U.S. patent application number 12/950670 was filed with the patent office on 2011-03-17 for imidazoyl pyridine compounds and salts thereof.
Invention is credited to Takashi Doko, Hiroaki Hagiwara, Daiju Hasegawa, Koichi Ito, Toshihiko Kaneko, Koki Kawano, Teiji KIMURA, Noritaka Kitazawa, Takehiko Miyagawa, Takeo Sasaki, Nobuaki Sato, Daisuke Shinmyo, Mamoru Takaishi, Toshiyuki Uemura, Yu Yoshida.
Application Number | 20110065696 12/950670 |
Document ID | / |
Family ID | 40408542 |
Filed Date | 2011-03-17 |
United States Patent
Application |
20110065696 |
Kind Code |
A1 |
KIMURA; Teiji ; et
al. |
March 17, 2011 |
IMIDAZOYL PYRIDINE COMPOUNDS AND SALTS THEREOF
Abstract
A compound represented by the formula (I): ##STR00001## or a
pharmacologically acceptable salt thereof, wherein Ar.sub.1
represents an imidazolyl group or the like which may be substituted
with a C1-6 alkyl group, Ar.sub.2 represents a phenyl group or the
like which may be substituted with a C1-6 alkoxy group, X.sub.1
represents a double bond or the like and Het represents a triazolyl
group or the like which may be substituted with a C1-6 alkyl group
or the like, is effective as a therapeutic or prophylactic agent
for a disease caused by A.beta..
Inventors: |
KIMURA; Teiji; (Tsukuba,
JP) ; Kitazawa; Noritaka; (Tsukuba, JP) ;
Kaneko; Toshihiko; (Tsukuba, JP) ; Sato; Nobuaki;
(Tsukuba, JP) ; Kawano; Koki; (Tsukuba, JP)
; Ito; Koichi; (Tsukuba, JP) ; Takaishi;
Mamoru; (Tsukuba, JP) ; Sasaki; Takeo;
(Tsukuba, JP) ; Yoshida; Yu; (Tsukuba, JP)
; Uemura; Toshiyuki; (Tsukuba, JP) ; Doko;
Takashi; (Tsukuba, JP) ; Shinmyo; Daisuke;
(Tsukuba, JP) ; Hasegawa; Daiju; (Tsukuba, JP)
; Miyagawa; Takehiko; (London, GB) ; Hagiwara;
Hiroaki; (Tsukuba, JP) |
Family ID: |
40408542 |
Appl. No.: |
12/950670 |
Filed: |
November 19, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12200731 |
Aug 28, 2008 |
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12950670 |
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60935824 |
Aug 31, 2007 |
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61025099 |
Jan 31, 2008 |
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61051751 |
May 9, 2008 |
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Current U.S.
Class: |
514/230.5 ;
514/259.31; 514/303; 514/338; 544/105; 544/263; 546/119;
546/272.4 |
Current CPC
Class: |
C07D 401/14 20130101;
C07D 403/10 20130101; A61P 25/00 20180101; C07D 409/14 20130101;
A61P 25/28 20180101; C07D 403/14 20130101 |
Class at
Publication: |
514/230.5 ;
546/119; 544/263; 546/272.4; 544/105; 514/303; 514/259.31;
514/338 |
International
Class: |
A61K 31/437 20060101
A61K031/437; C07D 471/04 20060101 C07D471/04; C07D 487/04 20060101
C07D487/04; C07D 498/04 20060101 C07D498/04; A61K 31/519 20060101
A61K031/519; A61K 31/4439 20060101 A61K031/4439; A61K 31/5383
20060101 A61K031/5383; A61P 25/00 20060101 A61P025/00; A61P 25/28
20060101 A61P025/28 |
Claims
1. A compound represented by the formula (I-1): ##STR00307## or a
pharmacologically acceptable salt thereof, wherein X.sub.1
represents --CR.sup.1.dbd.CR.sup.2-- (wherein R.sup.1 and R.sup.2
are the same or different and each represent (1) a hydrogen atom,
(2) a C1-6 alkyl group or (3) a halogen atom) and Het represents a
group which may be substituted with 1 to 3 substituents selected
from a C1-6 alkyl group, a halogen atom, a hydroxyl group and a
cyano group, and is represented by the following formula:
##STR00308## wherein R.sup.3 and R.sup.4 are the same or different
and each represents a substituent selected from Substituent Group
A1, X.sub.2 represents a methylene group which may be substituted
with a substituent selected from Substituent Group A1, or an oxygen
atom and n.sub.a represents an integer of 0 to 2; Substituent Group
A1: (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group,
(4) a cyano group, (5) a C1-6 alkyl group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, and
(6) A*(wherein A* represents an aromatic hydrocarbon ring selected
from a phenyl group and a naphthyl group, and a benzodioxolyl
group, which may be substituted with 1 to 3 substituents selected
from Substituent Group A2; Substituent Group A2: (1) a hydrogen
atom, (2) a halogen atom, (3) a hydroxyl group, (4) a C1-6 alkyl
group (wherein the C1-6 alkyl group may be substituted with 1 to 3
halogen atoms) and (5) a C1-6 alkoxy group (wherein the C1-6 alkoxy
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms).
2. The compound or pharmacologically acceptable salt thereof
according to claim 1, wherein Het represents a group which may be
substituted with 1 to 3 substituents selected from a C1-6 alkyl
group, a halogen atom, a hydroxyl group and a cyano group, and is
represented by one of the following formulas: ##STR00309## wherein
R.sup.3 and R.sup.4 are as defined in claim 1.
3. The compound or pharmacologically acceptable salt thereof
according to claim 1, wherein Het represents a group which may be
substituted with 1 to 3 substituents selected from a C1-6 alkyl
group, a halogen atom, a hydroxyl group and a cyano group, and is
represented by one of the following formulas: ##STR00310## wherein
R.sup.3 and R.sup.4 are as defined in claim 1.
4. The compound or pharmacologically acceptable salt thereof
according to claim 2, wherein R.sup.3 is selected from the group
consisting of a phenyl group and a naphthyl group, which may be
substituted with 1 to 3 substituents selected from the group
consisting of a halogen atom, a methyl group, trifluoromethyl group
and trifluoromethoxy group, and R.sup.4 is selected from the group
consisting of a hydrogen atom, a hydroxyl group, a cyano group and
a methyl group.
5. The compound or pharmacologically acceptable salt thereof
according to claim 2, wherein the compound is selected from the
group consisting of: 1)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyr-
idine, 2)
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-im-
idazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine, 3)
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
4)
(-)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridi-
ne, 5)
(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-im-
idazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]py-
ridine, 6)
(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-i-
midazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]p-
yridine, 7)
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne, 8)
(-)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H--
imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a-
]pyridine, 9)
(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
10)
(-)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
11)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, 12)
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl-
]vinyl}-8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, 13)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl-
]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
14)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
15)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,
16)
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
17)
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-im-
idazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine, 18)
(-)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imida-
zol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine, 19)
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(-
4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]tr-
iazolo[1,5-a]pyridine, 20)
(-)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, 21)
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e, 22)
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-m-
ethyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triaz-
olo[1,5-a]pyridine, 23)
(5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, 24)
(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, 25)
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-
-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,
and 26)
(S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4--
methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1-
,2,4]triazole, 27)
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, 28)
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imi-
dazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine, 29)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2--
yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
and 30)
(-)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne.
6. The compound or pharmacologically acceptable salt thereof
according to claim 2, wherein the compound is selected from the
group consisting of: 1)
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e, 2)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]-
pyridine, 3)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
4)
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
5)
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-meth-
yl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo-
[1,5-a]pyridine, 6)
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
7)
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine, 8)
(5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, 9)
(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, 10)
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, 11)
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imi-
dazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine, 12)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2--
yl]vinyl}-8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
and 13)
(-)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne.
7. A pharmaceutical composition comprising: the compound or
pharmacologically acceptable salt thereof according to claim 1 as
an active ingredient; and a pharmaceutically acceptable carrier.
Description
RELATED APPLICATIONS
[0001] The present application is a 37 CFR .sctn.1.53(b) divisional
of U.S. application Ser. No. 12/200,731 filed Aug. 28, 2008, which
claims priority of U.S. Provisional Application No. 60/935,824
filed Aug. 31, 2007, U.S. Provisional Application No. 61/025,099
filed Jan. 31, 2008, and U.S. Provisional Application No.
61/051,751 filed May 9, 2008. The contents of each of these
applications are hereby incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to a pharmaceutical, more
particularly, to a multi-cyclic cinnamide derivative effective for
treatment of a neurodegenerative disease caused by amyloid-.beta.
(hereinafter referred to as A.beta.) such as Alzheimer's disease or
Down's syndrome and a medicine, in particular, a medicine for
prevention or treatment of a disease caused by A.beta. comprising
the derivative as an active ingredient.
[0004] 2. Description of Related Art
[0005] Alzheimer's disease is a disease characterized by
degeneration and loss of neurons as well as formation of senile
plaques and neurofibrillary degeneration. Currently, Alzheimer's
disease is treated only with symptomatic treatment using a symptom
improving agent typified by an acetylcholinesterase inhibitor, and
a fundamental remedy to inhibit progression of the disease has not
yet been developed. It is necessary to develop a method for
controlling the cause of the onset of pathology in order to create
a fundamental remedy for Alzheimer's disease.
[0006] It is assumed that A.beta.-proteins as metabolites of
amyloid precursor proteins (hereinafter referred to as APP) are
highly involved in degeneration and loss of neurons and onset of
symptoms of dementia (see Non-Patent Documents 1 and 2, for
example). Main molecular species of A.beta.-protein are A.beta.40
consisting of 40 amino acids and A.beta.42 with two amino acids
added at the C-terminal. The A.beta.40 and A.beta.42 are known to
have high aggregability (see Non-Patent Document 3, for example)
and to be main components of senile plaques (see Non-Patent
Documents 3, 4 and 5, for example). Further, it is known that the
A.beta.40 and A.beta.42 are increased by mutation in APP and
presenilin genes which is observed in familial Alzheimer's disease
(see Non-Patent Documents 6, 7 and 8, for example). Accordingly, a
compound that reduces production of A.beta.40 and A.beta.42 is
expected as a progression inhibitor or prophylactic agent for
Alzheimer's disease.
[0007] A.beta. is produced by cleaving APP by .beta.-secretase and
subsequently by .gamma.-secretase. For this reason, attempts have
been made to create .gamma.-secretase and .beta.-secretase
inhibitors in order to reduce A.beta. production. Many of these
secretase inhibitors already known are, for example, peptides and
peptide mimetics such as L-685,458 (see Non-Patent Document 9, for
example), LY-411,575 (see Non-Patent Documents 10, 11 and 12, for
example) and LY-450,139 (see Non-Patent Documents 13, 14 and 15).
Nonpeptidic compounds are, for example, MRK-560 (see Non-Patent
Documents 16 and 17) and compounds having a plurality of aromatic
rings as disclosed in Patent Document 1. However, the compound
represented by the formula (VI) as disclosed in page 17 of the
specification differs from the compound of the present invention in
that the compound is limited to a compound having a
2-aminothiazolyl group as a main structure. [0008] [Non-Patent
Document 1] Klein W L, and seven others, Alzheimer's
disease-affected brain: Presence of oligomeric A.beta. ligands
(ADDLs) suggests a molecular basis for reversible memory loss,
Proceeding of the National Academy of Science USA, 2003, Sep., 2;
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and sixteen others, Antibodies against .beta.-amyloid slow
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critical for the seeding of amyloid formation: Implications for the
pathogenesis of Alzheimers' disease, Biochemistry, 1993, 32(18), p.
4693-4697. [0011] [Non-Patent Document 4] Glenner G G, and one
other, Alzheimer's disease: initial report of the purification and
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Biochemical and Biophysical Research Communications, 1984, May 16,
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1985, June, 82(12), p. 4245-4249. [0013] [Non-Patent Document 6]
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twenty others, Secreted amyloid .beta.-protein similar to that in
the senile plaques of Alzheimer's disease is increased in vivo by
the presenilin 1 and 2 and APP mutations linked to familial
Alzheimer's disease, Nature Medicine, 1996, August, 2(8), p.
864-870. [0015] [Non-Patent Document 8] Forman M S, and four
others, Differential effects of the swedish mutant amyloid
precursor protein on .beta.-amyloid accumulation and secretion in
neurons and normeuronal cells, The Journal of Biological Chemistry,
1997, Dec., 19, 272(51), p. 32247-32253. [0016] [Non-Patent
Document 9] Shearman M S, and nine others, L-685, 458, an Aspartyl
Protease Transition State Mimic, Is a Potent Inhibitor of Amyloid
.beta.-Protein Precursor .gamma.-Secretase Activity, Biochemistry,
2000, Aug., 1, 39(30), p. 8698-8704. [0017] [Non-Patent Document
10] Shearman M S, and six others, Catalytic Site-Directed
.gamma.-Secretase Complex Inhibitors Do Not Discriminate
Pharmacologically between Notch S3 and .beta.-APP Clevages,
Biochemistry, 2003, Jun., 24, 42(24), p. 7580-7586. [0018]
[Non-Patent Document 11] Lanz T A, and three others, Studies of
A.beta. pharmacodynamics in the brain, cerebrospinal fluid, and
plasma in young (plaque-free) Tg2576 mice using the
.gamma.-secretase inhibitor
N2-[(2S)-2-(3,5-difluorophenyl)-2-hydroxyethanoyl]-N-1-[(7S)-5-methyl-6-o-
xo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide
(LY-411575), The Journal of Pharmacology and Experimental
Therapeutics, 2004, April, 309(1), p. 49-55. [0019] [Non-Patent
Document 12] Wong G T, and twelve others, Chronic treatment with
the .gamma.-secretase inhibitor LY-411, 575 inhibits .beta.-amyloid
peptide production and alters lymphopoiesis and intestinal cell
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B D, and ten others, Stereoselective inhibition of amyloid beta
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inhibitor, Neurology of Aging 2004, 25, sup2, p. 571. [0021]
[Non-Patent Document 14] Lanz T A, and eighteen others,
Concentration-dependent modulation of amyloid-.beta. in vivo and in
vitro using the .gamma.-secretase inhibitor, LY-450139, The Journal
of Pharmacology and Experimantal Therapeutics, 2006, November,
319(2)p. 924-933. [0022] [Non-Patent Document 15] Siemers E R, and
thirteen others, Effects of a .gamma.-secretase inhibitor in a
randamized study of patients with Alzheimer disease, Neurology,
2006, 66, p. 602-604. [0023] [Non-Patent Document 16] Best J D, and
nine others, In vivo characterization of A.beta. (40) changes in
brain and cerebrospinal fluid using the novel .gamma.-secretase
inhibitor
N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1-
,1-trifluoromethanesulphonlamide (MK-560) in the rat, The Journal
of Pharmacology and Experimantal Therapeutics, 2006, May 317(2) p.
786-790. [0024] [Non-Patent Document 17] Best J D, and thirteen
others The novel .gamma.-secretase inhibitor
N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1-
,1-trifluoromethanesulphonlamide (MK-560) reduces amylid plaque
deposition without evidence notch-related pathology in the Tg2576
mouse, The Journal of Pharmacology and Experimantal Therapeutics,
2007, February, 320(2) p. 552-558. [0025] [Patent Document 1] WO
2004/110350
BRIEF SUMMARY OF THE INVENTION
[0026] As described above, a compound that inhibits production of
A.beta.40 and A.beta.42 from APP has been expected as a therapeutic
or prophylactic agent for a disease caused by A.beta. which is
typified by Alzheimer's disease. However, a nonpeptidic compound
having high efficacy which inhibits production of A.beta.40 and
A.beta.42 has not yet been known. Accordingly, there is a need for
a novel low-molecular-weight compound that inhibits production of
A.beta.40 and A.beta.42.
[0027] As a result of extensive studies, the present inventors have
found a nonpeptidic multi-cyclic compound that inhibits production
of A.beta.40 and A.beta.42 from APP and thus found a prophylactic
or therapeutic agent for a disease caused by A.beta. which is
typified by Alzheimer's disease. This finding has led to the
accomplishment of the present invention.
