2-yl)benzoic acid
##STR00040##
[0125] 1 N Aqueous sodium hydroxide solution (7.30 mL) was added to
a tetrahydrofuran (18 mL) solution of the compound obtained in
Reference Example 4 (0.920 g, 3.32 mmol) at room temperature. The
mixture was stirred at 60.degree. C. for 1.5 hours, and then
returned to room temperature. Subsequently, water and diethyl ether
were added to the reaction mixture, and the mixture was separated
into two layers. 1 N Aqueous hydrochloric acid solution (7.30 mL)
was added to the aqueous layer thus obtained, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (0.830 g, yield:
95%).
[0126] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0127] 13.54 (1H, br s), 8.67 (1H, s), 8.15-8.11 (1H, m), 8.04-7.97
(2H, m), 3.16-3.10 (2H, m), 1.15-1.12 (3H, m).
Reference Example 13
tert-Butyl
2-fluoro-4-(4-propionyl-2H-1,2,3-triazol-2-yl)benzoate
##STR00041##
[0129] N,N-Dimethylformamide di-tert-butylacetal (1.50 mL, 6.27
mmol) was added to a dichloromethane (16.5 mL) suspension of the
compound obtained in Reference Example 12 (0.920 g, 3.13 mmol) at
room temperature. The mixture was stirred at room temperature for
19 hours, and then N,N-dimethylformamide di-tert-butylacetal (6.00
mL, 25.1 mmol) was further added. The mixture was stirred at room
temperature for 22 hours. Subsequently, the solvent in the reaction
mixture was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(dichloromethane) to give the title compound (0.370 g, yield:
37%).
[0130] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0131] 8.26 (1H, s), 8.06-8.02 (1H, m), 7.98-7.90 (2H, m), 3.14
(2H, q, J=7 Hz), 1.62 (9H, s), 1.27 (3H, t, J=7 Hz).
Reference Example 14
tert-Butyl
2-fluoro-4-[4-(1-hydroxypropyl)-2H-1,2,3-triazol-2-yl]benzoate
##STR00042##
[0133] Sodium borohydride (100 mg, 2.52 mmol) was added to a
methanol (7 mL) and tetrahydrofuran (7 mL) solution of the compound
obtained in Reference Example 13 (0.366 g, 1.15 mmol) under ice
cooling. The mixture was stirred at the same temperature for 1
hour. Subsequently, water was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (25% ethyl acetate/hexane) to give
the title compound (0.381 g, quantitative).
[0134] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0135] 8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s),
4.93-4.89 (1H, m), 2.21-2.20 (1H, m), 2.01-1.88 (2H, m), 1.61 (9H,
s), 1.06-1.02 (3H, m).
Reference Example 15
tert-Butyl
2-fluoro-4-{4-[(1S)-1-hydroxypropyl]-2H-1,2,3-triazol-2-yl}benz-
oate
##STR00043##
[0137] Lipase (acrylic resin support, from Candida antarctica)
(45.4 mg), and vinyl acetate (0.138 mL, 1.49 mmol) were added to a
toluene (5.70 mL) solution of the compound obtained in Reference
Example 14 (0.369 g) at room temperature. The mixture was stirred
at room temperature for 24 hours. Subsequently, lipase (acrylic
resin support, from Candida antarctica) (45.4 mg), and vinyl
acetate (0.138 mL, 1.49 mmol) were further added. The mixture was
stirred at room temperature for 24 hours. Subsequently, the solid
in the reaction mixture was filtered. The solvent in the filtrate
thus obtained was distilled off under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(15%-25% ethyl acetate/hexane) to give an ingredient, which was
diluted with toluene (2.90 mL). Lipase (the same as the above)
(24.0 mg), and vinyl acetate (0.0722 mL, 0.781 mmol) were added to
the resulting mixture at room temperature. The mixture was stirred
at room temperature for 67 hours. Subsequently, the solid in the
reaction mixture was filtered. The solvent in the filtrate thus
obtained was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography (15%-25%
ethyl acetate/hexane) to give the title compound (0.179 g, yield:
49%).
[0138] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0139] 8.00-7.96 (1H, m), 7.89-7.81 (3H, m), 7.80 (3H, s),
4.93-4.89 (1H, m), 2.17-2.16 (1H, m), 2.00-1.90 (2H, m), 1.62 (9H,
s), 1.06-1.02 (3H, m).
Reference Example 16
tert-Butyl
4-(4-{(1R)-1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-t-
riazol-2-yl)-2-fluorobenzoate
##STR00044##
[0141] Di-tert-butyl azodicarboxylate (0.136 g, 0.589 mmol) was
added to a tetrahydrofuran (4 mL) solution of the compound obtained
in Reference Example 15 (0.172 g, 0.535 mmol),
cyclopropyl(4-hydroxyphenyl)methanone (95.5 mg, 0.589 mmol), and
triphenylphosphine (0.154 g, 0.589 mmol) at room temperature. The
mixture was stirred at room temperature for 22 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (12% ethyl acetate/hexane) to give the title
compound (0.293 g, yield: 74%).
[0142] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0143] 8.02-7.94 (3H, m), 7.89-7.81 (2H, m), 7.75 (1H, s),
7.03-6.99 (2H, m), 5.52-5.49 (1H, m), 2.62-2.56 (1H, m), 2.21-2.07
(2H, m), 1.62 (9H, s), 1.20-1.17 (2H, m), 1.10-1.07 (3H, m),
1.00-0.96 (2H, m).
Reference Example 17
4-(4-{(1R)-1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2-yl-
)-2-fluorobenzoic acid
##STR00045##
[0145] Trifluoroacetic acid (1.80 mL) was added to a
dichloromethane (5.40 mL) solution of the compound obtained in
Reference Example 16 (0.180 g, 0.387 mmol) at room temperature. The
mixture was stirred at room temperature for 2 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. Diethyl ether and hexane were added to the resulting
residue, and the precipitated solid was filtered to give the title
compound (0.114 g, yield: 72%).
[0146] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0147] 8.19-8.15 (1H, m), 7.99-7.89 (4H, m), 7.78 (1H, s),
7.03-6.99 (2H, m), 5.53-5.50 (1H, m), 2.63-2.56 (1H, m), 2.22-2.06
(2H, m), 1.21-1.17 (2H, m), 1.11-1.07 (3H, m), 1.01-0.96 (2H,
m).
Reference Example 18
4-(4-Acetyl-2H-1,2,3-triazol-2-yl)-2-fluorobenzoic acid
##STR00046##
[0149] 1 N Aqueous sodium hydroxide solution (25.1 mL) was added to
a tetrahydrofuran (60 mL) solution of the compound obtained in
Reference Example 8 (3.00 g, 11.4 mmol) at room temperature. The
mixture was stirred at 60.degree. C. for 1 hour, and then returned
to room temperature. Subsequently, water and diethyl ether were
added to the reaction mixture, and the mixture was separated into
two layers. 1 N Aqueous hydrochloric acid solution (25.1 mL) was
added to the aqueous layer thus obtained, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (3.02 g).
[0150] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0151] 8.26 (1H, s), 8.15-8.11 (1H, m), 8.03-7.95 (2H, m), 3.98
(3H, s).
Reference Example 19
tert-Butyl 4-(4-acetyl-2H-1,2,3-triazol-2-yl)-2-fluorobenzoate
##STR00047##
[0153] N,N-Dimethylformamide di-tert-butylacetal (16.4 mL, 68.4
mmol) was added to a dichloromethane (60 mL) suspension of the
compound obtained in Reference Example 18 (3.01 g) at room
temperature. The mixture was stirred at room temperature for 2.5
hours. Subsequently, the solvent in the reaction mixture was
distilled off under reduced pressure. The resulting residue was
purified by silica gel column chromatography (dichloromethane) to
give the title compound (2.64 g, yield: 76%).
[0154] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0155] 8.26 (1H, s), 8.06-7.91 (3H, m), 2.71 (3H, s), 1.63 (9H,
s).
Reference Example 20
tert-Butyl
2-fluoro-4-[4-(1-hydroxyethyl)-2H-1,2,3-triazol-2-yl]benzoate
##STR00048##
[0157] Sodium borohydride (0.756 g, 19.0 mmol) was added to a
methanol (52 mL) and tetrahydrofuran (52 mL) solution of the
compound obtained in Reference Example 19 (2.63 g, 8.63 mmol) under
ice cooling. The mixture was stirred at the same temperature for 1
hour. Subsequently, water was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (30% ethyl acetate/hexane) to give
the title compound (1.59 g, yield: 60%).
[0158] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0159] 8.01-7.97 (1H, m), 7.89-7.81 (3H, m), 5.18-5.12 (1H, m),
1.65 (3H, d, J=6 Hz), 1.62 (9H, s).
Reference Example 21
tert-Butyl
2-fluoro-4-{4-[(1S)-1-hydroxyethyl]-2H-1,2,3-triazol-2-yl}benzo-
ate
##STR00049##
[0161] Lipase (acrylic resin support, from Candida antarctica)
(0.195 g), and vinyl acetate (0.618 mL, 6.68 mmol) were added to a
toluene (24 mL) solution of the compound obtained in Reference
Example 20 (1.58 g) at room temperature. The mixture was stirred at
room temperature for 42 hours. Subsequently, the solid in the
reaction mixture was filtered. The solvent in the filtrate thus
obtained was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography (20%-28%
ethyl acetate/hexane) to give the title compound (0.710 g, yield:
45%).
[0162] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0163] .sup.1H-NMR (CDCl.sub.3) .delta.: 8.01-7.97 (1H, m),
7.89-7.81 (3H, m), 5.18-5.12 (1H, m), 1.65 (4H, d, J=6.4 Hz), 1.62
(9H, s).
Reference Example 22
5-(Methoxymethoxy)pyridin-2-carbonitrile
##STR00050##
[0165] 60% sodium hydride (3.62 g, 90.4 mmol) was added to an
N,N-dimethylformamide (70 mL) solution of
5-hydroxypyridin-2-carbonitrile (7.24 g, 60.3 mmol) at 0.degree.
C., and the mixture was stirred at the same temperature for 15
minutes. Subsequently, chloromethyl methyl ether (9.16 ml, 121
mmol) was added to the mixture little by little, and the resulting
mixture was further stirred at the same temperature for 45 minutes.
A saturated aqueous solution of ammonium chloride and water were
added to the reaction mixture, and the mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=75:25, v/v) to give the title compound (8.63 g, yield:
87%).
[0166] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0167] 8.46 (1H, dd, J=3, 1 Hz), 7.65 (1H, dd, J=9, 1 Hz), 7.45
(1H, dd, J=9, 3 Hz), 5.28 (2H, s), 3.50 (3H, s).
Reference Example 23
Cyclopropyl[5-(methoxymethoxy)pyridin-2-yl]methanone
##STR00051##
[0169] 0.7 M Cyclopropylmagnesium bromide-tetrahydrofuran solution
(72.9 mL, 51.0 mmol) was added to a tetrahydrofuran (68 mL)
solution of the compound obtained in Reference Example 22 (5.58 g,
34.0 mmol) at 0.degree. C. over 20 minutes, and the mixture was
stirred at the same temperature for 20 minutes. A saturated aqueous
solution of ammonium chloride and water were added to the reaction
mixture, and the mixture was extracted twice with ethyl acetate.
The organic layer thus obtained was washed with brine, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure to give the crude title compound (11.5
g).
Reference Example 24
Cyclopropyl(5-hydroxypyridin-2-yl)methanone
##STR00052##
[0171] 1 M Sulfuric acid (20 mL) was added to a tetrahydrofuran (20
mL) solution of the crude compound obtained in Reference Example 23
(5.72 g) at room temperature, and the mixture was stirred at
60.degree. C. for 2.5 hours. The reaction mixture was cooled to
room temperature, and then 5 M aqueous sodium hydroxide solution
was added to the reaction mixture to adjust the pH to 6.
Subsequently, the resulting mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=80:20.fwdarw.50:50, v/v) to give the title compound (2.77
g, yield: 52%).
[0172] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0173] 8.32 (1H, dd, J=3, 1 Hz), 8.00 (1H, d, J=9, 1 Hz), 7.27 (1H,
dd, J=9, 3 Hz), 3.43-3.35 (1H, m), 1.26-1.21 (2H, m), 1.12-1.06
(2H, m).
Reference Example 25
tert-Butyl
4-{4-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2-
H-1,2,3-triazol-2-yl}-2-fluorobenzoate
##STR00053##
[0175] Di-tert-butyl azodicarboxylate (0.583 g, 2.53 mmol) was
added to a tetrahydrofuran (14 mL) solution of the compound
obtained in Reference Example 21 (0.707 g, 2.30 mmol), the compound
obtained in Reference Example 24 (0.413 g, 2.53 mmol), and
triphenylphosphine (0.664 g, 2.53 mmol) at room temperature. The
mixture was stirred at room temperature for 18 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (20% ethyl acetate/hexane) to give the title
compound (1.08 g, quantitative).
[0176] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0177] 8.42 (1H, d, J=3 Hz), 8.02-7.98 (2H, m), 7.89-7.81 (3H, m),
7.37-7.34 (1H, m), 5.81-5.76 (1H, m), 3.45-3.38 (1H, m), 1.84 (3H,
d, J=7 Hz), 1.62 (9H, s), 1.22-1.18 (2H, m), 1.08-1.03 (2H, m).
Reference Example 26
4-{4-[(1R)-1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3-tri-
azol-2-yl}-2-fluorobenzoic acid
##STR00054##
[0179] Trifluoroacetic acid (10.7 mL) was added to a
dichloromethane (21.4 mL) solution of the compound obtained in
Reference Example 25 (0.108 g) at room temperature. The mixture was
stirred at room temperature for 1 hour. Subsequently, the solvent
in the reaction mixture was distilled off under reduced pressure. A
small amount of a saturated aqueous solution of sodium hydrogen
carbonate was added to the resulting residue, then a 10% aqueous
citric acid solution was added to the mixture, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (0.879 g, yield:
93%).
[0180] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0181] 8.45 (1H, d, J=3 Hz), 8.18-8.14 (1H, m), 8.01 (1H, d, J=9
Hz), 7.97-7.89 (2H, m), 7.85 (1H, s), 7.38-7.35 (1H, m), 5.83-5.78
(1H, m), 3.43-3.37 (1H, m), 1.85 (3H, d, J=6 Hz), 1.22-1.19 (2H,
m), 1.09-1.04 (2H, m).
Reference Example 27
(4-{1-[2-(4-Amino-3-fluorophenyl)-2H-1,2,3-triazol-4-yl]propoxy}phenyl)(cy-
clopropyl)methanone
##STR00055##
[0183] Diphenylphosphoryl azide (0.395 mL, 1.83 mmol) was added to
a tert-butanol (10 mL) solution of the compound obtained in
Reference Example 7 (0.500 g, 1.22 mmol) and triethylamine (0.340
mL, 2.44 mmol) at room temperature. The mixture was stirred at
90.degree. C. for 3.5 hours, and then returned to room temperature.
The solvent in the reaction mixture was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (20% ethyl acetate/hexane) to give a mixture
(0.616 g) containing tert-butyl
[4-(4-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2-yl)-2-
-fluorophenyl]carbamate.
[0184] Trifluoroacetic acid (6 mL) was added to a dichloromethane
(12 mL) solution of the mixture (0.610 g) described above at room
temperature. The mixture was stirred at room temperature for 2
hours. Subsequently, the solvent in the reaction mixture was
distilled off under reduced pressure. A saturated aqueous solution
of sodium hydrogen carbonate and water were added to the resulting
residue, and the mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, then the solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (25% ethyl
acetate/hexane) to give the title compound (242 mg, yield:
52%).
[0185] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0186] 7.97-7.93 (2H, m), 7.72-7.69 (1H, m), 7.64-7.61 (2H, m),
7.03-6.99 (2H, m), 6.86-6.82 (1H, m), 5.49-5.45 (1H, m), 3.85 (2H,
br s), 2.62-2.56 (1H, m), 2.20-2.04 (2H, m), 1.20-1.16 (2H, m),
1.09-1.05 (3H, m), 1.00-0.95 (2H, m).
Reference Example 28
(5-{(1R)-1-[2-(4-Amino-3-fluorophenyl)-2H-1,2,3-triazol-4-yl]ethoxy}pyridi-
n-2-yl)(cyclopropyl)methanone
##STR00056##
[0188] Diphenylphosphoryl azide (0.169 mL, 0.783 mmol) was added to
a tert-butanol (5 mL) solution of the compound obtained in
Reference Example 26 (0.207 g, 0.522 mmol) and triethylamine (0.146
mL, 1.04 mmol) at room temperature. The mixture was stirred at
90.degree. C. for 2.5 hours, and then returned to room temperature.
The solvent in the reaction mixture was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (15% ethyl acetate/hexane) to give a mixture
(0.287 g) containing tert-butyl
(4-{4-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3-t-
riazol-2-yl}-2-fluorophenyl)carbamate.
[0189] Trifluoroacetic acid (3 mL) was added to a dichloromethane
(6 mL) solution of the mixture (0.282 g) described above at room
temperature. The mixture was stirred at room temperature for 1
hour. Subsequently, the solvent in the reaction mixture was
distilled off under reduced pressure. A saturated aqueous solution
of sodium hydrogen carbonate and water were added to the resulting
residue, and the mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, then the solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (30% ethyl
acetate/hexane) to give the title compound (190 mg, yield:
99%).
[0190] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0191] 8.42 (1H, d, J=3 Hz), 8.00-7.98 (1H, m), 7.72-7.68 (2H, m),
7.64-7.61 (1H, m), 7.39-7.36 (1H, m), 6.87-6.83 (1H, m), 5.78-5.73
(1H, m), 3.44-3.37 (1H, m), 1.82 (3H, d, J=6 Hz), 1.21-1.18 (2H,
m), 1.08-1.03 (2H, m).
Reference Example 29
Ethyl
2-[3-fluoro-4-(methoxycarbonyl)phenyl]-2H-tetrazol-5-carboxylate
##STR00057##
[0193] Benzene sulfonyl hydrazide (2.55 g, 14.8 mmol) was added to
an ethanol (86 mL) solution of ethyl glyoxalate (50% toluene
solution, 4.53 g, 22.2 mmol) at room temperature. The mixture was
stirred at room temperature for 45 minutes. Subsequently, the
solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was diluted with pyridine (86 mL).
This mixture was designated reaction mixture A. On the other hand,
methyl 4-amino-2-fluorobenzoate (Bioorg. Med. Chem. 2009, 17,
7042-7051.) (2.50 g, 14.8 mmol) was suspended in a 4 N aqueous
hydrochloric acid solution (18 mL), and an aqueous (4 mL) solution
of sodium nitrite (1.12 g, 16.3 mmol) was added dropwise to the
resulting suspension under ice cooling. The mixture was stirred at
the same temperature for 15 minutes, and then the obtained reaction
mixture was added dropwise to the reaction mixture A under ice
cooling. The mixture was stirred at the same temperature for 4
hours. Subsequently, water was added to the reaction mixture, and
the resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (dichloromethane) to give the
title compound (2.01 g, yield: 46%).
[0194] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0195] 8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.62-4.57 (2H, m),
3.99 (3H, s), 1.52-1.49 (3H, m).
Reference Example 30
2-[3-Fluoro-4-(methoxycarbonyl)phenyl]-2H-tetrazol-5-carboxylic
acid
##STR00058##
[0197] An aqueous (20 mL) solution of lithium hydroxide monohydrate
(0.314 g, 7.48 mmol) was added to a mixed solution containing
tetrahydrofuran (40 mL) and the compound obtained in Reference
Example 29 (2.00 g, 6.80 mmol) under ice cooling. The mixture was
stirred at the same temperature for 18 hours. Subsequently, water
and diethyl ether were added to the reaction mixture, and the
mixture was separated into two layers. 1 N Aqueous hydrochloric
acid solution (7.48 mL) was added to the aqueous layer thus
obtained, and the mixture was extracted four times with
dichloromethane. The organic layer thus obtained was dried over
anhydrous sodium sulfate. The resulting mixture was filtered, and
then the solvent was distilled off under reduced pressure to give
the title compound (1.32 g, yield: 73%).
[0198] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0199] 8.23-8.10 (3H, m), 3.92 (3H, s).
Reference Example 31
Methyl
2-fluoro-4-{5-[methoxy(methyl)carbamoyl]-2H-tetrazol-2-yl}benzoate
##STR00059##
[0201] Triethylamine (1.63 mL, 11.7 mmol) was added to a
dichloromethane (26 mL) suspension of the compound obtained in
Reference Example 30 (1.30 g, 4.88 mmol), N,O-dimethylhydroxylamine
hydrochloride (0.572 g, 5.86 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.12
g, 5.86 mmol), and 1-hydroxybenzotriazole monohydrate (0.897 g,
5.86 mmol). The mixture was stirred at room temperature for 58
hours. Subsequently, water was added to the reaction mixture, and
the resulting mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, then the solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (10% ethyl
acetate/dichloromethane) to give the title compound (1.18 g, yield:
78%).
[0202] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0203] 8.21-8.18 (1H, m), 8.11-8.02 (2H, m), 3.99 (3H, s), 3.93
(3H, s), 3.46 (3H, br s).
Reference Example 32
Methyl 2-fluoro-4-(5-propionyl-2H-tetrazol-2-yl)benzoate
##STR00060##
[0205] Ethylmagnesium chloride (as an activator, 10 mol % zinc
chloride is contained, 1.0 mol/L tetrahydrofuran solution, 2.52 mL,
2.52 mmol) was added dropwise to a tetrahydrofuran (12 mL) solution
of the compound obtained in Reference Example 31 (0.600 g, 1.94
mmol) under ice cooling. The mixture was stirred at the same
temperature for 200 minutes, and then ethylmagnesium chloride (the
same as the above, 2.52 mL, 2.52 mmol) was further added. The
mixture was stirred at the same temperature for 1 hour.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (dichloromethane) to give the
title compound (0.420 g, yield: 78%).
[0206] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0207] 8.22-8.18 (1H, m), 8.13-8.06 (2H, m), 4.00 (3H, s),
3.30-3.25 (2H, m), 1.34-1.31 (3H, m).
Reference Example 33
Methyl
2-fluoro-4-[5-(1-hydroxypropyl)-2H-tetrazol-2-yl]benzoate
##STR00061##
[0209] Sodium borohydride (0.756 g, 19.0 mmol) was added to a
methanol (8.5 mL) suspension of the compound obtained in Reference
Example 32 (0.419 g, 1.51 mmol) under ice cooling. The mixture was
stirred at the same temperature for 2 hours. Subsequently, water
was added to the reaction mixture, and the resulting mixture was
extracted with ethyl acetate. The organic layer thus obtained was
dried over anhydrous sodium sulfate. The resulting mixture was
filtered, then the solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (10% ethyl acetate/dichloromethane) to give
the title compound (0.340 g, yield: 81%).
[0210] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0211] 8.18-8.14 (1H, m), 8.05-7.97 (2H, m), 5.11-5.06 (1H, m),
3.99 (3H, s), 2.65-2.63 (1H, m), 2.18-1.99 (2H, m), 1.08-1.05 (3H,
m).
Reference Example 34
Methyl
4-(5-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-2H-tetrazol-2-yl)-2-
-fluorobenzoate
##STR00062##
[0213] Di-tert-butyl azodicarboxylate (0.298 g, 1.30 mmol) was
added to a tetrahydrofuran (7 mL) solution of the compound obtained
in Reference Example 33 (0.330 g, 1.18 mmol),
cyclopropyl(4-hydroxyphenyl)methanone (0.210 g, 1.30 mmol), and
triphenylphosphine (0.340 g, 1.30 mmol) at room temperature. The
mixture was stirred at room temperature for 21 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (23% ethyl acetate/hexane) to give the title
compound (0.414 g, yield: 83%).
[0214] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0215] 8.17-8.13 (1H, m), 8.03-7.95 (4H, m), 7.08-7.05 (2H, m),
5.67-5.64 (1H, m), 3.98 (3H, s), 2.62-2.56 (1H, m), 2.38-2.21 (2H,
m), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.00-0.97 (2H, m).
Reference Example 35
4-(5-{1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-2H-tetrazol-2-yl)-2-fluoro-
benzoic acid
##STR00063##
[0217] 1 N Aqueous sodium hydroxide solution (2.13 mL) was added to
a tetrahydrofuran (8.2 mL) solution of the compound obtained in
Reference Example 34 (0.410 g, 0.966 mmol) at room temperature. The
mixture was stirred at 60.degree. C. for 3 hours, and then returned
to room temperature. Subsequently, water and diethyl ether were
added to the reaction mixture, and the mixture was separated into
two layers. 1 N Aqueous hydrochloric acid solution (2.13 mL) was
added to the aqueous layer thus obtained, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (0.396 g, yield:
100%).
[0218] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0219] 8.25-8.21 (1H, m), 8.06-7.96 (4H, m), 7.08-7.06 (2H, m),
5.68-5.65 (1H, m), 2.62-2.56 (1H, m), 2.39-2.22 (2H, m), 1.21-1.17
(2H, m), 1.13-1.10 (3H, m), 1.00-0.97 (2H, m).
Reference Example 36
Methyl 4-(5-acetyl-2H-tetrazol-2-yl)-2-fluorobenzoate
##STR00064##
[0221] Methylmagnesium bromide (0.99 mol/L tetrahydrofuran
solution, 3.00 mL, 2.97 mmol) was added dropwise to a
tetrahydrofuran (11.5 mL) solution of the compound obtained in
Reference Example 31 (0.575 g, 1.86 mmol) under ice cooling. The
mixture was stirred at the same temperature for 45 minutes.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted with ethyl acetate. The organic
layer thus obtained was dried over anhydrous sodium sulfate. The
resulting mixture was filtered, then the solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (dichloromethane) to give the
title compound (0.295 g, yield: 60%).
[0222] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0223] 8.23-8.06 (3H, m), 4.00 (3H, s), 2.86 (3H, s).
Reference Example 37
Methyl 2-fluoro-4-[5-(1-hydroxyethyl)-2H-tetrazol-2-yl]benzoate
##STR00065##
[0225] Sodium borohydride (97.5 mg, 2.45 mmol) was added to a mixed
methanol (4.4 mL) and tetrahydrofuran (4.4 mL) suspension of the
compound obtained in Reference Example 36 (0.294 g, 1.11 mmol)
under ice cooling. The mixture was stirred at the same temperature
for 30 minutes. Subsequently, water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was dried over anhydrous
sodium sulfate. The resulting mixture was filtered, then the
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography (12% ethyl
acetate/dichloromethane) to give the title compound (0.258 g,
yield: 87%).
[0226] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0227] 8.19-8.15 (1H, m), 8.05-7.97 (2H, m), 5.34-5.28 (1H, m),
3.99 (3H, s), 1.76 (3H, d, J=7 Hz).
Reference Example 38
Methyl
4-[5-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-2H-tetrazo-
l-2-yl]-2-fluorobenzoate
##STR00066##
[0229] Di-tert-butyl azodicarboxylate (0.276 g, 1.05 mmol) was
added to a tetrahydrofuran (7 mL) solution of the compound obtained
in Reference Example 37 (0.255 g, 0.958 mmol), the compound
obtained in Reference Example 24 (0.172 g, 1.05 mmol), and
triphenylphosphine (0.340 g, 1.30 mmol) at room temperature. The
mixture was stirred at room temperature for 18 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (20% ethyl acetate/hexane) to give the title
compound (0.345 g, yield: 88%).
[0230] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0231] 8.47-8.46 (1H, m), 8.18-8.14 (1H, m), 8.03-7.95 (3H, m),
7.45-7.42 (1H, m), 5.96-5.91 (1H, m), 3.98 (3H, s), 3.45-3.38 (1H,
m), 1.97 (3H, d, J=7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m).
Reference Example 39
4-[5-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-2H-tetrazol-2-yl]-
-2-fluorobenzoic acid
##STR00067##
[0233] 1 N Aqueous sodium hydroxide solution (1.80 mL) was added to
a tetrahydrofuran (6.7 mL) solution of the compound obtained in
Reference Example 38 (0.337 g, 0.819 mmol) at room temperature. The
mixture was stirred at 60.degree. C. for 75 minutes and then
returned to room temperature. Subsequently, water and diethyl ether
were added to the reaction mixture, and the mixture was separated
into two layers. 1 N Aqueous hydrochloric acid solution (1.80 mL)
was added to the aqueous layer thus obtained, and the mixture was
extracted twice with dichloromethane. The organic layer thus
obtained was dried over anhydrous sodium sulfate. The resulting
mixture was filtered, and then the solvent was distilled off under
reduced pressure to give the title compound (0.283 g, yield:
87%).
[0234] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0235] 8.49 (1H, d, J=3 Hz), 8.24-8.20 (1H, m), 8.06-7.98 (3H, m),
7.45 (1H, dd, J=9, 3 Hz), 5.97-5.92 (1H, m), 3.42-3.36 (1H, m),
1.98 (3H, d, J=7 Hz), 1.23-1.19 (2H, m), 1.09-1.04 (2H, m).
Reference Example 40
Methyl 4-(aminocarbonothioyl)-2-fluorobenzoate
##STR00068##
[0237] A sodium hydrogensulfide hydrate (9.22 g, 0.165 mol) was
added to an N,N-dimethylformamide (74 mL) suspension of methyl
4-cyano-2-fluorobenzoate (WO 2010/115751) (7.37 g, 41.1 mmol) and
magnesium chloride hexahydrate (10.0 g, 49.4 mmol) at room
temperature. The mixture was stirred at room temperature for 4
hours. Subsequently, water (148 mL) was added to the reaction
mixture, and the precipitated solid was filtered. The solid thus
obtained was added to 1 N aqueous hydrochloric acid solution (148
mL), and the mixture was stirred for 20 minutes. The solid in the
reaction mixture was filtered to give the title compound (7.63 g,
yield: 87%).
[0238] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm:
[0239] 10.21 (1H, s), 9.75 (1H, s), 7.94-7.90 (1H, m), 7.79-7.72
(2H, m), 3.88-3.87 (3H, m).
Reference Example 41
Methyl 2-fluoro-4-(5-formyl-1,3-thiazol-2-yl)benzoate
##STR00069##
[0241] 2-Bromomalonaldehyde (5.31 g, 35.2 mmol) was added to a
tetrahydrofuran (100 mL) suspension of the compound obtained in
Reference Example 40 (5.00 g, 23.5 mmol) and sodium hydrogen
carbonate (5.91 g, 70.4 mmol) at room temperature. The mixture was
stirred at 60.degree. C. for 5 hours, and then air-cooled.
Subsequently, water (1 L) was added to the reaction mixture, and
the precipitated solid was filtered. The solid thus obtained was
diluted with dichloromethane (300 mL), and stirred. Subsequently,
the solid in the reaction mixture was filtered. The solvent in the
filtrate thus obtained was distilled off under reduced pressure,
and the resulting residue was diluted with ethyl acetate (150 mL).
The mixture was stirred under reflux, then cooled on ice, and the
precipitated solid was filtered to give the title compound (4.08 g,
yield: 66%).
[0242] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm:
[0243] 10.12 (1H, m), 8.86-8.85 (1H, m), 8.05-8.02 (3H, m),
3.90-3.89 (3H, m).
Reference Example 42
Methyl 2-fluoro-4-[5-(1-hydroxyethyl)-1,3-thiazol-2-yl]benzoate
##STR00070##
[0245] Methylmagnesium bromide (1.12 mol/L tetrahydrofuran
solution, 8.75 mL, 9.80 mmol) was added dropwise to a
tetrahydrofuran (40 mL) suspension of the compound obtained in
Reference Example 41 (2.00 g, 7.54 mmol) under ice cooling. The
mixture was stirred at the same temperature for 2 hours.
Subsequently, a saturated aqueous solution of ammonium chloride was
added to the mixture to quench the reaction. Water was added to the
reaction mixture, and the resulting mixture was extracted with
ethyl acetate. The organic layer thus obtained was dried over
anhydrous sodium sulfate. The resulting mixture was filtered, then
the solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(50% ethyl acetate/hexane) to give the title compound (1.75 g,
yield: 83%).
[0246] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0247] 8.01-7.98 (1H, m), 7.73-7.71 (3H, m), 5.25-5.20 (1H, m),
3.96-3.95 (3H, m), 2.34-2.32 (1H, m), 1.67-1.65 (3H, m).
Reference Example 43
Methyl
4-(5-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)-2--
fluorobenzoate
##STR00071##
[0249] Di-tert-butyl azodicarboxylate (0.783 g, 3.40 mmol) was
added to a tetrahydrofuran (17 mL) solution of the compound
obtained in Reference Example 42 (0.870 g, 3.09 mmol),
cyclopropyl(4-hydroxyphenyl)methanone (0.552 g, 3.40 mmol), and
triphenylphosphine (0.892 g, 3.40 mmol) at room temperature. The
mixture was stirred at room temperature for 4 hours. Subsequently,
the solvent in the reaction mixture was distilled off under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (33%-43% ethyl acetate/hexane) to give the title
compound (0.464 g, yield: 35%).
[0250] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0251] 8.01-7.96 (3H, m), 7.82 (1H, m), 7.72-7.71 (1H, m),
7.70-7.69 (1H, m), 7.02-6.98 (2H, m), 5.81-5.77 (1H, m), 3.95 (3H,
s), 2.63-2.57 (1H, m), 1.83 (3H, d, J=6 Hz), 1.21-1.18 (2H, m),
1.02-0.97 (2H, m).
Reference Example 44
4-(5-{1-[4-(Cyclopropylcarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)-2-fluorob-
enzoic acid
##STR00072##
[0253] 1 N Aqueous sodium hydroxide solution (5.36 mL) was added to
a tetrahydrofuran (9.1 mL) solution of the compound obtained in
Reference Example 43 (0.456 g, 1.07 mmol) at room temperature. The
mixture was stirred at 80.degree. C. for 135 minutes, and then
returned to room temperature. Subsequently, water and diethyl ether
were added to the reaction mixture, and the mixture was separated
into two layers. 1 N Aqueous hydrochloric acid solution (5.36 mL)
was added to the aqueous layer thus obtained, and the mixture was
extracted with ethyl acetate. The organic layer thus obtained was
dried over anhydrous sodium sulfate. The resulting mixture was
filtered, then the solvent was distilled off under reduced
pressure, and thus the title compound (0.440 g, yield: 100%) was
obtained.
[0254] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0255] 13.44 (1H, br s), 8.10 (1H, s), 8.02-7.93 (3H, m), 7.83-7.79
(2H, m), 7.19-7.15 (2H, m), 6.20-6.15 (1H, m), 2.86-2.80 (1H, m),
1.75-1.74 (3H, m), 0.98-0.96 (4H, m).
Reference Example 45
Methyl
4-[5-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-thiazo-
l-2-yl]-2-fluorobenzoate
##STR00073##
[0257] Triphenylphosphine (102 mg, 0.391 mmol) and di-tert-butyl
azodicarboxylate (90.0 mg, 0.391 mmol) were added to a
tetrahydrofuran (1.8 mL) solution of the compound obtained in
Reference Example 42 (100 mg, 0.355 mmol) and the compound obtained
in Reference Example 24 (63.8 mg, 0.391 mmol) at room temperature,
and the mixture was stirred at the same temperature for 30 minutes.
The reaction mixture was concentrated under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=90:10.fwdarw.75:25, v/v) to
give the title compound (89.6 mg, yield: 59%).
[0258] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0259] 8.40 (1H, d, J=3 Hz), 8.03-7.97 (2H, m), 7.84 (1H, s),
7.73-7.69 (2H, m), 7.32 (1H, dd, J=9, 3 Hz), 5.82 (1H, q, J=6 Hz),
3.95 (3H, s), 3.45-3.37 (1H, m), 1.86 (4H, d, J=6 Hz), 1.22-1.17
(2H, m), 1.09-1.03 (2H, m).
Reference Example 46
2-[3-Fluoro-4-(methylthio)phenyl]-1,3-thiazol-5-carbaldehyde
##STR00074##
[0261] Sodium hydrogen carbonate (2.06 g, 24.6 mmol) and
bromomalonaldehyde (1.85 g, 12.3 mmol) were added to a
tetrahydrofuran (40 mL) solution of 4-(methylthio)thiobenzamide
(1.50 g, 8.18 mmol) at room temperature. The mixture was stirred at
60.degree. C. for 1.5 hours. After the reaction mixture was cooled
to room temperature, water was added to the reaction mixture, and
the resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was washed with a
hexane-ethyl acetate mixture (5:1, v/v) to give the title compound
(1.74 g, yield: 90%).
[0262] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0263] 10.03 (1H, s), 7.94 (2H, d, J=9 Hz), 7.31 (2H, d, J=9 Hz),
7.26 (1H, s), 2.54 (3H, s).
Reference Example 47
1-{2-[3-Fluoro-4-(methylthio)phenyl]-1,3-thiazol-5-yl}propan-1-ol
##STR00075##
[0265] Zinc chloride (403 mg, 2.96 mmol) was added to a
tetrahydrofuran (37 mL) solution of the compound obtained in
Reference Example 46 (1.74 g, 7.39 mmol) at 0.degree. C.,
subsequently, 1.00 M ethylmagnesium bromide-tetrahydrofuran
solution (8.87 mL, 8.87 mmol) was slowly added, and the mixture was
stirred at the same temperature for 30 minutes. Further, 1.00 M
ethylmagnesium bromide-tetrahydrofuran solution (8.87 mL, 8.87
mmol) was slowly added to the mixture, and the mixture was stirred
at the same temperature for 30 minutes. A saturated aqueous
solution of ammonium chloride was added to the reaction mixture,
and the mixture was extracted twice with ethyl acetate. The organic
layer thus obtained was washed with brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was washed with
diisopropyl ether to give the title compound (1.51 g, yield:
77%).
[0266] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0267] 7.83 (2H, d, J=9 Hz), 7.64 (1H, s), 7.28 (2H, d, J=9 Hz),
4.90 (1H, dd, J=7, 6 Hz), 2.52 (3H, s), 2.18 (1H, br s), 1.97-1.84
(2H, m), 1.00 (3H, t, J=7 Hz).
Reference Example 48
N-(4-Bromo-3-fluorobenzoyl)-L-serine methyl ester
##STR00076##
[0269] 1-Hydroxybenzotriazole monohydrate (839 mg, 5.48 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.05
g, 5.48 mmol) were added to an N,N-dimethylformamide (34 mL)
solution of 4-bromo-3-fluorobenzoic acid (1.00 g, 4.57 mmol) at
room temperature. The mixture was stirred at the same temperature
for 30 minutes, and then L-serine methyl ester hydrochloride (1.42
g, 9.13 mmol) and triethylamine (1.27 mL, 9.13 mmol) were added to
the mixture. The resulting mixture was further stirred at the same
temperature for 15 minutes. Water was added to the reaction
mixture, and the resulting mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with a
saturated aqueous solution of sodium hydrogen carbonate and brine,
and then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure to give the crude title
compound (1.63 g).
Reference Example 49
Methyl
(4S)-2-(4-bromo-3-fluorophenyl)-4,5-dihydro-1,3-oxazol-4-carboxylat-
e
##STR00077##
[0271] The crude compound obtained in Reference Example 48 (1.00 g)
was dissolved in dichloromethane (16 mL), and
N,N-diethylaminosulfur trifluoride (614 .mu.L, 4.69 mmol) was added
to the mixture at -78.degree. C. The mixture was stirred at the
same temperature for 1 hour, and then potassium carbonate (1.30 g,
9.37 mmol) was added to the mixture. The resulting mixture was
heated to room temperature over 40 minutes. Water was added to the
reaction mixture, and the resulting mixture was extracted twice
with dichloromethane. The organic layer thus obtained was dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=80:20.fwdarw.30:70,
v/v) to give the title compound (625 mg, yield: 74%).
[0272] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0273] 7.73 (1H, dd, J=9, 1 Hz), 7.66 (1H, dd, J=8, 1 Hz), 7.61
(1H, dd, J=8, 6 Hz), 4.95 (1H, dd, J=11, 8 Hz), 4.72 (1H, dd, J=9,
8 Hz), 4.62 (1H, dd, J=11, 9 Hz), 3.83 (3H, s).
Reference Example 50
Methyl 2-(4-bromo-3-fluorophenyl)-1,3-oxazol-4-carboxylate
##STR00078##
[0275] The compound obtained in Reference Example 49 (400 mg, 1.32
mmol) was dissolved in dichloromethane (6.6 mL), and
1,8-diazabicyclo[5.4.0]undec-7-ene (613 .mu.L, 4.10 mmol) and
bromotrichloromethane (404 .mu.L, 4.10 mmol) were added to the
mixture at room temperature. The mixture was stirred at the same
temperature for 30 minutes. Water was added to the reaction
mixture, and the resulting mixture was extracted twice with
dichloromethane. The organic layer thus obtained was dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=70:30.fwdarw.30:70,
v/v) to give the title compound (368 mg, yield: 93%).
[0276] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0277] 8.31 (1H, s), 7.87 (1H, dd, J=9, 2 Hz), 7.80 (1H, td, J=8, 2
Hz), 7.68 (1H, dd, J=8, 7 Hz), 3.97 (3H, s).
Reference Example 51
[2-(4-Bromo-3-fluorophenyl)-1,3-oxazol-4-yl]methanol
##STR00079##
[0279] The compound obtained in Reference Example 50 (363 mg, 1.21
mmol) was dissolved in dichloromethane (12 mL), and 1.02 M
diisobutylaluminium hydride-hexane solution (1.19 mL, 1.21 mmol)
was added to the mixture at -78.degree. C. The mixture was stirred
at the same temperature for 30 minutes. Further, 1.02 M
diisobutylaluminium hydride-hexane solution (1.19 mL, 1.21 mmol)
was added to the mixture, and the resulting mixture was stirred at
the same temperature for 1 hour. Subsequently, a saturated aqueous
solution of ammonium chloride (600 .mu.L) was added to the mixture
at room temperature, and the mixture was stirred at the same
temperature for 1 hour. The generated insoluble material was
removed by filtration through Celite, then the solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=75:25.fwdarw.50:50, v/v) to give the title compound (195
mg, yield: 59%).
[0280] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0281] 7.78 (1H, dd, J=9, 2 Hz), 7.71 (1H, dd, J=8, 2 Hz), 7.68
(1H, s), 7.65 (1H, dd, J=8, 7 Hz), 4.69 (2H, d, J=6 Hz), 2.06 (1H,
br s).
Reference Example 52
1-[2-(4-Bromo-3-fluorophenyl)-1,3-oxazol-4-yl]ethanol
##STR00080##
[0283] The compound obtained in Reference Example 51 (1.55 g, 5.70
mmol) was dissolved in dichloromethane (15 mL), and Dess-Martin
periodinane (3.62 g, 8.55 mmol) was added to the mixture at room
temperature. The mixture was stirred at the same temperature for 15
minutes. A saturated aqueous solution of sodium hydrogen carbonate
and 1 M aqueous sodium sulfite solution were added to the reaction
mixture. The mixture was stirred at room temperature for 5 minutes,
and then extracted twice with ethyl acetate. The organic layer thus
obtained was washed with a saturated aqueous solution of sodium
hydrogen carbonate and brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue (1.61 g) was dissolved in tetrahydrofuran (50
mL). Subsequently, 1.10 M methylmagnesium bromide-tetrahydrofuran
solution (5.70 mL, 6.27 mmol) was added to the mixture at 0.degree.
C. over 10 minutes, and the mixture was stirred at the same
temperature for 30 minutes. 1 M hydrochloric acid was added to the
reaction mixture, and the mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=70:30.fwdarw.50:50, v/v) to give the title compound (1.37
g, yield: 84%).
[0284] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0285] 7.78 (1H, dd, J=9, 2 Hz), 7.71 (1H, dd, J=8, 2 Hz), 7.64
(1H, dd, J=8, 7 Hz), 7.61 (1H, s), 4.95-4.88 (1H, m), 2.27 (1H, br
s), 1.58 (3H, d, J=6 Hz).
Reference Example 53
Methyl 2-fluoro-4-[4-(1-hydroxymethyl)-1,3-oxazol-2-yl]benzoate
##STR00081##
[0287] Triethylamine (2.00 mL, 14.4 mmol) and a
[1,1'-bis(diphenylphosphino)ferrocene]palladium(II)
dichloride-dichloromethane adduct (782 mg, 0.958 mmol) were added
to a dimethylformamide (25 mL)-methanol (25 mL) solution of the
compound obtained in Reference Example 52 (1.37 g, 4.79 mmol) at
room temperature, and the mixture was stirred at 80.degree. C. for
5 hours under carbon monoxide flow. The reaction mixture was cooled
to room temperature, then ethyl acetate and water were added to the
reaction mixture, and the mixture was vigorously stirred at room
temperature. The generated insoluble material was removed by
filtration through Celite, and then the mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=50:50, v/v) to give the title compound (1.06 g, yield:
83%).
[0288] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0289] 8.03 (1H, dd, J=8, 7 Hz), 7.87 (1H, dd, J=8, 1 Hz), 7.81
(1H, dd, J=11, 1 Hz), 7.65 (1H, s), 4.97-4.90 (1H, m), 3.96 (3H,
s), 2.27 (1H, d, J=5 Hz), 1.59 (3H, d, J=8 Hz).
Reference Example 54
4-(4-{1-[4-(Cyclopropylcarbonyl)phenoxyethyl}-1,3-oxazol-2-yl)-2-fluoroben-
zoic acid
##STR00082##
[0291] Triphenylphosphine (442 mg, 1.68 mmol) and di-tert-butyl
azodicarboxylate (388 mg, 1.68 mmol) were added to a
tetrahydrofuran solution (15 mL) of the compound obtained in
Reference Example 53 (406 mg, 1.53 mmol) and
cyclopropyl(4-hydroxyphenyl)methanone (273 mg, 1.68 mmol) at room
temperature. The mixture was stirred at the same temperature for 30
minutes. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=9:1.fwdarw.1:1, v/v).
Subsequently, the compound thus obtained was dissolved in
tetrahydrofuran (4 mL) and methanol (4 mL), then 2 M aqueous sodium
hydroxide solution (0.765 mL, 1.53 mmol) was added to the mixture,
and the resulting mixture was stirred at room temperature for 30
minutes. Water and a saturated aqueous solution of ammonium
chloride were added to the reaction mixture, and the mixture was
extracted three times with ethyl acetate. The extract was dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1.fwdarw.1:4,
v/v) to give the title compound (311 mg, yield: 51%).
[0292] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0293] 8.18-8.05 (1H, m), 8.00 (2H, d, J=9 Hz), 7.95-7.80 (2H, m),
7.66 (1H, s), 7.02 (2H, d, J=9 Hz), 5.55 (1H, q, J=6 Hz), 2.66-2.57
(1H, m), 1.76 (3H, d, J=7 Hz), 1.23-1.18 (2H, m), 1.03-0.98 (2H,
m).