[0028] Specifically, the present invention relates to the following
1) to 19):
1) A compound represented by the formula (I):
##STR00002##
or a pharmacologically acceptable salt thereof, wherein Ar.sub.1
represents an imidazolyl group which may be substituted with a C1-6
alkyl group, Ar.sub.2 represents a phenyl group or a pyridinyl
group, which may be substituted with 1 to 3 substituents selected
from the group consisting of (1) a hydrogen atom, (2) a halogen
atom, (3) a hydroxyl group and (4) a C1-6 alkoxy group, X.sub.1
represents --CR.sup.1.dbd.CR.sup.2-- (wherein R.sup.1 and R.sup.2
are the same or different and each represent (1) a hydrogen atom,
(2) a C1-6 alkyl group or (3) a halogen atom) and Het is monovalent
or divalent and represents (1) a 5-membered aromatic heterocyclic
group, (2) a 5-membered aromatic heterocyclic group condensed with
a 6- to 14-membered non-aromatic hydrocarbon ring group or (3) a
5-membered aromatic heterocyclic group condensed with a 5- to
14-membered non-aromatic heterocyclic group, which may be
substituted with 1 to 3 substituents selected from the following
Substituent Group A1 [Substituent Group A1: (1) a hydrogen atom,
(2) a halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a
nitro group, (6) a C3-8 cycloalkyl group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, (7) a
C2-6 alkenyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (8) a C2-6 alkynyl
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2, (9) a C3-8 cycloalkoxy group, (10) a
C3-8 cycloalkylthio group, (11) a formyl group, (12) a C1-6
alkylcarbonyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (13) a C1-6
alkylthio group which may be substituted with 1 to 3 substituents
selected from Substituent Group A2, (14) a C1-6 alkylsulfinyl group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (15) a C1-6 alkylsulfonyl group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (16) a hydroxyimino group, (17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (19) a C1-6 alkoxy
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2, (20) an amino group which may be
substituted with 1 or 2 substituents selected from Substituent
Group A2, (21) a carbamoyl group which may be substituted with 1 or
2 substituents selected from Substituent Group A2, (22) a 6- to
14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (23) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (25) a 5- to
14-membered non-aromatic heterocyclic group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy
group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) --X-A (wherein X represents an imino
group, --O-- or --S-- and A represents a 6- to 14-membered aromatic
hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2), (31) --CO-A (wherein A is as defined
above), (32) .dbd.CH-A (wherein A is as defined above), (33) a
carboxyl group, (34) a C1-6 alkoxycarbonyl group and (35) an azido
group; Substituent Group A2: (1) a hydrogen atom, (2) a halogen
atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro group,
(6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6
alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8
cycloalkylthio group, (11) a formyl group, (12) a C1-6
alkylcarbonyl group, (13) a C1-6 alkylthio group, (14) a C1-6
alkylsulfinyl group, (15) a C1-6 alkylsulfonyl group, (16) a
hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6
alkyl group (wherein the C1-6 alkyl group may be substituted with 1
to 3 substituents selected from the group consisting of a halogen
atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl group which
may be substituted with 1 to 3 halogen atoms and a pyridinyl group
which may be substituted with 1 to 3 halogen atoms), (19) a C1-6
alkoxy group (wherein the C1-6 alkoxy group may be substituted with
1 to 3 substituents selected from the group consisting of a halogen
atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl group which
may be substituted with 1 to 3 halogen atoms and a pyridinyl group
which may be substituted with 1 to 3 halogen atoms), (20) an amino
group which may be substituted with 1 or 2 C1-6 alkyl groups or
C1-6 alkylcarbonyl groups, (21) a carbamoyl group which may be
substituted with 1 or 2 C1-6 alkyl groups, (22) a 6- to 14-membered
aromatic hydrocarbon ring group, (23) a 5- to 14-membered aromatic
heterocyclic group, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group, (25) a 5- to 14-membered non-aromatic
heterocyclic group, (26) a C2-6 alkenyloxy group, (27) a C2-6
alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) --X-A' (wherein X represents an
imino group, --O--, --S-- or --SO.sub.2-- and A' represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
halogen atoms), (31) --CO-A' (wherein A' is as defined above) and
(32) .dbd.CH-A' (wherein A' is as defined above)]; 2) The compound
or pharmacologically acceptable salt thereof according to 1) above,
wherein the compound is represented by the formula (I-1), (I-2) or
(I-3):
##STR00003##
wherein X.sub.1 and Het are as defined above; 3) The compound or
pharmacologically acceptable salt thereof according to 1) above,
wherein the compound is represented by the formula (I-1) or (I-3);
4) The compound or pharmacologically acceptable salt thereof
according to 1) above, wherein the compound is represented by the
formula (I-1); 5) The compound or pharmacologically acceptable salt
thereof according to 1) above, wherein X.sub.1 represents
--CR.sup.1.dbd.CR.sup.2-- (wherein R.sup.1 and R.sup.2 are the same
or different and each represent a hydrogen atom or a fluorine atom;
6) The compound or pharmacologically acceptable salt thereof
according to 1) above, wherein X.sub.1 represents --CH.dbd.CH--; 7)
The compound or pharmacologically acceptable salt thereof according
to 1) above, wherein Het represents a triazolyl group which may be
substituted with 1 or 2 substituents selected from Substituent
Group A1; 8) The compound or pharmacologically acceptable salt
thereof according to 1) above, wherein Het represents a group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A1 and is represented by the following
formula:
##STR00004##
wherein R.sup.3 and R.sup.4 are the same or different and each
represent a substituent selected from Substituent Group A1, or
R.sup.3 and R.sup.4 are taken together with a carbon atom to which
they are bonded to form .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2), X.sub.2
represents a methylene group which may be substituted with a
substituent selected from Substituent Group A1, or an oxygen atom
and n.sub.a represents an integer of 0 to 2; 9) The compound or
pharmacologically acceptable salt thereof according to 1) above,
wherein Het represents a group which may be substituted with 1 to 3
substituents selected from Substituent Group A1 and is represented
by the following formula:
##STR00005##
wherein R.sup.5 and R.sup.6 are the same or different and each
represent a substituent selected from Substituent Group A1, X.sub.3
represents a methylene group which may be substituted with a
substituent selected from Substituent Group A1, or an oxygen atom
and n.sub.b represents an integer of 0 to 2; 10) The compound or
pharmacologically acceptable salt thereof according to 1) above,
wherein Het represents a group which may be substituted with 1 to 3
substituents selected from Substituent Group A1 and is represented
by the following formula:
##STR00006##
wherein n.sub.2 represents an integer of 0 to 3; 11) The compound
or pharmacologically acceptable salt thereof according to 6) above,
wherein n.sub.2 represents 0 or 2; 12) The compound or
pharmacologically acceptable salt thereof according to 1) above,
wherein Het represents a group which may be substituted with 1 to 3
substituents selected from Substituent Group A1 and is represented
by the following formula:
##STR00007##
wherein n.sub.d represents an integer of 0 to 3; 13) The compound
or pharmacologically acceptable salt thereof according to 1) above,
wherein Het represents a group which may be substituted with 1 to 3
substituents selected from Substituent Group A1 and is represented
by the following formulas:
##STR00008##
wherein R.sup.3 and R.sup.4 are as defined above; The compound or
pharmacologically acceptable salt thereof according to 1) above,
wherein Substituent Group A1 is a group consisting of (1) a
hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a
cyano group, (5) a C3-8 cycloalkyl group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, (6) a
C1-6 alkyl group which may be substituted with 1 to 3 substituents
selected from Substituent Group A2, (7) a 6- to 14-membered
aromatic hydrocarbon ring group which may be substituted with 1 to
3 substituents selected from Substituent Group A2, (8) a 5- to
14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, (9) a
6- to 14-membered non-aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (10) a 5- to 14-membered non-aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (11) --X-A (wherein X represents an imino
group, --O-- or --S-- and A represents a 6- to 14-membered aromatic
hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic
group, which may be substituted with 1 to 3 substituents selected
from Substituent Group A2), (12) .dbd.CH-A (wherein A represents a
6- to 14-membered aromatic hydrocarbon ring group or a 5- to
14-membered aromatic heterocyclic group, which may be substituted
with 1 to 3 substituents selected from Substituent Group A2) and
(13) an azido group; The compound or pharmacologically acceptable
salt thereof according to 1) above, wherein Substituent Group A2 is
a group consisting of (1) a hydrogen atom, (2) a halogen atom, (3)
a C1-6 alkyl group (wherein the C1-6 alkyl group may be substituted
with 1 to 3 substituents selected from the group consisting of a
halogen atom and a C1-6 alkoxy group) and (4) a C1-6 alkoxy group
(wherein the C1-6 alkoxy group may be substituted with a halogen
atom); 16) The compound or pharmacologically acceptable salt
thereof according to 1) above, wherein the compound is selected
from the following group: [0029] 1)
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0030] 2)
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0031] 3)
(-)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-
-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine, [0032] 4)
(-)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol,
[0033] 5)
(+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,
[0034] 6)
8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0035] 7)
8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0036] 8)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vin-
yl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole, [0037]
9)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyridi-
ne, [0038] 10)
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0039] 11)
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0040] 12)
(-)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridi-
ne, [0041] 13)
(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-
, [0042] 14)
(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0043] 15)
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne, [0044] 16)
(-)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0045] 17)
(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0046] 18)
(-)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0047] 19)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0048] 20)
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0049] 21)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, [0050]
22)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0051] 23)
(+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0052] 24)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0053] 25)
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0054] 26)
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e-8-carbonitrile, [0055] 27)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,
[0056] 28)
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0057] 29)
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0058] 30)
(-)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imida-
zol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine, [0059] 31)
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine, [0060] 32)
(-)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0061] 33)
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and [0062] 34)
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine, [0063] 35)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-t-
rifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0064] 36)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-t-
rifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,
[0065] 37)
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-met-
hyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, [0066] 38)
(5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, [0067] 39)
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-
-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,
and [0068] 40)
(S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1-
H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]tri-
azole; 17) A medicine comprising the compound or pharmacologically
acceptable salt thereof according to any of 1) to 16) above as an
active ingredient; 18) The medicine according to 17) above for
preventing or treating a disease caused by amyloid-.beta.; and 19)
The medicine according to 18) above, wherein the disease caused by
amyloid-.beta. is Alzheimer's disease, dementia, Down's syndrome or
amyloidosis.
[0069] The compound of the general formula (I) or pharmacologically
acceptable salt thereof according to the present invention and the
prophylactic or therapeutic agent for a disease caused by A.beta.
according to the present invention are novel inventions that have
not yet been described in any documents.
[0070] Meanings of symbols, terms and the like used in the present
specification will be explained and the present invention will be
described in detail below.
[0071] In the present specification, a structural formula of a
compound may represent a certain isomer for convenience. However,
the present invention includes all isomers and isomer mixtures such
as geometric isomers which can be generated from the structure of a
compound, optical isomers based on asymmetric carbon, stereoisomers
and tautomers. The present invention is not limited to the
description of a chemical formula for convenience and may include
any one of the isomers or mixtures thereof. Accordingly, the
compound of the present invention may have an asymmetric carbon
atom in the molecule and exist as an optically active compound or
racemate, and the present invention includes each of the optically
active compound and the racemate without limitations. Although
crystal polymorphs of the compound may be present, the compound is
not limited thereto as well and may be present as a single crystal
form or a mixture of single crystal forms. The compound may be an
anhydride or hydrate.
[0072] The "disease caused by A.beta." refers to a wide variety of
diseases such as Alzheimer's disease (see, for example, Klein W L,
and seven others, Alzheimer's disease-affected brain: Presence of
oligomeric A.beta. ligands (ADDLs) suggests a molecular basis for
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Implications for the pathogenesis of Alzheimers' disease,
Biochemistry, 1993, May 11, 32(18), p. 4693-4697; Glenner G G, and
one other, Alzheimer's disease; initial report of the purification
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Biochemical and biophysical research communications, 1984, May 16,
120(3), p. 885-890; Masters C L, and six others, Amyloid plaque
core protein in Alzheimer disease and Down syndrome, Proceeding
National Academy of Science USA, 1985, June, 82(12), p. 4245-4249;
Gouras G K, and eleven others, Intraneuronal A.beta.42 accumulation
in human brain, American journal of pathology, 2000, January,
156(1), p. 15-20; Scheuner D, and twenty others, Secreted amyloid
.beta.-protein similar to that in the senile plaques of Alzheimer's
disease is increased in vivo by the presenilin 1 and 2 and APP
mutations linked to familial Alzheimer's disease, Nature Medicine,
1996, August, 2(8), p. 864-870; Forman M S, and four others,
Differential effects of the swedish mutant amyloid precursor
protein on .beta.-amyloid accumulation and secreti in neurons and
normeuronal cells, The journal of biological chemistry, 1997, Dec.
19, 272(51), p. 32247-32253), senile dementia (see, for example,
Blass J P, Brain metabolism and brain disease: Is metabolic
deficiency the proximate cause of Alzheimer dementia? Journal of
Neuroscience Research, 2001, Dec. 1, 66(5), p. 851-856),
frontotemporal dementia (see, for example, Evin G, and eleven
others, Alternative transcripts of presenilin-1 associated with
frontotemporal dementia, Neuroreport, 2002, Apr. 16, 13(5), p.
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others, Accumulation of amyloid precursor protein in brain lesions
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171(1-2), p. 63-66), Down's syndrome (see, for example, Teller J K,
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January, 2(1), p. 93-95; Tokuda T, and six others, Plasma levels of
amyloid .beta. proteins A.beta.1-40 and A.beta.1-42(43) are
elevated in Down's syndrome, Annals of Neurology, 1997, February,
41(2), p. 271-273), cerebral angiopathy (see, for example, Hayashi
Y, and nine others, Evidence for presenilin-1 involvement in
amyloid angiopathy in the Alzheimer's disease-affected brain, Brain
Research, 1998, Apr. 13, 789(2), p. 307-314; Barelli H, and fifteen
others, Characterization of new polyclonal antibodies specific for
40 and 42 amino acid-long amyloid .beta. peptides: their use to
examine the cell biology of presenilins and the
immunohistochemistry of sporadic Alzheimer's disease and cerebral
amyloid angiopathy cases, Molecular Medicine, 1997, October, 3(10),
p. 695-707; Calhoun M E, and ten others, Neuronal overexpression of
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USA, 1999, Nov. 23, 96(24), p. 14088-14093; Dermaut B, and ten
others, Cerebral amyloid angiopathy is a pathogenic lesion in
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2001, December, 124(12), p. 2383-2392), hereditary cerebral
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and nine others, Presenile Alzheimer dementia characterized by
amyloid angiopathy and large amyloid core type senile plaques in
the APP 692Ala- ->Gly mutation, Acta Neuropathologica(Berl),
1998, September, 96(3), p. 253-260; Herzig M C, and fourteen
others, A.beta. is targeted to the vasculature in a mouse model of
hereditary cerebral hemorrhage with amyloidosis, Nature
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p. 5991-5994; Levy E, and eight others, Mutation of the Alzheimer's
disease amyloid gene in hereditary cerebral hemorrhage, Dutch type,
Science, 1990, Jun. 1, 248(4959), p. 1124-1126), cognitive
impairment (see, for example, Laws S M, and seven others,
Association between the presenilin-1 mutation Glu318Gly and
complaints of memory impairment, Neurobiology of Aging, 2002,
January-February, 23(1), p. 55-58), dysmnesia and learning
disability (see, for example, Vaucher E, and five others, Object
recognition memory and cholinergic parameters in mice expressing
human presenilin 1 transgenes, Experimental Neurology, 2002 June,
175(2), p. 398-406; Morgan D, and fourteen others, A.beta. peptide
vaccination prevents memory loss in an animal model of Alzheimer's
disease, Nature, 2000 Dec. 21-28, 408(6815), p. 982-985; Moran P M,
and three others, Age-related learning deficits in transgenic mice
expressing the 751-amino acid isoform of human .beta.-amyloid
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1995, Jun. 6, 92(12), p. 5341-5345), amyloidosis, cerebral ischemia
(see, for example, Laws S M, and seven others, Association between
the presenilin-1 mutation Glu318Gly and complaints of memory
impairment, Neurobiology of Aging, 2002, January-February, 23(1),
p. 55-58; Koistinaho M, and ten others, .beta.-amyloid precursor
protein transgenic mice that harbor diffuse A.beta. deposits but do
not form plaques show increased ischemic vulnerability: Role of
inflammation, Proceeding National Academy of Science USA, 2002,
Feb. 5, 99(3), p. 1610-1615; Zhang F, and four others, Increased
susceptibility to ischemic brain damage in transgenic mice
overexpressing the amyloid precursor protein, The journal of
neuroscience, 1997, Oct. 15, 17(20), p. 7655-7661), vascular
dementia (see, for example, Sadowski M, and six others, Links
between the pathology of Alzheimer's disease and vascular dementia,
Neurochemical Research, 2004, June, 29(6), p. 1257-1266),
ophthalmoplegia (see, for example, O'Riordan S, and seven others,
Presenilin-1 mutation(E280G), spastic paraparesis, and cranial MRI
white-matter abnormalities, Neurology, 2002, Oct. 8, 59(7), p.
1108-1110), multiple sclerosis (see, for example, Gehrmann J, and
four others, Amyloid precursor protein (APP) expression in multiple
sclerosis lesions, Glia, 1995, October, 15(2), p. 141-51; Reynolds
W F, and six others, Myeloperoxidase polymorphism is associated
with gender specific risk for Alzheimer's disease, Experimental
Neurology, 1999, January, 155(1), p. 31-41), head injury, skull
injury (see, for example, Smith DH, and four others, Protein
accumulation in traumatic brain injury, NeuroMolecular Medicine,
2003, 4(1-2), p. 59-72), apraxia (see, for example,
Matsubara-Tsutsui M, and seven others, Molecular evidence of
presenilin 1 mutation in familial early onset dementia, American
journal of Medical Genetics, 2002, Apr. 8, 114(3), p. 292-298),
prion disease, familial amyloid neuropathy, triplet repeat disease
(see, for example, Kirkitadze M D, and two others, Paradigm shifts
in Alzheimer's disease and other neurodegenerative disorders: the
emerging role of oligomeric assemblies, Journal of Neuroscience
Research, 2002, Sep. 1, 69(5), p. 567-577; Evert B O, and eight
others, Inflammatory genes are upreglulated in expanded
ataxin-3-expressing cell lines and spinocerebellar ataxia type 3
brains, The Journal of Neuroscience, 2001, Aug. 1, 21(15), p.
5389-5396; Mann D M, and one other, Deposition of amyloid(A4)
protein within the brains of persons with dementing disorders other
than Alzheimer's disease and Down's syndrome, Neuroscience Letters,
1990, Feb. 5, 109(1-2), p. 68-75), Parkinson's disease (see, for
example, Primavera J, and four others, Brain accumulation of
amyloid-.beta. in Non-Alzheimer Neurodegeneration, Jornal of
Alzheimer's Disease, 1999, October, 1(3), p. 183-193), Lewy body
dementia (see, for example, Giasson B I, and two others,
Interactions of amyloidogenic proteins. NeuroMolecular Medicine,
2003, 4(1-2), p. 49-58; Masliah E, and six others, .beta.-amyloid
peptides enhance .alpha.-synuclein accumulation and neuronal
deficits in a trancgenic mouse model linking Alzheimer's disease
and Parkinson's disease, Proceeding National Academy of Science
USA, 2001, Oct. 9, 98(21), p. 12245-12250; Barrachina M, and six
others, Amyloid-.beta. deposition in the cerebral cortex in
Dementia with Lewy bodies is accompanied by a relative increase in
A.beta.PP mRNA isoforms containing the Kunitz protease inhibitor,
Neurochemistry International, 2005, February, 46(3), p. 253-260;
Primavera J, and four others, Brain accumulation of amyloid-.beta.
in Non-Alzheimer Neurodegeneration, Jornal of Alzheimer's Disease,
1999, Oct., 1(3), p. 183-193), parkinsonism-dementia complex (see,
for example, Schmidt ML, and six others, Amyloid plaques in Guam
amyotrophic lateral sclerosis/parkinsonism-dementia complex contain
species of A.beta. similar to those found in the amyloid plaques of
Alzheimer's disease and pathological aging, Acta Neuropathologica
(Berl), 1998, February, 95(2), p. 117-122; Ito H, and three others,
Demonstration of (3 amyloid protein-containing neurofibrillary
tangles in parkinsonism-dementia complex on Guam, Neuropathology
and applied neurobiology, 1991, Oct., 17(5), p. 365-373),
frontotemporal dementia and parkinsonism linked to chromosome 17
(see, for example, Rosso S M, and three others, Coexistent tau and
amyloid pathology in hereditary frontotemporal dementia with tau
mutations, Annals of the New York academy of sciences, 2000, 920,
p. 115-119), argyrophilic grain dementia (see, for example, Tolnay
M, and four others, Low amyloid(A.beta.) plaque load and relative
predominance of diffuse plaques distinguish argyrophilic grain
disease from Alzheimer's disease, Neuropathology and applied
neurobiology, 1999, August, 25(4), p. 295-305), Niemann-Pick
disease (see, for example, Jin L W, and three others, Intracellular
accumulation of amyloidogenic fragments of amyloid-(3 precursor
protein in neurons with Niemann-Pick type C defects is associated
with endosomal abnormalities, American Journal of Pathology, 2004,
March, 164(3), p. 975-985), amyotrophic lateral sclerosis (see, for
example, Sasaki S, and one other, Immunoreactivity of
.beta.-amyloid precursor protein in amyotrophic lateral sclerosis,
Acta Neuropathologica(Berl), 1999, May, 97(5), p. 463-468; Tamaoka
A, and four others, Increased amyloid .beta. protein in the skin of
patients with amyotrophic lateral sclerosis, Journal of neurology,
2000, August, 247(8), p. 633-635; Hamilton R L, and one other,
Alzheimer disease pathology in amyotrophic lateral sclerosis, Acta
Neuropathologica, 2004, June, 107(6), p. 515-522; Turner B J, and
six others, Brain .beta.-amyloid accumulation in transgenic mice
expressing mutant superoxide dismutase 1, Neurochemical Research,
2004, December, 29(12), p. 2281-2286), hydrocephalus (see, for
example, Weller R O, Pathology of cerebrospinal fluid and
interstitial fluid of the CNS: Significance for Alzheimer disease,
prion disorders and multiple sclerosis, Journal of Neuropathology
and Experimental Neurology, 1998, October, 57(10), p. 885-894;
Silverberg G D, and four others, Alzheimer's disease,
normal-pressure hydrocephalus, and senescent changes in CSF
circulatory physiology: a hypothesis, Lancet neurology, 2003,
August, 2(8), p. 506-511; Weller R O, and three others, Cerebral
amyloid angiopathy: Accumulation of A.beta. in interstitial fluid
drainage pathways in Alzheimer's disease, Annals of the New York
academy of sciences, 2000, April, 903, p. 110-117; Yow H Y, and one
other, A role for cerebrovascular disease in determining the
pattern of .beta.-amyloid deposition in Alzheimer's disease,
Neurology and applied neurobiology, 2002, 28, p. 149; Weller R O,
and four others, Cerebrovasculardisease is a major factor in the
failure of elimination of A.beta. from the aging human brain,
Annals of the New York academy of sciences, 2002, November, 977, p.
162-168), paraparesis (see, for example, O'Riordan S, and seven
others, Presenilin-1 mutation(E280G), spastic paraparesis, and
cranial MRI white-matter abnormalities, Neurology, 2002, Oct. 8,
59(7), p. 1108-1110; Matsubara-Tsutsui M, and seven others,
Molecular evidence of presenilin 1 mutation in familial early onset
dementia, American journal of Medical Genetics, 2002, Apr. 8,
114(3), p. 292-298; Smith M J, and eleven others, Variable
phenotype of Alzheimer's disease with spastic paraparesis, Annals
of Neurology, 2001, 49(1), p. 125-129; Crook R, and seventeen
others, A variant of Alzheimer's disease with spastic pararesis and
unusual plaques due to deletion of exon 9 of presenilin 1, Nature
Medicine, 1998, April; 4(4), p. 452-455), progressive supranuclear
palsy (see, for example, Barrachina M, and six others,
Amyloid-.beta. deposition in the cerebral cortex in Dementia with
Lewy bodies is accompanied by a relative increase in A.beta.PP mRNA
isoforms containing the Kunitz protease inhibitor, Neurochemistry
International, 2005, February, 46(3), p. 253-260; Primavera J, and
four others, Brain accumulation of amyloid-.beta. in Non-Alzheimer
Neurodegeneration, Jornal of Alzheimer's Disease, 1999, October,
1(3), p. 183-193), intracerebral hemorrhage (see, for example,
Atwood C S, and three others, Cerebrovascular requirement for
sealant, anti-coagulant and remodeling molecules that allow for the
maintenance of vascular integrity and blood supply, Brain Research
Reviews, 2003, September, 43(1), p. 164-78; Lowenson J D, and two
others, Protein aging: Extracellular amyloid formation and
intracellular repair, Trends in cardiovascular medicine, 1994,
4(1), p. 3-8), convulsion (see, for example, Singleton A B, and
thirteen others, Pathology of early-onset Alzheimer's disease cases
bearing the Thr113-114ins presenilin-1 mutation, Brain, 2000,
December, 123(Pt12), p. 2467-24'74), mild cognitive impairment
(see, for example, Gattaz W F, and four others, Platelet
phospholipase A2 activity in Alzheimer's disease and mild cognitive
impairment, Journal of Neural Transmission, 2004, May, 111(5), p.
591-601; Assini A, and fourteen others, Plasma levels of amyloid
.beta.-protein 42 are increased in women with mild cognitive
impairment, Neurology, 2004, Sep. 14, 63(5), p. 828-831),
arteriosclerosis (see, for example, De Meyer G R, and eight others,
Platelet phagocytosis and processing of .beta.-amyloid precursor
protein as a mechanism of macrophage activation in atherosclerosis,
Circulation Reserach, 2002, Jun. 14, 90(11), p. 1197-1204).
[0073] The "5-membered aromatic heterocyclic group", "6- to
14-membered aromatic hydrocarbon ring group", "5- to 14-membered
aromatic heterocyclic group", "6- to 14-membered non-aromatic
hydrocarbon ring group" and "5- to 14-membered non-aromatic
heterocyclic group" in the compound represented by the formula (I)
of the present invention which is effective for treatment or
prevention of a disease caused by A.beta. are defined as
follows.
[0074] The "5-membered aromatic heterocyclic group" is a 5-membered
aromatic heterocyclic group containing one or more hetero atoms
selected from the group consisting of a nitrogen atom, a sulfur
atom and an oxygen atom such as:
##STR00009##
[0075] The "6- to 14-membered aromatic hydrocarbon ring group"
refers to a monocyclic, bicyclic or tricyclic aromatic hydrocarbon
ring group having 6 to 14 carbon atoms. Preferable examples of the
group include 6- to 14-membered monocyclic, bicyclic, or tricyclic
aromatic hydrocarbon ring groups such as a phenyl group, an indenyl
group, a naphthyl group, an azulenyl group, a heptalenyl group, a
biphenyl group, a fluorenyl group, a phenalenyl group, a
phenanthrenyl group and an anthracenyl group.
[0076] The "5- to 14-membered aromatic heterocyclic group" refers
to a monocyclic, bicyclic or tricyclic aromatic heterocyclic group
having 5 to 14 carbon atoms. Preferable examples of the group
include (1) nitrogen-containing aromatic heterocyclic groups such
as a pyrrolyl group, a pyridyl group, a pyridazinyl group, a
pyrimidinyl group, a pyrazinyl group, a pyrazolinyl group, an
imidazolyl group, an indolyl group, an isoindolyl group, an
indolizinyl group, a purinyl group, an indazolyl group, a quinolyl
group, an isoquinolyl group, a quinolizinyl group, a phthalazinyl
group, a naphthyridinyl group, a quinoxalinyl group, a quinazolinyl
group, a cinnolinyl group, a pteridinyl group, an imidazotriazinyl
group, a pyrazinopyridazinyl group, an acridinyl group, a
phenanthridinyl group, a carbazolyl group, a perimidinyl group, a
phenanthrolinyl group and a phenacyl group, (2) sulfur-containing
aromatic heterocyclic groups such as a thienyl group and a
benzothienyl group, (3) oxygen-containing aromatic heterocyclic
groups such as a furyl group, a pyranyl group, a cyclopentapyranyl
group, a benzofuranyl group and an isobenzofuranyl group and (4)
aromatic heterocyclic groups containing two or more hetero atoms
selected from the group consisting of a nitrogen atom, a sulfur
atom and an oxygen atom such as a thiazolyl group, an isothiazolyl
group, a benzothiazolinyl group, a benzothiadiazolyl group, a
phenothiazinyl group, an isoxazolyl group, a furazanyl group, a
phenoxazinyl group, a pyrazoloxazolyl group, an imidazothiazolyl
group, a thienofuryl group, a furopyrrolyl group and a
pyridooxazinyl group.
[0077] The "6- to 14-membered non-aromatic hydrocarbon ring group"
refers to a cyclic aliphatic hydrocarbon group having 6 to 14
carbon atoms. Examples of the group include cyclic aliphatic
hydrocarbon groups having 6 to 14 carbon atoms such as a
cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a
cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a
spiro[3.4]octanyl group, a decanyl group, an indanyl group, a
1-acenaphthenyl group, a cyclopentacyclooctenyl group, a
benzocyclooctenyl group, an indenyl group, a tetrahydronaphthyl
group, a 6,7,8,9-tetrahydro-5H-benzocycloheptenyl group and a
1,4-dihydronaphthalenyl group.
[0078] The "5- to 14-membered non-aromatic heterocyclic group" 1)
has 5 to 14 ring-forming atoms, 2) contains 1 to 5 hetero atoms
such as a nitrogen atom, --O-- or --S-- in the ring-forming atoms,
and 3) may contain one or more carbonyl groups, double bonds or
triple bonds in the ring, and refers not only to a 5- to
14-membered non-aromatic monocyclic heterocyclic group but also to
a saturated heterocyclic group condensed with an aromatic
hydrocarbon ring group or a saturated hydrocarbon ring group or
saturated heterocyclic group condensed with an aromatic
heterocyclic group. Specific examples of the 5- to 14-membered
non-aromatic heterocyclic group include an azetidinyl ring, a
pyrrolidinyl ring, a piperidinyl ring, an azepanyl ring, an
azocanyl ring, a tetrahydrofuranyl ring, a tetrahydropyranyl ring,
a morpholinyl ring, a thiomorpholinyl ring, a piperazinyl ring, a
thiazolidinyl ring, a dioxanyl ring, an imidazolinyl ring, a
thiazolinyl ring, a 1,2-benzopyranyl ring, an isochromanyl ring, a
chromanyl ring, an indolinyl ring, an isoindolinyl ring, an
azaindanyl group, an azatetrahydronaphthyl group, an azachromanyl
group, a tetrahydrobenzofuranyl group, a tetrahydrobenzothienyl
group, a 2,3,4,5-tetrahydro-benzo[b]thienyl group, a
3,4-dihydro-2H-benzo[b][1,4]dioxepinyl group, an indan-1-onyl
group, a 6,7-dihydro-5H-cyclopentapyrazinyl group, a
6,7-dihydro-5H-[1]pyridinyl group, a 6,7-dihydro-5H-[1]pyridinyl
group, a 5,6-dihydro-4H-cyclopenta[b]thienyl group, a
4,5,6,7-tetrahydro-benzo[b]thienyl group, a
3,4-dihydro-2H-naphthale-1-onyl group, a
2,3-dihydro-isoindol-1-onyl group, a
3,4-dihydro-2H-isoquinolin-1-onyl group and a
3,4-dihydro-2H-benzo[1,4]oxapinyl group.
[0079] Substituent groups A1 and A2 refer to the following
groups.
[0080] Substituent Group A1 refers to (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro
group, (6) a C3-8 cycloalkyl group which may be substituted with 1
to 3 substituents selected from Substituent Group A2, (7) a C2-6
alkenyl group which may be substituted with 1 to 3 substituents
selected from Substituent Group A2, (8) a C2-6 alkynyl group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (9) a C3-8 cycloalkoxy group, (10) a C3-8
cycloalkylthio group, (11) a formyl group, (12) a C1-6
alkylcarbonyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (13) a C1-6
alkylthio group which may be substituted with 1 to 3 substituents
selected from Substituent Group A2, (14) a C1-6 alkylsulfinyl group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (15) a C1-6 alkylsulfonyl group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (16) a hydroxyimino group, (17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (19) a C1-6 alkoxy
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2, (20) an amino group which may be
substituted with 1 or 2 substituents selected from Substituent
Group A2, (21) a carbamoyl group which may be substituted with 1 or
2 substituents selected from Substituent Group A2, (22) a 6- to
14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (23) a 5- to 14-membered aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (25) a 5- to
14-membered non-aromatic heterocyclic group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (26) a C2-6 alkenyloxy group, (27) a C2-6 alkynyloxy
group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) --X-A (wherein X represents an imino
group, --O-- or --S-- and A represents a 6- to 14-membered aromatic
hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2), (31) --CO-A (wherein A is as defined
above), (32) .dbd.CH-A (wherein A is as defined above), (33) a
carboxyl group, (34) a C1-6 alkoxycarbonyl group or (35) an azido
group.
[0081] Substituent Group A2 refers to (1) a hydrogen atom, (2) a
halogen atom, (3) a hydroxyl group, (4) a cyano group, (5) a nitro
group, (6) a C3-8 cycloalkyl group, (7) a C2-6 alkenyl group, (8) a
C2-6 alkynyl group, (9) a C3-8 cycloalkoxy group, (10) a C3-8
cycloalkylthio group, (11) a formyl group, (12) a C1-6
alkylcarbonyl group, (13) a C1-6 alkylthio group, (14) a C1-6
alkylsulfinyl group, (15) a C1-6 alkylsulfonyl group, (16) a
hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6
alkyl group (wherein the C1-6 alkyl group may be substituted with 1
to 3 substituents selected from the group consisting of a halogen
atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl group which
may be substituted with 1 to 3 halogen atoms and a pyridinyl group
which may be substituted with 1 to 3 halogen atoms), (19) a C1-6
alkoxy group (wherein the C1-6 alkoxy group may be substituted with
1 to 3 substituents selected from the group consisting of a halogen
atom, a hydroxyl group, a C1-6 alkoxy group, a phenyl group which
may be substituted with 1 to 3 halogen atoms and a pyridinyl group
which may be substituted with 1 to 3 halogen atoms), (20) an amino
group which may be substituted with 1 or 2 C1-6 alkyl groups or
C1-6 alkylcarbonyl groups, (21) a carbamoyl group which may be
substituted with 1 or 2 C1-6 alkyl groups, (22) a 6- to 14-membered
aromatic hydrocarbon ring group, (23) a 5- to 14-membered aromatic
heterocyclic group, (24) a 6- to 14-membered non-aromatic
hydrocarbon ring group, (25) a 5- to 14-membered non-aromatic
heterocyclic group, (26) a C2-6 alkenyloxy group, (27) a C2-6
alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) --X-A' (wherein X represents an
imino group, --O--, --S-- or --SO.sub.2-- and A' represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
halogen atoms), (31) --CO-A' (wherein A' is as defined above) or
(32) .dbd.CH-A' (wherein A' is as defined above).
[0082] The "halogen atom" refers to a fluorine atom, a chlorine
atom, a bromine atom, an iodine atom or the like and is preferably
a fluorine atom, a chlorine atom or a bromine atom.
[0083] The "C3-8 cycloalkyl group" refers to a cyclic alkyl group
having 3 to 8 carbon atoms. Preferable examples of the group
include a cyclopropyl group, a cyclobutyl group, a cyclopentyl
group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl
group.
[0084] The "C2-6 alkenyl group" refers to an alkenyl group having 2
to 6 carbon atoms. Preferable examples of the group include linear
or branched alkenyl groups such as a vinyl group, an allyl group, a
1-propenyl group, an isopropenyl group, a 1-buten-1-yl group, a
1-buten-2-yl group, a 1-buten-3-yl group, a 2-buten-1-yl group and
a 2-buten-2-yl group.
[0085] The "C2-6 alkynyl group" refers to an alkynyl group having 2
to 6 carbon atoms. Preferable examples of the group include linear
or branched alkynyl groups such as an ethynyl group, a 1-propynyl
group, a 2-propynyl group, a butynyl group, a pentynyl group and a
hexynyl group.
[0086] The "C3-8 cycloalkoxy group" refers to a cyclic alkyl group
having 3 to 8 carbon atoms in which one hydrogen atom is replaced
by an oxygen atom. Preferable examples of the group include a
cyclopropoxy group, a cyclobutoxy group, a cyclopentoxy group, a
cyclohexoxy group, a cycloheptyloxy group and a cyclooctyloxy
group.
[0087] The "C3-8 cycloalkylthio group" refers to a cyclic alkyl
group having 3 to 8 carbon atoms in which one hydrogen atom is
replaced by a sulfur atom. Preferable examples of the group include
a cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio
group, a cyclohexylthio group, a cycloheptylthio group and a
cyclooctylthio group.
[0088] The "C1-6 alkoxy group" refers to an alkyl group having 1 to
6 carbon atoms in which a hydrogen atom is replaced by an oxygen
atom. Preferable examples of the group include a methoxy group, an
ethoxy group, an n-propoxy group, an i-propoxy group, an n-butoxy
group, an i-butoxy group, a sec-butoxy group, a tert-butoxy group,
an n-pentoxy group, an i-pentoxy group, a sec-pentoxy group, a
tert-pentoxy group, an n-hexoxy group, an i-hexoxy group, a
1,2-dimethylpropoxy group, a 2-ethylpropoxy group, a
1-methyl-2-ethylpropoxy group, a 1-ethyl-2-methylpropoxy group, a
1,1,2-trimethylpropoxy group, a 1,1,2-trimethylpropoxy group, a
1,1-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a
2-ethylbutoxy group, a 1,3-dimethylbutoxy group, a 2-methylpentoxy
group, a 3-methylpentoxy group and a hexyloxy group.
[0089] The "C1-6 alkylthio group" refers to an alkyl group having 1
to 6 carbon atoms in which one hydrogen atom is replaced by a
sulfur atom. Preferable examples of the group include a methylthio
group, an ethylthio group, an n-propylthio group, an i-propylthio
group, an n-butylthio group, an i-butylthio group, a tert-butylthio
group, an n-pentylthio group, an i-pentylthio group, a
neopentylthio group, an n-hexylthio group and a 1-methylpropylthio
group.
[0090] The "C1-6 alkylcarbonyl group" refers to an alkyl group
having 1 to 6 carbon atoms in which one hydrogen atom is replaced
by a carbonyl group. Preferable examples of the group include an
acetyl group, a propionyl group and a butyryl group.
[0091] The "C1-6 alkylsulfinyl group" refers to an alkyl group
having 1 to 6 carbon atoms in which one hydrogen atom is
substituted with a sulfinyl group. Preferable examples of the group
include a methylsulfinyl group, an ethylmethylsulfinyl group, an
n-propylsulfinyl group, an i-propylsulfinyl group, an
n-butylsulfinyl group, an i-butylsulfinyl group, a
tert-butylsulfinyl group, an n-pentylsulfinyl group, an
i-pentylsulfinyl group, a neopentylsulfinyl group, an
n-hexylsulfinyl group and a 1-methylpropylsulfinyl group.
[0092] The "C1-6 alkylsulfonyl group" refers to an alkyl group
having 1 to 6 carbon atoms in which one hydrogen atom is replaced
by a sulfonyl group. Preferable examples of the group include a
methanesulfonyl group and an ethanesulfonyl group.
[0093] The "C1-6 alkoxyimino group" refers to an imino group in
which a hydrogen atom is replaced by a C1-6 alkoxy group.
Preferable examples of the group include a methoxyimino group and
an ethoxyimino group.
[0094] The "C1-6 alkyl group" refers to an alkyl group having 1 to
6 carbon atoms. Preferable examples of the group include linear or
branched alkyl groups such as a methyl group, an ethyl group, an
n-propyl group, an i-propyl group, an n-butyl group, an i-butyl
group, a tert-butyl group, an n-pentyl group, an i-pentyl group, a
neopentyl group, an n-hexyl group, a 1-methylpropyl group, an
1,2-dimethylpropyl group, a 1-ethylpropyl group, a
1-methyl-2-ethylpropyl group, a 1-ethyl-2-methylpropyl group, a
1,1,2-trimethylpropyl group, a 1-methylbutyl group, a 2-methylbutyl
group, a 1,1-dimethylbutyl group, a 2,2-dimethylbutyl group, a
2-ethylbutyl group, a 1,3-dimethylbutyl group, a 2-methylpentyl
group and a 3-methylpentyl group.
[0095] The "C2-6 alkenyloxy group" refers to an alkenyl group
having 2 to 6 carbon atoms in which one hydrogen atom is replaced
by an oxygen atom. Preferable examples of the group include linear
or branched alkenyloxy groups such as a vinyloxy group, an allyloxy
group, a 1-propenyloxy group, an isopropenyloxy group, a
1-buten-1-yloxy group, a 1-buten-2-yloxy group, a 1-buten-3-yloxy
group, a 2-buten-1-yloxy group and a 2-buten-2-yloxy group.
[0096] The "C2-6 alkynyloxy group" refers to an alkynyl group
having 2 to 6 carbon atoms in which one hydrogen atom is replaced
by an oxygen atom. Preferable examples of the group include linear
or branched alkynyloxy groups such as an ethynyloxy group, a
1-propynyloxy group, a 2-propynyloxy group, a butynyloxy group, a
pentynyloxy group and a hexynyloxy group.
[0097] The "C3-8 cycloalkylsulfonyl group" refers to a cyclic alkyl
group having 3 to 8 carbon atoms in which one hydrogen atom is
replaced by a sulfonyl group. Preferable examples of the group
include a cyclopropylsulfonyl group, a cyclobutylsulfonyl group, a
cyclopentylsulfonyl group, a cyclohexylsulfonyl group, a
cycloheptylsulfonyl group and a cyclooctylsulfonyl group.
[0098] The "C3-8 cycloalkylsulfinyl group" refers to a cyclic alkyl
group having 3 to 8 carbon atoms in which one hydrogen atom is
replaced by a sulfinyl group. Preferable examples of the group
include a cyclopropylsulfinyl group, a cyclobutylsulfinyl group, a
cyclopentylsulfinyl group, a cyclohexylsulfinyl group, a
cycloheptylsulfinyl group and a cyclooctylsulfinyl group.
[0099] The "C1-6 alkoxycarbonyl group" refers to a carbonyl group
in which a hydrogen atom is substituted with a C1-6 alkyl group.
Preferable examples of the group include an ethoxycarbonyl
group.
[0100] Examples of the pyridinyl group as Ar.sub.2 which may be
substituted with a hydroxyl group include a tautomer represented by
the following formula:
##STR00010##
[0101] Examples of the "Het which is a group represented by the
following formula":
##STR00011##
wherein R.sup.3 and R.sup.4 are the same or different and each
represent a substituent selected from Substituent Group A1, or
R.sup.3 and R.sup.4 are taken together with a carbon atom to which
they are bonded to form .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2), X.sub.2
represents a methylene group or an oxygen atom and n.sub.a
represents an integer of 0 to 2, include groups represented by the
formulas:
##STR00012##
wherein R.sup.3 and R.sup.4 are the same or different and each
represent a substituent selected from Substituent Group A1, or
R.sup.3 and R.sup.4 are taken together with a carbon atom to which
they are bonded to form .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2).
[0102] Examples of the "Het represented by the following
formula":
##STR00013##
wherein R.sup.3 and R.sup.4 are taken together with a carbon atom
to which they are bonded to form .dbd.CH-A, include:
##STR00014##
[0103] Examples of the "Het which is a group represented by the
following formula":
##STR00015##
wherein R.sup.5 and R.sup.6 are the same or different and each
represent a substituent selected from Substituent Group A1, X.sub.3
represents a methylene group or an oxygen atom and n.sub.b
represents an integer of 0 to 2, include:
##STR00016##
wherein R.sup.5 and R.sup.6 are the same or different and each
represent a substituent selected from Substituent Group A1.
[0104] Examples of the "Het which is a group represented by the
following formula":
##STR00017##
wherein n.sub.c represents an integer of 0 to 3, include:
##STR00018##
[0105] Examples of the "Het which is a group represented by the
following formula":
##STR00019##
wherein n.sub.d represents an integer of 0 to 3, include:
##STR00020##
[0106] In the present invention, the "pharmacologically acceptable
salt" is not particularly limited insofar as it is a
pharmacologically acceptable salt formed with the compound of the
general formula (I) which is a prophylactic or therapeutic agent
for a disease caused by A.beta.. Preferable specific examples of
the salt include hydrohalides (such as hydrofluorides,
hydrochlorides, hydrobromides and hydroiodides), inorganic acid
salts (such as sulfates, nitrates, perchlorates, phosphates,
carbonates and bicarbonates), organic carboxylates (such as
acetates, oxalates, maleates, tartrates, fumarates and citrates),
organic sulfonates (such as methanesulfonates,
trifluoromethanesulfonates, ethanesulfonates, benzenesulfonates,
toluenesulfonates and camphorsulfonates), amino acid salts (such as
aspartates and glutamates), quaternary amine salts, alkali metal
salts (such as sodium salts and potassium salts) and alkali earth
metal salts (such as magnesium salts and calcium salts).
[0107] Next, the compound of the formula (I) of the present
invention will be described.