Reference Example 55
4-[4-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-yl]--
2-fluorobenzoic acid
##STR00083##
[0295] Triphenylphosphine (1.14 g, 4.35 mmol) and di-tert-butyl
azodicarboxylate (1.00 g, 4.35 mmol) were added to a
tetrahydrofuran (20 mL) solution of the compound obtained in
Reference Example 53 (1.05 mg, 3.96 mmol) and the compound obtained
in Reference Example 24 (646 mg, 3.96 mmol) at 0.degree. C., and
the mixture was stirred at the same temperature for 5 minutes, and
then further stirred at room temperature for 30 minutes. The
solvent was distilled off under reduced pressure, the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=90:10.fwdarw.75:25, v/v) to give a product,
and the product (1.16 g) thus obtained was dissolved in
tetrahydrofuran (4.0 mL)-methanol (4.0 mL) mixture. Subsequently, 1
M aqueous sodium hydroxide solution (4.0 mL) was added to the
resulting mixture at room temperature, and the mixture was stirred
at the same temperature for 15 minutes. The reaction mixture was
concentrated under reduced pressure, then water was added to the
resulting reaction mixture, and the aqueous layer was washed with
diethyl ether. 1 M Sulfuric acid was added to the mixture to adjust
the pH to 6, and then the resulting mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was washed with a hexane-diisopropyl ether (2:1, v/v) mixture to
give the title compound (904 mg, yield: 58%).
[0296] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0297] 8.45 (1H, d, J=3 Hz), 8.12 (1H, dd, J=8, 7 Hz), 8.02 (1H, d,
J=9 Hz), 7.90 (1H, dd, J=8, 2 Hz), 7.84 (1H, dd, J=11, 2 Hz), 7.71
(1H, d, J=1 Hz), 7.37 (1H, dd, J=9, 3 Hz), 5.58 (1H, q, J=7 Hz),
3.45-3.37 (1H, m), 1.81 (3H, d, J=7 Hz), 1.24-1.19 (2H, m),
1.10-1.04 (2H, m).
Reference Example 56
(4-{1-[2-(4-Amino-3-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}phenyl)(cycloprop-
yl)methanone
##STR00084##
[0299] Triethylamine (0.121 mL, 0.865 mmol) and diphenylphosphoryl
azide (0.186 mL, 0.865 mmol) were added to a tert-butanol (15 mL)
solution of the compound obtained in Reference Example 54 (311 mg,
0.786 mmol) at room temperature, and the mixture was heated at
60.degree. C. for 5 hours. After the reaction mixture was cooled to
room temperature, water was added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v). Subsequently, a methylene chloride (1
mL) solution of trifluoroacetic acid (1 mL) was added to a
methylene chloride (2 mL) solution of the compound thus obtained at
room temperature, and the resulting mixture was stirred at the same
temperature for 30 minutes. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=9:1.fwdarw.1:2,
v/v) to give the title compound (123 mg, yield: 44%).
[0300] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0301] 7.98 (2H, d, J=9 Hz), 7.67-7.61 (2H, m), 7.51 (1H, s), 7.02
(2H, d, J=7 Hz), 6.81 (1H, dd, J=9, 8 Hz), 5.52 (1H, q, J=6 Hz),
3.27 (2H, bs), 2.64-2.56 (1H, m), 1.74 (3H, d, J=6 Hz), 1.22-1.18
(2H, m), 1.02-0.96 (2H, m).
Reference Example 57
(5-{1-[2-(4-Amino-3-fluorophenyl)-1,3-oxazol-4-yl]ethoxy}pyridin-2-yl)(cyc-
lopropyl)methanone
##STR00085##
[0303] Triethylamine (0.174 mL, 1.25 mmol) and diphenylphosphoryl
azide (0.268 mL, 1.25 mmol) were added to a tert-butanol (5 mL)
solution of the compound obtained in Reference Example 55 (411 mg,
1.04 mmol) at room temperature, and the mixture was heated at
90.degree. C. for 6 hours. After the reaction mixture was cooled to
room temperature, water was added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v). Subsequently, trifluoroacetic acid (2
mL) was added to a methylene chloride (2 mL) solution of the
compound thus obtained at room temperature, and the mixture was
stirred at the same temperature for 30 minutes. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:2, v/v) to give the title compound (326 mg,
yield: 86%).
[0304] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0305] 8.49-8.48 (1H, m), 8.02 (1H, d, J=9 Hz), 7.65-7.60 (2H, m),
7.57 (1H, s), 7.43-7.39 (1H, m), 6.81 (1H, dd, J=9, 9 Hz), 5.57
(1H, q, J=6 Hz), 3.45-3.38 (1H, m), 1.78 (3H, d, J=6 Hz), 1.25-1.20
(2H, m), 1.10-1.06 (2H, m).
Reference Example 58
tert-Butyl
2-fluoro-4-{5-[(1S)-1-hydroxyethyl]-1,2,4-oxadiazol-3-yl}benzoa-
te
##STR00086##
[0307] 1-Hydroxybenzotriazole monohydrate (16.7 g, 109 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (41.8
g, 218 mmol) were added to a dimethylformamide (540 mL) solution of
(2S)-2-acetoxy propionic acid (14.4 g, 109 mmol) at room
temperature, and the mixture was stirred at the same temperature
for 30 minutes. Subsequently, tert-butyl
4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO 2011/016469) (27.7
g, 109 mmol) was added to the mixture. The resulting mixture was
stirred at the same temperature for 10 minutes, and then further
stirred at 90.degree. C. for 3 hours. The reaction mixture was
cooled to room temperature, then water and a 10% aqueous solution
of sodium chloride were added to the reaction mixture, and the
mixture was extracted twice with ethyl acetate. The organic layer
thus obtained was washed with a 10% aqueous solution of sodium
chloride and a saturated aqueous solution of sodium hydrogen
carbonate, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=95:5.fwdarw.85:15, v/v) to give a compound,
and then the compound (32.1 g, 91.6 mmol) thus obtained was
dissolved in methanol (360 mL). Potassium carbonate (12.7 g, 91.6
mmol) was added to the mixture under ice cooling, and the resulting
mixture was stirred at the same temperature for 30 minutes. 2 M
Hydrochloric acid was added to the reaction mixture to adjust the
pH to 6.0, and then the solvent was distilled off under reduced
pressure. Water was added to the residue, and the mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was washed
with hexane to give the title compound (26.4 g, yield: 93%).
[0308] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0309] 7.97 (1H, t, J=8 Hz), 7.90 (1H, d, J=8 Hz), 7.84 (1H, d, J=5
Hz), 5.18 (1H, q, J=7 Hz), 1.73 (4H, d, J=7 Hz), 1.60 (9H, s);
[0310] MS (FAB) m/z: 309 [M+H].sup.+.
Reference Example 59
4-{5-[(1R)-1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-1,2,4-oxadia-
zol-3-yl}-2-fluorobenzoic acid
##STR00087##
[0312] Triphenylphosphine (468 mg, 1.78 mmol) and di-tert-butyl
azodicarboxylate (411 mg, 1.78 mmol) were added to a
tetrahydrofuran (8.0 mL) solution of the compound obtained in
Reference Example 58 (500 mg, 1.62 mmol) and the compound obtained
in Reference Example 24 (291 mg, 1.78 mmol) at room temperature,
and the mixture was stirred at the same temperature for 1 hour. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=90:10.fwdarw.75:25, v/v) to give a crude
product, and then the crude product (1.18 g) thus obtained was
dissolved in acetonitrile (5.0 mL). Subsequently, concentrated
sulfuric acid (400 .mu.L) was added to the mixture at room
temperature, and the resulting mixture was stirred at 80.degree. C.
for 30 minutes. After the reaction mixture was cooled to room
temperature, water was added to the reaction mixture, and the pH of
the resulting mixture was adjusted to 6 by using a saturated
aqueous solution of sodium hydrogen carbonate. The mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was washed with brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=70:30.fwdarw.0:100, v/v) to
give the title compound (431 mg, yield: 67%).
[0313] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0314] 8.48 (1H, d, J=3 Hz), 8.13 (1H, dd, J=8, 7 Hz), 8.04 (1H, d,
J=9 Hz), 7.95 (1H, dd, J=8, 2 Hz), 7.90 (1H, dd, J=11, 2 Hz), 7.40
(1H, dd, J=9, 3 Hz), 5.80 (1H, q, J=7 Hz), 3.44-3.37 (1H, m), 1.97
(3H, d, J=7 Hz), 1.24-1.19 (2H, m), 1.11-1.05 (2H, m).
Reference Example 60
1-(5-Hydroxypyridin-2-yl)-2-methylpropan-1-one
##STR00088##
[0316] 1.0 M Isopropylmagnesium chloride-tetrahydrofuran solution
(104 mL, 104 mmol) was slowly added to a tetrahydrofuran (80 mL)
solution of 5-hydroxypyridin-2-carbonitrile (5.00 g, 41.6 mmol) at
0.degree. C., and the mixture was stirred at the same temperature
for 3 hours. 1 M Hydrochloric acid was added to the reaction
mixture, subsequently, a saturated aqueous solution of sodium
hydrogen carbonate was added to the resulting mixture to adjust the
pH to 6, and then the mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=80:20.fwdarw.50:50, v/v) to give the title compound (3.35
g, yield: 49%).
[0317] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0318] 8.31 (1H, d, J=3 Hz), 8.00 (1H, d, J=9 Hz), 7.31 (1H, dd,
J=9, 3 Hz), 4.05-3.98 (1H, m), 1.20 (6H, d, J=7 Hz).
Reference Example 61
2-[(6-Isobutyrylpyridin-3-yl)oxy]butyric acid
##STR00089##
[0320] Potassium carbonate (4.81 g, 34.8 mmol) was added to an
acetonitrile (23 mL) solution of the compound obtained in Reference
Example 60 (2.83 g, 17.1 mmol) and ethyl 2-bromobutyrate (4.97 g,
25.5 mmol) at room temperature, and the mixture was stirred at
80.degree. C. for 45 minutes. After the reaction mixture was cooled
to room temperature, water was added to the reaction mixture, and
the resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=100:0.fwdarw.85:15,
v/v) to give a compound, and the compound (4.89 g) thus obtained
was dissolved in tetrahydrofuran (20 mL)-methanol (20 mL).
Subsequently, 1 M aqueous sodium hydroxide solution (20.6 mL) was
added to the resulting mixture at room temperature, and the mixture
was stirred at the same temperature for 1.5 hours. The reaction
mixture was concentrated under reduced pressure, and water was
added to the reaction mixture, and then the aqueous layer was
washed with diethyl ether. 2 M Hydrochloric acid was added to the
resulting mixture to adjust the pH to acidic, and then the mixture
was extracted twice with ethyl acetate. The organic layer thus
obtained was washed with brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was washed with hexane to give
the title compound (4.36 g, yield: 100%).
[0321] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0322] 8.35 (1H, d, J=3 Hz), 8.05 (1H, d, J=9 Hz), 7.26 (1H, d,
J=9, 3 Hz), 4.74 (1H, dd, J=7, 5 Hz), 4.04-3.95 (1H, m), 2.17-2.03
(2H, m), 1.19 (6H, d, J=7 Hz), 1.14 (3H, t, J=7 Hz).
Reference Example 62
Methyl
2-fluoro-4-(5-{1-[(6-isobutyrylpyridin-3-yl)oxy]propyl}-1,2,4-oxadi-
azol-3-yl)benzoate
##STR00090##
[0324] 1-Hydroxybenzotriazole monohydrate (722 mg, 4.71 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.81
g, 9.43 mmol) were added to an N,N-dimethylformamide (10 mL)
solution of the compound obtained in Reference Example 61 (1.18 g,
4.71 mmol) at room temperature, and the mixture was stirred at the
same temperature for 15 minutes. Subsequently, methyl
4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO 2011/016469),
(1.00 g, 4.71 mmol) was added to the mixture, and the resulting
mixture was stirred at the same temperature for 15 minutes, and
then further stirred at 100.degree. C. for 2.5 hours. After the
reaction mixture was cooled to room temperature, water was added to
the reaction mixture, and the resulting mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
a saturated aqueous solution of sodium hydrogen carbonate and
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=100:0.fwdarw.70:30, v/v) to give the title compound (1.68
g, yield: 84%).
[0325] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0326] 8.42 (1H, d, J=3 Hz), 8.05 (1H, dd, J=8, 7 Hz), 8.03 (1H, d,
J=9 Hz), 7.92 (1H, dd, J=8, 2 Hz), 7.86 (1H, dd, J=11, 2 Hz), 7.36
(1H, dd, J=9, 3 Hz), 5.54 (1H, dd, J=7, 6 Hz), 4.07-4.00 (1H, m),
3.97 (3H, s), 2.38-2.24 (2H, m), 1.18 (6H, d, J=7 Hz), 1.16 (3H, t,
J=7 Hz).
Reference Example 63
2-Fluoro-4-(5-{1-[(6-isobutyrylpyridin-3-yl)oxy]propyl}-1,2,4-oxadiazol-3--
yl)benzoic acid
##STR00091##
[0328] 1 M Aqueous sodium hydroxide solution (4.72 mL, 4.72 mmol)
was added to a tetrahydrofuran (5.0 mL)-methanol (5.0 mL) solution
of the compound obtained in Reference Example 62 (1.68 g, 3.93
mmol) at room temperature, and the mixture was stirred at the same
temperature for 15 minutes. The reaction mixture was concentrated
under reduced pressure, then water was added to the reaction
mixture, and the aqueous layer was washed with diethyl ether. 1 M
Hydrochloric acid was added to the resulting mixture to adjust the
pH to acidic, and then the mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was washed
with a hexane-diisopropyl ether mixture to give the title compound
(1.50 g, yield: 93%).
[0329] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0330] 8.45 (1H, d, J=3 Hz), 8.14 (1H, dd, J=8, 7 Hz), 8.05 (1H, d,
J=9 Hz), 7.96 (1H, dd, J=8, 1 Hz), 7.90 (1H, dd, J=11, 1 Hz), 7.38
(1H, dd, J=9, 3 Hz), 5.56 (1H, dd, J=7, 6 Hz), 4.08-3.98 (1H, m),
2.41-2.23 (2H, m), 1.18 (6H, d, J=7 Hz), 1.17 (3H, t, J=7 Hz).
Reference Example 64
1-[5-(Methoxymethoxy)pyridin-2-yl]-3-methylbutan-1-one
##STR00092##
[0332] 1.0 M Isobutylmagnesium bromide-tetrahydrofuran solution
(9.14 mL, 9.14 mmol) was slowly added to a tetrahydrofuran (12 mL)
solution of the compound obtained in Reference Example 22 (1.00 g,
6.09 mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 1.5 hours. 2 M Hydrochloric acid was added to the
reaction mixture, subsequently, a saturated aqueous solution of
sodium hydrogen carbonate was added to the reaction mixture to
adjust the pH to basic, and then the resulting mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was washed with brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=100:0.fwdarw.80:20, v/v) to
give the title compound (1.24 g, yield: 91%).
[0333] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0334] 8.41 (1H, d, J=3 Hz), 8.03 (1H, d, J=9 Hz), 7.44 (1H, dd,
J=9, 3 Hz), 5.27 (2H, s), 3.50 (3H, s), 3.05 (2H, d, J=7 Hz),
2.36-2.26 (1H, m), 0.99 (6H, d, J=6 Hz).
Reference Example 65
2-(1,1-Difluoro-3-methylbutyl)-5-(methoxymethoxy)pyridine
##STR00093##
[0336] N,N-Diethylaminosulfur trifluoride (868 .mu.L, 6.62 mmol)
and ethanol (single drop) were added to the compound obtained in
Reference Example 64 (493 mg, 2.21 mmol) at room temperature, and
the mixture was stirred at the same temperature for 6 days. A
saturated aqueous solution of sodium hydrogen carbonate was added
to the reaction mixture, and the mixture was extracted twice with
dichloromethane. The organic layer thus obtained was dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=100:0.fwdarw.85:15,
v/v) to give the title compound (144 mg, yield: 27%).
[0337] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0338] 8.42 (1H, d, J=3 Hz), 7.56 (1H, d, J=9 Hz), 7.43 (1H, dd,
J=9, 3 Hz), 5.23 (2H, s), 3.50 (3H, s), 2.22 (2H, td, J=18, 7 Hz),
1.93-1.84 (1H, m), 0.95 (6H, d, J=7 Hz).
Reference Example 66
6-(1,1-Difluoro-3-methylbutyl)pyridin-3-ol
##STR00094##
[0340] 2 M Hydrochloric acid (2.0 mL) was added to a
tetrahydrofuran (2.0 mL) solution of the compound obtained in
Reference Example 65 (137 mg, 0.559 mmol) at room temperature, and
the mixture was stirred at 50.degree. C. for 3 hours. The reaction
mixture was cooled to room temperature, and then 1 M aqueous sodium
hydroxide solution was added to the reaction mixture to adjust the
pH to 7. Subsequently, the resulting mixture was extracted three
times with ethyl acetate. The organic layer thus obtained was
washed with brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was washed with a hexane-dichloromethane mixture
to give the title compound (88.0 mg, yield: 79%).
[0341] (500 MHz, CDCl.sub.3) .delta. ppm:
[0342] 8.27 (1H, d, J=2 Hz), 7.54 (1H, d, J=9 Hz), 7.25 (1H, dd,
J=9, 2 Hz), 2.20 (2H, td, J=18, 7 Hz), 1.92-1.83 (1H, m), 0.94 (6H,
d, J=7 Hz).
Reference Example 67
(2S)-2-Acetoxy butyric acid
##STR00095##
[0344] Sodium acetate (11.9 g, 146 mmol) and tert-butyl nitrite
(15.0 g, 146 mmol) were added to an acetic acid (300 mL) solution
of (2S)-2-aminobutyric acid (10.0 g, 97.0 mmol) under ice cooling,
and the mixture was stirred at 60.degree. C. for 2 hours. After the
reaction mixture was cooled to room temperature, the solvent was
distilled off under reduced pressure, then water was added to the
reaction mixture, and the resulting mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
water and brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and further, the
resulting residue was azeotropically boiled twice with 1,4-dioxane
(50 mL) to give the title compound (8.4 g, yield: 60%).
[0345] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0346] 5.00 (1H, m), 2.15 (3H, s), 1.94-1.90 (2H, m), 1.03 (3H, t,
J=7 Hz);
[0347] MS (FAB) m/z: 147 [M+H].sup.+.
Reference Example 68
tert-Butyl
4-{5-[(1S)-1-acetoxypropyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzo-
ate
##STR00096##
[0349] 1-Hydroxybenzotriazole monohydrate (7.2 g, 53.0 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (20.3
g, 159 mmol) were added to an N,N-dimethylformamide (200 mL)
solution of the compound obtained in Reference Example 67 (7.8 g,
53.0 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. The compound obtained in Reference
Example 2 (13.5 g, 53.0 mmol) was added, and the mixture was
stirred for 30 minutes, and further stirred at 100.degree. C. for 3
hours. After the reaction mixture was returned to room temperature,
water was added to the reaction mixture, and the resulting mixture
was extracted twice with ethyl acetate. The organic layer thus
obtained was washed with water and a 10% aqueous solution of sodium
chloride, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=95:5.fwdarw.85:15, v/v) to give the title compound (14.7 g,
yield: 76%).
[0350] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0351] 7.96 (1H, t, J=8 Hz), 7.90 (1H, dd, J=8, 2 Hz), 7.84 (1H,
dd, J=11, 2 Hz), 5.92 (1H, t, J=7 Hz), 2.21 (3H, s), 2.16-2.08 (2H,
m), 1.62 (9H, s), 1.05 (3H, t, J=7 Hz);
[0352] MS (FAB) m/z: 365 [M+H].sup.+.
Reference Example 69
tert-Butyl
2-fluoro-4-{5-[(1S)-1-hydroxypropyl]-1,2,4-oxadiazol-3-yl}benzo-
ate
##STR00097##
[0354] Potassium carbonate (8.4 g, 61 mmol) was added to a methanol
(100 mL) solution of the compound obtained in Reference Example 68
(14.7 g, 40.3 mmol) under ice cooling, and the mixture was stirred
at the same temperature for 30 minutes. 2 N Hydrochloric acid was
added to the reaction mixture at the same temperature until a pH
value of 6.0 was obtained. The reaction mixture was extracted twice
with ethyl acetate, and the organic layer thus obtained was washed
with water and brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=95:5.fwdarw.80:20, v/v) to give the title
compound (12.9 g, yield: 84%).
[0355] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0356] 7.97 (1H, t, J=8 Hz), 7.91 (1H, d, J=8 Hz), 7.85 (1H, d,
J=11 Hz), 4.98 (1H, q, J=6 Hz), 2.54 (1H, brs), 2.14-1.96 (2H, m),
1.62 (9H, s), 1.08 (3H, t, J=7 Hz);
[0357] MS (FAB.sup.+) m/z: 323 [M+H].sup.+.
Reference Example 70
tert-Butyl
4-{5-[(1R)-1-{[6-(1,1-difluoro-3-methylbutyl)pyridin-3-yl]oxy}p-
ropyl]-1,2,4-oxadiazol-3-yl}-2-fluorobenzoate
##STR00098##
[0359] Triphenylphosphine (57.4 mg, 0.219 mmol) and di-tert-butyl
azodicarboxylate (50.4 mg, 0.219 mmol) were added to a
tetrahydrofuran (1.0 mL) solution of the compound obtained in
Reference Example 69 (70.5 mg, 0.219 mmol) and the compound
obtained in Reference Example 66 (40.0 mg, 0.199 mmol) at 0.degree.
C., and the mixture was stirred at the same temperature for 10
minutes, and then further stirred at room temperature for 3 hours.
The reaction mixture was concentrated under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=100:0.fwdarw.90:10, v/v) to
give the title compound (87.0 mg, yield: 87%).
[0360] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0361] 8.46 (1H, d, J=3 Hz), 8.12 (1H, dd, J=8, 7 Hz), 7.96 (1H, d,
J=8 Hz), 7.90 (1H, d, J=11 Hz), 7.58 (1H, d, J=9 Hz), 7.37 (1H, dd,
J=9, 3 Hz), 5.49 (1H, dd, J=7, 6 Hz), 2.38-2.13 (4H, m), 1.91-1.82
(1H, m), 1.16 (3H, t, J=7 Hz), 0.94 (6H, d, J=7 Hz).
Reference Example 71
4-Amino-3-fluoro-N'-hydroxybenzenecarboxyimidamide
##STR00099##
[0363] A 50% aqueous solution of Hydroxylamine (2.18 mL, 33.1 mmol)
was added to a 2-propanol (44 mL) solution of
4-amino-3-fluorobenzonitrile (3.00 g, 22.0 mmol) at room
temperature, and the mixture was stirred at 70.degree. C. for 5
hours. After the reaction mixture was cooled to room temperature,
the solvent was distilled off under reduced pressure, and the
resulting residue was washed with a hexane-ethyl acetate (4:1, v/v)
mixture to give the title compound (3.67 g, yield: 98%).
[0364] .sup.1H-NMR (500 MHz, DMSO-d.sub.6) .delta. ppm:
[0365] 9.35 (1H, s), 7.27 (1H, dd, J=13, 2 Hz), 7.21 (1H, dd, J=8,
2 Hz), 6.71 (1H, dd, J=9, 8 Hz), 5.63 (2H, s), 5.33 (2H, s).
Reference Example 72
Acetic acid
(1S)-1-[3-(4-amino-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propyl
##STR00100##
[0367] 1-Hydroxybenzotriazole monohydrate (577 mg, 3.77 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.44
g, 7.53 mmol) were added to a N,N-dimethylformamide (19 mL)
solution of the compound obtained in Reference Example 67 (550 mg,
3.77 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. Subsequently, the compound
obtained in Reference Example 71 (637 mg, 3.77 mmol) was added to
the mixture, and the resulting mixture was stirred at the same
temperature for 15 minutes, and then further stirred at 100.degree.
C. for 1 hour. The reaction mixture was cooled to room temperature.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=90:10.fwdarw.60:40,
v/v) to give the title compound (563 mg, yield: 62%).
[0368] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0369] 7.74-7.66 (2H, m), 6.82 (1H, dd, J=9, 8 Hz), 5.90 (1H, dd,
J=7, 6 Hz), 4.03 (1H, s), 2.19 (3H, d, J=4 Hz), 2.16-2.04 (2H, m),
1.03 (2H, t, J=8 Hz).
Reference Example 73
(1S)-1-[3-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propan-1-ol
##STR00101##
[0371] Potassium carbonate (417 mg, 3.02 mmol) was added to a
methanol (10 mL) solution of the compound obtained in Reference
Example 72 (562 mg, 2.01 mmol) at room temperature, and the mixture
was stirred at the same temperature for 15 minutes. 1 M
Hydrochloric acid was added to the reaction mixture, and the
mixture was extracted twice with ethyl acetate. The organic layer
thus obtained was washed with brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was washed with a hexane-ethyl
acetate mixture to give the title compound (438 mg, yield:
92%).
[0372] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0373] 7.74-7.66 (2H, m), 6.83 (1H, dd, J=9, 8 Hz), 4.92 (1H, dd,
J=7, 6 Hz), 4.04 (2H, br s), 2.64 (1H, br s), 2.11-1.93 (2H, m),
1.06 (3H, t, J=8 Hz).
Reference Example 74
[4-({(1R)-1-[3-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]propyl}oxy)ph-
enyl](cyclopropyl)methanone
##STR00102##
[0375] Triphenylphosphine (243 mg, 0.927 mmol) and di-tert-butyl
azodicarboxylate (214 mg, 0.927 mmol) were added to a
tetrahydrofuran (4.2 mL) solution of the compound obtained in
Reference Example 73 (200 mg, 0.843 mmol) and
cyclopropyl(4-hydroxyphenyl)methanone (150 mg, 0.927 mmol) at
0.degree. C., and the mixture was stirred at the same temperature
for 5 minutes, and then further stirred at room temperature for 1.5
hours. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=85:15.fwdarw.70:30, v/v) to
give the title compound (279 mg, yield: 87%).
[0376] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0377] 7.98 (2H, d, J=9 Hz), 7.72-7.65 (2H, m), 7.03 (2H, d, J=9
Hz), 6.81 (1H, dd, J=9, 8 Hz), 5.47 (1H, dd, J=7, 6 Hz), 4.04 (2H,
s), 2.62-2.56 (1H, m), 2.33-2.16 (2H, m), 1.22-1.17 (2H, m), 1.12
(3H, t, J=7 Hz), 1.01-0.96 (2H, m).
Reference Example 75
2-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]propionic acid
##STR00103##
[0379] Potassium carbonate (1.27 g, 9.19 mmol) was added to an
acetonitrile (10 mL) solution of the compound obtained in Reference
Example 24 (1.00 g, 6.13 mmol) and methyl 2-bromopropionate (1.02
g, 6.13 mmol) at room temperature, and the mixture was stirred at
80.degree. C. for 3 hours. After the reaction mixture was cooled to
room temperature, water was added to the reaction mixture, and the
resulting mixture was extracted once with toluene. The organic
layer thus obtained was washed with 1 M aqueous sodium hydroxide
solution and brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue (1.44 g) was dissolved in tetrahydrofuran (7.0
mL)-methanol (7.0 mL). 1 M Aqueous sodium hydroxide solution (6.93
mL, 6.93 mmol) was added to the mixture at room temperature, and
the mixture was stirred at the same temperature for 30 minutes. The
reaction mixture was concentrated under reduced pressure, then
water was added to the resulting reaction mixture, and the aqueous
layer was washed with diethyl ether. 1 M Sulfuric acid was added to
the mixture to adjust the pH to 6, and then the resulting mixture
was extracted twice with ethyl acetate. The organic layer thus
obtained was washed with brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was washed with a
hexane-diisopropyl ether (10:1, v/v) mixture to give the title
compound (1.27 g, yield: 88%).
[0380] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0381] 8.38 (1H, d, J=3 Hz), 8.03 (1H, d, J=9 Hz), 7.26 (1H, dd,
J=9, 2 Hz), 4.93 (1H, q, J=7 Hz), 3.41-3.35 (1H, m), 1.74 (3H, d,
J=7 Hz), 1.25-1.20 (2H, m), 1.10-1.05 (2H, m).
Reference Example 76
(5-{1-[3-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-5-yl]ethoxy}pyridin-2-yl-
)(cyclopropyl)methanone
##STR00104##
[0383] 1-Hydroxybenzotriazole monohydrate (215 mg, 1.40 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (489
mg, 2.55 mmol) were added to a N,N-dimethylformamide (6.4 mL)
solution of the compound obtained in Reference Example 75 (300 mg,
1.28 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. Subsequently, the compound
obtained in Reference Example 71 (216 mg, 1.28 mmol) was added to
the mixture, and the resulting mixture was stirred at the same
temperature for 15 minutes, and then further stirred at 100.degree.
C. for 1 hour. The reaction mixture was cooled to room temperature.
Subsequently, water was added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=90:10.fwdarw.50:50,
v/v) to give the title compound (401 mg, yield: 85%).
[0384] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0385] 8.46 (1H, d, J=3 Hz), 8.02 (1H, d, J=9 Hz), 7.69 (1H, dd,
J=12, 2 Hz), 7.67 (1H, dd, J=8, 2), 7.38 (1H, dd, J=9, 3 Hz), 6.82
(1H, dd, J=9, 8 Hz), 5.73 (1H, q, J=7 Hz), 4.06 (2H, s), 3.46-3.93
(1H, m), 1.93 (3H, d, J=7 Hz), 1.23-1.19 (2H, m), 1.10-1.04 (2H,
m).
Reference Example 77
2-Fluoro-4-(5-{1-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-1,2,-
4-oxadiazol-3-yl)aniline
##STR00105##
[0387] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(2.66 g, 14.3 mmol) was added to a N,N-dimethylformamide (60 mL)
solution of 2-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]butyric
acid (WO 2011/016469) (4.16 g, 14.3 mmol) at room temperature, and
the mixture was stirred at the same temperature for 20 minutes. The
compound obtained in Reference Example 71 (2.35 g, 14.3 mmol) was
added, and then the mixture was heated at 100.degree. C. for 3.5
hours. After the reaction mixture was cooled to room temperature,
water was added to the reaction mixture, and the resulting mixture
was extracted three times with ethyl acetate, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=9:1.fwdarw.1:2,
v/v) to give the title compound (2.06 g, yield: 35%).
[0388] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0389] 8.03 (2H, d, J=9 Hz), 7.76-7.68 (2H, m), 7.10 (2H, d, J=9
Hz), 6.85 (1H, dd, J=9, 8 Hz), 5.49 (1H, t, J=7 Hz), 4.08 (2H, bs),
3.34-3.24 (m, 1H), 2.38-2.20 (2H, m), 1.47 (6H, d, J=7 Hz), 1.13
(3H, t, J=8 Hz).
Reference Example 78
2-Fluoro-4-(5-{(1R)-1-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]propyl}-
-1,2,4-oxadiazol-3-yl)aniline
##STR00106##
[0391] N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride
(2.53 g, 13.2 mmol) was added to a N,N-dimethylformamide (50 mL)
solution of
(2R)-2-[4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenoxy]butyric acid
(WO 2011/016469) (1.49 g, 8.80 mmol) at room temperature, and the
mixture was stirred at the same temperature for 15 minutes. The
compound obtained in Reference Example 71 (2.55 g, 8.80 mmol) was
added to the mixture, and then the mixture was heated at
100.degree. C. for 3 hours. After the reaction mixture was cooled
to room temperature, water was added to the reaction mixture, and
the resulting mixture was extracted three times with ethyl acetate.
The organic layer thus obtained was washed with water, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and the resulting residue was purified by
silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:2, v/v) to give the title compound (1.69 g,
yield: 45%).
[0392] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0393] 8.00 (2H, d, J=9 Hz), 7.73-7.65 (2H, m), 7.06 (2H, d, J=9
Hz), 6.81 (1H, dd, J=9, 8 Hz), 5.46 (1H, t, J=7 Hz), 3.30-3.19 (m,
1H), 2.32-2.17 (2H, m), 1.43 (6H, d, J=7 Hz), 1.13 (3H, t, J=8
Hz).
Reference Example 79
tert-Butyl 2-fluoro-4-formylbenzoate
##STR00107##
[0395] tert-Butyl 4-amino(hydroxyimino)methyl-2-fluorobenzoate (WO
2011/016469) (3.90 g, 17.6 mmol) was dissolved in ethanol (40 mL)
and acetic acid (40 mL). Raney nickel (ca. 10 g) was added to the
mixture at room temperature, and the resulting mixture was stirred
for 1 hour under hydrogen flow. After the insoluble material was
removed by filtration through Celite, water was added to the
filtrate, and the resulting mixture was extracted three times with
ethyl acetate, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and then water
and a saturated aqueous solution of sodium hydrogen carbonate were
added to the mixture. The resulting mixture was extracted with
ethyl acetate, and dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=95:5.fwdarw.2:1, v/v) to give the title compound (2.21 g,
yield: 56%).
[0396] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0397] 10.0 (1H, d, J=2 Hz), 8.01 (1H, dd, J=8, 7 Hz), 7.69 (1H, d,
J=8, 2 Hz), 7.61 (1H, dd, J=10, 2 Hz), 1.61 (9H, s).
Reference Example 80
4-(tert-Butoxycarbonyl)-3-fluorobenzoic acid
##STR00108##
[0399] The compound obtained in Reference Example 79 (1.54 g, 6.87
mmol) was dissolved in tert-butanol (15 mL) and water (15 mL), then
sodium dihydrogen phosphate dihydrate (5.36 g, 34.3 mmol),
2-methyl-2-butene (7.30 mL, 68.7 mmol), and sodium chlorite (2.35
g, 20.6 mmol) were added to the mixture at room temperature, and
the resulting mixture was stirred at room temperature for 30
minutes. Water was added to the reaction mixture, and the resulting
mixture was extracted three times with ethyl acetate. The organic
layer thus obtained was washed with water, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was washed with hexane
to give the title compound (1.16 g, yield: 70%).
[0400] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0401] 7.97-7.89 (2H, m), 7.83 (1H, dd, J=11, 1 Hz), 1.62 (9H,
s).
Reference Example 81
2-[4-(Cyclopropylcarbonyl)phenoxy]propionic acid
##STR00109##
[0403] Potassium carbonate (6.39 g, 46.2 mmol) was added to an
acetonitrile (200 mL) solution of
cyclopropyl(4-hydroxyphenyl)methanone (5.00 g, 30.8 mmol) and
methyl 2-bromopropionate (5.66 g, 33.9 mmol) at room temperature,
and the mixture was stirred at 80.degree. C. for 2.5 hours. After
the reaction mixture was cooled to room temperature, ethyl acetate
was added to the reaction mixture, and the insoluble material was
removed by filtration through Celite. The filtrate was concentrated
to around half volume under reduced pressure, then water was added
to the filtrate, and the resulting mixture was extracted once with
ethyl acetate. The organic layer thus obtained was washed with
water, and then dried over anhydrous magnesium sulfate. The solvent
was distilled off under reduced pressure, and a mixture containing
methyl 2-[4-(cyclopropylcarbonyl)phenoxy]propionate (7.99 g) was
obtained. The mixture (7.99 g) thus obtained was dissolved in
methanol (100 mL), then 2 M aqueous sodium hydroxide solution (31
mL, 62 mmol) was added to the mixture at room temperature, and the
resulting mixture was stirred at the same temperature for 1 hour.
The reaction mixture was concentrated under reduced pressure, then
water was added to the reaction mixture, and 2 M sulfuric acid was
added to the resulting mixture to adjust the pH to 2. The resulting
mixture was extracted twice with ethyl acetate. The organic layer
thus obtained was washed with brine, and then dried over anhydrous
magnesium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (methylene chloride:methanol=9:1.fwdarw.8:1,
v/v) to give the title compound (7.03 g, yield: 98%).
[0404] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0405] 8.01-7.99 (2H, m), 6.95-6.93 (2H, m), 4.88 (2H, q, J=7 Hz),
2.65-2.59 (1H, m), 1.70 (3H, d, J=7 Hz), 1.24-1.20 (2H, m),
1.03-1.01 (2H, m).
Reference Example 82
2-[4-(Cyclopropylcarbonyl)phenoxy]propanenitrile
##STR00110##
[0407] Carbonyldiimidazole (1.07 g, 6.60 mmol) was added to a
tetrahydrofuran (15 mL) solution of the compound obtained in
Reference Example 81 (1.03 g, 4.40 mmol) at room temperature, and
the mixture was stirred at the same temperature for 40 minutes. A
28% aqueous ammonia solution (7 mL, excess amount) was added to the
mixture at room temperature, and the resulting mixture was stirred
at the same temperature for 20 minutes. Water was added to the
reaction mixture, and the resulting mixture was extracted three
times with ethyl acetate, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1.fwdarw.ethyl acetate,
v/v). Subsequently, trifluoroacetic anhydride (0.612 mL, 4.40 mmol)
was added to a methylene chloride (20 mL) solution of the compound
thus obtained and pyridine (0.708 mL, 8.79 mmol) at 0.degree. C.,
and the mixture was stirred at the same temperature for 20 minutes.
Water and a saturated aqueous solution of ammonium chloride were
added to the reaction mixture at 0.degree. C., and the mixture was
extracted three times with methylene chloride. The organic layer
thus obtained was washed with water and a 1 M aqueous sodium
hydroxide solution sequentially, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=9:1.fwdarw.2:1, v/v) to
give the title compound (867 mg, yield: 92%).
[0408] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0409] 8.06 (2H, d, J=9 Hz), 7.06 (2H, d, J=9 Hz), 4.99 (1H, q, J=7
Hz), 2.67-2.58 (1H, m), 1.84 (3H, d, J=7 Hz), 1.39-1.32 (2H, m),
1.06-1.01 (2H, m).
Reference Example 83
(1Z)-2-[4-(Cyclopropylcarbonyl)phenoxy]-N'-hydroxypropanimidamide
##STR00111##
[0411] A 50% aqueous hydroxyl amine solution (0.328 mL, 5.52 mmol)
was added to an ethanol (4 mL) solution of the compound obtained in
Reference Example 82 (594 mg, 2.76 mmol) at room temperature, and
the mixture was stirred at the same temperature for 30 minutes. The
solvent was distilled off under reduced pressure to give the title
compound (648 mg, yield: 95%).
[0412] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0413] 8.00 (2H, d, J=9 Hz), 7.06 (2H, d, J=9 Hz), 4.87 (1H, q, J=7
Hz), 4.68 (2H, bs), 2.64-2.57 (2H, m), 1.64 (3H, d, J=7 Hz),
1.25-1.18 (2H, m), 1.04-0.98 (2H, m).
Reference Example 84
4-(3-{1-[4-(Cyclopropylcarbonyl)phenoxy]ethyl}-1,2,4-oxadiazol-5-yl)-2-flu-
orobenzoic acid
##STR00112##
[0415] 1-Hydroxybenzotriazole monohydrate (574 mg, 3.75 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.44
g, 7.49 mmol) were added to an N,N-dimethylformamide (20 mL)
solution of the compound obtained in Reference Example 80 (900 mg,
3.75 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. The compound obtained in Reference
Example 83 (930 mg, 3.75 mmol) was added to the mixture at room
temperature, and the resulting mixture was stirred at room
temperature for 20 minutes, and then heated at 90.degree. C. for 6
hours. After the reaction mixture was cooled to room temperature,
water and a saturated aqueous solution of sodium hydrogen carbonate
were added to the reaction mixture. The resulting mixture was
extracted three times with ethyl acetate. The organic layer thus
obtained was washed with a 10% aqueous solution of sodium chloride,
and then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v) to give a mixture containing
tert-butyl
4-(3-{1-[4-(cyclopropylcarbonyl)phenoxy]ethyl}-1,2,4-oxadiazol-5-yl)-2-fl-
uorobenzoate. Subsequently, a methylene chloride (2 mL) solution of
trifluoroacetic acid (2 mL) was added to a methylene chloride (4
mL) solution of the mixture thus obtained at room temperature, and
the resulting mixture was stirred at the same temperature for 30
minutes. Trifluoroacetic acid (2 mL) was added to the mixture at
room temperature, and the resulting mixture was stirred at the same
temperature for 20 minutes. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1.fwdarw.1:4,
v/v) to give the title compound (655 mg, yield: 44%).
[0416] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0417] 8.20-8.14 (1H, m), 8.03-7.92 (4H, m), 7.08 (2H, d, J=9 Hz),
5.72 (1H, q, J=7 Hz), 2.63-2.56 (1H, m), 1.87 (3H, d, J=6 Hz),
1.21-1.17 (2H, m), 1.01-0.96 (2H, m).
Reference Example 85
(4-{1-[5-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}phenyl)(cycl-
opropyl)methanone
##STR00113##
[0419] Triethylamine (0.193 mL, 1.39 mmol) and diphenylphosphoryl
azide (0.299 mL, 1.39 mmol) were added to a tert-butanol (6 mL)
solution of the compound obtained in Reference Example 84 (499 mg,
1.26 mmol) at room temperature, and the mixture was heated at
80.degree. C. for 6 hours. After the reaction mixture was cooled to
room temperature, water was added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v). Subsequently, a methylene chloride (1
mL) solution of trifluoroacetic acid (1 mL) was added to a
methylene chloride (2 mL) solution of the compound thus obtained at
room temperature, and the mixture was stirred at the same
temperature for 30 minutes. Trifluoroacetic acid (1 mL) was added
to the mixture at room temperature, and the resulting mixture was
stirred at the same temperature for 30 minutes. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:2, v/v) to give the title compound (255 mg,
yield: 55%).
[0420] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0421] 7.98 (2H, d, J=9 Hz), 7.76-7.72 (2H, m), 7.08 (2H, d, J=9
Hz), 6.82 (1H, t, J=9 Hz), 5.66 (1H, q, J=7 Hz), 2.64-2.57 (1H, m),
1.84 (3H, d, J=6 Hz), 1.21-1.17 (2H, m), 1.02-0.95 (2H, m).
Reference Example 86
2-[4-(Cyclopropylcarbonyl)phenoxy]butanamide
##STR00114##
[0423] Tripotassium phosphate (8.17 g, 38.5 mmol) and ethyl
2-bromobutyrate (4.77 mL, 32.6 mmol) were added to an acetone (24
mL) solution of cyclopropyl(4-hydroxyphenyl)methanone (4.80 g, 29.6
mmol) at room temperature, and the mixture was stirred for 4 hours
under reflux. Tripotassium phosphate (1.57 g, 7.40 mmol) and ethyl
2-bromobutyrate (1.08 mL, 7.40 mmol) were added to the mixture at
room temperature, and the resulting mixture was stirred for 3 hours
under reflux. After the reaction mixture was cooled to room
temperature, water was added to the reaction mixture, and the
resulting mixture was extracted once with acetone. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=20:1.fwdarw.1:1, v/v). Subsequently, the compound thus
obtained was dissolved in water (45 mL), then 5 M aqueous sodium
hydroxide solution (8.78 mL, 44.4 mmol) was added to the mixture at
room temperature, and the resulting mixture was stirred at the same
temperature for 2 hours. Water and a saturated aqueous solution of
ammonium chloride were added to the reaction mixture, and the
mixture was extracted three times with ethyl acetate, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure. Carbonyldiimidazole (7.20 g, 44.4 mmol) was
added to a tetrahydrofuran (150 mL) solution of the compound thus
obtained (7.35 g, 29.5 mmol) at room temperature, and the mixture
was stirred at the same temperature for 30 minutes. A 28% aqueous
ammonia solution (30 mL, excess amount) was added to the mixture at
room temperature, and the resulting mixture was stirred at the same
temperature for 30 minutes. Water was added to the reaction
mixture, and the resulting mixture was extracted three times with
ethyl acetate, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1.fwdarw.ethyl acetate, v/v) to give the
title compound (6.41 g, yield: 87%).
[0424] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0425] 8.02 (2H, d, J=9 Hz), 6.99 (2H, d, J=9 Hz), 6.28 (1H, bs),
5.74 (1H, bs), 4.62 (1H, dd, J=6, 5 Hz), 2.66-2.52 (1H, m),
2.10-1.95 (2H, m), 1.25-1.20 (2H, m), 1.10-1.00 (5H, m).
Reference Example 87
2-[4-(Cyclopropylcarbonyl)phenoxy]butanenitrile
##STR00115##
[0427] Trifluoroacetic anhydride (3.61 mL, 25.9 mmol) was added to
a methylene chloride (130 mL) solution of the compound obtained in
Reference Example 86 (6.41 g, 25.9 mmol) and pyridine (4.18 mL,
51.8 mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 30 minutes. Water and a saturated aqueous solution
of ammonium chloride were added to the reaction mixture at
0.degree. C., and the mixture was extracted three times with
methylene chloride. The organic layer thus obtained was washed with
1 M hydrochloric acid and 1 M aqueous sodium hydroxide solution
sequentially, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=9:1.fwdarw.2:1, v/v) to give the title
compound (5.81 g, yield: 98%).
[0428] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0429] 8.05 (2H, d, J=9 Hz), 7.07 (2H, d, J=9 Hz), 4.83 (1H, t, J=6
Hz), 2.67-2.60 (1H, m), 2.19-2.12 (2H, m), 1.28-1.17 (5H, m),
1.06-0.97 (2H, m).
Reference Example 88
(1Z)-2-[4-(Cyclopropylcarbonyl)phenoxy]-N'-hydroxybutanimidamide
##STR00116##
[0431] A 50% aqueous hydroxyl amine solution (3.01 mL, 50.7 mmol)
was added to an ethanol (120 mL) solution of the compound obtained
in Reference Example 87 (5.81 g, 25.3 mmol) at room temperature,
and the mixture was stirred at room temperature for 30 minutes. The
solvent was distilled off under reduced pressure to give the title
compound (6.61 g, yield: 95%).
[0432] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0433] 7.98 (2H, d, J=9 Hz), 7.07 (2H, d, J=9 Hz), 4.70 (2H, s),
4.62-4.55 (1H, m), 3.72 (1H, dq, J=7, 6 Hz), 2.64-2.53 (1H, m),
2.08-1.82 (2H, m), 1.23-1.17 (2H, m), 1.09-0.92 (5H, m).
Reference Example 89
tert-Butyl
4-(3-{1-[4-(cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-
-5-yl)-2-fluorobenzoate
##STR00117##
[0435] 1-Hydroxybenzotriazole monohydrate (255 mg, 1.66 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (398
mg, 2.08 mmol) were added to an N,N-dimethylformamide (7 mL)
solution of the compound obtained in Reference Example 80 (333 mg,
1.38 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. The compound obtained in Reference
Example 89 (363 mg, 1.38 mmol) was added to the mixture at room
temperature, and the resulting mixture was stirred at room
temperature for 20 minutes, and then heated at 90.degree. C. for 6
hours. After the reaction mixture was cooled to room temperature,
water and a saturated aqueous solution of sodium hydrogen carbonate
were added to the reaction mixture. The resulting mixture was
extracted three times with ethyl acetate, and the organic layer
thus obtained was washed with a 10% aqueous solution of sodium
chloride, then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v) to give the title compound (330 mg,
yield: 51%).