[0108] In the compound of the formula (I) or pharmacologically
acceptable salt thereof, Ar.sub.1 is preferably an imidazolyl group
substituted with a C1-6 alkyl group, and Ar.sub.1 is more
preferably an imidazolyl group substituted with a methyl group.
[0109] In the compound of the formula (I) or pharmacologically
acceptable salt thereof, Ar.sub.2 is preferably a pyridinyl group
or a phenyl group which may be substituted with a halogen atom, a
hydroxyl group or a C1-6 alkoxy group, Ar.sub.2 is more preferably
a phenyl group or a pyridinyl group, substituted with a C1-6 alkoxy
group, Ar.sub.2 is particularly preferably a phenyl group or a
pyridinyl group, substituted with a methoxy group, and Ar.sub.2 is
most preferably a pyridinyl group substituted with a methoxy
group.
[0110] In the compound of the formula (I) or pharmacologically
acceptable salt thereof, X.sub.1 is preferably
--CR.sup.1.dbd.CR.sup.2--, wherein R.sup.1 and R.sup.2 are the same
or different and each represent a hydrogen atom or a fluorine atom,
and X.sub.1 is most preferably --CH.dbd.CH--.
[0111] In the compound of the formula (I) or pharmacologically
acceptable salt thereof, Ar.sub.1 and Ar more preferably have the
following structural formulas:
##STR00021##
and most preferably have the following structural formulas:
##STR00022##
[0112] In the compound of the formula (I) or pharmacologically
acceptable salt thereof, Het is preferably a triazolyl group which
may be substituted with 1 or 2 substituents selected from
Substituent Group A1,
[0113] Het is preferably a group which may be substituted with 1 to
3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00023##
wherein R.sup.3 and R.sup.4 are the same or different and each
represent a substituent selected from Substituent Group A1, or
R.sup.3 and R.sup.4 are taken together with a carbon atom to which
they are bonded to form .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2), X.sub.2
represents an oxygen atom or a methylene group which may be
substituted with a substituent selected from Substituent Group A1
and n.sub.a represents an integer of 0 to 2,
[0114] Het is preferably a group which may be substituted with 1 to
3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00024##
wherein R.sup.5 and R.sup.6 are the same or different and each
represent a substituent selected from Substituent Group A1, X.sub.3
represents a methylene group which may be substituted with a
substituent selected from Substituent Group A1, or an oxygen atom
and n.sub.b represents an integer of 0 to 2,
[0115] Het is preferably a group which may be substituted with 1 to
3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00025##
wherein n.sub.c represents an integer of 0 to 3, or
[0116] Het is preferably a group which may be substituted with 1 to
3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00026##
wherein n.sub.d represents an integer of 0 to 3,
[0117] Het is more preferably a group which may be substituted with
1 to 3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00027##
wherein R.sup.3 and R.sup.4 are the same or different and each
represent a substituent selected from Substituent Group A1, or
R.sup.3 and R.sup.4 are taken together with a carbon atom to which
they are bonded to form .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2), X.sub.2
represents a methylene group which may be substituted with a
substituent selected from Substituent Group A1, or an oxygen atom
and n.sub.a represents an integer of 0 to 2, and
[0118] Het is more preferably a group which may be substituted with
1 to 3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00028##
wherein n.sub.c represents an integer of 0 to 3, and
[0119] Het is most preferably a group which may be substituted with
1 to 3 substituents selected from Substituent Group A1 and is
represented by the following formula:
##STR00029##
[0120] Substituent Group A1 is preferably a group consisting of (1)
a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a
cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (7) a C2-6 alkenyl group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (8) a C2-6 alkynyl group which may be substituted with 1
to 3 substituents selected from Substituent Group A2, (9) a C3-8
cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl
group, (12) a C1-6 alkylcarbonyl group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, (13) a
C1-6 alkylthio group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (14) a C1-6
alkylsulfinyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (15) a C1-6
alkylsulfonyl group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (16) a
hydroxyimino group, (17) a C1-6 alkoxyimino group, (18) a C1-6
alkyl group which may be substituted with 1 to 3 substituents
selected from Substituent Group A2, (19) a C1-6 alkoxy group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (20) an amino group which may be substituted
with 1 or 2 substituents selected from Substituent Group A2, (21) a
carbamoyl group which may be substituted with 1 or 2 substituents
selected from Substituent Group A2, (22) a 6- to 14-membered
aromatic hydrocarbon ring group which may be substituted with 1 to
3 substituents selected from Substituent Group A2, (23) a 5- to
14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 substituents selected from Substituent Group A2, (24) a
6- to 14-membered non-aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (25) a 5- to 14-membered non-aromatic heterocyclic group
which may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (26) a C2-6 alkenyloxy group, (27) a C2-6
alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl group, (29) a C3-8
cycloalkylsulfonyl group, (30) --X-A (wherein X represents an imino
group, --O-- or --S-- and A represents a 6- to 14-membered aromatic
hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic
group which may be substituted with 1 to 3 substituents selected
from Substituent Group A2), (31) --CO-A (wherein A is as defined
above), (32) .dbd.CH-A (wherein A is as defined above), (33) a
carboxyl group, (34) a C1-6 alkoxycarbonyl group and (35) an
azidoazido group.
[0121] Substituent Group A1 is more preferably a group consisting
of (1) a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group,
(4) a cyano group, (5) a C3-8 cycloalkyl group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (6) a C1-6 alkyl group which may be substituted with 1 to
3 substituents selected from Substituent Group A2, (7) a 6- to
14-membered aromatic hydrocarbon ring group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (8) a 5- to 14-membered aromatic heterocyclic group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A2, (9) a 6- to 14-membered non-aromatic
hydrocarbon ring group which may be substituted with 1 to 3
substituents selected from Substituent Group A2, (10) a 5- to
14-membered non-aromatic heterocyclic group which may be
substituted with 1 to 3 substituents selected from Substituent
Group A2, (11) --X-A (wherein X represents an imino group, --O-- or
--S-- and A represents a 6- to 14-membered aromatic hydrocarbon
ring group or a 5- to 14-membered aromatic heterocyclic group which
may be substituted with 1 to 3 substituents selected from
Substituent Group A2), (12) .dbd.CH-A (wherein A represents a 6- to
14-membered aromatic hydrocarbon ring group or a 5- to 14-membered
aromatic heterocyclic group which may be substituted with 1 to 3
substituents selected from Substituent Group A2) and (13) an
azidoazido group.
[0122] When Substituent Group A1 is a 6- to 14-membered aromatic
hydrocarbon ring group or a 5- to 14-membered aromatic heterocyclic
group, Substituent Group A2 is preferably a group consisting of (1)
a hydrogen atom, (2) a halogen atom, (3) a hydroxyl group, (4) a
cyano group, (5) a nitro group, (6) a C3-8 cycloalkyl group, (7) a
C2-6 alkenyl group, (8) a C2-6 alkynyl group, (9) a C3-8
cycloalkoxy group, (10) a C3-8 cycloalkylthio group, (11) a formyl
group, (12) a C1-6 alkylcarbonyl group, (13) a C1-6 alkylthio
group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6 alkylsulfonyl
group, (16) a hydroxyimino group, (17) a C1-6 alkoxyimino group,
(18) a C1-6 alkyl group (wherein the C1-6 alkyl group may be
substituted with 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (20) an amino group which may be substituted with 1
or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups, (21) a
carbamoyl group which may be substituted with 1 or 2 C1-6 alkyl
groups, (22) a 6- to 14-membered aromatic hydrocarbon ring group,
(23) a 5- to 14-membered aromatic heterocyclic group, (24) a 6- to
14-membered non-aromatic hydrocarbon ring group, (25) a 5- to
14-membered non-aromatic heterocyclic group, (26) a C2-6 alkenyloxy
group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl
group, (29) a C3-8 cycloalkylsulfonyl group, (30) --X-A' (wherein X
represents an imino group, --O--, --S-- or --SO.sub.2-- and A'
represents a 6- to 14-membered aromatic hydrocarbon ring group or a
5- to 14-membered aromatic heterocyclic group which may be
substituted with 1 to 3 halogen atoms), (31) --CO-A' (wherein A' is
as defined above) and (32) .dbd.CH-A' (wherein A' is as defined
above);
[0123] more preferably a group consisting of (1) a hydrogen atom,
(2) a halogen atom, (3) a nitro group, (4) a C1-6 alkylcarbonyl
group, (5) a C1-6 alkylthio group, (6) a C1-6 alkyl sulfonyl group,
(7) a C1-6 alkyl group (wherein the C1-6 alkyl group may be
substituted with 1 to 3 substituents selected from the group
consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (8) a C1-6 alkoxy group (wherein the C1-6 alkoxy
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (9) an amino group which may be substituted with 1
or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups and (10) a 5-
to 14-membered aromatic heterocyclic group; and
[0124] most preferably a group consisting of (1) a hydrogen atom,
(2) a halogen atom, (3) a C1-6 alkyl group (wherein the C1-6 alkyl
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom and a C1-6 alkoxy group) and (4)
a C1-6 alkoxy group (wherein the C1-6 alkoxy group may be
substituted with a halogen atom).
[0125] When Substituent Group A1 is a 6- to 14-membered
non-aromatic hydrocarbon ring group or a 5- to 14-membered
non-aromatic heterocyclic group, Substituent Group A2 is preferably
a group consisting of (1) a hydrogen atom, (2) a halogen atom, (3)
a hydroxyl group, (4) a cyano group, (5) a nitro group, (6) a C3-8
cycloalkyl group, (7) a C2-6 alkenyl group, (8) a C2-6 alkynyl
group, (9) a C3-8 cycloalkoxy group, (10) a C3-8 cycloalkylthio
group, (11) a formyl group, (12) a C1-6 alkylcarbonyl group, (13) a
C1-6 alkylthio group, (14) a C1-6 alkylsulfinyl group, (15) a C1-6
alkylsulfonyl group, (16) a hydroxyimino group, (17) a C1-6
alkoxyimino group, (18) a C1-6 alkyl group (wherein the C1-6 alkyl
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (19) a C1-6 alkoxy group (wherein the C1-6 alkoxy
group may be substituted with 1 to 3 substituents selected from the
group consisting of a halogen atom, a hydroxyl group, a C1-6 alkoxy
group, a phenyl group which may be substituted with 1 to 3 halogen
atoms and a pyridinyl group which may be substituted with 1 to 3
halogen atoms), (20) an amino group which may be substituted with 1
or 2 C1-6 alkyl groups or C1-6 alkylcarbonyl groups, (21) a
carbamoyl group which may be substituted with 1 or 2 C1-6 alkyl
groups, (22) a 6- to 14-membered aromatic hydrocarbon ring group,
(23) a 5- to 14-membered aromatic heterocyclic group, (24) a 6- to
14-membered non-aromatic hydrocarbon ring group, (25) a 5- to
14-membered non-aromatic heterocyclic group, (26) a C2-6 alkenyloxy
group, (27) a C2-6 alkynyloxy group, (28) a C3-8 cycloalkylsulfinyl
group, (29) a C3-8 cycloalkylsulfonyl group, (30) --X-A' (wherein X
represents an imino group, --O--, --S-- or --SO.sub.2-- and A'
represents a 6- to 14-membered aromatic hydrocarbon ring group or a
5- to 14-membered aromatic heterocyclic group which may be
substituted with 1 to 3 halogen atoms), (31) --CO-A' (wherein A' is
as defined above) and (32) .dbd.CH-A' (wherein A' is as defined
above); and
[0126] more preferably a group consisting of (1) a hydrogen atom,
(2) a C1-6 alkylcarbonyl group, (3) a C1-6 alkyl group (wherein the
C1-6 alkyl group may be substituted with 1 to 3 substituents
selected from the group consisting of a halogen atom, a hydroxyl
group, a C1-6 alkoxy group, a phenyl group which may be substituted
with 1 to 3 halogen atoms and a pyridinyl group which may be
substituted with 1 to 3 halogen atoms), (4) a 6- to 14-membered
aromatic hydrocarbon ring group, (5) --X-A' (wherein X represents
an imino group, --O--, --S-- or --SO.sub.2-- and A' represents a 6-
to 14-membered aromatic hydrocarbon ring group or a 5- to
14-membered aromatic heterocyclic group which may be substituted
with 1 to 3 halogen atoms) and (6) --CO-A' (wherein A' is as
defined above).
[0127] The compound or pharmacologically acceptable salt, wherein
the compound is at least one selected from the following group, for
example, is particularly suitable and useful as a therapeutic or
prophylactic agent for a disease caused by amyloid-(3 such as
Alzheimer's disease, senile dementia, Down's syndrome or
amyloidosis. [0128] 1)
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0129] 2)
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0130] 3)
(-)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-
-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine, [0131] 4)
(-)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol,
[0132] 5)
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,
[0133] 6)
8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0134] 7)
8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0135] 8)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vin-
yl}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole, [0136]
9)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo-[1,5-a]pyridi-
ne, [0137] 10)
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0138] 11)
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0139] 12)
(-)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridi-
ne, [0140] 13)
(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-
, [0141] 14)
(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0142] 15)
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne, [0143] 16)
(-)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0144] 17)
(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
[0145] 18)
(-)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0146] 19)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0147] 20)
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0148] 21)
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine, [0149]
22)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0150] 23)
(+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0151] 24)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0152] 25)
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0153] 26)
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e-8-carbonitrile, [0154] 27)
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine,
[0155] 28)
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0156] 29)
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0157] 30)
(-)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imida-
zol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine, [0158] 31)
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine, [0159] 32)
(-)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine, [0160] 33)
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and [0161] 34)
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine, [0162] 35)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-t-
rifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine,
[0163] 36)
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-t-
rifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,
[0164] 37)
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-met-
hyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, [0165] 38)
(5R,8S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine, [0166] 39)
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-1-yl]vinyl}-
-7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]triazole,
and [0167] 40)
(S)-7-(5-fluoro-2-trifluoromethyphanyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1-
H-imidazol-1-yl)pyridine-1-yl]vinyl}-6,7-dihydro-5H-pyrro[1,2-b][1,2,4]tri-
azole.
[0168] Methods for preparing the compound of the general formula
(I) of the present invention will be described below.
[0169] The compound represented by the general formula (I):
##STR00030##
wherein Ar.sub.1, Ar.sub.2, X.sub.1 and Het are as defined above,
is synthesized according to a method such as the following General
Preparation Method 1 to General Preparation Method 8, for example.
It is obvious that, in order to prepare the compound of the present
invention conveniently, the method comprises a protection reaction
step and a deprotection reaction step appropriately, using a
protecting group known to a person skilled in the art which is
suitably selected for each step (see T. Greene et al., "Protective
Groups in Organic Synthesis", John Wiley & Sons, Inc., New
York, 1981). It is also obvious that, in order to prepare the
compound of the present invention conveniently, all isomers and
isomer mixtures such as geometric isomers which can be generated
from the structure of the compound, optical isomers based on
asymmetric carbon, stereoisomers, and tautomers can be prepared as
a single compound by a technique known to a person skilled in the
art which is suitable for each step such as fractional
crystallization or column chromatography.
[General Preparation Method 1]
[0170] Typically used General Preparation Method 1 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00031##
[0171] In the formula, the following partial structure (formula
III-3, III-4, III-6, III-7 or III-8):
##STR00032##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2 and X.sub.1 are as defined above;
X.sub.5, X.sub.6, Y.sub.10 and Y.sub.11 are the same or different
and each represent a carbon atom, a nitrogen atom or a sulfur atom;
R.sup.10, R.sup.11 and R.sup.12 are the same or different and
represent groups selected from the above Substituent Group A1 which
may optionally form a ring; L.sub.1 represents a halogen atom such
as a chlorine atom, a bromine atom or an iodine atom, a sulfonate
group such as a methanesulfonate group, a p-toluenesulfonate group
or a trifluoromethanesulfonate group, or a hydroxyl group; L.sub.2
represents a halogen atom such as a chlorine atom, a bromine atom
or an iodine atom, a sulfonate group such as a methanesulfonate
group, a p-toluenesulfonate group or a trifluoromethanesulfonate
group, a boronic acid group or a boronate group such as a boronic
acid pinacol ester group; X.sub.4 represents a carbon atom or an
oxygen atom; nd, ne, ni and nj each represent an integer of 1 to 2;
and nl represents an integer of 0 to 2.
[0172] The above General Preparation Method 1 includes a method of
condensing a carboxylic acid compound (1) with a compound (2a) in
Step 1-1 to convert the carboxylic acid compound (1) into an ester
compound (3) and reacting the ester compound (3) with ammonia, an
ammonium salt or formamide in Step 1-2 to prepare a compound of the
general formula (I-9); a method of reacting the compound of the
general formula (I-9) with a compound (2b) in Step 1-3 to prepare a
compound of the general formula (I-4); a method of reacting the
ester compound (3) with ammonia, an ammonium salt or formamide in
Step 1-4 to convert the ester compound (3) into an oxazole compound
(21) and then reacting the oxazole compound (21) with an amine
compound (22) in Step 1-5 to prepare a compound of the general
formula (I-4); a method of preparing a compound of the general
formula (I-6) or a compound of the general formula (I-7) from the
compound of the general formula (I-9) in Step 1-6; a method of
preparing a compound of the general formula (I-6) or a compound of
the general formula (I-7) from the oxazole compound (21) in Step
1-7; a method of preparing a compound of the general formula (I-8)
from the ester compound (3) and ammonia, an ammonium salt or
formamide in Step 1-8; and a method of preparing a compound of the
general formula (I-8) from the oxazole compound (21) in Step
1-9.
[Preparation of Compound of General Formula (I-6) or Compound of
General Formula (I-7)]
[0173] The compound of the general formula (I-6) or the compound of
the general formula (I-7) can be prepared from a compound of the
general formula (I-9) by intramolecular cyclization reaction
according to Step 1-6. Specifically, Step 1-6 as an intramolecular
cyclization reaction may employ a known method described in many
documents such as N-alkylation reaction (see The Journal of Organic
Chemistry, 1977, vol. 42, p. 3925, for example). The compound can
also be prepared from an oxazole compound (21) by intramolecular
cyclization reaction according to Step 1-7. Specifically, Step 1-7
may employ a method of forming a triazole or imidazole ring and
cyclizing the second ring at the same time in the presence or
absence of a nitrogen atom source (see The Chemistry of
Heterocyclic Compounds. Imidazole and Derivatives, Part I, p. 33,
Inters. Publish. 1953, for example).
[0174] Step 1-6 is preferably, for example, a method of stirring a
compound of the general formula (I-9), wherein X.sub.1 is
--CR.sup.1.dbd.CR.sup.21-- and R.sup.21 represents a C1-6 alkyl
group substituted with a halogen atom or a C1-6 alkoxy group
substituted with a halogen atom, or R.sup.11 represents a C1-6
alkyl group (wherein the C1-6 alkyl group is substituted with a
halogen atom, a C1-6 alkoxy group substituted with a halogen atom
or a C1-6 alkylamino group substituted with a halogen atom), in a
solvent in the presence of 1.0 to 10.0 equivalents of a base with
respect to the compound of the general formula (I-9). The base used
varies according to the starting material and is not particularly
limited. Preferable examples of the base include alkali metal
hydrides (such as sodium hydride and lithium hydride), alkali metal
salts (such as potassium carbonate, sodium carbonate and cesium
carbonate), metal alkoxides (such as sodium methoxide and
tert-butyl potassium) and organometallic salts (such as lithium
diisopropyl amide and lithium hexamethyldisilazane). The solvent
used varies according to the starting material, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl
ether; halogenated solvents such as methylene chloride,
1,2-dichloroethane and chloroform; polar solvents such as
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene and benzene; and a mixture thereof. The reaction
temperature must be a temperature that can complete the reaction
without promoting formation of an undesirable by-product, and is
preferably -78.degree. C. to 200.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0175] Step 1-7 is preferably, for example, a method of stirring an
oxazole compound (21), wherein X.sub.1 is
--CR.sup.1.dbd.CR.sup.21-- and R.sup.21 represents a C1-6 alkyl
group substituted with a halogen atom or a C1-6 alkoxy group
substituted with a halogen atom, or R.sup.11 represents a C1-6
alkyl group (wherein the C1-6 alkyl group is substituted with a
halogen atom, a C1-6 alkoxy group substituted with a halogen atom
or a C1-6 alkylamino group substituted with a halogen atom), in a
solvent in the presence of 1.0 to 100 equivalents of ammonia or an
ammonium salt such as ammonium acetate with respect to the oxazole
compound (21). Step 1-7 may also be a method of stirring an oxazole
compound (21), wherein X.sub.1 is --CR.sup.1.dbd.CR.sup.21-- and
R.sup.21 represents a C1-6 alkyl group substituted with an amino
group or a C1-6 alkoxy group substituted with an amino group, or
R.sup.11 represents a C1-6 alkyl group (wherein the C1-6 alkyl
group is substituted with an amino group, a C1-6 alkoxy group
substituted with an amino group or a C1-6 alkylamino group
substituted with an amino group), in a solvent. The solvent used is
not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include nonpolar solvents such as toluene and benzene; alcohol
solvents such as methanol and ethanol; organic acids such as acetic
acid; water; and a mixture thereof. The reaction temperature must
be a temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 250.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound of General Formula (I-8)]
[0176] The compound of the general formula (I-8) can be prepared
from an ester compound (3) according to Step 1-8 using ammonia, an
ammonium salt or formamide as a nitrogen source, for example. The
compound can also be prepared from an oxazole compound (21)
according to Step 1-9 using ammonia, an ammonium salt or formamide
as a nitrogen source, for example. Specifically, Step 1-8 or Step
1-9 varies according to the starting material and is not
particularly limited insofar as the conditions are similar to those
in this reaction. A known method described in many documents may be
used for the reaction (see The Chemistry of Heterocyclic Compounds.