[0436] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0437] 8.02-7.92 (4H, m), 7.88 (1H, d, J=9 Hz), 7.08 (2H, d, J=9
Hz), 5.46 (1H, t, J=7 Hz), 2.65-2.56 (1H, m), 2.36-2.12 (2H, m),
1.61 (9H, s), 1.23-1.17 (2H, m), 1.11 (3H, t, J=7 Hz), 1.02-0.96
(2H, m).
Reference Example 90
4-(3-{1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-5-yl)-2-fl-
uorobenzoic acid
##STR00118##
[0439] A methylene chloride (1 mL) solution of trifluoroacetic acid
(1 mL) was added to a methylene chloride (3 mL) solution of the
compound obtained in Reference Example 89 at room temperature, and
the mixture was stirred at the same temperature for 30 minutes.
Trifluoroacetic acid (1 mL) was added to the mixture at room
temperature, and the resulting mixture was stirred at the same
temperature for 30 minutes. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1.fwdarw.1:4,
v/v) to give the title compound (300 mg, yield: 53%).
[0440] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0441] 8.17 (1H, dd, J=8, 7 Hz), 8.03-7.92 (4H, m), 7.08 (2H, d,
J=9 Hz), 5.47 (1H, t, J=7 Hz), 2.63-2.56 (1H, m), 2.34-2.10 (2H,
m), 1.22-1.15 (2H, m), 1.11 (3H, t, J=8 Hz), 1.02-0.95 (2H, m).
Reference Example 91
(4-{1-[5-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-3-yl]propyl}phenyl)(cycl-
opropyl)methanone
##STR00119##
[0443] Triethylamine (0.112 mL, 0.804 mmol) and diphenylphosphoryl
azide (0.173 mL, 0.804 mmol) were added to a tert-butanol (4 mL)
solution of the compound obtained in Reference Example 90 (300 mg,
0.731 mmol) at room temperature, and the mixture was heated at
60.degree. C. for 6 hours. After the reaction mixture was cooled to
room temperature, water was added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:1, v/v). Subsequently, a methylene chloride (1
mL) solution of trifluoroacetic acid (1 mL) was added to a
methylene chloride (2 mL) solution of the compound thus obtained at
room temperature, and the mixture was stirred at the same
temperature for 30 minutes. Trifluoroacetic acid (1 mL) was added
to the mixture at room temperature, and the resulting mixture was
stirred at the same temperature for 30 minutes. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=9:1.fwdarw.1:2, v/v) to give the title compound (128 mg,
yield: 46%).
[0444] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0445] 7.995 (2H, d, J=9 Hz), 7.80-7.73 (2H, m), 7.08 (2H, d, J=9
Hz), 6.82 (1H, t, J=9 Hz), 5.39 (1H, t, J=7 Hz), 4.24 (2H, s),
2.64-2.56 (1H, m), 2.34-2.10 (2H, m), 1.24-1.20 (2H, m), 1.09 (1H,
t, J=7 Hz), 1.04-0.96 (2H, m).
Reference Example 92
2-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]propanamide
##STR00120##
[0447] 1,1'-Carbonyldiimidazole (788 mg, 4.86 mmol) was added to a
tetrahydrofuran (8.0 mL) solution of the compound obtained in
Reference Example 75 (953 mg, 4.05 mmol) at 0.degree. C., and the
mixture was stirred at the same temperature for 30 minutes.
Subsequently, a 28% aqueous ammonia solution (1.0 mL) was added to
the mixture, and further the resulting mixture was stirred at the
same temperature for 15 minutes. Water was added to the reaction
mixture, and the resulting mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with brine, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure to give the crude title compound (1.09
g).
Reference Example 93
(1Z)-2-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}-N-hydroxypropanimidamide
##STR00121##
[0449] Trifluoroacetic anhydride (676 .mu.L, 4.86 mmol) was added
slowly to a dichloromethane (8.0 mL) solution of the compound
obtained in Reference Example 92 (1.09 g) and pyridine (786 .mu.L,
9.72 mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 15 minutes, and then further stirred at room
temperature for 1.5 hours. Water was added to the reaction mixture,
and the resulting mixture was extracted twice with ethyl acetate.
The organic layer thus obtained was washed with 0.5 M sulfuric acid
and brine, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue (1.20 g) thus obtained was dissolved in 2-propanol (8.0
mL). A 50% aqueous hydroxyl amine solution (401 .mu.L, 6.08 mmol)
was added to the mixture at room temperature, and the resulting
mixture was stirred at 60.degree. C. for 20 minutes. The solvent
was distilled off under reduced pressure to give the crude title
compound (1.30 g).
Reference Example 94
4-[3-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiazol-5-
-yl]-2-fluorobenzoic acid
##STR00122##
[0451] 1-Hydroxybenzotriazole monohydrate (675 mg, 4.41 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (1.54
g, 8.02 mmol) were added to an N,N-dimethylformamide (10 mL)
solution of 4-(methoxycarbonyl)-3-fluorobenzoic acid (J. Med. Chem.
2009, 52, 5950-5966.) (794 mg, 4.01 mmol) at room temperature, and
the mixture was stirred at the same temperature for 30 minutes.
Subsequently, an N,N-dimethylformamide (10 mL) solution of the
crude
(1Z)-2-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}-N-hydroxypropaneimidami-
de (999 mg) obtained in Reference Example 93 was added to the
mixture, and the resulting mixture was stirred at the same
temperature for 15 minutes, and then further stirred at 100.degree.
C. for 5 hours. After the reaction mixture was cooled to room
temperature, water was added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=95:5.fwdarw.75:25, v/v)
to give a compound, and the compound (457 mg, 1.11 mmol) thus
obtained was dissolved in tetrahydrofuran (2.0 mL)-methanol (2.0
mL). Subsequently, 1 M aqueous sodium hydroxide solution (2.22 mL,
2.22 mmol) was added to the resulting mixture at room temperature,
and the mixture was stirred at the same temperature for 15 minutes.
The reaction mixture was concentrated under reduced pressure, then
water was added to the reaction mixture, and the aqueous layer was
washed with diethyl ether. 1 M Sulfuric acid was added to the
resulting mixture to adjust the pH to 6, and then the mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was washed with brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue was washed with a hexane-diisopropyl ether
(10:1, v/v) mixture to give the title compound (364 mg, yield:
83%).
[0452] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0453] 8.48 (1H, d, J=3 Hz), 8.17 (1H, dd, J=8, 7 Hz), 8.02 (1H, d,
J=9 Hz), 8.01 (1H, dd, J=8, 2 Hz), 7.95 (1H, dd, J=10, 2 Hz), 7.43
(1H, dd, J=9, 3 Hz), 5.75 (1H, q, J=6.5 Hz), 3.45-3.38 (1H, m),
1.91 (3H, d, J=7 Hz), 1.22-1.17 (2H, m), 1.09-1.03 (2H, m).
Reference Example 95
tert-Butyl
4-[3-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4--
oxadiazol-5-yl]-2-fluorophenyl}carbamic acid
##STR00123##
[0455] Diphenylphosphoryl azide (84.1 .mu.L, 0.390 mmol) was added
to a tert-butanol (1.5 mL) solution of the compound obtained in
Reference Example 94 (155 mg, 0.390 mmol) and triethylamine (108
.mu.L, 0.780 mmol) at room temperature, and the mixture was stirred
at 90.degree. C. for 3.5 hours. After the reaction mixture was
cooled to room temperature, water was added to the reaction
mixture, and the resulting mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with a
saturated aqueous solution of sodium hydrogen carbonate and brine,
and then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (dichloromethane:ethyl
acetate=100:0.fwdarw.90:10, v/v) to give the title compound (120
mg, yield: 66%).
[0456] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0457] 8.47 (1H, d, J=3 Hz), 8.34 (1H, t, J=8 Hz), 8.00 (1H, d, J=9
Hz), 7.90 (1H, dd, J=8, 2 Hz), 7.83 (1H, dd, J=11, 2 Hz), 7.42 (1H,
dd, J=9, 3 Hz), 6.98-6.94 (1H, m), 5.70 (1H, q, J=7 Hz), 3.45-3.39
(1H, m), 1.89 (3H, d, J=7 Hz), 1.54 (9H, s), 1.22-1.17 (2H, m),
1.09-1.03 (2H, m).
Reference Example 96
(5-{1-[5-(4-Amino-3-fluorophenyl)-1,2,4-oxadiazol-3-yl]ethoxy}pyridin-2-yl-
)(cyclopropyl)methanone
##STR00124##
[0459] Trifluoroacetic acid (1.0 mL) was added to a dichloromethane
(1.0 mL) solution of the compound obtained in Reference Example 95
(118 mg, 0.252 mmol) at room temperature, and the mixture was
stirred at the same temperature for 1 hour. The reaction mixture
was concentrated under reduced pressure, then a saturated aqueous
solution of sodium hydrogen carbonate was added to the reaction
mixture, and the resulting mixture was extracted twice with ethyl
acetate. The organic layer thus obtained was washed with a
saturated aqueous solution of sodium hydrogen carbonate and brine,
and then dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=80:20.fwdarw.50:50, v/v) to give the title compound (91.6
mg, yield: 99%).
[0460] H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0461] 8.47 (1H, d, J=3 Hz), 8.00 (1H, d, J=9 Hz), 7.77-7.71 (2H,
m), 7.42 (1H, dd, J=9, 3 Hz), 6.82 (1H, t, J=9 Hz), 5.67 (1H, q,
J=7 Hz), 4.25 (2H, s), 3.46-3.39 (1H, m), 1.87 (3H, d, J=7 Hz),
1.22-1.17 (2H, m), 1.08-1.03 (2H, m).
Reference Example 97
(2S)-2-(4-Methoxyphenoxy)butanamide
##STR00125##
[0463] Sodium hydride (3.21 g, ca. 60% in oil, 80.6 mmol) was added
to a 1,4-dioxane (100 mL) solution of 4-methoxyphenol (2.50 g, 20.1
mmol) at room temperature, and the mixture was stirred at room
temperature for 10 minutes. (2S)-2-Chlorobutyric acid (2.95 g, 24.2
mmol) was added to the mixture at 100.degree. C., and then the
resulting mixture was heated at 100.degree. C. for 30 minutes.
After the reaction mixture was cooled to room temperature, water
and 2 M hydrochloric acid were added to the reaction mixture. The
resulting mixture was extracted three times with ethyl acetate, and
the organic layer thus obtained was washed with water, and then
dried over anhydrous sodium sulfate. The solvent was distilled off
under reduced pressure, and thus a mixture containing
(2S)-2-(4-methoxyphenoxy)butyric acid was obtained.
Carbonyldiimidazole (4.89 g, 30.2 mmol) was added to a
tetrahydrofuran (100 mL) solution of the mixture described above,
and the resulting mixture was stirred at room temperature for 30
minutes. Subsequently, a 28% aqueous ammonia solution (50 mL,
excess amount) was added to the mixture at room temperature, and
the resulting mixture was stirred for 20 minutes. Water was added
to the reaction mixture, and the resulting mixture was extracted
three times with ethyl acetate. The organic layer thus obtained was
washed with water, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1.fwdarw.1:4, v/v) to give the title
compound (3.66 g, yield: 87%).
[0464] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0465] 6.95-6.84 (4H, m), 6.49-6.35 (1H, m), 5.53-5.36 (1H, m),
4.45 (1H, dd, J=7, 4 Hz), 3.80 (3H, s), 2.06-1.90 (2H, m), 1.08
(3H, t, J=7 Hz).
Reference Example 98
(2S)-2-(4-Methoxyphenoxy)butanenitrile
##STR00126##
[0467] Trifluoroacetic anhydride (0.655 mL, 4.78 mmol) was added to
a methylene chloride (5 mL) solution of the compound obtained in
Reference Example 97 (1.00 g, 4.78 mmol) and pyridine (0.753 mL,
9.56 mmol) at 0.degree. C., and the mixture was stirred at the same
temperature for 20 minutes. After the mixture was stirred at room
temperature for 1 hour, the reaction mixture was diluted with
diethyl ether, and water and a saturated aqueous solution of
ammonium chloride were added to the mixture. The resulting mixture
was extracted three times with diethyl ether, and the organic layer
thus obtained was washed with 1 M hydrochloric acid, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=9:1.fwdarw.1:1,
v/v) to give the title compound (859 mg, yield: 94%).
[0468] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0469] 7.01 (2H, d, J=9 Hz), 6.90 (2H, d, J=9 Hz), 4.65 (1H, t, J=7
Hz), 3.82 (3H, s), 2.10 (2H, dq, J=7, 7 Hz), 1.22 (3H, t, J=7
Hz).
Reference Example 99
(1Z,2S)--N'-Hydroxy-2-(4-methoxyphenoxy)butanimidamide
##STR00127##
[0471] A 50% aqueous hydroxyl amine solution (0.788 mL, 13.5 mmol)
was added to an ethanol (20 mL) solution of the compound obtained
in Reference Example 98 (859 mg, 4.49 mmol) at room temperature,
and the mixture was stirred at 70.degree. C. for 2 hours. After the
reaction mixture was cooled to room temperature, the solvent was
distilled off under reduced pressure to give the title compound
(1.15 g, yield: quantitative).
[0472] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0473] 6.95 (2H, d, J=9 Hz), 6.83 (2H, d, J=9 Hz), 4.70 (2H, bs),
4.38 (1H, dd, J=7, 6 Hz), 3.77 (3H, s), 2.02-1.80 (2H, m), 1.06
(3H, t, J=7 Hz).
Reference Example 100
tert-Butyl
2-fluoro-4-{3-[(1S)-1-(4-methoxyphenoxy)propyl]-1,2,4-oxadiazol-
-5-yl}benzoate
##STR00128##
[0475] 1-Hydroxybenzotriazole monohydrate (320 mg, 2.09 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (802
mg, 4.18 mmol) were added to an N,N-dimethylformamide (10 mL)
solution of the compound obtained in Reference Example 80 (502 mg,
2.09 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. The compound obtained in Reference
Example 99 (469 mg, 2.09 mmol) was added to the mixture at room
temperature, and the resulting mixture was stirred at room
temperature for 20 minutes, and then heated at 90.degree. C. for 8
hours. After the reaction mixture was cooled to room temperature,
water was added to the reaction mixture. The mixture was extracted
three times with ethyl acetate, then washed with a saturated
aqueous solution of sodium hydrogen carbonate and a 10% aqueous
solution of sodium chloride sequentially, and dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=9:1.fwdarw.2:1, v/v) to
give the title compound (349 mg, yield: 39%).
[0476] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0477] 8.03-7.89 (3H, m), 6.97 (2H, d, J=9 Hz), 6.81 (2H, d, J=9
Hz), 5.25 (1H, dd, J=7, 6 Hz), 3.76 (3H, s), 2.30-2.07 (2H, m),
1.63 (9H, s), 1.10 (3H, t, J=7 Hz).
Reference Example 101
tert-Butyl
2-fluoro-4-{3-[(1S)-1-hydroxypropyl]-1,2,4-oxadiazol-5-yl}benzo-
ate
##STR00129##
[0479] The compound obtained in Reference Example 100 (349 mg,
0.813 mmol) was dissolved in acetonitrile (8 mL) and water (8 mL),
then ammonium cerium (IV) nitrate (1.34 g, 2.44 mmol) was added to
the mixture at 0.degree. C., and the resulting mixture was stirred
at the same temperature for 30 minutes. Water was added to the
reaction mixture, and the resulting mixture was extracted three
times with diethyl ether. The organic layer thus obtained was
washed three times with water, then further washed with a saturated
aqueous solution of sodium hydrogen carbonate, and dried over
anhydrous sodium sulfate. Methanol was added to the mixture, and
the generated insoluble material was removed by filtration. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=9:1.fwdarw.1:2, v/v) to give the title
compound (226 mg, yield: 86%).
[0480] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0481] 8.02 (1H, dd, J=8, 7 Hz), 7.95 (1H, dd, J=8, 2 Hz), 7.89
(1H, dd, J=11, 1 Hz), 4.92-4.86 (1H, m), 2.40-2.32 (1H, m),
2.08-1.95 (2H, m), 1.62 (9H, s), 1.05 (3H, t, J=7 Hz).
Reference Example 102
4-(3-{(1R)-1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-1,2,4-oxadiazol-5-yl)-
-2-fluorobenzoic acid
##STR00130##
[0483] Triphenylphosphine (188 mg, 0.714 mmol) and di-tert-butyl
azodicarboxylate (165 mg, 0.714 mmol) were added to a
tetrahydrofuran (6 mL) solution of the compound obtained in
Reference Example 101 (210 mg, 0.650 mmol) and
cyclopropyl(4-hydroxyphenyl)methanone (105 mg, 0.650 mmol) at room
temperature, and the mixture was stirred at the same temperature
for 30 minutes. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=9:1.fwdarw.1:1, v/v).
Subsequently, trifluoroacetic acid (1 mL) was added to a methylene
chloride (3 mL) solution of the compound thus obtained at room
temperature, and the mixture was stirred at the same temperature
for 30 minutes. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=2:1.fwdarw.1:4, v/v) to
give the title compound (153 mg, yield: 58%).
[0484] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0485] 8.20-8.13 (1H, m), 8.04-7.92 (4H, m), 7.08 (2H, d, J=8 Hz),
5.50-5.44 (1H, m), 2.85-2.55 (1H, m), 2.38-2.10 (2H, m), 1.22-1.16
(2H, m), 1.11 (3H, t, J=7 Hz), 1.04-0.96 (2H, m).
Reference Example 103
4-[5-(Trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenol
##STR00131##
[0487] Pyridine (15.9 mL, 197 mmol) and trifluoroacetic anhydride
(10.1 mL, 72.6 mmol) were added to an N,N-dimethylformamide (100
mL) solution of N',4-dihydroxybenzenecarboxyimidamide (WO
2011/016469) (10.0 g, 65.7 mmol) at 0.degree. C., and the mixture
was stirred at 0.degree. C. for 15 minutes. After that, the mixture
was heated to 80.degree. C., and stirred for 2 hours. After the
reaction mixture was cooled to room temperature, water and 2 M
hydrochloric acid were added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a 10% aqueous solution
of sodium chloride, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure. The resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=95:5, v/v), and then washed with hexane to
give the title compound (15.0 g, yield: 99%).
[0488] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0489] 8.02 (2H, d, J=9 Hz), 6.96 (2H, d, J=9 Hz), 5.39 (1H, br
s).
Reference Example 104
4-[3-(Trifluoromethyl)-1,2,4-oxadiazol-5-yl]phenol
##STR00132##
[0491] Potassium tert-butoxide (4.48 g, 40.0 mmol) was added to an
N,N-dimethylformamide (20 mL) solution of hydroxyl amine
hydrochloride (2.78 g, 40.0 mmol) at room temperature, and the
mixture was stirred for 15 minutes. The compound obtained in
Reference Example 103 (2.30 g, 10.0 mmol) was added to the mixture
at room temperature, and the mixture was stirred at the same
temperature for 2.5 hours. Water and a 10% aqueous solution of
sodium chloride were added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (hexane:ethyl
acetate=4:1.fwdarw.1:4, v/v) to give the title compound (1.35 g,
yield: 59%).
[0492] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0493] 8.02 (2H, m), 7.02 (2H, d, J=9 Hz).
Reference Example 105
(1R)--N-Benzyl-1-[(2R)-1,4-dioxaspiro[4,5]deca-4-yl]ethanamine
##STR00133##
[0495] A toluene (100 mL) solution of anhydrous sodium sulfate
(38.2 g, 269 mmol) and benzylamine (19.2 g, 179 mmol) were added to
a toluene (100 mL) solution of
2,3-O-cyclohexylidene-L-glyceraldehyde (J. Org. Chem., 2005, 70,
6346-6352.) (30.5 g, 179 mmol) at room temperature, and the mixture
was stirred at the same temperature for 1 hour, and then left to
stand at the same temperature overnight. The resulting insoluble
material was removed by filtration through a cotton plug, and then
the solvent was distilled off under reduced pressure to give a
crude product (49.2 g). The crude product was dissolved in
tetrahydrofuran (400 mL), then boron trifluoride-diethyl ether
complex (22.5 mL, 179 mmol) was added to the mixture at -78.degree.
C., and the resulting mixture was stirred at the same temperature
for 10 minutes. Subsequently, 3.0 M methylmagnesium bromide-diethyl
ether solution (89.6 mL, 269 mmol) was added to the mixture at
-78.degree. C. over 30 minutes, and then the resulting mixture was
heated to 0.degree. C. over 5 hours or more. The reaction mixture
was poured into a saturated aqueous solution of sodium hydrogen
carbonate (300 mL), and then the mixture was stirred at room
temperature for 3 minutes. Subsequently, the insoluble material was
removed by filtration through Celite. The solvent was distilled off
under reduced pressure, and then the mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was purified by silica gel column chromatography (hexane:diethyl
ether=2:1, v/v) to give the title compound (37.8 g, yield:
77%).
[0496] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0497] 7.37-7.29 (4H, m), 7.28-7.21 (1H, m), 4.05-3.98 (2H, m),
3.93-3.85 (2H, m), 3.74 (1H, d, J=13 Hz), 2.89-2.80 (1H, m),
1.71-1.29 (10H, m), 1.10 (3H, d, J=6 Hz).
Reference Example 106
(1R)-1-[(2R)-1,4-Dioxaspiro[4,5]deca-4-yl]ethanamine
##STR00134##
[0499] 20% Palladium hydroxide on carbon (1.89 g) was added to an
ethanol (300 mL) solution of the compound obtained in Reference
Example 105 (37.8 g, 137 mmol) at room temperature, and the mixture
was stirred at 60.degree. C. for 2.5 hours in a hydrogen
atmosphere. After the reaction mixture was cooled to room
temperature, the insoluble material was removed by filtration
through Celite. The solvent was distilled off under reduced
pressure to give the title compound (26.7 g).
[0500] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0501] 3.99 (1H, dd, J=7, 6 Hz), 3.93 (1H, td, J=6, 5 Hz), 3.80
(1H, dd, J=7, 6 Hz), 3.07 (1H, qd, J=7, 5 Hz), 1.67-1.30 (10H, m),
1.07 (3H, dd, J=7 Hz).
Example 1
4-{4-[(1R)-1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3-tri-
azol-2-yl}-N-[(1R,2R)-2,3-dihydroxy-1-methylpropyl]-2-fluorobenzamide
##STR00135##
[0503] An N,N-dimethylformamide (2.2 mL) solution of the
(1R)-1-[(2R)-1,4-dioxaspiro[4.5]deca-2-yl]ethanamine (206 mg, 1.11
mmol) obtained in Reference Example 106 was added to an
N,N-dimethylformamide (4.4 mL) solution of the compound obtained in
Reference Example 26 (220 mg, 0.555 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (213
mg, 1.11 mmol), and 1-hydroxybenzotriazole monohydrate (85.0 mg,
0.555 mmol) at room temperature, and the mixture was stirred at the
same temperature for 22.5 hours. Water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was washed with water, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (33% ethyl acetate/hexane) to
give
4-{4-[(1R)-1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3-tr-
iazol-2-yl}-N-{(1R)-1-[(2R)-1,4-dioxaspiro[4.5]deca-2-yl]ethyl}-2-fluorobe-
nzamide (308 mg, yield: 99%).
[0504] Acetic acid (4.8 mL) and water (1.2 mL) were added to the
compound described above (306 mg, 0.543 mmol), and the mixture was
stirred at 80.degree. C. for 135 minutes. The mixture was returned
to room temperature, and the solvent in the reaction mixture was
distilled off under reduced pressure. A saturated aqueous solution
of sodium hydrogen carbonate and water were added to the resulting
residue, and the mixture was extracted with dichloromethane. The
organic layer thus obtained was dried over anhydrous sodium
sulfate. The resulting mixture was filtered, then solvent was
distilled off under reduced pressure, and the resulting residue was
purified by silica gel column chromatography (66%-99% ethyl
acetate/hexane) to give the title compound (147 mg, yield:
56%).
[0505] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0506] 8.42 (1H, d, J=2.7 Hz), 8.24-8.20 (1H, m), 8.01-7.97 (2H,
m), 7.89-7.85 (1H, m), 7.83 (1H, s), 7.37-7.34 (1H, m), 6.88-6.83
(1H, m), 5.81-5.76 (1H, m), 4.26-4.21 (1H, m), 3.73-3.65 (2H, m),
3.51-3.47 (1H, m), 3.44-3.38 (1H, m), 3.23-3.19 (1H, m), 2.83-2.81
(1H, m), 1.84 (3H, d, J=6.3 Hz), 1.42 (3H, d, J=7.0 Hz), 1.22-1.18
(2H, m), 1.08-1.03 (2H, m);
[0507] MS (ES) m/z: 484 [M+H].sup.+.
Example 2
1-[4-(4-{1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-2H-1,2,3-triazol-2-yl)--
2-fluorophenyl]-3-(2-hydroxyethyl)urea
##STR00136##
[0509] Triphosgene (78.0 mg, 0.263 mmol) was added to a
tetrahydrofuran (4 mL) solution of the compound obtained in
Reference Example 27 (200 mg, 0.526 mmol) and
N,N-diisopropylethylamine (0.179 mL, 1.05 mmol) at room
temperature. The mixture was stirred at room temperature for 5
minutes, and then 2-aminoethanol (63.0 .mu.L, 1.05 mmol) was added
to the mixture. After the resulting mixture was stirred at room
temperature for 30 minutes, water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (66%-99% ethyl acetate/hexane) to give the
title compound (188 mg, yield: 77%).
[0510] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0511] 8.23-8.19 (1H, m), 7.95 (2H, d, J=8.6 Hz), 7.80-7.75 (2H,
m), 7.67 (1H, s), 7.09 (1H, br s), 7.01 (2H, d, J=9.0 Hz),
5.52-5.46 (2H, m), 3.81-3.78 (2H, m), 3.48-3.44 (2H, m), 2.63-2.56
(2H, m), 2.22-2.02 (2H, m), 1.19-1.16 (2H, m), 1.09-1.05 (3H, m),
0.99-0.97 (2H, m);
[0512] MS (ES) m/z: 468 [M+H].sup.+.
Example 3
1-(4-{4-[(1R)-1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-2H-1,2,3--
triazol-2-yl}-2-fluorophenyl)-3-(2-hydroxyethyl)urea
##STR00137##
[0514] Triphosgene (75.9 mg, 0.256 mmol) was added to a
tetrahydrofuran (5 mL) solution of the compound obtained in
Reference Example 28 (188 mg, 0.512 mmol) and
N,N-diisopropylethylamine (0.174 mL, 1.02 mmol) at room
temperature. The mixture was stirred at room temperature for 5
minutes, and then 2-aminoethanol (61.3 .mu.L, 1.02 mmol) was added
to the mixture. The resulting mixture was stirred at room
temperature for 4 hours, then water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography (66%-99% ethyl acetate/hexane) to give the
title compound (79.1 mg, yield: 34%).
[0515] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0516] 8.42 (1H, d, J=2.7 Hz), 8.25-8.21 (1H, m), 7.99 (1H, d,
J=8.6 Hz), 7.82-7.76 (2H, m), 7.74 (1H, s), 7.38-7.35 (1H, m), 6.89
(1H, br s), 5.79-5.74 (1H, m), 5.28-5.24 (1H, m), 3.82-3.80 (2H,
m), 3.50-3.46 (2H, m), 3.44-3.38 (1H, m), 2.35 (1H, m), 1.83 (3H,
d, J=6.7 Hz), 1.21-1.18 (2H, m), 1.08-1.03 (2H, m);
[0517] MS (ES) m/z: 455 [M+H].sup.+.
[0518] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00001 TABLE 1 Exam- ple Compound name Structural formula
NMR 4 4-(4-{1-[4- (Cyclopropylcarbonyl) phenoxy]propyl}- 2H-1,2,3-
triazol-2-yl)-2- fluoro-N-[(1R)- 2-hydroxy-1- methylethyl]
benzamide ##STR00138## .sup.1H NMR (400 MHz, CDCl.sub.3) .delta.
ppm: 8.25-8.21 (1H, m), 7.99-7.95 (3H, m), 7.87-7.84 (1H, m), 7.76
(1H, s), 7.02- 7.00 (2H, m), 6.91- 6.86 (1H, m), 5.52- 5.49 (1H,
m), 4.34 (1H, m), 3.84-3.79 (1H, m), 3.71-3.66 (1H, m), 2.62-2.53
(2H, m), 2.21-2.06 (2H, m), 1.33 (3H, d, J = 7.0 Hz), 1.20-1.17
(2H, m), 1.10-1.07 (3H, m), 0.99-0.97 (2H, m). MS (ES) m/z: 467 [M
+ H].sup.+. 5 4-(4-{1-[4- (Cyclopropylcarbonyl) phenoxy]propyl}-
2H-1,2,3- triazol-2-yl)-2- fluoro-N-[(3S)- 2-oxopyrrolidin-
3-yl]benzamide ##STR00139## .sup.1H NMR (400 MHz, CDCl.sub.3)
.delta. ppm: 8.25-8.20 (1H, m), 7.99-7.94 (3H, m), 7.89-7.85 (1H,
m), 7.76 (1H, s), 7.31- 7.26 (1H, m), 7.02- 6.99 (2H, m), 5.87 (1H,
m), 5.52-5.49 (1H, m), 4.62-4.56 (1H, m), 3.50-3.46 (2H, m),
2.97-2.90 (1H, m), 2.62-2.56 (1H, m), 2.23-2.04 (3H, m), 1.21-1.17
(2H, m), 1.10-1.07 (3H, m), 1.00-0.96 (2H, m); MS (ES) m/z: 492 [M
+ H].sup.+. 6 4-(4-{1-[4- (Cyclopropylcarbonyl) phenoxy]ethyl}-
2H-1,2,3- triazol-2-yl)-2- fluoro-N-[(1R)- 2-hydroxy-1-
methylethyl] benzamide ##STR00140## .sup.1H NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.25-8.21 (1H, m), 7.99-7.96 (3H, m),
7.87-7.84 (1H, m), 7.80 (1H, s), 7.03- 7.01 (2H, m), 6.92- 6.87
(1H, m), 5.78- 5.73 (1H, m), 4.35 (1H, m), 3.84-3.79 (1H, m),
3.71-3.66 (1H, m), 2.62-2.57 (2H, m), 1.80 (3H, d, J = 6.3 Hz),
1.33 (3H, d, J = 6.6 Hz), 1.20- 1.18 (2H, m), 1.00- 0.97 (2H, m);
MS (ES) m/z: 453 [M + H].sup.+. 7 4-(4-{(1R)-1-[4-
(Cyclopropylcarbonyl) phenoxy]propyl}- 2H-1,2,3- triazol-2-yl)-2-
fluoro-N-[(1R)- 2-hydroxy-1- methylethyl] benzamide ##STR00141##
.sup.1H NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.25-8.21 (1H, m),
7.99-7.95 (3H, m), 7.87-7.84 (1H, m), 7.76 (1H, s), 7.02- 7.00 (2H,
m), 6.91- 6.86 (1H, m), 5.52- 5.49 (1H, m), 4.34 (1H, m), 3.84-3.79
(1H, m), 3.71-3.66 (1H, m), 2.62-2.53 (2H, m), 2.21-2.06 (2H, m),
1.33 (3H, d, J = 6.7 Hz), 1.20-1.17 (2H, m), 1.10-1.07 (3H, m),
0.99-0.97 (2H, m); MS (ES) m/z: 467 [M + H].sup.+.
TABLE-US-00002 TABLE 2 Example Compound name Structural formula NMR
8 4-{4-[(1R)-1-{[6- (Cyclopropyl- carbonyl)pyridin-3-
yl]oxy}ethyl]-2H- 1,2,3-triazol-2- yl}-2-fluoro-N- [(1R)-2-hydroxy-
1- methylethyl] benzamide ##STR00142## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.43 (1H, d, J = 2.3 Hz), 8.25-8.21 (1H,
m), 8.01-7.96 (2H, m), 7.87-7.84 (1H, m), 7.83 (1H, s), 7.37-7.34
(1H, m), 6.91-6.87 (1H, m), 5.81-5.76 (1H, m), 4.37-4.32 (1H, m),
3.83-3.80 (1H, m), 3.71-3.66 (1H, m), 3.44-3.38 (1H, m), 2.55 (1H,
m), 1.84 (3H, d, J = 6.7 Hz), 1.33 (3H, d, J = 6.7 Hz), 1.23-1.18
(2H, m), 1.08-1.04 (2H, m); MS (ES) m/z: 454 [M + H].sup.+. 9
4-{4-[(1R)-1-{[6- (Cyclopropyl- carbonyl)pyridin-3-
yl]oxy}ethyl]-2H- 1,2,3-triazol-2- yl}-N-[(2S)-2,3-
dihydroxypropyl]- 2-fluorobenzamide ##STR00143## .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. ppm: 8.43 (1H, d, J = 2.3 Hz), 8.26-8.21
(1H, m), 8.01-7.97 (2H, m), 7.89-7.86 (1H, m), 7.83 (1H, s),
7.37-7.34 (1H, s), 7.21-7.15 (1H, m), 5.81-5.76 (1H, m), 3.95-3.91
(1H, m), 3.75-3.61 (4H, m), 3.44-3.38 (1H, m), 2.94-2.93 (1H, m),
2.79-2.76 (1H, m), 1.84 (3H, d, J = 6.7 Hz), 1.22-1.18 (2H, m),
1.08-1.04 (2H, m); MS (ES) m/z: 470 [M + H].sup.+. 10
4-{4-[(1R)-1-{[6- (Cyclopropyl- carbonyl)pyridin-3-
yl]oxy}ethyl]-2H- 1,2,3-triazol-2- yl}-2-fluoro-N- [(3S)-2-
oxopyrrolidin-3- yl]benzamide ##STR00144## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.43 (1H, d, J = 2.7 Hz), 8.25-8.21 (1H,
m), 8.01-7.96 (2H, m), 7.89-7.85 (1H, m), 7.83 (1H, s), 7.37-7.34
(1H, m), 7.30-7.26 (5H, m), 5.83-5.76 (2H, m), 4.62-4.56 (1H, m),
3.50-3.38 (3H, m), 2.97-2.90 (1H, m), 2.18-2.07 (1H, m), 1. 84 (3H,
d, J = 6.7 Hz), 1.23-1.18 (2H, m), 1.08-1.04 (2H, m); MS (ES) m/z:
479 [M + H].sup.+. 11 1-[4-(4-{1-[4- (Cyclopropyl-
carbonyl)phenoxy] propyl}-2H-1,2,3- triazol-2-yl)-2-
fluorophenyl]urea ##STR00145## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm: 8.24-8.20 (1H, m), 7.97-7.94 (2H, m), 7. 83-7.78 (2H,
m), 7.69 (1H, s), 7.03- 6.99 (2H, m), 6.78- 6.77 (1H, m), 5.50-
5.47 (1H, m), 4.79 (2H, s), 2.63-2.56 (1H, m), 2.20-2.04 (2H, m),
1.20-1.17 (2H, m), 1.09-1.06 (3H, m), 1.00-0.96 (2H, m); MS (ES)
m/z: 424 [M + H].sup.+.?
Example 12
4-(5-{1-[4-(Cyclopropylcarbonyl)phenoxy]propyl}-2H-tetrazol-2-yl)-2-fluoro-
-N-[(1R)-2-hydroxy-1-methylethyl]benzamide
##STR00146##
[0520] D-Alaninol (82.6 .mu.L, 1.07 mmol) was added to an
N,N-dimethylformamide (6 mL) solution of the compound obtained in
Reference Example 35 (292 mg, 0.712 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (273
mg, 1.42 mmol), and 1-hydroxybenzotriazole monohydrate (109 mg,
0.712 mmol) at room temperature, and the mixture was stirred at the
same temperature for 17 hours. Water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was washed with water, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (66% ethyl acetate/hexane) to
give the title compound (221 mg, yield: 66%).
[0521] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0522] 8.32-8.28 (1H, m), 8.08-8.05 (1H, m), 7.99-7.93 (3H, m),
7.09-7.05 (2H, m), 6.92-6.87 (1H, m), 5.67-5.64 (1H, m), 4.35 (1H,
m), 3.85-3.80 (1H, m), 3.72-3.66 (1H, m), 2.62-2.56 (1H, m),
2.39-2.19 (3H, m), 1.33 (3H, d, J=6.6 Hz), 1.20-1.16 (2H, m),
1.13-1.09 (3H, m), 1.01-0.96 (2H, m);
[0523] MS (FAB) m/z: 468 [M+H].sup.+.
[0524] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00003 TABLE 3 Example Compound name Structural formula NMR
13 N-Cyclopropyl-4- (5-{1-[4- (cyclopropyl- carbonyl)
phenoxy]propyl}- 2H-tetrazol-2- yl)-2- fluorobenzamide ##STR00147##
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.34-8.30 (1H, m),
8.07-8.04 (1H, m), 7.98-7.91 (3H, m), 7.08-7.05 (2H, m), 6.82-6.79
(1H, m), 5.66-5.63 (1H, m), 3.00-2.93 (1H, m), 2.62-2.55 (1H, m),
2.40-2.19 (2H, m), 1.20-1.16 (2H, m), 1.13-1.09 (3H, m), 1.00-0.96
(2H, m), 0.94-0.89 (2H, m), 0.68-0.64 (2H, m); MS (ES) m/z: 450 [M
+ H].sup.+. 14 N-Cyclopropyl-4- [5-{1-{ [6- (cyclopropyl- carbonyl)
pyridin-3- yl]oxy}ethyl)-2H- tetrazol-2-yl]-2- fluorobenzamide
##STR00148## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
8.46-8.46 (1H, m), 8.35-8.31 (1H, m), 8.07-7.91 (3H, m), 7.44-7.42
(1H, m), 6.83-6.80 (1H, m), 5.95-5.90 (1H, m), 3.41 (1H, m), 2.96
(1H, m), 1.96 (3H, d, J = 6.6 Hz), 1.19- 1.18 (2H, m), 1.07- 1.05
(2H, m), 0.93- 0.91 (2H, m), 0.67- 0.66 (2H, m); MS (ES) m/z: 437
[M + H].sup.+.
Example 15
4-(5-{1-[4-(Cyclopropylcarbonyl)phenoxy]ethyl}-1,3-thiazol-2-yl)-2-fluoro--
N-[(1R)-2-hydroxy-1-methylethyl]benzamide
##STR00149##
[0526] D-Alaninol (0.123 mL, 1.59 mmol) was added to an
N,N-dimethylformamide (8.7 mL) solution of the compound obtained in
Reference Example 44 (435 mg, 1.06 mmol),
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (405
mg, 2.11 mmol), and 1-hydroxybenzotriazole monohydrate (162 mg,
1.06 mmol) at room temperature, and the mixture was stirred at the
same temperature for 17 hours. Water was added to the reaction
mixture, and the resulting mixture was extracted with ethyl
acetate. The organic layer thus obtained was washed with water, and
then dried over anhydrous sodium sulfate. The solvent was distilled
off under reduced pressure, and the resulting residue was purified
by silica gel column chromatography (ethyl acetate) to give the
title compound (372 mg, yield: 75%).
[0527] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0528] 8.16-8.12 (1H, m), 8.00-7.97 (2H, m), 7.81 (1H, [0529] s),
7.74 (1H, s), 7.72-7.71 (1H, m), 7.02-6.98 (2H, m), 6.93-6.88 (1H,
m), 5.81-5.77 (1H, m), 4.35-4.31 (1H, m), 3.83-3.78 (1H, m),
3.70-3.65 (1H, m), 2.63-2.56 (2H, m), 1.83 (3H, d, J=6.6 Hz), 1.31
(3H, d, J=7.0 Hz), 1.21-1.18 (2H, m), 1.02-0.97 (2H, m).
[0530] MS (ES) m/z: 469 [M+H].sup.+.
Example 16
4-[5-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-thiazol-2-yl]-
-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide
##STR00150##
[0532] A 1 M aqueous sodium hydroxide solution (2.0 mL) was added
to a tetrahydrofuran (2.0 mL)-methanol (2.0 mL) solution of the
compound obtained in Reference Example 45 (77.3 mg, 0.181 mmol) at
room temperature, and the mixture was stirred at the same
temperature for 15 minutes. Water was added to the reaction
mixture, subsequently, 1 M sulfuric acid was added to the reaction
mixture to adjust the pH to 4, and then the resulting mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was washed with brine, and then dried over anhydrous sodium
sulfate. The solvent was distilled off under reduced pressure, and
the resulting residue (83.9 mg) thus obtained was dissolved in
N,N-dimethylformamide (1.0 mL). 1-Hydroxybenzotriazole monohydrate
(33.3 mg, 0.218 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (41.7
mg, 0.218 mmol) were added to the mixture at room temperature, and
the resulting mixture was stirred at the same temperature for 30
minutes. Subsequently, a N,N-dimethylformamide (1.0 mL) solution of
(R)-2-amino-1-propanol (40.8 mg, 0.544 mmol) was added to the
resulting mixture at 0.degree. C., and the mixture was stirred at
the same temperature for 1 hour, and then further stirred at room
temperature for 16 hours. Water was added to the reaction mixture,
and the resulting mixture was extracted twice with ethyl acetate.
The organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=50:50.fwdarw.0:100,
v/v) to give the title compound (74.6 mg, yield: 88%).
[0533] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0534] 8.40 (1H, d, J=3 Hz), 8.15 (1H, t, J=8 Hz), 8.00 (1H, d, J=9
Hz), 7.83 (1H, s), 7.75-7.71 (2H, m), 7.32 (1H, dd, J=9, 3 Hz),
6.93-6.85 (1H, m), 5.82 (1H, q, J=6 Hz), 4.38-4.29 (1H, m),
3.83-3.77 (1H, m), 3.71-3.64 (1H, m), 3.45-3.37 (1H, m), 2.53 (1H,
t, J=6 Hz), 1.86 (3H, d, J=6 Hz), 1.32 (3H, d, J=7 Hz), 1.22-1.17
(2H, m), 1.09-1.03 (2H, m);
[0535] MS (ES) m/z: 470 [M+H].sup.+.
Example 17
5-Isopropyl-3-[4-(1-{2-[4-(methylsulfonyl)phenyl]-1,3-thiazol-5-yl}propoxy-
)phenyl]-1,2,4-oxadiazol
##STR00151##
[0537] Triphenylphosphine (523 mg, 1.99 mmol) and di-tert-butyl
azodicarboxylate (459 mg, 1.99 mmol) were added to a
tetrahydrofuran (10 mL) solution of the compound obtained in
Reference Example 47 (529 mg, 1.99 mmol) and
4-(5-isopropyl-1,2,4-oxadiazol-3-yl)phenol (WO 2011/016470) (407
mg, 1.99 mmol) at room temperature, and the mixture was stirred at
the same temperature for 1 hour. Subsequently, a 4 M hydrogen
chloride-1,4-dioxane solution (5.0 mL) was added to the resulting
mixture, and the mixture was stirred at the same temperature for 18
hours. Water was added to the reaction mixture, and the resulting
mixture was extracted twice with ethyl acetate. The organic layer
thus obtained was washed with brine, and then dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure, then the resulting residue was purified by silica gel
column chromatography (hexane:ethyl acetate=90:10.fwdarw.60:40,
v/v) to give a compound, and the compound (684 mg) thus obtained
was dissolved in dichloromethane (14 mL). Subsequently,
m-chloroperbenzoic acid (762 mg, 2.87 mmol) was added to the
resulting mixture at 0.degree. C. The mixture was stirred at the
same temperature for 15 minutes, and then further stirred at room
temperature for 12 hours. A saturated aqueous solution of sodium
hydrogen carbonate was added to the reaction mixture, and the
resulting mixture was extracted twice with dichloromethane. The
organic layer thus obtained was washed with 1.5 M aqueous sodium
sulfite solution, and then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=75:25.fwdarw.50:50, v/v) to give the title
compound (389 mg, yield: 40%).
[0538] .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm:
[0539] 8.09 (2H, d, J=8 Hz), 7.99 (2H, d, J=8 Hz), 7.97 (2H, d, J=9
Hz), 7.82 (1H, s), 7.02 (2H, d, J=9 Hz), 5.49 (1H, dd, J=7, 6 Hz),
3.28-3.22 (1H, m), 3.07 (3H, s), 2.26-2.17 (1H, m), 2.09-2.00 (1H,
m), 1.43 (6H, d, J=7 Hz), 1.09 (3H, t, J=7 Hz).
[0540] MS (ES) m/z: 484 [M+H].sup.+.
Example 18
4-[4-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-yl]--
2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide
##STR00152##
[0542] 1-Hydroxybenzotriazole monohydrate (116 mg, 0.757 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (145
mg, 0.757 mmol) were added to an N,N-dimethylformamide (3.2 mL)
solution of the compound obtained in Reference Example 55 (250 mg,
0.631 mmol) at room temperature, and the mixture was stirred at the
same temperature for 15 minutes. Subsequently, an
N,N-dimethylformamide (1.0 mL) solution of (R)-2-amino-1-propanol
(142 mg, 1.89 mmol) was added at 0.degree. C., and the mixture was
further stirred at the same temperature for 10.5 minutes. Water was
added to the reaction mixture, and the resulting mixture was
extracted twice with ethyl acetate. The organic layer thus obtained
was washed with a saturated aqueous solution of sodium hydrogen
carbonate and brine, and then dried over anhydrous sodium sulfate.
The solvent was distilled off under reduced pressure, and the
resulting residue was purified by silica gel column chromatography
(hexane:ethyl acetate=50:50.fwdarw.0:100, v/v) to give the title
compound (235 mg, yield: 82%).
[0543] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0544] 8.43 (1H, d, J=2 Hz), 8.19 (1H, t, J=8 Hz), 8.01 (1H, d, J=9
Hz), 7.92 (1H, dd, J=8, 1 Hz), 7.80 (1H, dd, J=12, 1 Hz), 7.68 (1H,
s), 7.36 (1H, dd, J=9, 2 Hz), 6.96-6.88 (1H, m), 5.56 (1H, q, J=7
Hz), 4.39-4.30 (1H, m), 3.84-3.78 (1H, m), 3.71-3.65 (1H, m),
3.45-3.40 (1H, m), 2.51 (1H, t, J=5 Hz), 1.80 (3H, d, J=7 Hz), 1.32
(3H, d, J=7 Hz), 1.22-1.19 (2H, m), 1.09-1.04 (2H, m).