Imidazole and Derivatives, Part I, p. 33, Inters. Publish. 1953,
for example). The reaction is preferably a method of stirring an
ester compound (3) or an oxazole compound (21) and 1.0 to 100.0
equivalents of ammonia or an ammonium salt such as ammonium acetate
with respect to the ester compound (3) or the oxazole compound (21)
in a solvent, for example. The solvent used is not particularly
limited insofar as the solvent does not inhibit the reaction and
allows the starting material to be dissolved therein to a certain
extent. Preferable examples of the solvent include nonpolar
solvents such as toluene and benzene; alcohol solvents such as
methanol and ethanol; organic acids such as acetic acid; water; and
a mixture thereof. Formamide may optionally be used as a nitrogen
atom source and a solvent. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 250.degree. C., for example. The yield may be
improved when the reaction is performed using a tight container.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound of General Formula (I-4)]
[0177] The compound of the general formula (I-4) can be prepared by
reacting a compound of the general formula (I-9) with a compound of
the general formula (2b) according to Step 1-3. Specifically, Step
1-3 may employ a known method described in many documents such as
N-alkylation reaction (see The Journal of Organic Chemistry, 1977,
vol. 42, p. 3925, for example) or N-arylation reaction (see The
Journal of Organic Chemistry, 2001, vol. 66, p. 7892; Journal of
Medicinal Chemistry, 1981, vol. 24, p. 1139; or Journal of
Medicinal Chemistry, 1991, vol. 39, p. 2671, for example).
[0178] N-alkylation reaction is preferably, for example, a method
of stirring a compound of the general formula (I-9) and 1.0 to 10.0
equivalents of a compound (2b), wherein L.sub.2 represents a
halogen atom such as a chlorine atom, a bromine atom or an iodine
atom or a sulfonate group such as a methanesulfonate group, a
p-toluenesulfonate group or a trifluoromethanesulfonate group, with
respect to the compound of the general formula (I-9) in a solvent
in the presence of 1.0 to 10.0 equivalents of a base with respect
to the compound of the general formula (I-9). The base used varies
according to the starting material and is not particularly limited.
Preferable examples of the base include alkali metal hydrides (such
as sodium hydride and lithium hydride), alkali metal salts (such as
potassium carbonate, sodium carbonate and cesium carbonate) and
metal alkoxides (such as sodium methoxide and potassium
tert-butoxide). The solvent used varies according to the starting
material, and is not particularly limited insofar as the solvent
does not inhibit the reaction and allows the starting material to
be dissolved therein to a certain extent. Preferable examples of
the solvent include ether solvents such as tetrahydrofuran,
1,4-dioxane and diethyl ether; halogenated solvents such as
methylene chloride, 1,2-dichloroethane and chloroform; polar
solvents such as N,N-dimethylformamide and N-methylpyrrolidone;
nonpolar solvents such as toluene and benzene; and a mixture
thereof. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably 0.degree. C. to 200.degree. C., for
example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0179] N-arylation reaction may be i) Ullmann reaction, ii) a
coupling reaction of an arylboronic acid derivative using a copper
compound or iii) nucleophilic substitution reaction.
[0180] In the case of i) Ullmann reaction, there are no specific
limitations to the reaction conditions. Ullmann reaction is
preferably, for example, a method of stirring a compound of the
general formula (I-9) and 1.0 to 10.0 equivalents of a compound
(2b), wherein L.sub.2 represents a halogen atom such as a chlorine
atom, a bromine atom or an iodine atom, with respect to the
compound of the general formula (I-9) in a solvent in the presence
of 0.01 to 1.0 equivalent of a copper reagent such as copper,
copper bromide or copper iodide with respect to the compound of the
general formula (I-9) with 1.0 to 10.0 equivalents of a base added
with respect to the compound of the general formula (I-9). The base
used varies according to the starting material and is not
particularly limited. Preferable examples of the base include
alkali metal salts (such as potassium carbonate, sodium carbonate,
potassium acetate, sodium acetate and cesium carbonate) and metal
alkoxides (such as sodium methoxide and potassium tert-butoxide).
The solvent used varies according to the starting material, the
reagent and the like, and is not particularly limited insofar as
the solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include ether solvents such as
tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated
solvents such as methylene chloride, 1,2-dichloroethane and
chloroform; alcohol solvents such as amyl alcohol and isopropyl
alcohol; polar solvents such as N,N-dimethylformamide and
N-methylpyrrolidone; nonpolar solvents such as toluene, benzene and
dichlorobenzene; and a mixture thereof. The reaction temperature
must be a temperature that can complete the reaction without
promoting formation of an undesirable by-product, and is preferably
room temperature to 200.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization.
[0181] The ii) coupling reaction of an arylboronic acid derivative
using a copper compound is preferably, for example, a method of
stirring a compound of the general formula (I-9) and 1.0 to 10.0
equivalents of a compound (2b), wherein L.sub.2 represents a
boronic acid group or a boronate group such as a boronic acid
pinacol ester group, with respect to the compound of the general
formula (I-9) in a solvent in the presence of 0.01 to 1.0
equivalent of a copper reagent such as copper, copper bromide or
copper iodide with respect to the compound of the general formula
(I-9) with 1.0 to 10.0 equivalents of a base added with respect to
the compound of the general formula (I-9). The base used varies
according to the starting material, the solvent used and the like,
and is not particularly limited insofar as the base does not
inhibit the reaction. Preferable examples of the base include
organic bases such as triethylamine, pyridine and
tetramethylethylenediamine; alkali metal salts such as potassium
carbonate, sodium carbonate, potassium acetate, sodium acetate and
cesium carbonate; and metal alkoxides such as sodium methoxide and
potassium tert-butoxide. The copper reagent used varies according
to the starting material and is not particularly limited.
Preferable examples of the copper reagent include copper acetate
and
di-.mu.-hydroxo-bis[(N,N,N',N'-tetramethylethylenediamine)copper
(II)] chloride. The solvent used varies according to the starting
material, the reagent and the like, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include ether solvents such as
tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated
solvents such as methylene chloride, 1,2-dichloroethane and
chloroform; polar solvents such as ethyl acetate,
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; and a mixture
thereof. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 200.degree. C.,
for example. Good results such as reduction in the reaction time
and improvement of the yield can be achieved when the reaction is
performed in an oxygen atmosphere or air stream. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization.
[0182] In iii) nucleophilic substitution reaction, a compound of
the general formula (I-9) and 2.0 to 5.0 equivalents of a compound
(2b), wherein L.sub.2 represents a halogen atom such as a chlorine
atom, a bromine atom or an iodine atom or a sulfonate group such as
a methanesulfonate group, a p-toluenesulfonate group or a
trifluoromethanesulfonate group, with respect to the compound of
the general formula (I-9) are preferably stirred in a solvent in
the presence or absence of 1.0 to 5.0 equivalents of a base with
respect to the compound of the general formula (I-9), for example.
The base used varies according to the starting material and is not
particularly limited. Preferable examples of the base include
sodium hydride, sodium hydroxide, potassium hydroxide, potassium
carbonate, sodium carbonate, cesium carbonate, barium carbonate,
pyridine, lutidine and triethylamine. The solvent used varies
according to the starting material, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include acetonitrile,
tetrahydrofuran, dimethyl sulfoxide, N,N-dimethylformamide and
N-methylpyrrolidine. The base may optionally be used as a solvent.
The reaction temperature must be a temperature that can complete
the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 150.degree. C.,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique or/and
crystallization.
[0183] The compound of the general formula (I-4) can be prepared by
reacting an oxazole compound (21) with an amine compound (22)
according to Step 1-5. Specifically, Step 1-5 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A known
method described in many documents may be used for the reaction
(see Heterocyclic Compounds, vol. 5, Wiley, New York, N.Y. 1950, p.
214, for example). Preferably, an oxazole compound (21) and 1.0 to
100.0 equivalents of an amine compound (22) with respect to the
oxazole compound (21) are stirred in a solvent, for example. The
solvent used is not particularly limited insofar as the solvent
does not inhibit the reaction and allows the starting material to
be dissolved therein to a certain extent. Preferable examples of
the solvent include ether solvents such as tetrahydrofuran,
1,4-dioxane and diethyl ether; halogenated solvents such as
methylene chloride, 1,2-dichloroethane and chloroform; alcohol
solvents such as amyl alcohol and isopropyl alcohol; polar solvents
such as N,N-dimethylformamide and N-methylpyrrolidone; nonpolar
solvents such as toluene, benzene and dichlorobenzene; organic
acids such as acetic acid; water; and a mixture thereof. The amine
compound (22) to be reacted may be used as a solvent. The reaction
temperature must be a temperature that can complete the reaction
without promoting formation of an undesirable by-product, and is
preferably room temperature to 200.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound of General Formula (I-9)]
[0184] The compound of the general formula (I-1) can be prepared
from an ester compound (3) according to Step 1-2 using ammonia, an
ammonium salt or formamide as a nitrogen atom source, for example.
Specifically, Step 1-2 varies according to the starting material
and is not particularly limited insofar as the conditions are
similar to those in this reaction. A known method described in many
documents may be used for the reaction (see The Chemistry of
Heterocyclic Compounds. Imidazole and Derivatives, Part I, p. 33,
Inters. Publish. 1953, for example). The reaction is preferably a
method of stirring an ester compound (3) and 1.0 to 100.0
equivalents of ammonia or an ammonium salt such as ammonium acetate
with respect to the ester compound (3) in a solvent, for example.
The solvent used is not particularly limited insofar as the solvent
does not inhibit the reaction and allows the starting material to
be dissolved therein to a certain extent. Preferable examples of
the solvent include nonpolar solvents such as toluene and benzene;
alcohol solvents such as methanol and ethanol; organic acids such
as acetic acid; water; and a mixture thereof. Formamide may
optionally be used as a nitrogen atom source and a solvent. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably room temperature to 250.degree. C., for example.
The yield may be improved when the reaction is performed using a
tight container. Under preferable reaction conditions, the reaction
is completed in 1 to 24 hours, and the progress of the reaction can
be monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[Preparation of Ester Compound (3)]
[0185] The ester compound (3) is prepared by condensation reaction
of a carboxylic acid compound (1) with a compound (2a) according to
Step 1-1. Specifically, Step 1-1 varies according to the starting
material and is not particularly limited insofar as the conditions
are similar to those in this reaction. A known method described in
many documents may be used for the reaction. Preferable examples of
the reaction include i) nucleophilic substitution reaction of a
carboxylic acid compound (1) with a compound (2a), wherein L.sub.1
represents a halogen atom such as a chlorine atom, a bromine atom
or an iodine atom or a sulfonate group such as a methanesulfonate
group, a p-toluenesulfonate group or a trifluoromethanesulfonate
group (see Shin Jikken Kagaku Koza (New Courses in Experimental
Chemistry), vol. 22, Yuki Gosei (Organic Synthesis) [IV], edited by
The Chemical Society of Japan, Maruzen Co., Ltd., November 1992, p.
49-50, for example) and ii) dehydration condensation reaction of a
carboxylic acid compound (1) with a compound (2a) (see Shin Jikken
Kagaku Koza (New Courses in Experimental Chemistry), vol. 22, Yuki
Gosei (Organic Synthesis) [IV], edited by The Chemical Society of
Japan, Maruzen Co., Ltd., November 1992, p. 43-47, for
example).
[0186] i) Nucleophilic substitution reaction is preferably, for
example, a method of stirring a carboxylic acid compound (1) and
1.0 to 10.0 equivalents of a compound (2a) with respect to the
carboxylic acid compound (1) in a solvent in the presence of 1.0 to
10.0 equivalents of a base with respect to the carboxylic acid
compound (1). The base used varies according to the starting
material and is not particularly limited. Preferable examples of
the base include alkali metal hydroxides such as sodium hydroxide
and lithium hydroxide; alkali metal carbonates such as sodium
carbonate; alkali metal salts of alcohols such as sodium methoxide
and potassium tert-butoxide; organic bases such as triethylamine,
pyridine and diazabicyclononene; organic metals such as butyl
lithium and lithium diisobutylamide; alkali metal hydrides such as
sodium hydride; and alkali metal ammonium salts such as sodium
amide. The solvent used varies according to the starting material
and the base used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include polar solvents such as
nitromethane, acetonitrile, 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; halogenated solvents such as chloroform
and methylene chloride; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0187] ii) Dehydration condensation reaction is preferably, for
example, a method of stirring a carboxylic acid compound (1) and
1.0 to 10.0 equivalents of a compound (2a) with respect to the
carboxylic acid compound (1) in a solvent in the presence of 0.1 to
10.0 equivalents of a condensing agent with respect to the
carboxylic acid compound (1). The condensing agent used varies
according to the starting material and is not particularly limited.
Preferable examples of the condensing agent include inorganic acids
such as hydrochloric acid and sulfuric acid; organic acids such as
p-toluenesulfonic acid and methanesulfonic acid; and
1,3-dicyclohexylcarbodiimide,
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate, diethyl cyanophosphonate,
bis(2-oxo-3-oxazolidinyl)phosphonic chloride and diphenylphosphoryl
azide. Preferably, 1.0 to 5.0 equivalents of N-hydroxysuccinimide,
N-hydroxybenzotriazole or dimethylaminopyridine may be added in
order to make the reaction efficiently proceed, for example. The
solvent used varies according to the starting material and the
condensing agent used, and is not particularly limited insofar as
the solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include halogenated solvents such as
chloroform, methylene chloride and 1,2-dichloroethane; polar
solvents such as tetrahydrofuran and N,N-dimethylformamide; and a
mixed solvent thereof. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably ice-cold
temperature to 150.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique or/and crystallization.
[Preparation of Oxazole Compound (21)]
[0188] The oxazole compound (21) can be prepared by reacting an
ester compound (3) with ammonia, an ammonium salt or formamide as a
nitrogen atom source according to Step 1-4, for example.
Specifically, Step 1-4 varies according to the starting material
and is not particularly limited insofar as the conditions are
similar to those in this reaction. A known method described in many
documents may be used for the reaction (see Synthesis, 1998, vol.
9, p. 1298, for example). Preferably, an ester compound (3) and 1.0
to 100.0 equivalents of ammonia or an ammonium salt such as
ammonium acetate with respect to the ester compound (3) are stirred
in a solvent, for example. The solvent used is not particularly
limited insofar as the solvent does not inhibit the reaction and
allows the starting material to be dissolved therein to a certain
extent. Preferable examples of the solvent include nonpolar
solvents such as toluene and benzene; alcohol solvents such as
methanol and ethanol; organic acids such as acetic acid; water; and
a mixture thereof. Formamide may optionally be used as a nitrogen
atom source and a solvent. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 250.degree. C., for example. The yield may be
improved when the reaction is performed using a tight container.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound (2b)]
[0189] The compound (2b) is commercially available or can be
prepared by a method known to a person skilled in the art (see Shin
Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.
19, Yuki Gosei (Organic Synthesis) [I], edited by The Chemical
Society of Japan, Maruzen Co., Ltd., September 1992, p. 363-482;
and Shin Jikken Kagaku Koza (New Courses in Experimental
Chemistry), vol. 24, Yuki Gosei (Organic Synthesis) [VI], edited by
The Chemical Society of Japan, Maruzen Co., Ltd., June 1992, p.
61-90, for example).
[Preparation of Compound (22)]
[0190] The compound (22) is commercially available or can be
prepared by a method known to a person skilled in the art (see Shin
Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.
20, Yuki Gosei (Organic Synthesis) [II], edited by The Chemical
Society of Japan, Maruzen Co., Ltd., July 1992, p. 279-372, for
example).
[Preparation of Compound (2a)]
[0191] The compound (2a) is commercially available or can be
prepared by a method known to a person skilled in the art (see Shin
Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.
19, Yuki Gosei (Organic Synthesis) [I], edited by The Chemical
Society of Japan, Maruzen Co., Ltd., September 1992, p. 363-482;
and Shin Jikken Kagaku Koza (New Courses in Experimental
Chemistry), vol. 20, Yuki Gosei (Organic Synthesis) [II], edited by
The Chemical Society of Japan, Maruzen Co., Ltd., July 1992, p.
1-110, for example).
[Preparation of Carboxylic Acid Compound (1)]
##STR00033##
[0193] In the formula, Ar.sub.1, Ar.sub.2, R.sup.1 and X.sub.1 are
as defined above; V.sub.1 represents a protecting group for a
carboxylic group such as a methyl group, an ethyl group, a benzyl
group, an allyl group, a triphenylmethyl group, a tert-butyl group
or a tert-butyldimethylsilyl group; L.sub.3 and L.sub.6 each
represent a hydrogen atom, a halogen atom such as a fluorine atom,
a chlorine atom, a bromine atom or an iodine atom, a sulfonate
group such as a trifluoromethanesulfonate group, a trialkyltin
group or a leaving group such as a boronic acid or boronate group;
L.sub.4 represents a formyl group, an alkanoyl group such as an
acetyl group, an alkoxycarbonyl group such as a methyl ester group,
a halogen atom such as a fluorine atom, a chlorine atom, a bromine
atom or an iodine atom, a sulfonate group such as a
trifluoromethanesulfonate group, a trialkyltin group or a boronic
acid or boronate group; L.sub.5 represents a halogen atom such as a
fluorine atom, a chlorine atom, a bromine atom or an iodine atom or
a sulfonate group such as a trifluoromethanesulfonate group; W
represents a phosphate group such as a diethylphosphonyl group, a
diphenylphosphonyl group or a bis(2,2,2-trifluoroethyl)phosphonyl
group, a phosphonium salt such as triphenylphosphonium bromide or a
silyl group such as a trimethylsilyl group; R.sup.26 is as defined
for the R.sup.1; R.sup.13 is as defined for the R.sup.2; and
R.sup.14 and R.sup.15 each represent a C1-6 alkyl group.
[0194] The carboxylic acid compound (1) is prepared by hydrolysis
of an ester compound (8) according to Step 2-3. Specifically, Step
2-3 varies according to the starting material and is not
particularly limited insofar as the conditions are similar to those
in this reaction. A known method described in many documents may be
used for the reaction (see Shin Jikken Kagaku Koza (New Courses in
Experimental Chemistry), vol. 22, Yuki Gosei (Organic Synthesis)
[IV], edited by The Chemical Society of Japan, Maruzen Co., Ltd.,
November 1992, p. 6-11, for example). Preferably, an ester compound
(8) is stirred in a solvent in the presence of 1.0 to 100.0
equivalents of a base or acid with respect to the ester compound
(8), for example. The base used varies according to the starting
material and is not particularly limited. Preferable examples of
the base include sodium hydride, sodium hydroxide, potassium
hydroxide, potassium carbonate, sodium carbonate, cesium carbonate
and barium carbonate. The acid used varies according to the
starting material and is not particularly limited. Preferable
examples of the acid include inorganic acids such as hydrochloric
acid and sulfuric acid; organic acids such as trifluoroacetic acid
and p-toluenesulfonic acid; and Lewis acids such as boron
trichloride. The solvent used varies according to the starting
material, and is not particularly limited insofar as the solvent
does not inhibit the reaction and allows the starting material to
be dissolved therein to a certain extent. Preferable examples of
the solvent include alcohol solvents such as methanol, ethanol and
ethylene glycol; ether solvents such as tetrahydrofuran;
halogenated solvents such as dichloromethane and chloroform; water;
and a mixed solvent thereof. In the case of acid hydrolysis, an
organic acid such as acetic acid or formic acid may be used as a
solvent. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 100.degree. C.,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique or/and
crystallization.
[Preparation of Ester Compound (8)]
[0195] The ester compound (8) can be prepared as shown by the above
reaction formula, but the preparation is not limited thereto.
Specifically, the ester compound (8) can be prepared by reacting a
compound (4) with a compound (5) in Step 2-1 to obtain a carbonyl
compound (6) and then condensing the carbonyl compound (6) by
condensation reaction such as Horner-Emmons reaction, Wittig
reaction or Peterson reaction in Step 2-2, for example.
Alternatively, the ester compound (8) can be prepared by subjecting
a carbonyl compound (6) as a starting material to Step 2-4 to
prepare a compound (10) and condensing the compound (10) with a
compound (11) by condensation reaction such as Horner-Emmons
reaction, Wittig reaction or Peterson reaction in Step 2-5.
Alternatively, the ester compound (8) can be prepared by forming
Ar.sub.1 in a compound (17) from an amino compound (13) as a
starting material through three-stage reaction in Step 2-7 and then
performing coupling reaction of the compound (17) with a compound
(18a) or compound (18b) according to Step 2-11. The ester compound
(8) can also be prepared by converting a compound (15) as a
starting material into a compound (17) according to Step 2-9 and
then subjecting the compound (17) to Step 2-11.
[Conversion of Carbonyl Compound (6) into Ester Compound (8) and
Conversion of Compound (10) into Ester Compound (8)]
[0196] A carbonyl compound (6) can be converted into the ester
compound (8) and a compound (10) can be converted into the ester
compound (8) by a method known to a person skilled in the art. For
example, the ester compound (8) can be prepared from a carbonyl
compound (6) and a compound (7) according to Step 2-2.
Alternatively, the ester compound (8) can be prepared from a
compound (10) and a compound (11) according to Step 2-5.
Specifically, coupling reaction in Step 2-2 or Step 2-5 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
method known to a person skilled in the art may be used for the
reaction. Preferable examples of the method include Wittig
reaction, Horner-Emmons reaction and Peterson reaction (see Shin
Jikken Kagaku Koza (Courses in Experimental Chemistry), vol. 19,
Yuki Gosei (Organic Synthesis) [I], edited by The Chemical Society
of Japan, Maruzen Co., Ltd., June 1992, p. 57-85, for example).
[0197] In Wittig reaction, a compound (7) or compound (10), wherein
W represents a phosphonium salt, and 0.5 to 2.0 equivalents of a
carbonyl compound (6) or a compound (11) with respect to the
compound (7) or compound (10) are preferably stirred in a solvent
in the presence of 1.0 to 5.0 equivalents of a base with respect to
the compound (7) or compound (10), for example. This reaction may
be a method of first treating a compound (7) or compound (10) and a
base to form a phosphorus ylide and then adding a carbonyl compound
(6) or a compound (11) to the ylide; or a method of adding a base
in the presence of a compound (7) or compound (10) and a carbonyl
compound (6) or a compound (11). This reaction is preferably
performed in the presence of a solvent from the viewpoint of
handleability and stirring efficiency. The solvent used varies
according to the starting material and the base used, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
polar solvents such as nitromethane, acetonitrile,
1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl
sulfoxide; ether solvents such as tetrahydrofuran, 1,4-dioxane and
1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene and
xylene; alcohol solvents such as ethanol and methanol; halogenated
solvents such as chloroform and methylene chloride; water; and a
mixed solvent thereof. The base used varies according to the
starting material and the solvent. Preferable examples of the base
include alkali metal hydroxides such as sodium hydroxide and
lithium hydroxide; alkali metal carbonates such as sodium
carbonate; alkali metal salts of alcohols such as sodium methoxide
and potassium tert-butoxide; organic bases such as triethylamine,
pyridine and diazabicyclononene; organic metals such as butyl
lithium and lithium diisobutylamide; and alkali metal hydrides such
as sodium hydride. The reaction temperature must be a temperature
that can complete the reaction without promoting formation of an
undesirable by-product, and is preferably -78 to 150.degree. C.,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0198] In Horner-Emmons reaction, a compound (7) or compound (10),
wherein W represents a phosphite group, and 0.5 to 2.0 equivalents
of a carbonyl compound (6) or a compound (11) with respect to the
compound (7) or compound (10) are preferably stirred in a solvent
in the presence of 1.0 to 5.0 equivalents of a base with respect to
the compound (7) or compound (10), for example. This reaction may
be a method of first treating a compound (7) or compound (10) and a
base to form a carbanion and then adding a carbonyl compound (6) or
a compound (11) to the carbanion; or a method of adding a base in
the presence of a compound (7) or compound (10) and a carbonyl
compound (6) or a compound (11). This reaction is preferably
performed in the presence of a solvent from the viewpoint of
handleability and stirring efficiency. The solvent used varies
according to the starting material and the base used, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
polar solvents such as 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; water; and a mixed solvent thereof. The
base used varies according to the starting material and the
solvent. Preferable examples of the base include alkali metal
hydroxides such as sodium hydroxide and lithium hydroxide; alkali
metal carbonates such as sodium carbonate; alkali metal salts of
alcohols such as sodium methoxide and potassium tert-butoxide;
organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; alkali metal hydrides such as sodium
hydride; and alkali metal ammonium salts such as sodium amide. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0199] In Peterson reaction, a compound (7) or compound (10),
wherein W represents a silyl group, and 0.5 to 2.0 equivalents of a
carbonyl compound (6) or a compound (11) with respect to the
compound (7) or compound (10) are preferably stirred in a solvent
in the presence of 1.0 to 5.0 equivalents of a base with respect to
the compound (7) or compound (10), for example. This reaction may
be a method of first treating a compound (7) or compound (10) and a
base to form a carbanion and then adding a carbonyl compound (6) or
a compound (11) to the carbanion; or a method of adding a base in
the presence of a compound (7) or compound (10) and a carbonyl
compound (6) or a compound (11). This reaction is preferably
performed in the presence of a solvent from the viewpoint of
handleability and stirring efficiency. The solvent used varies
according to the starting material and the base used, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
polar solvents such as 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; water; and a mixed solvent thereof. The
base used varies according to the starting material and the
solvent. Preferable examples of the base include alkali metal
hydroxides such as sodium hydroxide and lithium hydroxide; alkali
metal carbonates such as sodium carbonate; alkali metal salts of
alcohols such as sodium methoxide and potassium tert-butoxide;
organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; alkali metal hydrides such as sodium
hydride; and alkali metal ammonium salts such as sodium amide. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Conversion of Compound (17) into Ester Compound (8)]
[0200] A compound (17) can be converted into the ester compound (8)
by a method known to a person skilled in the art. The ester
compound (8) can be prepared from a compound (17) together with a
compound (18a) or compound (18b) according to Step 2-11, for
example. Specifically, the coupling reaction in Step 2-11 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
method known to a person skilled in the art may be used for the
reaction. Preferable examples of the method include Mizoroki-Heck
reaction (see R. F. Heck, "Org. Reactions.", 1982, vol. 27, p. 345,
for example), Suzuki-Miyaura reaction (see A. Suzuki, "Chem. Rev.",
1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K.
Sonogashira, "Comprehensive Organic Synthesis", 1991, vol. 3, p.
521) and Stille coupling reaction (see J. K. Stille, "Angew. Chem.
Int. Ed. Engl.", 1986, vol. 25, p. 508, for example).
[0201] In Mizoroki-Heck reaction, a halogen compound or triflate
compound (17), wherein L.sub.4 represents a chlorine atom, a
bromine atom, an iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, is preferably coupled with 1.0 to
5.0 equivalents of an alkene compound (18a; wherein L.sub.6 is a
hydrogen atom) with respect to the compound (17) in the presence of
0.01 to 0.2 equivalent of a transition metal catalyst with respect
to the compound (17), for example. This reaction is preferably
performed in the presence of a solvent from the viewpoint of
handleability and stirring efficiency. The solvent used varies
according to the starting material and the transition metal
catalyst used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include acetonitrile, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere. The transition
metal catalyst is preferably a palladium complex, for example, and
more preferably a known palladium complex such as palladium (II)
acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). It is also preferable to
appropriately add a phosphorus ligand (preferably
triphenylphosphine, tri-o-tolylphosphine, tri-tert-butylphosphine
or 2-(di-tert-butylphosphino)biphenyl, for example) in order to
make the reaction efficiently proceed. A preferable result may be
achieved in the presence of a base. The base used is not
particularly limited insofar as the base is used in a coupling
reaction similar to this reaction. Preferable examples of the base
include triethylamine, N,N-diisopropylethylamine,
N,N-dicyclohexylmethylamine and tetrabutylammonium chloride. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique.
[0202] In Suzuki-Miyaura reaction, a halogen compound or
trifluoromethanesulfonate compound (17), wherein L.sub.4 represents
a chlorine atom, a bromine atom, an iodine atom or a sulfonate
group such as a trifluoromethanesulfonate group, is preferably
coupled with 1.0 to 5.0 equivalents of a boronic acid compound or
boronate compound (18a; wherein L.sub.6 is a boronic acid or
boronate group) with respect to the compound (17) in the presence
of 0.01 to 0.5 equivalent of a transition metal catalyst with
respect to the compound (17), for example. This reaction is
preferably performed in the presence of a solvent from the
viewpoint of handleability and stirring efficiency. The solvent
used varies according to the starting material and the transition
metal catalyst used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include acetonitrile, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixed
solvent thereof. The reaction temperature must be a temperature
that can complete the coupling reaction, and is preferably room
temperature to 200.degree. C. This reaction is performed preferably
in an inert gas atmosphere, and more preferably in a nitrogen or
argon atmosphere. Under preferable reaction conditions, the
reaction is completed in 1 to 24 hours, and the progress of the
reaction can be monitored by a known chromatography technique. The
transition metal catalyst is preferably a known palladium complex,
and more preferably a known palladium complex such as palladium
(II) acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0), or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand
(preferably triphenylphosphine, tri-o-tolylphosphine,
tricyclohexylphosphine, or tri-tert-butylphosphine, for example)
may be appropriately added in order to make the reaction
efficiently proceed. A quaternary ammonium salt, preferably
tetrabutylammonium chloride or tetrabutylammonium bromide, for
example, may also be appropriately added in order to make the
reaction efficiently proceed. In this reaction, a preferable result
may be achieved in the presence of a base. The base used at this
time varies according to the starting material, the solvent used
and the like, and is not particularly limited. Preferable examples
of the base include sodium hydroxide, barium hydroxide, potassium
fluoride, cesium fluoride, sodium carbonate, potassium carbonate,
cesium carbonate and potassium phosphate. Under preferable reaction
conditions, the reaction is completed in 1 to 24 hours, and the
progress of the reaction can be monitored by a known chromatography
technique. In this reaction, the desired ester compound (8) can be
efficiently obtained even when the compound (18a) is a halide or a
trifluoromethanesulfonate compound, wherein L.sub.6 is a chlorine
atom, a bromine atom, an iodine atom or a trifluoromethanesulfonate
group, for example, and the compound (17) is a boronic acid
compound or boronate compound, wherein L.sub.4 is a boronic acid or
boronate group, for example.
[0203] The reaction conditions in Sonogashira reaction vary
according to the starting material, the solvent and the transition
metal catalyst, and are not particularly limited insofar as the
conditions are similar to those in this reaction. A method known to
a person skilled in the art may be used for the reaction.
Preferably, a compound (17), wherein L.sub.4 represents a chlorine
atom, a bromine atom, an iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, and 1.0 to 5.0 equivalents of an
alkyne compound (18b) with respect to the compound (17) are stirred
in a solvent, for example. Preferable examples of the solvent used
include acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl
sulfoxide. More preferable examples of the solvent include
tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone and
N,N-dimethylformamide. The reaction temperature must be a
temperature that can complete the coupling reaction, and is
preferably room temperature to 150.degree. C. This reaction is
performed preferably in an inert gas atmosphere, and more
preferably in a nitrogen or argon atmosphere. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. The transition metal catalyst is
preferably 0.01 to 0.5 equivalent with respect to the compound (17)
of a known palladium complex, and more preferably a known palladium
complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand
(preferably triphenylphosphine, tri-o-tolylphosphine or
tri-tert-butylphosphine, for example) may be appropriately added,
for example, in order to make the reaction efficiently proceed. In
the reaction, a metal halide or a quaternary ammonium salt,
preferably copper (I) iodide, lithium chloride, tetrabutylammonium
fluoride or silver (I) oxide, for example, may be added. A
preferable result may be achieved in the presence of a base. The
base used here is not particularly limited insofar as the base is
used in a coupling reaction similar to this reaction. Preferable
examples of the base include basic solvents such as diethylamine,
triethylamine, N,N-diisopropylethylamine, piperidine and
pyridine.
[0204] In Stille coupling reaction, a trialkyltin compound (17),
wherein L.sub.4 represents an alkyltin group, and 1.0 to 5.0
equivalents of a halide or a trifluoromethanesulfonate compound
(18a), wherein L.sub.6 represents a chlorine atom, a bromine atom,
an iodine atom or a trifluoromethanesulfonate group, with respect
to the compound (17) are preferably stirred in a solvent in the
presence of 0.01 to 0.2 equivalent of a transition metal catalyst
with respect to the compound (17), for example. It is preferable to
appropriately use 0.1 to 5.0 equivalents of copper (I) halide
or/and lithium chloride in order to make the reaction efficiently
proceed. Preferable examples of the solvent used in this reaction
include toluene, xylene, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone and dimethyl
sulfoxide. The reaction temperature must be a temperature that can
complete the coupling reaction, and is preferably room temperature
to 150.degree. C. The preferable transition metal catalyst is a
palladium complex, preferably a known palladium complex such as
palladium (II) acetate, dichlorobis(triphenylphosphine)palladium
(II), tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0), for example, and more
preferably tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0), for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique.
[Preparation of Carbonyl Compound (6)]
[0205] The carbonyl compound (6) can be prepared from a compound
(4) as a starting material according to Step 2-1, for example.
Specifically, Step 2-1 varies according to the starting material
and is not particularly limited insofar as the conditions are
similar to those in this reaction. A method known to a person
skilled in the art may be used for the reaction. For example, a
compound (4) and 1.0 to 5.0 equivalents of a compound (5) with
respect to the compound (4) are stirred in a solvent in the
presence or absence of 1.0 to 5.0 equivalents of a base with
respect to the compound (4) (see D. D. Davey et al., "J. Med.
Chem.", 1991, vol. 39, p. 2671-2677). Preferable examples of the
base used include sodium hydride, sodium hydroxide, potassium
hydroxide, potassium carbonate, sodium carbonate, cesium carbonate,
barium carbonate, pyridine, lutidine and triethylamine. The solvent
used varies according to the starting material, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
acetonitrile, tetrahydrofuran, dimethyl sulfoxide,
N,N-dimethylformamide and N-methylpyrrolidine. The base may
optionally be used as a solvent. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 150.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique or/and crystallization.
[0206] The carbonyl compound (6) can also be prepared from a
compound (17) as a starting material according to Step 2-10, for
example. Specifically, Step 2-10 varies according to the starting
material and is not particularly limited insofar as the conditions
are similar to those in this reaction. A method known to a person
skilled in the art may be used for the reaction. For example, it is
possible to use a two-stage method of converting a compound (17),
wherein L.sub.4 represents a chlorine atom, a bromine atom, an
iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, into a vinyl compound by Stille
coupling reaction using 1.0 to 5.0 equivalents of a vinyltin
compound with respect to the compound (17) and then oxidizing the
carboxylic acid by ozone oxidation reaction (see S. S. Chandran et
al., "Bioorg. Med. Chem. Lett.", 2001, vol. 11, p. 1493-1496, for
example). It is also possible to use carbon monoxide insertion
reaction using a transition metal catalyst (see T. Okano et al.,
"Bull. Chem. Soc. Jpn.", 1994, vol. 67, p. 2329-2332, for
example).
[Preparation of Compound (4)]
[0207] The compound (4) is commercially available or can be
obtained by a technique known to a person skilled in the art. If
not commercially available, the preferable compound (4), wherein
L.sub.3 represents a fluorine atom, a chlorine atom or a bromine
atom, can be obtained by oxidizing a corresponding alcohol compound
by an oxidation reaction known to a person skilled in the art; or
the carbonyl compound can be obtained by reducing a corresponding
ester compound by a known reduction reaction.
[Preparation of Compound (5)]
[0208] The compound (5) used in this step is commercially available
or can be obtained by a technique known to a person skilled in the
art. (see M. Komoto et al., "Agr. Biol. Chem.", 1968, vol. 32, p.
983-98'7; or J. M. Kokosa et al., "J. Org. Chem.", 1983, vol. 48,
p. 3605-3607, for example).
[Preparation of compound (7)]
##STR00034##
[0209] In the formula R.sup.13, W, L.sub.5 and V.sub.1 are as
defined above.
[0210] The above reaction formula shows an example of a method for
preparing the phosphonate compound (7). Specifically, the
phosphonate compound (7) is commercially available or can be
obtained by a method shown in the above Step 3-1 to Step 3-3 and
known to a person skilled in the art (see C. Patois et al., "Synth.
Commun", 1991, vol. 22, p. 2391; or J. A. Jackson et al., "J. Org.
Chem.", 1989, vol. 20, p. 5556, for example). Step 3-1 is a step of
obtaining the desired phosphonate compound (7) by stirring a
phosphonate compound (20a) and 1.0 to 2.0 equivalents of an alkyl
halide compound (19a) with respect to the phosphonate compound
(20a) in a solvent in the presence of 1.0 to 1.5 equivalents of a
base with respect to the phosphonate compound (20a) to introduce
R.sub.13, for example. Step 3-2 is a step of obtaining the desired
phosphonate compound (7) by stirring a phosphonate compound (19b)
and 1.0 to 2.0 equivalents of a halogenated formate compound (20b)
with respect to the phosphonate compound (19b) in a solvent in the
presence of 1.0 to 1.5 equivalents of a base with respect to the
phosphonate compound (19b). Step 3-3 is a step of obtaining the
desired phosphonate compound (7) by stirring a phosphonic acid
halide compound (19c) and 1.0 to 2.0 equivalents of an ester
compound (20c) with respect to the phosphonic acid halide compound
(19c) in a solvent in the presence of 1.0 to 1.5 equivalents of a
base with respect to the phosphonic acid halide compound (19c). The
base used varies according to the starting material and is not
particularly limited. Preferable examples of the base include
sodium hydride, n-butyl lithium, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide and sodium bis(trimethylsilyl)amide. The
solvent used varies according to the starting material, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
hexane, toluene, diethyl ether, tetrahydrofuran,
N,N-dimethylformamide, hexamethylphosphoric triamide and a mixed
solvent thereof. The reaction temperature must be a temperature
that can complete the reaction without promoting formation of an
undesirable by-product, and is preferably -78.degree. C. to
100.degree. C. Under preferable reaction conditions, the reaction
is completed in 1 to 24 hours, and the progress of the reaction can
be monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique or/and
crystallization. The desired phosphonate compound (7) can be
efficiently obtained by modification of R.sub.13 by a technique
known to a person skilled in the art.
[0211] The alkyl halide compound (19a), phosphonate compound (19b),
phosphonic acid halide compound (19c), phosphonate compound (20a),
halogenated formate compound (20b) and ester compound (20c) used in
this step are commercially available or can be obtained by a
technique known to a person skilled in the art.
[Preparation of Compound (10)]
[0212] The compound (10) can be prepared from a compound (6) and a
compound (9) according to Step 2-4. Specifically, Step 2-4 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
method known to a person skilled in the art may be used for the
reaction (see Journal of the American Chemistry, 1961, vol. 83, p.
173, for example). Preferably, a compound (6) and 1.0 to 10.0
equivalents of a compound (9) with respect to the compound (6) are
stirred in a solvent in the presence of 1.0 to 10.0 equivalents of
a base with respect to the compound (6), for example. The base used
varies according to the starting material and is not particularly
limited. Preferable examples of the base include organic bases such
as 1,8-diazabicyclo[5,4,0]-7-undecene and diisopropylamine; and
alkali metal salts such as potassium carbonate and sodium
carbonate. The solvent used varies according to the starting
material, and is not particularly limited insofar as the solvent
does not inhibit the reaction and allows the starting material to
be dissolved therein to a certain extent. Preferable examples of
the solvent include hexane, toluene, diethyl ether,
tetrahydrofuran, N,N-dimethylformamide, hexamethylphosphoric
triamide and a mixed solvent thereof. The reaction temperature must
be a temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably
-78.degree. C. to 100.degree. C. Under preferable reaction
conditions, the reaction is completed in 1 to 24 hours, and the
progress of the reaction can be monitored by a known chromatography
technique. An undesirable by-product can be removed by a technique
known to a person skilled in the art such as a conventional
chromatography technique or/and crystallization.