[0545] MS (ES) m/z: 454 [M+H].sup.+.
Example 19
N-Cyclopropyl-4-[4-(1-{[6-(cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-
-oxazol-2-yl]-2-fluorobenzamide
##STR00153##
[0547] 1-Hydroxybenzotriazole monohydrate (30.3 mg, 0.180 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (56.9
mg, 0.270 mmol) were added to an N,N-dimethylformamide (2 mL)
solution of the compound obtained in Reference Example 55 (78.4 mg,
0.180 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. Subsequently, cyclopropylamine
(20.0 .mu.L, 0.340 mmol) was added to the mixture, and the
resulting mixture was further stirred at the same temperature for
30 minutes. Water, a saturated aqueous solution of sodium hydrogen
carbonate, and a 10% aqueous solution of sodium chloride were added
to the mixture. The resulting mixture was extracted three times
with ethyl acetate, and dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure, and the resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=2:1.fwdarw.1:4, v/v) to give the title
compound (69.0 mg, yield: 80%).
[0548] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0549] 8.42 (1H, d, J=3 Hz), 8.21 (1H, dd, J=8, 8 Hz), 8.01 (1H, d,
J=9 Hz), 7.91 (1H, dd, J=8, 2 Hz), 7.78 (1H, dd, J=13, 2 Hz), 7.67
(1H, s), 7.36 (1H, dd, J=9, 3 Hz), 6.90-6.80 (1H, m), 5.56 (1H, q,
J=7 Hz), 3.47-3.40 (1H, m), 3.00-2.92 (1H, m), 1.79 (3H, d, J=6
Hz), 1.23-1.18 (2H, m), 1.10-1.04 (2H, m), 0.93-0.88 (2H, m),
0.68-0.62 (2H, m).
[0550] MS (ES) m/z: 436 [M+H].sup.+.
Example 20
1-{4-[4-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,3-oxazol-2-y-
l]-2-fluorophenyl}-3-(2-hydroxyethyl)urea
##STR00154##
[0552] Diisopropylethylamine (25.8 .mu.L, 0.148 mmol) and
triphosgene (10.9 mg, 37.0 .mu.mol) were added to a tetrahydrofuran
(1 mL) solution of the compound obtained in Reference Example 57
(27.2 mg, 74.0 .mu.mol) at room temperature, and the mixture was
stirred at room temperature for 20 minutes. Ethanolamine (20.0
.mu.L, 0.285 mmol) was added to the mixture at room temperature,
and the resulting mixture was stirred at the same temperature for
30 minutes. Water was added to the reaction mixture, and the
resulting mixture was extracted three times with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate, and then dried over
anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1.fwdarw.ethyl
acetate, v/v) to give the title compound (22.7 mg, yield: 67%).
[0553] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0554] 8.42 (1H, d, J=2 Hz), 8.27 (1H, dd J=9, 8 Hz), 8.00 (1H, d,
J=9 Hz), 7.76 (1H, d, J=9 Hz), 7.70 (1H, dd, J=12, 2 Hz), 7.58 (1H,
s), 7.36 (1H, dd, J=9, 3 Hz), 7.15-7.04 (1H, m), 5.53 (1H, q, J=6
Hz), 5.42-5.36 (1H, m), 3.85-3.76 (2H, m), 3.50-3.38 (3H, m),
2.46-2.39 (1H, m), 1.78 (3H, d, J=7 Hz), 1.23-1.17 (2H, m),
1.09-1.02 (2H, m).
[0555] MS (FAB) m/z: 455 [M+H].sup.+.
[0556] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00004 TABLE 4 Example Compound name Structural formula NMR
21 4-(4-{1-[4- (Cyclopropyl- carbonyl)phenoxy] ethyl}-1,3-
oxazol-2-yl)-2- fluoro-N-[(1R)- 2-hydroxy-1- methylethyl] benzamide
##STR00155## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.19
(1H, dd, J = 8, 8 Hz), 7.99 (2H, d, J = 9 Hz), 7.92 (1H, d, J = 8
Hz), 7.80 (1H, d, J = 12 Hz), 7.64 (1H, s), 7.02 (2H, d, J = 7 Hz),
6.96-6.87 (1H, m), 5.54 (1H, q, J = 7 Hz), 4.40-4.30 (1H, m),
3.86-3.79 (1H, m), 3.71-3.66 (1H, m), 2.65-2.58 (1H, m), 2.53-2.48
(1H, m), 1.76 (3H, d, J = 6 Hz), 1.32 (3H, d, J = 7 Hz), 1.22-1.17
(2H, m), 1.02-0.97 (2H, m). MS (ES) m/z: 453 [M + H].sup.+. 22
4-(4-{1-[4- (Cyclopropyl- carbonyl)phenoxy] ethyl}-1,3-
oxazol-2-yl)-2- fluoro-N-[2- hydroxy-1- (hydroxymethyl)
ethyl]benzamide ##STR00156## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm: 8.19 (1H, dd, J = 8, 8 Hz), 7.99 (2H, d, J = 9 Hz),
7.92 (1H, dd, J = 8, 2 Hz), 7.81 (1H, dd, J = 13, 2 Hz), 7.64 (1H,
s), 7.56-7.48 (1H, m), 7.02 (2H, dd, J = 7, 2 Hz), 5.54 (1H, q, J =
6 Hz), 4.28-4.21 (1H, m), 4.05-3.90 (4H, m), 2.66-2.59 (1H, m),
2.53-2.46 (2H, m), 1.76 (3H, d, J = 6 Hz), 1.23-1.18 (2H, m),
1.02-0.97 (2H, m). MS (ES) m/z: 469 [M+H].sup.+. 23 1-[4-{4-{1-[4-
(Cyclopropyl- carbonyl)phenoxy] ethyl}-1,3- oxazol-2-yl)-2-
fluorophenyl] urea ##STR00157## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm: 8.64 (1H, d, J = 2 Hz), 8.36 (1H, dd, J = 9, 8 Hz),
8.21 (1H, s), 8.00 (2H, d, J = 9 Hz), 7.71-7.65 (2H, m), 7.15 (2H,
d, J = 9 Hz), 6.36 (2H, s), 5.71 (1H, q, J = 6 Hz), 2.83 (1H, dddd,
J = 6 Hz), 1.65 (3H, d, J = 7 Hz), 0.97 (4H, d, J = 6 Hz). MS (ES)
m/z: 410 [M + H].sup.+.
TABLE-US-00005 TABLE 5 Example Compound name Structural formula NMR
24 1-[4-(4-{1-[4- (Cyclopropyl- carbonyl) phenoxy] ethyl}-1,3-
oxazol-2-yl)-2- fluorophenyl]- 3-(2- hydroxyethyl) urea
##STR00158## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.27
(1H, dd, J = 9, 8 Hz), 7.98 (2H, d, J = 9 Hz), 7.79-7.71 (2H, m),
7.55 (1H, s), 7.02 (2H, d, J = 9 Hz), 6.98-6.89 (1H, m), 5.51 (1H,
q, J = 6 Hz), 5.25-5.19 (1H, m), 3.81 (2H, dd, J = 6, 5 Hz), 3.48
(2H, dd, J = 6, 5 Hz), 2.65- 2.58 (1H, m), 2.29-2.24 (1H, m), 1.75
(3H, d, J = 7 Hz), 1.23-1.18 (2H, m), 1.02-0.96 (2H, m). MS (ES)
m/z: 454 [M + H].sup.+. 25 1-{4-[4-(1-{[6- (Cyclopropyl- carbonyl)
pyridin-3- yl]oxy}ethyl)- 1,3-oxazol-2- yl]-2- fluorophenyl} urea
##STR00159## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.42
(1H, d, J = 2 Hz), 8.28 (1H, dd, J = 8, 8 Hz), 8.00 (1H, d, J = 9
Hz), 7. 78 (1H, d, J = 9 Hz), 7.73 (1H, d, J = 11 Hz), 7.59 (1H,
s), 7.36 (1H, dd, J = 9, 2 Hz) , 6.94 (1H, s), 5.54 (1H, q, J = 6
Hz), 4.84 (2H, s), 3.47-3.38 (1H, m), 1. 78 (3H, d, J = 6 Hz),
1.24-1.18 (2H, m), 1.09-1.03 (2H, m). MS (ES) m/z: 411 [M +
H].sup.+.
Examples 26
4-{5-[(1R)-1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl]-1,2,4-oxadia-
zol-3-yl}-2-fluoro-N-[(1R)-2-hydroxy-1-methylethyl]benzamide
##STR00160##
[0558] 1-Hydroxybenzotriazole monohydrate (46.2 mg, 0.302 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (57.9
mg, 0.302 mmol) were added to an N,N-dimethylformamide (1.3 mL)
solution of the compound obtained in Reference Example 59 (100 mg,
0.252 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. Subsequently, an
N,N-dimethylformamide (1.0 mL) solution of (R)-2-amino-1-propanol
(56.7 mg, 0.755 mmol) was added to the mixture at 0.degree. C., and
the resulting mixture was further stirred at the same temperature
for 1 hour. Water was added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography (hexane:ethyl acetate=50:50.fwdarw.0:100,
v/v) to give the title compound (102 mg, yield: 89%).
[0559] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0560] 8.47 (1H, d, J=3 Hz), 8.21 (1H, t, J=8 Hz), 8.03 (1H, d, J=9
Hz), 7.98 (1H, dd, J=8, 1 Hz), 7.85 (1H, dd, J=12, 1 Hz), 7.39 (1H,
dd, J=9, 3 Hz), 6.97-6.85 (1H, m), 5.78 (1H, J=7 Hz), 4.40-4.29
(1H, m), 3.81 (1H, dd, J=11, 3 Hz), 3.68 (1H, dd, J=11, 6 Hz),
3.47-3.37 (1H, m), 2.49 (1H, br s), 1.95 (3H, d, J=7 Hz), 1.32 (3H,
d, J=7 Hz), 1.24-1.18 (2H, m), 1.10-1.04 (2H, m);
[0561] MS (ES) m/z: 455 [M+H].sup.+.
[0562] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00006 TABLE 6 Example Compound name Structural formula NMR
27 4-{5-[(1R)-1- {[6- (Cyclopropyl- carbonyl) pyridin-3-
yl]oxy}ethyl]- 1,2,4- oxadiazol-3- yl}-2-fluoro- N-[2-hydroxy- 1-
(hydroxymethyl) ethyl]benzamide ##STR00161## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.47 (1H, d, J = 3 Hz), 8.20 (1H, t, J = 8
Hz), 8.03 (1H, d, J = 9 Hz), 7.98 (1H, dd, J = 8, 1 Hz), 7.85 (1H,
dd, J = 12, 1 Hz), 7.56-7.46 (1H, m), 7.39 (1H, dd, J = 9, 3 Hz),
5.79 (1H, q, J = 7 Hz), 4.28- 4.20 (1H, m), 4.04- 3.98 (2H, m),
3.97- 3.88 (2H, m), 3.46- 3.38 (1H, m), 2.58 (2H, br s), 1.96 (3H,
d, J = 7 Hz), 1.23-1.19 (2H, m), 1.10-1.05 (2H, m); MS (ES) m/z:
471 [M + H].sup.+. 28 N-Cyclopropyl- 4-{5-[(1R)-1- {[6-
(cyclopropyl- carbonyl) pyridin-3- yl]oxy}ethyl]- 1,2,4-
oxadiazol-3- yl}-2- fluorobenzamide ##STR00162## .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. ppm: 8.46 (1H, d, J = 3 Hz), 8.23 (1H, t,
J = 8 Hz), 8.03 (1H, d, J = 9 Hz), 7.97 (1H, dd, J = 8, 1 Hz), 7.82
(1H, dd, J = 12, 1 Hz), 7.39 (1H, dd, J = 9, 3 Hz), 6.89-6.81 (1H,
m), 5.78 (1H, q, J = 7 Hz), 3.46-3.39 (1H, m), 3.00-2.92 (1H, m),
1.96 (3H, d, J = 7 Hz), 1.23- 1.19 (2H, m), 1.10- 1.04 (2H, m),
0.94- 0.88 (2H, m), 0.68- 0.63 (2H, m); MS (ES) m/z: 437 [M +
H].sup.+. 29 2-Fluoro-N- [(1R)-2- hydroxy-1- methylethyl]-
4-(5-{1-[(6- isobutyryl- pyridin-3- yl)oxy]propyl}- 1,2,4-
oxadiazol-3- yl)benzamide hydrochloride ##STR00163## .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta. ppm: 8.42 (1H, d, J = 3 Hz), 8.21
(1H, t, J = 8 Hz), 8.04 (1H, d, J = 9 Hz), 7.98 (1H, dd, J = 8, 2
Hz), 7.85 (1H, dd, J = 12, 2 Hz), 7.36 (1H, dd, J = 9, 3 Hz),
6.94-6.87 (1H, m), 5.54 (1H, dd, J = 7, 6 Hz), 4.37- 4.31 (1H, m),
4.07- 4.00 (1H, m), 3.81 (1H, dd, J = 11, 4 Hz), 3.68 (1H, dd, J =
11, 6 Hz), 2.39-2.24 (2H, m), 1.32 (3H, d, J = 7 Hz), 1.18 (6H, d,
J = 7 Hz), 1.16 (3H, t, J = 7 Hz); MS (ES) m/z: 471 [M +
H].sup.+.
TABLE-US-00007 TABLE 7 Example Compound name Structural formula NMR
30 4-{5-[(1R)-1- {[6-(1,1- Difluoro-3- methylbutyl) pyridin-3-
yl]oxy}propyl]- 1,2,4- oxadiazol-3- yl}-2-fluoro- N-(2-
hydroxyethyl) benzamide ##STR00164## .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. ppm: 8.42 (1H, d, J = 3 Hz), 8.23 (1H, t, J = 8
Hz), 7.99 (1H, dt, J = 8, 1 Hz), 7.86 (1H, dd, J = 12, 1 Hz), 7.57
(1H, d, J = 9 Hz), 7.35 (1H, dd, J = 9, 3 Hz), 7.24-7.16 (1H, m),
5.48 (1H, dd, J = 7, 6 Hz), 3.88 (2H, t, J = 5 Hz), 3.69 (2H, q, J
= 5 Hz), 2.37-2.12 (5H, m), 1.92-1.80 (1H, m), 1.15 (3H, t, J = 7
Hz), 0.94 (6H, d, J = 7 Hz); MS (ES) m/z: 493 [M + H].sup.+. 31
4-{5-[(1R)-1- {[6- (Cyclopropyl- carbonyl) pyridin-3-
yl]oxy}propyl]- 1,2,4- oxadiazol-3- yl}-2-fluoro- N-[(1R)-2-
hydroxy-1- methylethyl] benzamide ##STR00165## .sup.1H-NMR (400
MHz, CDCl.sub.3) .delta. ppm: 8.46 (1H, d, J = 3 Hz), 8.21 (1H, t,
J = 8 Hz), 8.02 (1H, d, J = 9 Hz), 7.97 (1H, dd, J = 8, 2 Hz), 7.84
(1H, dd, J = 12, 2 Hz), 7.37 (1H, dd, J = 9, 3 Hz), 6.92-6.89 (1H,
m), 5.55 (1H, dd, J = 7, 6 Hz), 4.38- 4.31 (1H, m), 3.81 (1H, dd, J
= 11, 4 Hz), 3.68 (1H, dd, J = 11, 6 Hz) , 3.45-3.39 (1H, m) , 2.46
(1H, br s), 2.40-2.23 (2H, m), 1.32 (3H, d, J = 7 Hz), 1.21-1.20
(2H, m), 1.16 (3H, t, J = 7 Hz), 1.08-1.06 (2H, m); MS (FAB) m/z:
469 [M + H].sup.+.
Examples 32
1-{4-[5-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiazo-
l-3-yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea
##STR00166##
[0564] Triethylamine (75.7 .mu.L, 0.543 mmol), and triphosgene
(40.3 mg, 0.136 mmol) were added to a tetrahydrofuran (2.7 mL)
solution of the compound obtained in Reference Example 76 (100 mg,
0.271 mmol) at 0.degree. C., and the mixture was stirred at the
same temperature for 15 minutes. Subsequently, a tetrahydrofuran
(1.0 mL) solution of 2-aminoethanol (85.6 mg, 1.36 mmol) was added
to the mixture, and then the resulting mixture was further stirred
at the same temperature for 15 minutes. Water was added to the
reaction mixture, and the resulting mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was washed with hexane-dichloromethane (2:1, v/v) to give the title
compound (105 mg, yield: 85%).
[0565] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0566] 8.76 (1H, d, J=3 Hz), 8.57 (1H, d, J=3 Hz), 8.39 (1H, dd,
J=9, 8 Hz), 7.97 (1H, d, J=9 Hz), 7.75-7.68 (3H, m), 6.93 (1H, t,
J=6 Hz), 6.28 (1H, q, J=7 Hz), 4.79 (1H, t, J=5 Hz), 3.46 (2H, q,
J=5 Hz), 3.43-3.38 (1H, m), 3.18 (2H, td, J=6, 5 Hz), 1.84 (3H, d,
J=7 Hz), 1.09-0.98 (4H, m).
[0567] MS (ES) m/z: 456 [M+H].sup.+.
[0568] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00008 TABLE 8 Example Compound name Structural formula NMR
33 1-[4-(5- {(1R)-1-[4- (Cyclopropyl- carbonyl) phenoxy] propyl}-
1,2,4- oxadiazol-3- yl)-2- fluorophenyl] urea ##STR00167##
.sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 8.30 (1H, dd, J = 9,
8 Hz), 7.98 (2H, d, J = 9 Hz), 7.87-7.83 (1H, m), 7.78 (1H, dd, J =
12, 2 Hz), 7.03 (2H, d, J = 9 Hz), 6.82 (1H, d, J = 4 Hz), 5.49
(1H, dd, J = 7, 6 Hz), 4.75 (2H, s), 2.63-2.56 (1H, m), 2.35-2.17
(2H, m), 1.21-1.17 (2H, m), 1.13 (3H, t, J = 7 Hz), 1.02-0.96 (2H,
m); MS (ES) m/z: 425 [M + H].sup.+. 34 1-[4-(5- {(1R)-1-[4-
(Cyclopropyl- carbonyl) phenoxy] propyl}- 1,2,4- oxadiazol-3-
yl)-2- fluorophenyl]- 3-[2- hydroxy-1- {hydroxymethyl) ethyl]urea
##STR00168## .sup.1H-NMR (500 MHz, CDCl.sub.3) .delta. ppm: 8.16
(1H, t, J = 8 Hz), 7.94 (2H, d, J = 9 Hz), 7.80 (1H, s), 7.68 (1H,
d, J = 8 Hz), 7.60 (1H, d, J = 12 Hz), 7.00 (2H, d, J = 9 Hz),
6.38-6.30 (1H, m), 5.45 (1H, dd, J = 7, 6 Hz), 3.93-3.70 (7H, m),
2.60-2.52 (1H, m), 2.28-2.13 (2H, m), 1.19-1.13 (2H, m), 1.09 (3H,
t, J = 7.3 Hz), 1.00-0.94 (2H, m); MS (ES) m/z: 499 [M + H].sup.+.
35 1-{4-[5-(1- {[6- (Cyclopropyl- carbonyl) pyridin-3-
yl]oxy}ethyl)- 1,2,4- oxadiazol-3- yl]-2- fluorophenyl} urea
##STR00169## .sup.1H-NMR (400 MHz, DMSO- d.sub.6) .delta. ppm: 8.70
(1H, d, J = 3 Hz), 8.57 (1H, d, J = 3 Hz), 8.40 (1H, t, J = 9 Hz),
7.97 (1H, d, J = 9 Hz), 7.75-7.69 (3H, m), 6.38 (2H, s), 6.28 (1H,
q, J = 7 Hz), 3.43-3.38 (1H, m), 1.84 (3H, d, J = 7 Hz), 1.09-0.99
(4H, m). MS (ES) m/z: 412 [M + H].sup.+.
TABLE-US-00009 TABLE 9 Example Compound name Structural formula NMR
36 1-[2-Fluoro-4- (5-{1-[4-(5- isopropyl- 1,2,4- oxadiazol-3-
yl)phenoxy] propyl}-1,2,4- oxazol-3- yl)phenyl]-3- (2-
hydroxyethyl) urea ##STR00170## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm: 8.28 (1H, dd, J = 8, 8 Hz), 8.00 (2H, d, J = 8 Hz),
7.83 (1H, d, J = 9 Hz), 7.76 (1H, d, J = 12 Hz), 7.06 (2H, d, J = 7
Hz), 5.47 (1H, t, J = 6 Hz), 5.43-5.34 (1H, m), 3.80 (2H, dt, J =
5, 5 Hz), 3.47 (2H, dt, J = 5, 5 Hz), 3.25 (1H, dq, J = 7, 7 Hz),
2.47-2.37 (1H, m), 2.34-2.16 (2H, m), 1.43 (6H, d, J = 7 Hz), 1.13
(3H, t, J = 7 Hz). MS (ES) m/z: 511 [M + H].sup.+. 37 1-(2-
Fluoroethyl)-3- [2-fluoro-4-(5- {1-[4-(5- isopropyl- 1,2,4-
oxadiazol-3- yl)phenoxy] propyl}-1,2,4- oxadiazol-3- yl)phenyl]urea
##STR00171## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.29
(1H, dd, J = 8, 8 Hz) , 7. 99 (2H, d, J = 9 Hz), 7. 84 (1H, d, J =
9 Hz), 7.77 (1H, dd, J = 12, 1 Hz), 7.06 (2H, d, J = 9 Hz), 6.78
(1H, bs), 5.47 (1H, t, J = 6 Hz), 5.23 (1H, bs), 4.61 (1H, dd, J =
5, 5 Hz), 4.51 (1H, dd, J = 5, 4 Hz), 3.65 (2H, dt, J = 5, 5 Hz),
3.59 (1H, dt, J = 5, 5 Hz), 3.25 (1, dq, J = 1, 7 Hz), 2.31-2.17
(2H, m), 1.43 (6H, d, J = 7 Hz), 1.13 (3H, t, J = 7 Hz). MS (FAB)
m/z: 513 [M + H].sup.+. 38 1-[2-Fluoro-4- (5-{1-[4-(5- isopropyl-
1,2,4- oxadiazol-3- yl)phenoxy] propyl}-1,2,4- oxadiazol-3-
yl)phenyl]-3- [(2S)-2- hydroxypropyl] urea ##STR00172## .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. ppm: 8.29 (1H, dd, J = 8, 8 Hz), 8.00
(2H, d, J = 9 Hz), 7.84 (1H, d, J = 9 Hz), 7.77 (1H, d, J = 12 Hz)
, 7.06 (2H, d, J = 9 Hz), 5.47 (1H, t, J = 7 Hz), 5.30 (1H, bs),
4.06- 3.96 (1H, m), 3.53-3.44 (1H, m), 3.31-3.10 (2H, m), 2.34-2.16
(3H, m), 1.43 (6H, d, J = 7 Hz), 1.25 (3H, d, J = 6 Hz), 1.13 (3H,
t, J = 7 Hz). MS (FAB) m/z: 525 [M + H].sup.+.