[Preparation of Compound (9)]
[0213] The compound (9) used in this step is commercially available
or can be obtained by a technique known to a person skilled in the
art.
[Preparation of Compound (11)]
[0214] The compound (11) used in this step is commercially
available or can be obtained by a technique known to a person
skilled in the art.
[Preparation of Amine Compound (13)]
[0215] The amine compound (13) is commercially available or can be
obtained by a technique known to a person skilled in the art.
Preferably, the compound can be prepared from a nitro compound (12)
as a starting material according to Step 2-6. Specifically,
reduction reaction in Step 2-6 varies according to the starting
material and is not particularly limited insofar as the conditions
are similar to those in this reaction. A method known to a person
skilled in the art may be used for the reaction (see Shin Jikken
Kagaku Koza (New Courses in Experimental Chemistry), vol. 14, Yuki
Kagobutsu No Gosei To Hannou (Synthesis and Reaction of Organic
Compounds) [III], edited by The Chemical Society of Japan, Maruzen
Co., Ltd., February 1978, p. 1333-1341, for example). The reaction
is preferably a catalytic reduction method using a metal catalyst
or a reduction method using a metal, for example. The catalytic
reduction method is preferably performed in a hydrogen atmosphere
at normal pressure to 100 atm. Preferable examples of the metal
catalyst used in this reaction include platinum, platinum oxide,
platinum black, Raney nickel and palladium-carbon. The solvent used
in the present reaction varies according to the starting material,
and is not particularly limited insofar as the solvent does not
inhibit the reaction and allows the starting material to be
dissolved therein to a certain extent. Preferable examples of the
solvent include methanol, ethanol, diethyl ether, tetrahydrofuran,
methylene chloride, chloroform and ethyl acetate. An acidic
substance such as acetic acid or hydrochloric acid may be
appropriately added in order to make the reaction efficiently
proceed. The reduction method using a metal preferably employs
zinc, iron or tin, for example, and is preferably performed under
acidic conditions using hydrochloric acid, acetic acid or ammonium
chloride, for example. The solvent used in the present reaction
varies according to the starting material, and is not particularly
limited insofar as the solvent does not inhibit the reaction and
allows the starting material to be dissolved therein to a certain
extent. Preferable examples of the solvent include methanol,
ethanol and 2-propanol. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 100.degree. C. Under preferable reaction conditions,
the reaction is completed in 1 to 24 hours, and the progress of the
reaction can be monitored by a known chromatography technique. An
undesirable by-product can be removed by a technique known to a
person skilled in the art such as a conventional chromatography
technique or/and crystallization.
[0216] The preferable amine compound (13) can also be prepared from
a compound (15) as a starting material which is commercially
available or can be obtained by a technique known to a person
skilled in the art, according to coupling reaction in Step 2-8.
Specifically, the coupling reaction in Step 2-8 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A method
known to a person skilled in the art may be used for the reaction.
Preferably, for example, it is possible to use a two-stage method
of performing coupling reaction of benzophenone imine using a
transition metal catalyst and then performing a known benzophenone
removal reaction treatment (see S. L. Buchwald et al., "Tetrahedron
Lett.", 1997, vol. 38, p. 6367-6370; or J. F. Hartwig et al., "J.
Am. Chem. Soc.", 1998, vol. 120, p. 827-828, for example). In the
coupling reaction of benzophenone imine, a compound (15) and 1.0 to
10.0 equivalents of benzophenone imine with respect to the compound
(15) are stirred in a solvent in the presence of 0.01 to 0.2
equivalent of a catalyst with respect to the compound (15).
Preferable examples of the catalyst that can be used include known
palladium complexes such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) and
tris(dibenzylideneacetone)dipalladium (0); and known nickel
catalysts such as (1,5-cyclooctadiene)nickel (0). Preferably, a
phosphorus ligand such as triphenylphosphine, tri-o-tolylphosphine,
tri-tert-butylphosphine, 2-(di-tert-butylphosphino)biphenyl,
2,2'-bis(diphenylphosphino)-1,1'-binaphthyl,
1,2-bis(diphenylphosphino)ethane or
1,1'-bis(diphenylphosphino)ferrocene may be appropriately added in
order to make the reaction efficiently proceed, for example. A
preferable result may be achieved in the presence of a base. The
base used is not particularly limited insofar as the base is used
in a coupling reaction similar to this reaction. Preferable
examples of the base include sodium hydroxide, barium hydroxide,
potassium fluoride, cesium fluoride, sodium carbonate, potassium
carbonate, cesium carbonate, potassium phosphate and sodium
tert-butoxide. The solvent used varies according to the starting
material and the transition metal catalyst used, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
acetonitrile, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane,
benzene, toluene, xylene, 1-methyl-2-pyrrolidone and
N,N-dimethylformamide. The reaction temperature must be a
temperature that can complete the coupling reaction, and is
preferably room temperature to 100.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere. A method known
to a person skilled in the art may be used for the treatment after
the second stage (see T. W. Green, "Protective Groups in Organic
Synthesis", John Wiley & Sons, Inc., 1981). An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique or/and
crystallization.
[0217] In the preferable amine compound (13), L.sub.4 can be
modified by a method known to a person skilled in the art, and a
hydrogen atom in L.sub.4 can be preferably converted into a halogen
substituent (see Shin Jikken Kagaku Koza (New Courses in
Experimental Chemistry), vol. 14, Yuki Kagobutsu No Gosei To Hannou
(Synthesis and Reaction of Organic Compounds) [I], edited by The
Chemical Society of Japan, Maruzen Co., Ltd., November 1977, p.
354-360, for example).
[Preparation of Nitro Compound (12)]
[0218] The nitro compound (12) is commercially available or can be
obtained by a technique known to a person skilled in the art. If
not commercially available, the preferable compound (12), wherein
L.sub.4 represents a fluorine atom, a chlorine atom, a bromine atom
or an iodine atom, can be efficiently obtained from a corresponding
precursor by a nitration reaction known to a person skilled in the
art (see Shin Jikken Kagaku Koza (New Courses in Experimental
Chemistry), vol. 14, Yuki Kagobutsu No Gosei To Hannou (Synthesis
and Reaction of Organic Compounds) [III], edited by The Chemical
Society of Japan, Maruzen Co., Ltd., February 1978, p. 1261-1300,
for example).
[Preparation of Compound (17)]
[0219] The compound (17) can be obtained by a technique known to a
person skilled in the art. Preferably, the compound (17) can be
prepared i) from a compound (15) as a starting material according
to Step 2-9 or ii) from an amine compound (13) as a starting
material according to Step 2-7, for example.
[0220] In the case of i), Step 2-9 is performed by the same method
as in the above Step 2-1.
[0221] In the case of ii), an amine compound (13) can be
efficiently converted into the compound (17) in Step 2-7 by
treating the amine compound (13) with a mixed solvent of acetic
anhydride and formic acid in a first stage, condensing the compound
with a compound (14) under basic conditions in a second stage, and
heating the condensate with ammonium acetate and acetic acid in a
third stage, for example. In the first stage, a compound (13) is
stirred in a mixed solvent of 2.0 to 10.0 equivalents of acetic
anhydride with respect to the compound (13) and 10.0 to 20.0
equivalents of formic acid with respect to the compound (13) at
ice-cold temperature to 50.degree. C. In the second stage, 1.0 to
5.0 equivalents of a base is preferably used with respect to the
compound (13). Examples of the base include sodium hydride, sodium
hydroxide, potassium hydroxide, lithium hydroxide, n-butyl lithium,
lithium diisopropylamide, lithium bis(trimethylsilyl)amide and
sodium bis(trimethylsilyl)amide. The solvent used in the present
reaction varies according to the starting material, and is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
diethyl ether, tetrahydrofuran, dimethyl sulfoxide and
N,N-dimethylformamide. Preferably, potassium iodide or sodium
iodide may be added, for example, in order to make the reaction
efficiently proceed. The reaction temperature must be a temperature
that can complete the reaction without promoting formation of an
undesirable by-product, and is preferably room temperature to
100.degree. C., for example. In the third stage, the condensate is
preferably treated in a mixture of 5.0 to 10.0 equivalents of
ammonium acetate with respect to the compound (13) and 10.0 to 20.0
equivalents of acetic acid with respect to the compound (13) at 50
to 100.degree. C. Under preferable reaction conditions, the
reaction is completed in 1 to 24 hours, and the progress of the
reaction can be monitored by a known chromatography technique. An
undesirable by-product can be removed by a technique known to a
person skilled in the art such as a conventional chromatography
technique or/and crystallization.
[0222] The compound (14) used in the second stage of this step is
commercially available or can be obtained by a technique known to a
person skilled in the art. If not commercially available, the
preferable compound (14) can be prepared from a corresponding
carbonyl compound by a halogenation reaction known to a person
skilled in the art (see Shin Jikken Kagaku Koza (New Courses in
Experimental Chemistry), vol. 19, Yuki Gosei (Organic Synthesis)
[I], edited by The Chemical Society of Japan, Maruzen Co., Ltd.,
June 1992, p. 363-482, for example).
[0223] L.sub.4 in the compound (17) can be modified by a technique
known to a person skilled in the art, and can be preferably
converted into, for example, an iodine group (see S. L. Buchwald et
al., "J. Am. Chem. Soc.", 2002, vol. 124, p. 14844-14845, for
example), a lower alkyltin group (see J. Marti et al., "Synth.
Commun", 2000, vol. 30, p. 3023-3030, for example) or a boron group
(see N. Miyaura et al., "J. Org. Chem.", 1995, vol. 60, p.
7508-7510, for example). The compounds (18a) and (18b) are
commercially available or can be obtained by a technique known to a
person skilled in the art.
[0224] The compound of the general formula (I-9), general formula
(I-4) or general formula (I-6), wherein two of R.sup.10, R.sup.11
and R.sup.12 form a ring, can be prepared from the compound (2a) as
a starting material, wherein R.sup.10 and R.sup.11 form a ring, by
the same method as above. When the method as above is performed
using the compound (2a) as a starting material, wherein R.sup.10 or
R.sup.11 represents an alkyl group substituted with a halogen atom
such as a chlorine atom, a bromine atom or an iodine atom, the
compound of the general formula (I-9), general formula (I-4) or
general formula (I-6), wherein two of R.sup.10, R.sup.11 and
R.sup.12 form a ring, can be prepared in Step 1-2, Step 1-5, Step
1-6 or Step 1-7.
[General Preparation Method 2]
[0225] Typically used General Preparation Method 2 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00035##
[0226] In the formula, the following partial structure (formula
III-3, III-4, III-6, III-7 or III-8):
##STR00036##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.4, X.sub.5, X.sub.6,
Y.sub.10, Y.sub.11, R.sup.10, R.sup.11, R.sup.12, nd, ne, ni, nj
and nl are as defined above; Y.sub.13 represents a carboxyl group,
an ester group, a thioester group, a dithioester group, a nitrile
group, a thioimino ether group or an iminoether group; Y.sub.14
represents an oxygen atom, a nitrogen atom or a sulfur atom; and
P.sub.1 represents a protecting group for an amino group such as a
methyl carbamate group, a benzyl carbamate group, a tert-butyl
carbamate group, an allyl group, an acetyl group or a formyl
group.
[0227] The above General Preparation Method 2 includes a method of
reacting a compound (1a) with an amine compound (23a) or amine
compound (23b) according to Step 4-1 or Step 4-5 to convert the
compound (1a) into a compound (24) or compound (26), or converting
a compound (1a) into a compound (24) or compound (26) according to
Step 4-9 or Step 4-10 which is a three-stage reaction including
deprotection, and further reacting the resulting compound (24) or
compound (26) with ammonia, an ammonium salt or formamide in Step
4-2 or Step 4-6 to prepare a compound of the general formula (I-9),
the general formula (I-4), the general formula (I-6), the general
formula (I-7) or the general formula (I-8); a method of once
converting a compound (24) or compound (26) into an oxazole
compound (25) or a compound (27) by dehydration reaction in Step
4-3 or Step 4-7, and then reacting the oxazole compound (25) or the
compound (27) with ammonia, an ammonium salt, formamide or an amine
compound (22) in Step 4-4, Step 4-8 or Step 4-12 to prepare a
compound of the general formula (I-9), the general formula (I-4),
the general formula (I-6), the general formula (I-7) or the general
formula (I-8); and a method of reacting a compound (1a) with an
amine compound (23a) according to Step 4-11 to prepare a compound
of the general formula (I-9), the general formula (I-6), the
general formula (I-7) or the general formula (I-8).
[Preparation of Compound of General Formula (I-4)]
[0228] The compound of the general formula (I-4) can be prepared by
i) reacting a compound (26) in the presence of an acid or base and
optionally in the presence of ammonia, an ammonium salt, formamide
or the like according to Step 4-6. The compound can also be
prepared by ii) reacting a compound (25) or compound (27) with an
amine compound (22), ammonia, an ammonium salt, formamide or the
like according to Step 4-4 or Step 4-8.
[0229] The method i), specifically, Step 4-6 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A known
method described in many documents may be used for the reaction
(see Heterocyclic Compounds, Vol. 5, Wiley, New York, N.Y. 1957, p.
503; and Journal of Heterocyclic Chemistry, 1982, vol. 19, p. 193,
for example). Preferably, a compound (26), wherein Y.sub.14
represents an oxygen atom or a sulfur atom, is stirred in a solvent
in the presence of 1.0 to 100.0 equivalents of ammonia, an ammonium
salt such as ammonium acetate or ammonium carbonate or formamide
with respect to the compound (26), for example. The solvent used is
not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include ether solvents such as tetrahydrofuran, 1,4-dioxane and
diethyl ether; halogenated solvents such as methylene chloride,
1,2-dichloroethane and chloroform; alcohol solvents such as amyl
alcohol and isopropyl alcohol; polar solvents such as
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; organic acids such as
acetic acid; water; and a mixture thereof. Formamide may be used as
a solvent. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 200.degree. C.,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0230] Alternatively, a compound (26), wherein Y.sub.4 represents a
nitrogen atom, is stirred in a solvent in the presence or absence
of 0.1 to 10 equivalents of an acid, base or organic salt with
respect to the compound (26). Preferable examples of the acid, base
or organic salt used include inorganic acids such as hydrochloric
acid and sulfuric acid; organic acids, such as p-toluenesulfonic
acid and methanesulfonic acid; organic bases such as pyridine and
dimethylamino pyridine; and organic salts such as pyridinium
p-toluenesulfonate and tetrabutylammonium hydroxide. The solvent
used is not particularly limited insofar as the solvent does not
inhibit the reaction and allows the starting material to be
dissolved therein to a certain extent. Preferable examples of the
solvent that can be used include ether solvents such as
tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated
solvents such as methylene chloride, 1,2-dichloroethane and
chloroform; alcohol solvents such as methanol, ethanol, amyl
alcohol and isopropyl alcohol; polar solvents such as
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; water; and a mixture
thereof. The above acid, base or organic salt may be used as a
solvent. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 200.degree. C.,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0231] The method ii), specifically, Step 4-4 or Step 4-8 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
known method described in many documents may be used for the
reaction (see Heterocyclic Compounds, vol. 5, Wiley, New York, N.Y.
1950, p. 214; and The Journal of Organic Chemistry, 1962, vol. 27,
p. 3240, for example). For example, an oxazole compound (25) or a
compound (27) and 1.0 to 100.0 equivalents of an amine compound
(22), ammonia, an ammonium salt such as ammonium acetate or
ammonium carbonate or formamide with respect to the compound (25)
or compound (27) are stirred in a solvent. The solvent used is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl
ether; halogenated solvents such as methylene chloride,
1,2-dichloroethane and chloroform; alcohol solvents such as amyl
alcohol and isopropyl alcohol; polar solvents such as
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; organic acids such as
acetic acid; water; and a mixture thereof. The amine source to be
reacted may be used as a solvent. The reaction temperature must be
a temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 200.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization. The amine compound (22) used in this step is
commercially available or can be obtained by a technique known to a
person skilled in the art.
[Preparation of Compound of General Formula (I-9), General Formula
(I-6), General Formula (I-7) and General Formula (I-8)]
[0232] The compound of the general formula (I-9), the general
formula (I-6), the general formula (I-7) or the general formula
(I-8) can be prepared by i) reacting a compound (24) or compound
(25) in the presence of ammonia, an ammonium salt, formamide or the
like according to Step 4-2 or Step 4-12. The compound can also be
prepared by ii) reacting a compound (1a) with an amine compound
(23a) according to Step 4-11.
[0233] The method i), specifically, Step 4-2 or Step 4-12 is the
same method as in Step 4-6.
[0234] The method ii), specifically, Step 4-11 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A known
method described in many documents may be used for the reaction
(see Journal of the Chemical Society, 1962, p. 5149; and Journal of
Medicinal Chemistry, 1983, vol. 26, p. 1187, for example). For
example, a compound (1a), wherein Y.sup.13 represents a nitrile
group, a thioimino ether group or an imino ether group, and 1.0 to
5.0 equivalents of an amine compound (23a) with respect to the
compound (1a) are stirred in a solvent. The solvent used is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl
ether; halogenated solvents such as methylene chloride,
1,2-dichloroethane and chloroform; alcohol solvents such as
methanol, ethanol, butanol, amyl alcohol and isopropyl alcohol;
polar solvents such as N,N-dimethylformamide and
N-methylpyrrolidone; nonpolar solvents such as toluene, benzene and
dichlorobenzene; organic acids such as acetic acid; water; and a
mixture thereof. The yield may be improved when performing reaction
in the presence of 1.0 to 10.0 equivalents of an organic amine such
as triethylamine, diisopropylamine or pyridine or an alkali metal
salt such as potassium carbonate or sodium carbonate with respect
to the compound (1a). The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably room
temperature to 200.degree. C., for example. Under preferable
reaction conditions, the reaction is completed in 1 to 72 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound (24) and Compound (26)]
[0235] The compound (24) or compound (26) can be prepared by
reacting a compound (1a) with an amine compound (23a) or amine
compound (23b) according to Step 4-1 or Step 4-5. Specifically,
Step 4-1 or Step 4-5 varies according to the starting material and
is not particularly limited insofar as the conditions are similar
to those in this reaction. A known method described in many
documents may be used for the reaction (see Shin Jikken Kagaku Koza
(New Courses in Experimental Chemistry), vol. 22, Yuki Gosei
(Organic Synthesis) [IV], edited by The Chemical Society of Japan,
Maruzen Co., Ltd., November 1992, p. 137-163; and Organic
Synthesis, 1941, I, p. 5, for example). For example, a compound
(1a), wherein Y.sub.13 represents a carboxyl group, and 1.0 to 10.0
equivalents of a compound (23a) or compound (23b) with respect to
the compound (1a) are stirred in a solvent in the presence of 0.1
to 10.0 equivalents of a condensing agent with respect to the
compound (1a). The condensing agent used varies according to the
starting material and is not particularly limited. Preferable
examples of the condensing agent include inorganic acids such as
hydrochloric acid and sulfuric acid; organic acids such as
p-toluenesulfonic acid and methanesulfonic acid,
1,3-dicyclohexylcarbodiimide,
1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate, diethyl cyanophosphonate and
bis(2-oxo-3-oxazolidinyl)phosphonic chloride. Preferably, 1.0 to
5.0 equivalents of N-hydroxysuccinimide, N-hydroxybenzotriazole or
dimethylaminopyridine may be added with respect to the compound
(1a) in order to make the reaction efficiently proceed, for
example. The solvent used varies according to the starting material
and the condensing agent used, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include halogenated solvents
such as chloroform, methylene chloride and 1,2-dichloroethane; and
polar solvents such as tetrahydrofuran and N,N-dimethylformamide.
The reaction temperature must be a temperature that can complete
the reaction without promoting formation of an undesirable
by-product, and is preferably ice-cold temperature to 150.degree.
C., for example. Under preferable reaction conditions, the reaction
is completed in 1 to 24 hours, and the progress of the reaction can
be monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique or/and
crystallization.