TABLE-US-00010 TABLE 10 Ex- Com- am- pound ple name Structural
formula NMR 39 2-({[2- Fluoro- 4-(5- {1-[4-(5- isopropyl- 1,2,4-
oxadiazol- 3- yl) phenoxy] propyl}- 1,2,4- oxadiazol- 3- yl)phenyl]
carbamoyl} amino) ethyl methyl carbonate ##STR00173## .sup.1H-NMR
(500 MHz, CDCl.sub.3) .delta. ppm: 8.29 (1H, dd, J = 8, 8 Hz), 8.00
(2H, d, J = 9 Hz), 7.84 (1H, d, J = 9 Hz), 7.77 (1H, dd, J = 12, 2
Hz), 7.06 (2H, d, J = 9 Hz), 6.74- 6.68 (1H, m), 5.47 (1H, t, J = 7
Hz), 5.21-5.17 (1H, m), 4.29 (2H, t, J = 5 Hz), 3.82 (3H, s), 3.61
(2H, dt, J = 5, 5 Hz), 3.25 (1H, dq, J = 7, 7 Hz), 2.33-2.17 (2H,
m), 1.43 (6H, d, J = 7 Hz), 1.13 (3H, t, J = 7 Hz). MS (FAB) m/z:
56 9 [M + H].sup.+. 40 2-({ [2- Fluoro- 4-(5- {1-[4-(5- isopropyl-
1,2,4- oxadiazol- 3-yl) phenoxy] propyl}- 1,2,4- oxadiazol- 3-yl)
phenyl] carbamoyl} amino) ethyl ethyl carbamate ##STR00174##
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.30 (1H, dd, J = 9,
8 Hz), 8.00 (2H, d, J = 9 Hz), 7.83 (1H, d, J = 8 Hz), 7.76 (1H, d,
J = 12 Hz), 7.06 (2H, d, J = 9 Hz), 6.80-6.74 (1H, m), 5.47 (1H, t,
J = 6 Hz), 5.43- 5.37 (1H, m), 4.78- 4.70 (1H, m), 4.2 7- 4.18 (2H,
m), 3.59- 3.51 (2H, m), 3.28- 3.16 (3H, m), 2.32- 2.15 (2H, m),
1.43 (6H, d, J = 7 Hz), 1.16-1.08 (6H, m). MS (FAB) m/z: 582 [M +
H].sup.+. 41 1-[2- Fluoro- 4-{5- {(1R)-1- [4-(5- isopropyl- 1,2,4-
oxadiazol- 3-yl) phenoxy] propyl}- 1,2,4- oxadiazol- 3-yl) phenyl]-
3- methyl- urea ##STR00175## .sup.1H-NMR (400 MHz, CDCl.sub.3)
.delta. ppm: 8.31 (1H, dd, J = 9, 8 Hz), 8.00 (2H, d, J = 9 Hz),
7.84 (1H, d, J = 8 Hz) , 7.76 (1H, d, J = 12, 2 Hz), 7.06 (2H, d, J
= 9 Hz), 6.66- 6.59 (1H, m), 5.47 (1H, t, J = 7 Hz), 4.80-4.68 (1H,
m), 3.25 (1H, dq, J = 7, 7 Hz), 2.90 (3H, s), 2.32- 2.18 (2H, m),
1.43 (6H, d, J = 7 Hz), 1.13 (3H, t, J = 7 Hz). MS (ES) m/z: 481 [M
+ H].sup.+.
Example 42
4-[3-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiazol-5-
-yl]-2-fluoro-N-[2-hydroxy-1-(hydroxymethyl)ethyl]benzamide
##STR00176##
[0570] 1-Hydroxybenzotriazole monohydrate (32.4 mg, 0.211 mmol) and
N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (40.5
mg, 0.211 mmol) were added to an N,N-dimethylformamide (1.0 mL)
solution of the compound obtained in Reference Example 94 (70.0 mg,
0.176 mmol) at room temperature, and the mixture was stirred at the
same temperature for 30 minutes. Subsequently, an
N,N-dimethylformamide (1.0 mL) solution of 2-amino-1,3-propanediol
(48.2 mg, 0.528 mmol) was added to the mixture at 0.degree. C., and
the resulting mixture was further stirred at the same temperature
for 1.5 hours. Water was added to the reaction mixture, and the
resulting mixture was extracted twice with ethyl acetate. The
organic layer thus obtained was washed with a saturated aqueous
solution of sodium hydrogen carbonate and brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off under
reduced pressure, and the resulting residue was purified by silica
gel column chromatography
(dichloromethane:methanol=100:0.fwdarw.90:10, v/v) to give the
title compound (73.7 mg, yield: 89%).
[0571] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm:
[0572] 8.47 (1H, d, J=3 Hz), 8.26 (1H, dd, J=9, 8 Hz), 8.04 (1H,
dd, J=8, 1 Hz), 8.01 (1H, d, J=9 Hz), 7.93 (1H, dd, J=12, 1 Hz),
7.57-7.46 (1H, m), 7.43 (1H, dd, J=9, 3 Hz), 5.74 (1H, q, J=7 Hz),
4.28-4.22 (1H, m), 4.04-3.99 (2H, m), 3.97-3.91 (2H, m), 3.45-3.39
(1H, m), 2.46 (2H, dd, J=7, 5 Hz), 1.91 (3H, d, J=7 Hz), 1.22-1.17
(2H, m), 1.09-1.03 (2H, m);
[0573] MS (ES) m/z: 471 [M+H].sup.+.
Example 43
1-{4-[3-(1-{[6-(Cyclopropylcarbonyl)pyridin-3-yl]oxy}ethyl)-1,2,4-oxadiazo-
l-5-yl]-2-fluorophenyl}-3-(2-hydroxyethyl)urea
##STR00177##
[0575] Triethylamine (35.0 .mu.L, 0.251 mmol), and triphosgene
(18.6 mg, 0.0627 mmol) were added to a tetrahydrofuran (1.0 mL)
solution of the compound obtained in Reference Example 96 (46.2 mg,
0.125 mmol) at 0.degree. C., and the mixture was stirred at the
same temperature for 15 minutes. Subsequently, a tetrahydrofuran
(1.0 mL) solution of 2-aminoethanol (23.7 mg, 0.376 mmol) was added
to the mixture, and then the resulting mixture was further stirred
at the same temperature for 15 minutes. Water was added to the
reaction mixture, and the resulting mixture was extracted twice
with ethyl acetate. The organic layer thus obtained was washed with
brine, and then dried over anhydrous sodium sulfate. The solvent
was distilled off under reduced pressure, and the resulting residue
was washed with a hexane-dichloromethane (2:1, v/v) to give the
title compound (49.4 mg, yield: 87%).
[0576] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. ppm:
[0577] 8.92 (1H, d, J=3 Hz), 8.52 (1H, d, J=3 Hz), 8.48 (1H, t, J=8
Hz), 7.94 (1H, d, J=9 Hz), 7.91-7.85 (2H, m), 7.67 (1H, dd, J=9, 3
Hz), 7.01 (1H, t, J=5 Hz), 6.08 (1H, q, J=7 Hz), 4.80 (1H, t, J=5
Hz), 3.6 (2H, td, J=6, 5 Hz), 3.42-3.37 (1H, m), 3.19 (2H, td, J=6,
5 Hz), 1.77 (3H, d, J=7 Hz), 1.07-0.98 (4H, m);
[0578] MS (ES) m/z: 456 [M+H].sup.+.
[0579] By using a compound obtained in a Reference Example or a
compound obtained in an Example, the compounds in the following
Tables were obtained by reference to the above Examples.
TABLE-US-00011 TABLE 11 Example Compound name Structural formula
NMR 44 4-(3-{1-[4- (Cyclopropyl- carbonyl) phenoxy] ethyl}-1,2,4-
oxadiazol-5- yl)-2-fluoro-N- [(1R)-2- hydroxy-1- methylethyl]
benzamide ##STR00178## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta.
ppm: 8.29-8.23 (1H, m), 8.04 (1H, d, J = 8 Hz), 7.99 (2H, d, J = 9
Hz), 7.92 (1H, d, J = 12 Hz), 7.09 (2H, d, J = 9 Hz), 6.97- 6.88
(1H, m), 5.75-5.68 (1H, m), 4.35 (1H, bs), 3.87-3.78 (1H, m),
3.72-3.66 (1H, m), 2.65-2.56 (1H, m), 2.38-2.32 (1H, m), 1.87 (3H,
d, J = 6 Hz), 1.33 (3H, d, J = 7 Hz), 1.22- 1.18 (2H, m), 1.03-0.96
(2H, m). MS (ES) m/z: 454 [M + H].sup.+. 45 4-{3-{1-[4-
(Cyclopropyl- carbonyl) phenoxy] ethyl}-1,2,4- oxadiazol-5-
yl)-2-fluoro-N- [2-hydroxy-1- (hydroxymethyl) ethyl]benzamide
##STR00179## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.25
(1H, d, J = 8 Hz), 8.04 (1H, d, J = 8 Hz), 7.99 (2H, d, J = 9 Hz),
7.93 (1H, d, J = 12 Hz), 7.57-7.49 (1H, s), 7.09 (2H, d, J = 9 Hz),
5.78-5.69 (1H, m), 4.25 (1H, bs), 4.06-3.90 (4H, m), 2.65-2.58 (1H,
m), 2.50-2.43 (2H, m), 1.87 (3H, d, J = 6 Hz), 1.123-1.18 (2H, m),
1.04-0.96 (2H, m). MS (ES) m/z: 470 [M + H].sup.+. 46
1-[4-(3-{1-[4- (Cyclopropyl- carbonyl) phenoxy] ethyl}-1,2,4-
oxadiazol-5- yl)-2- fluorophenyl]- 3-(2- hydroxyethyl) urea
##STR00180## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.39
(1H, dd, J = 9, 8 Hz), 7.98 (2H, d, J = 9 Hz), 7.88 (1H, d, J = 9
Hz), 7.80 (1H, d, J = 12 Hz), 7.08 (2H, d, J = 9 Hz), 5.68 (1H, q,
J = 7 Hz), 5.60-5.48 (1H, m), 3.85-3.78 (2H, m), 3.51-3.45 (2H, m),
2.65-2.58 (1H, m), 2.48-2.32 (1H, m), 1.84 (3H, d, J = 6 Hz),
1.24-1.17 (2H, m), 1.04-0.97 (2H, m). MS (ES) m/z: 455 [M +
H].sup.+.
TABLE-US-00012 TABLE 12 Example Compound name Structural formula
NMR 47 1-[4-(3-{1-[4- (Cyclopropyl- carbonyl) phenoxy]
ethyl}-1,2,4- oxadiazol-5- yl)-2- fluorophenyl] urea ##STR00181##
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.41 (1H, dd, J = 8,
7 Hz), 7.97 (2H, d, J = 9 Hz), 7.90 (1H, d, J = 9 Hz), 7.82 (1H, d,
J = 11 Hz), 7.16- 7.05 (3H, m), 5.68 (1H, q, J = 7 Hz), 4.90 (2H,
s), 2.65-2.58 (1H, m), 1.84 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m),
1.02-0.96 (2H, m). MS (ES) m/z: 411 [M + H].sup.+. 48
1-[4-(3-{1-[4- (Cyclopropyl- carbonyl) phenoxy] propyl}- 1,2,4-
oxadiazol-5- yl)-2- fluorophenyl]- 3-(2- hydroxyethyl) urea
##STR00182## .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.39
(1H, dd, J = 8, 8 Hz), 7.97 (2H, d, J = 9 Hz), 7.88 (1H, d, J = 9
Hz), 7.80 (1H, d, J = 11 Hz), 7.08 (2H, d, J = 9 Hz), 5.59-5.49
(1H, m), 5.41 (1H, t, J = 7 Hz), 3.85-3.77 (2H, m), 3.47 (2H, dt, J
= 5, 5 Hz), 2.62-2.56 (1H, m), 2.44-2.12 (3H, m), 1.22-1.13 (2H,
m), 1.10 (3H, t, J = 7 Hz), 1.04-0.96 (2H, m). MS (ES) m/z: 469 [M
+ H].sup.+. 49 1-[4-(3-{1-[4- (Cyclopropyl- carbonyl) phenoxy]
propyl}- 1,2,4- oxadiazol-5- yl)-2- fluorophenyl] urea ##STR00183##
.sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. ppm: 8.42 (1H, dd, J = 8,
8 Hz), 7.97 (2H, d, J = 9 Hz), 7.90 (1H, d, J = 8 Hz), 7.81 (1H,
dd, J = 11, 2 Hz), 7.20-7.17 (1H, m), 7.08 (2H, d, J = 9 Hz), 5.41
(1H, t, J = 7 Hz), 4.94 (2H, s), 2.64-2.56 (1H, m), 2.32-2.13 (2H,
m), 1.22-1.15 (2H, m), 1.09 (3H, t, J = 7 Hz), 1.04-0.96 (2H, m).
MS (ES) m/z: 425 [M + H].sup.+.
TABLE-US-00013 TABLE 13 Example Compound name Structural formula
NMR 50 4-[3-(1-{[6- (Cyclopropyl- carbonyl) pyridin-3-
yl]oxy}ethyl)- 1,2,4-oxadiazol- 5-yl]-2-fluoro-N- [(1R)-2-hydroxy-
1- methylethyl] benzamide ##STR00184## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.47 (1H, d, J = 3 Hz), 8.26 (1H, t, J = 8
Hz), 8.03 (1H, dd, J = 8, 1 Hz), 8.01 (1H, d, J = 9 Hz), 7.91 (1H,
dd, J = 12, 1 Hz), 7.42 (1H, dd, J = 9, 3 Hz), 6.97-6.85 (1H, m),
5.74 (1H, q, J = 6 Hz), 4.39- 4.29 (1H, m), 3.85-3.77 (1H, m),
3.73-3.64 (1H, m), 3.46- 3.38 (1H, m), 2.34 (1H, t, J = 6 Hz), 1.90
(3H, d, J = 6 Hz), 1.33 (3H, d, J = 7 Hz), 1.22-1.17 (2H, m), 1.09-
1.03 (2H, m); MS (ES) m/z: 455 [M + H].sup.+. 51 N-Cyclopropyl-4-
[3-(1-{[6- {cyclopropyl- carbonyl) pyridin-3- yl]oxy}ethyl)-
1,2,4-oxadiazol- 5-yl]-2- fluorobenzamide ##STR00185## .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. ppm: 8.47 (1H, d, J = 3 Hz), 8.28
(1H, t, J = 8 Hz), 8.03 (1H, d, J = 8, 2 Hz), 8.01 (1H, d, J = 9
Hz), 7.89 (1H, dd, J = 12, 2 Hz), 7.42 (1H, dd, J = 9, 3 Hz),
6.87-6.80 (1H, m), 5.74 (1H, q, J = 7 Hz), 3.45- 3.38 (1H, m),
2.99-2.93 (1H, m), 1.90 (3H, d, J = 7 Hz), 1.22- 1.17 (2H, m),
1.08-1.03 (2H, m), 0.94-0.89 (2H, m), 0.69- 0.63 (2H, m). MS (ES)
m/z: 437 [M + H].sup.+. 52 1-{4-[3-(1-{[6- (Cyclopropyl- carbonyl)
pyridin-3- yl]oxy}ethyl)- 1,2,4-oxadiazol- 5-yl]-2-
fluorophenyl}urea ##STR00186## .sup.1H-NMR (400 MHz, DMSO-d.sub.6)
.delta. ppm: 8.85 (1H, d, J = 3 Hz), 8.52 (1H, d, J = 3 Hz), 8.48
(1H, dd, J = 9, 8 Hz), 7.94 (1H, d, J = 9 Hz), 7.90-7.85 (2H, m),
7.68 (1H, dd, J = 9, 3 Hz), 6.46 (2H, s), 6.09 (1H, q, J = 7 Hz),
3.42- 3.37 (1H, m), 1.77 (3H, d, J = 7 Hz), 1.07-0.98 (4H, m); MS
(ES) m/z: 412 [M + H].sup.+.
TABLE-US-00014 TABLE 14 Example Compound name Structural formula
NMR 53 4-(3-{(1R)-1- [4- (Cyclopropyl- carbonyl) phenoxy] propyl}-
1,2,4- oxadiazol-5- yl)-2-fluoro- N-[(1R)-2- hydroxy-1-
methylethyl] benzamide ##STR00187## .sup.1H-NMR (500 MHz,
CDCl.sub.3) .delta. ppm: 8.25 (1H, dd, J = 11, 8 Hz), 8.02 (1H, d,
J = 8 Hz), 7.98 (2H, d, J = 9 Hz), 7.91 (1H, d, J = 11 Hz), 7.08
(2H, d, J = 9 Hz), 6.96-6.88 (1H, m), 5.46 (1H, t, J = 7 Hz), 4.34
(1H, bs), 3.84-3.79 (1H, m), 3.71- 3.66 (1H, m), 2.63-2.56 (1H, m),
2.43-2.22 (3H, m), 1.32 (3H, d, J = 7 Hz), 1.19-1.15 (2H, m), 1.11
(3H, t, J = 7 Hz), 0.98-0.95 (2H, m). MS (ES) m/z: 468 [M +
H].sup.+. 54 4-{3-{(1R)-1- [4- (Cyclopropyl- carbonyl) phenoxy]
propyl}- 1,2,4- oxadiazol-5- yl)-2-fluoro- N-[2-hydroxy- 1-
(hydroxymethyl) ethyl]benzamide ##STR00188## .sup.1H-NMR (400 MHz,
CDCl.sub.3) .delta. ppm: 8.25 (1H, dd, J = 8, 8 Hz), 8.04 (1H, d, J
= 8 Hz), 7.98 (2H, d, J = 9 Hz), 7.93 (1H, d, J = 11 Hz), 7.57-
7.48 (1H, m), 7.08 (2H, d, J = 9 Hz), 5.46 (1H, t, J = 7 Hz), 4.25
(1H, bs), 4.05-3.90 (4H, m), 2.64-2.56 (1H, m), 2.51- 2.45 (2H, m),
2.34-2.12 (2H, m), 1.20-1.17 (2H, m), 1.11 (3H, t, J = 7 Hz),
1.02-0.97 (2H, m). MS (ES) m/z: 484 [M + H].sup.+. 55
2-Fluoro-N-[2- hydroxy-1- (hydroxymethyl) ethyl]-4-{3-
[(1R)-1-{4-[3- (trifluoro- methyl)-1,2,4- oxadiazol-5- yl]phenoxy}
propyl]-1,2,4- oxadiazol-5- yl}benzamide ##STR00189## .sup.1H-NMR
(400 MHz, CDCl.sub.3) .delta. ppm: 8.25 (1H, dd, J = 8, 8 Hz), 8.11
(2H, d, J = 9 Hz), 8.04 (1H, d, J = 9 Hz), 7.93 (1H, d, J = 12 Hz),
7.56- 7.47 (1H, m), 7.18 (2H, d, J = 9 Hz), 5.48 (1H, t, J = 7 Hz),
4.28-4.23 (1H, m), 4.04-3.90 (4H, m), 2.40- 2.17 (4H, m), 1.12 (3H,
t, J = 7 Hz). MS (ES) m/z: 552 [M + H].sup.+.
Formulation Example
[0580] 5 g of each of the compounds obtained in the Examples, 90 g
of lactose, 34 g of corn starch, 20 g of crystalline cellulose, and
1 g of magnesium stearate were mixed with a blender, and then the
mixture was tableted with a tableting machine. Thereby, tablets
were obtained.
Test Example 1
Mouse oGTT (Oral Glucose Tolerance Test)
[0581] Each compound was suspended in a 0.5 w/v % methyl cellulose
solution by grinding in an agate mortar at a concentration of 1
mg/mL. Male C57/BL6J mice (Charles River Laboratories Japan, Inc.)
were purchased at 6 to 8 weeks of age, and then used at 9 to 13
weeks of age. The mice were fasted between 17:00 and 18:00 one day
before the test day, and the test was started after 16 to 17 hours
of the fasting. Five mice were used for each group. After
collecting blood from the tail vein, a suspension of the compound
was administered orally at a dosage of 10 mg/kg. The 0.5 w/v %
methyl cellulose solution was administered to a negative control
group. Blood was collected from the tail vein 25 minutes after the
administration of the compound, and then a 30 w/v % glucose
solution was administered orally at a volume of 10 mL/kg 30 minutes
after the compound administration. Blood was collected from the
tail vein 15, 30, 60 and 120 minutes after the glucose
administration. Each of the blood samples was centrifuged to obtain
the plasma, and the plasma glucose level (mg/dL) was measured with
a glucose analyzer (Glucoloader-GXT, A&T Corp.). The plasma
glucose AUC (mg/dLmin) in each mouse was calculated using the
plasma glucose levels at 5 minutes before and 15, 30, 60 and 120
minutes after the glucose administration. The arithmetic mean of
the AUC was calculated for each group and the percentage decrease
in plasma glucose AUC (%) compared with the negative control group
was calculated as an index of the efficacy.
[0582] As a result, all of the obtained compounds showed a 4% or
more percentage decrease in plasma glucose AUC.
Test Example 2
Rat oGTT and Measurement of Plasma Compound Concentration
[0583] Each compound is suspended in a vehicle (0.5 w/v % methyl
cellulose or 20 w/v % cyclodextrin solution) at a concentration of
1 to 10 mg/mL to prepare a suspension. As necessary, the prepared
suspension is diluted with the above-described vehicle in a
stepwise fashion, and multiple doses of the suspension are
prepared. Male Zucker fatty rats (Charles River Laboratories Japan,
Inc.) or Zucker diabetic fatty (ZDF) rats (Charles River
Laboratories Japan, Inc.) can be used at 10 to 18 weeks of age. Two
days before the oGTT, plasma glucose, body weight, and plasma
insulin concentrations are measured, and rats are equally allocated
to each group (n=5 to 8) based on these parameters. The rats are
fasted from around 15:00 one day before the oGTT day. On the oGTT
day, the suspension prepared by the method described above is
administered orally to the rats at a volume of 1 to 5 mL/kg, and 30
minutes after the dosing, a 25 to 50 w/v % glucose solution is
administered orally at a volume of 4 to 5 mL/kg. Blood is collected
from the tail vein before the administration of the compound, 5
minutes before the administration of glucose, and 30, 60, 120, and
180 minutes after the administration of glucose. The obtained blood
samples are centrifuged to separate the plasma, and the plasma
glucose level is measured with a glucose analyzer (Glucoloader-GXT,
A&T Corp.). The plasma glucose AUC in each rat is calculated
using the plasma glucose levels before and after the glucose
administration. The arithmetic mean of the AUC is calculated in
each group and the percentage decrease in the AUC (%) compared with
the vehicle-administered group is calculated as an index of the
efficacy.
[0584] The plasma samples obtained by the method described above
are used for measurement of the plasma concentration of the test
compound. In order to quantify the plasma concentration of the test
compound, blood is additionally collected 4 to 8 hours and 24 hours
after the administration of the compound. The plasma is subjected
to protein removal, and applied to a liquid chromatography/mass
analyzer to quantify the plasma concentration of the test
compound.
Test Example 3
Assessment for the Protective Effect on Pancreatic .beta. Cells
[0585] The protective effect of the test compound on pancreatic
.beta. cells can be confirmed with reference to the method
described in Junko Ogawa, et al., Life Sciences, Vol. 65, No. 12,
pp. 1287-1296 (1999).
INDUSTRIAL APPLICABILITY
[0586] The compounds of the present invention or pharmaceutically
acceptable salts thereof are capable of treating and/or preventing
type 1 diabetes, type 2 diabetes, gestational diabetes,
hyperglycemia due to other factors, impaired glucose tolerance,
diabetes-associated diseases, diabetic complications and the like,
and are therefore useful as an active ingredient of a
pharmaceutical composition for protecting .beta. cells or the
pancreas.
* * * * *