[0236] Alternatively, a compound (1a), wherein Y.sub.13 represents
a cyano group, an imino ether group or a thioimino ether group, and
1.0 to 100.0 equivalents of an amine compound (23a) or amine
compound (23b) with respect to the compound (1a) are stirred in a
solvent. The solvent used is not particularly limited insofar as
the solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include ether solvents such as
tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated
solvents such as methylene chloride, 1,2-dichloroethane and
chloroform; alcohol solvents such as methanol, ethanol and
isopropyl alcohol; polar solvents such as N,N-dimethylformamide and
N-methylpyrrolidone; nonpolar solvents such as toluene, benzene and
dichlorobenzene; organic acids such as acetic acid; organic bases
such as pyridine; water; and a mixture thereof. The amine compound
(23a) or amine compound (24b) may be used as a solvent. The yield
may be improved when using 0.1 to 1.0 equivalent of an inorganic
acid such as hydrochloric acid, a Lewis acid such as
trifluoroborate or an organic acid such as p-toluenesulfonic acid
with respect to the compound (1a) or when using 1.0 to 10.0
equivalents of an organic base such as triethylamine, pyridine or
diisopropylethylamine with respect to the compound (1a). The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably 0 to 200.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0237] The compound (24) or compound (26) can also be prepared from
a compound (1a) according to Step 4-9 or Step 4-10. Specifically,
Step 4-9 or Step 4-10 consists of a three-stage reaction including
a deprotection step. In a first stage, a compound (1a) is condensed
with a compound (23c) or compound (23d) by dehydration. In a second
stage, the protecting group is deprotected. In a third stage, the
condensate is condensed with a compound (23e).
[0238] The first-stage condensation reaction may be performed by
the same method as in Step 4-1. The second-stage deprotection
reaction varies according to the starting material and is not
particularly limited insofar as the conditions are similar to those
in this reaction. A known method described in many documents may be
used for the reaction (see T. W. Green, "Protective Groups in
Organic Synthesis", John Wiley & Sons, Inc., 1999, p. 615-626).
Preferably, the condensation compound in the first stage, wherein
P.sub.1 represents a tert-butyl carbamate group, is stirred in a
solvent in the presence of 1.0 to 100.0 equivalents of an acid with
respect to the compound, for example. Examples of the acid used
include inorganic acids such as hydrochloric acid and sulfuric
acid; and organic acids such as trifluoroacetic acid and
methanesulfonic acid. The solvent used is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include ethyl acetate, methanol,
ethanol, 1,4-dioxane, methylene chloride, chloroform, methanol,
isopropyl alcohol, N,N-dimethylformamide and N-methylpyrrolidone.
The reaction temperature must be a temperature that can complete
the reaction without promoting formation of an undesirable
by-product, and is preferably 0 to 100.degree. C., for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0239] The third-stage condensation reaction may be performed by
the same method as in Step 4-1.
[Preparation of Compound (1a)]
[0240] The compound (1a) can be prepared from a compound (4) or
compound (17) by the same method as in the above Step 2-1 or Step
2-10.
[Preparation of Compound (25) and Compound (27)]
[0241] The compound (25) or compound (27) can be prepared from the
compound (24) or compound (26) by dehydration reaction according to
Step 4-3 or Step 4-7. Specifically, Step 4-3 or Step 4-7 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
known method described in many documents may be used for the
reaction (see The Chemistry of Heterocyclic Compounds, 45; Wiley,
New York, 1986, p. 1, for example). For example, the compound (24)
or compound (26) is stirred in a solvent in the presence of 1.0 to
100.0 equivalents of a dehydration reagent with respect to the
compound (24) or compound (26). The dehydration reagent used varies
according to the starting material and is not particularly limited.
Preferable examples of the dehydration reagent include phosphorus
oxychloride, thionyl chloride, phosgene, triphosgene,
carbonyldiimidazole, hydrochloric acid, sulfuric acid,
p-toluenesulfonic acid, methanesulfonic acid,
triphenylphosphine-carbon tetrachloride and
triphenylphosphine-carbon tetrabromide. The solvent used is not
particularly limited insofar as the solvent does not inhibit the
reaction and allows the starting material to be dissolved therein
to a certain extent. Preferable examples of the solvent include
ether solvents such as tetrahydrofuran, 1,4-dioxane and diethyl
ether; halogenated solvents such as methylene chloride,
1,2-dichloroethane and chloroform; polar solvents such as
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; and a mixture
thereof. The dehydration reagent may be used as a solvent. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably 0 to 200.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound (23a), Compound (23b), Compound (23c),
Compound (23d) and Compound (23e)]
[0242] The compound (23a), compound (23b), compound (23c), compound
(23d) and compound (23e) are commercially available or can be
obtained by a technique known to a person skilled in the art.
[General Preparation Method 3]
[0243] Typically used General Preparation Method 3 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00037##
[0244] In the formula, the following partial structure (formula
III-4, III-5, III-7 or III-8):
##STR00038##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10,
Y.sub.11, R.sup.10, R.sup.11, R.sup.12, L.sub.2, L.sub.4, nd, ne,
ni and nj are as defined above; and Pr represents a protecting
group for a heterocycle nitrogen atom such as a trityl group, a
methoxymethyl group, a benzyl group or a methanesulfonic acid
group.
[0245] The above General Preparation Method 3 includes a method of
reacting a compound (17) with a heterocyclic compound (28) in Step
5-1 to prepare a compound of the general formula (I-4), the general
formula (I-7) or the general formula (I-8); and a method of
reacting a compound (17) with a heterocyclic compound (29) having a
protecting group in Step 5-2 to once convert the compound (17) into
a compound of the general formula (I-5) having a protecting group
and then deprotecting the protecting group of the compound of the
general formula (I-5) and subsequently reacting the compound with a
compound (2b) in Step 5-3 to prepare a compound of the general
formula (I-4), the general formula (I-7) or the general formula
(I-8).
[Preparation of Compounds of General Formula (I-4) and (I-5)]
[0246] The compound of the general formula (I-4) or (I-5) can be
prepared by i) reacting a compound (17) with a compound (28) or
compound (29) according to Step 5-1 or Step 5-2.
[0247] The compound of the general formula (I-4) can also be
prepared by ii) deprotecting the protecting group of the compound
of the general formula (I-5) and then reacting the compound with a
compound (2b) according to Step 5-3.
[0248] The method i), specifically, Step 5-1 or Step 5-2 varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
known method described in many documents such as Mizoroki-Heck
reaction (see R. F. Heck, "Org. Reactions.", 1982, vol. 27, p. 345,
for example) or Sonogashira reaction (see K. Sonogashira,
"Comprehensive Organic Synthesis", 1991, vol. 3, p. 521, for
example) may be used for the reaction.
[0249] In Mizoroki-Heck reaction, a compound (17), wherein L.sub.4
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of a compound (28) or compound (29), wherein
X.sub.1 represents an alkenyl group, with respect to the compound
(17) are stirred in a solvent in the presence of 0.01 to 0.5
equivalent of a transition metal catalyst with respect to the
compound (17), for example. The transition metal catalyst used is
preferably a palladium complex, for example, and more preferably a
known palladium complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine,
tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl may
be preferably added, for example, in order to make the reaction
efficiently proceed. A preferable result may be achieved in the
presence of a base. The base used is not particularly limited
insofar as the base is used in a coupling reaction similar to this
reaction. Preferable examples of the base include triethylamine,
N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine and
tetrabutylammonium chloride. The solvent used varies according to
the starting material and the transition metal catalyst used, and
is not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C., for
example. This reaction is performed preferably in an inert gas
atmosphere, and more preferably in a nitrogen or argon atmosphere,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0250] In Sonogashira reaction, a compound (17), wherein L.sub.4
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of a compound (28) or compound (29), wherein
X.sub.1 represents an alkynyl group, with respect to the compound
(17) are stirred in a solvent in the presence of 0.01 to 0.5
equivalent of a transition metal catalyst with respect to the
compound (17), for example. The transition metal catalyst used is
preferably a known palladium complex, for example, and more
preferably a known palladium complex such as palladium (II)
acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine or
tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. In the reaction, a
good result may be achieved when adding a metal halide or a
quaternary ammonium salt, preferably copper (I) iodide, lithium
chloride, tetrabutylammonium fluoride or silver (I) oxide, for
example. A preferable result may be achieved in the presence of a
base. The base used here is not particularly limited insofar as the
base is used in a coupling reaction similar to this reaction.
Preferable examples of the base include diethylamine,
triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
Preferable examples of the solvent used include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and
dimethyl sulfoxide. More preferable examples of the solvent include
tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone and
N,N-dimethylformamide. The reaction temperature must be a
temperature that can complete the coupling reaction, and is
preferably room temperature to 150.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere, for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0251] The method ii), specifically, Step 5-3 consists of
first-stage deprotection reaction and second-stage reaction with a
compound (2b). The first-stage deprotection reaction varies
according to the starting material and is not particularly limited
insofar as the conditions are similar to those in this reaction. A
known method described in many documents may be used for the
reaction (see T. W. Green, "Protective Groups in Organic
Synthesis", John Wiley & Sons, Inc., 1999, p. 615-626).
Preferably, the compound of the general formula (I-5) is stirred in
a solvent in the presence of 1.0 to 100.0 equivalents of an acid or
base with respect to the compound of the general formula (I-5), for
example. Preferable Examples of the acid used include inorganic
acids such as hydrochloric acid and sulfuric acid; and organic
acids such as trifluoroacetic acid, methanesulfonic acid and
p-toluenesulfonic acid. Preferable examples of the base used
include alkali metal hydroxides such as sodium hydroxide and
potassium hydroxide; alkali metal carbonates such as potassium
carbonate and sodium carbonate; and organic amines such as ammonia
and methylamine. The solvent used is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, ethyl acetate,
methanol, ethanol, benzene, toluene, xylene, chloroform, methylene
chloride, water and a mixed solvent thereof. The acid or base may
be used as a solvent. The reaction temperature must be a
temperature that can complete the deprotection reaction, and is
preferably room temperature to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization. The second stage reaction of the compound (I-5)
with the compound (2b) may be performed by the same method as in
Step 1-3.
[Preparation of Compound (28)]
##STR00039##
[0253] In the formula, X.sub.1, Y.sub.10, Y.sub.11, Y.sub.14,
R.sup.10, R.sup.11 and R.sup.12 are as defined above; L.sub.7
represents a hydrogen atom, a halogen atom such as a chlorine atom,
a bromine atom or an iodine atom, a sulfonate group such as a
trifluoromethanesulfonate group, a trialkyltin group or a leaving
group such as a boronic acid or boronate group; and Y.sub.15
represents an oxygen atom, or a nitrogen atom which may be
substituted with a substituent selected from the above Substituent
Group A1.
[0254] The compound (28) can be prepared by i) condensing a
compound (31) with an alkene or alkyne compound according to Step
6-1. The compound (28) can also be prepared by ii) cyclizing a
compound (32) according to Step 6-2.
[0255] The method i), specifically, Step 6-1 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A known
method described in many documents such as Mizoroki-Heck reaction
(see R. F. Heck, "Org. Reactions.", 1982, vol. 27, p. 345, for
example), Suzuki-Miyaura reaction (see A. Suzuki, "Chem. Rev.",
1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K.
Sonogashira, "Comprehensive Organic Synthesis", 1991, vol. 3, p.
521) or Stille coupling reaction (see J. K. Stille, "Angew. Chem.
Int. Ed. Engl.", 1986, vol. 25, p. 508, for example) may be used
for the reaction.
[0256] In Mizoroki-Heck reaction, a compound (31), wherein L.sub.7
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of an alkene compound, wherein the alkene
compound refers to a compound having a double bond in the molecule,
with respect to the compound (31) are stirred in a solvent in the
presence of 0.01 to 0.2 equivalent of a transition metal catalyst
with respect to the compound (31), for example. The transition
metal catalyst used is preferably a palladium complex, for example,
and more preferably a known palladium complex such as palladium
(II) acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine,
tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl may
be preferably added, for example, in order to make the reaction
efficiently proceed. A preferable result may be achieved in the
presence of a base. The base used is not particularly limited
insofar as the base is used in a coupling reaction similar to this
reaction. Preferable examples of the base include triethylamine,
N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine and
tetrabutylammonium chloride. The solvent used varies according to
the starting material and the transition metal catalyst used, and
is not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C., for
example. This reaction is performed preferably in an inert gas
atmosphere, and more preferably in a nitrogen or argon atmosphere,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0257] In Suzuki-Miyaura reaction, a compound (31), wherein L.sub.7
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of an alkene or alkyne boronic acid or boronate
compound, wherein the boronic acid or boronate compound refers to a
boronic acid or boronate compound directly bonded to a double bond
or triple bond, with respect to the compound (31) are stirred in a
solvent in the presence of 0.01 to 0.5 equivalent of a transition
metal catalyst with respect to the compound (31), for example. The
transition metal catalyst used is preferably a known palladium
complex, and more preferably a known palladium complex such as
palladium (II) acetate, dichlorobis(triphenylphosphine)palladium
(II), tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine
or tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. A quaternary
ammonium salt, preferably tetrabutylammonium chloride or
tetrabutylammonium bromide, for example, may also be added in order
to make the reaction efficiently proceed. In this reaction, a
preferable result may be achieved in the presence of a base. The
base used at this time varies according to the starting material,
the solvent used and the like, and is not particularly limited.
Preferable examples of the base include sodium hydroxide, barium
hydroxide, potassium fluoride, cesium fluoride, sodium carbonate,
potassium carbonate, cesium carbonate and potassium phosphate. The
solvent used varies according to the starting material and the
transition metal catalyst used, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide,
water and a mixed solvent thereof. The reaction temperature must be
a temperature that can complete the coupling reaction, and is
preferably room temperature to 200.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere, for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization. The desired compound (28) can also be obtained
from a combination of the boronic acid compound or boronate
compound (31), wherein L.sub.7 represents a boronic acid group or a
boronate group, with a halogenated alkene compound or an enol
trifluoromethanesulfonate compound by the same method as above.
[0258] In Sonogashira reaction, a compound (31), wherein L.sub.7
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of an alkyne compound, wherein the alkyne
compound refers to a compound having HC.ident.C-- in the molecule,
with respect to the compound (31) are stirred in a solvent in the
presence of 0.01 to 0.5 equivalent of a transition metal catalyst
with respect to the compound (31), for example. The transition
metal catalyst used is preferably a known palladium complex, for
example, and more preferably a known palladium complex such as
palladium (II) acetate, dichlorobis(triphenylphosphine)palladium
(II), tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine or
tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. In the reaction, a
good result may be achieved when adding a metal halide or a
quaternary ammonium salt, preferably copper (I) iodide, lithium
chloride, tetrabutylammonium fluoride or silver (I) oxide, for
example. A preferable result may be achieved in the presence of a
base. The base used here is not particularly limited insofar as the
base is used in a coupling reaction similar to this reaction.
Preferable examples of the base include diethylamine,
triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
Preferable examples of the solvent used include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and
dimethyl sulfoxide. More preferable examples of the solvent include
tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone and
N,N-dimethylformamide. The reaction temperature must be a
temperature that can complete the coupling reaction, and is
preferably room temperature to 150.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere, for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0259] In Stille coupling reaction, a compound (31), wherein
L.sub.7 represents a chlorine atom, a bromine atom, an iodine atom
or a trifluoromethanesulfonate group, and 1.0 equivalent or more of
a trialkyltin compound, wherein the trialkyltin compound refers to
an alkyltin compound directly bonded to a double bond or triple
bond, with respect to the compound (31) are stirred in a solvent in
the presence of 0.01 to 0.2 equivalent of a transition metal
catalyst with respect to the compound (31), for example. The
transition metal catalyst used is preferably a palladium complex,
for example, and more preferably a known palladium complex such as
palladium (II) acetate, dichlorobis(triphenylphosphine)palladium
(II), tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). In order to make the
reaction efficiently proceed, 0.1 to 5.0 equivalents of copper (I)
halide or/and lithium chloride may be added. Preferable examples of
the solvent used include toluene, xylene, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone and dimethyl
sulfoxide. The reaction temperature must be a temperature that can
complete the coupling reaction, and is preferably room temperature
to 150.degree. C., for example. This reaction is performed
preferably in an inert gas atmosphere, and more preferably in a
nitrogen or argon atmosphere, for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization. The desired compound (28) can also be obtained
from a combination of the tin compound (31), wherein L.sub.7
represents a trialkyltin group, with a halogenated alkene compound
or enol trifluoromethanesulfonate compound by the same method as
above. The halogenated alkene compound refers to a compound of
which the hydrogen atom bonded to the double bond in the molecule
is replaced by a halogen atom. The enol trifluoromethanesulfonate
compound refers to a compound of which the hydrogen atom of the
enol ester group in the molecule is replaced by a
trifluoromethanesulfonyl group.
[0260] The method ii), specifically, Step 6-2 may be performed by
the same method as in Step 4-2 or Step 4-6.
[Preparation of Compound (31)]
[0261] The compound (31) is commercially available or prepared by a
method known to a person skilled in the art. If not commercially
available, the compound (31), wherein L.sub.7 is a boronic acid
group or a boronate group, can be prepared by a method known to a
person skilled in the art, for example, although the method varies
according to the starting material (see Shin Jikken Kagaku Koza
(New Courses in Experimental Chemistry), vol. 22, Yuki Gosei
(Organic Synthesis) [VI], edited by The Chemical Society of Japan,
Maruzen Co., Ltd., September 1992, p. 61-90, for example). The
compound (31), wherein L.sub.7 is a trialkyltin group, can be
prepared by a method known to a person skilled in the art, although
the method varies according to the starting material (see Shin
Jikken Kagaku Koza (New Courses in Experimental Chemistry), vol.
22, Yuki Gosei (Organic Synthesis) [VI], edited by The Chemical
Society of Japan, Maruzen Co., Ltd., September 1992, p. 179-201,
for example).
[Preparation of Compound (32)]
[0262] The compound (32) is commercially available or prepared by a
method known to a person skilled in the art. If not commercially
available, the compound (32) can be prepared by the same method as
in Step 1-1 or Step 4-1, for example.
[Preparation of Compound (29)]
[0263] The compound (29) is commercially available or can be
prepared by the same method as in the case of the compound (28) if
not commercially available.
[0264] The compound of the general formula (I-7) or the general
formula (I-8) can be prepared from the compound (28) or compound
(29), wherein two of R.sup.10, R.sup.11 and R.sup.12 form a ring,
as a starting material by the same method as above.
[General Preparation Method 4]
[0265] Typically used General Preparation Method 4 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00040##
[0266] In the formula, the following partial structure (formula
III-4, III-5, III-7 or III-8):
##STR00041##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10,
Y.sub.11, R.sup.10, R.sup.11, R.sup.12, L.sub.2, Pr, nd, ne, ni and
nj are as defined above; and L.sub.7 and L.sub.7' each represent a
halogen atom such as hydrogen, chlorine, bromine or iodine, a
sulfonate group such as a trifluoromethanesulfonate group or a
trialkyltin group or a leaving group such as a boron acid or
boronate group.
[0267] The above General Preparation Method 4 includes a method of
condensing a compound (33) with a heterocyclic compound (34a) in
Step 7-1 to prepare a compound of the general formula (I-4), the
general formula (I-7) or the general formula (I-8); and a method of
condensing a compound (33) with a heterocyclic compound (34b)
having a protecting group in Step 7-2 to convert the compound (33)
into a compound of the general formula (I-5) having a protecting
group and then deprotecting the protecting group of the compound of
the general formula (I-5) and subsequently reacting the compound
with a compound (2b) in Step 5-3 to prepare a compound of the
general formula (I-4), the general formula (I-7) or the general
formula (I-8).
[Preparation of Compound of General Formula (I-4) and Compound of
General Formula (I-5)]
[0268] The compound of the general formula (I-4) or the compound of
the general formula (I-5) can be prepared by reacting a compound
(33) with a compound (34a) or compound (34b) according to Step 7-1
or Step 7-2. Specifically, Step 7-1 or Step 7-2 varies according to
the starting material and is not particularly limited insofar as
the conditions are similar to those in this reaction. A known
method described in many documents may be used for the reaction.
Preferable examples of the method include Mizoroki-Heck reaction
(see R. F. Heck, "Org. Reactions.", 1982, vol. 27, p. 345, for
example), Suzuki-Miyaura reaction (see A. Suzuki, "Chem. Rev.",
1995, vol. 95, p. 2457, for example), Sonogashira reaction (see K.
Sonogashira, "Comprehensive Organic Synthesis", 1991, vol. 3, p.
521) and Stille coupling reaction (see J. K. Stille, "Angew. Chem.
Int. Ed. Engl.", 1986, vol. 25, p. 508, for example).
[0269] In Mizoroki-Heck reaction, a compound (33), wherein L.sub.7'
represents a hydrogen atom and X.sub.1 represents an alkenyl group,
and 0.5 to 5.0 equivalents of a compound (34a) or compound (34b),
wherein L.sub.7 represents a chlorine atom, a bromine atom, an
iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, with respect to the compound (33)
are stirred in a solvent in the presence of 0.01 to 1.0 equivalent
of a transition metal catalyst with respect to the compound (33),
for example. The transition metal catalyst used is preferably a
palladium complex, for example, and more preferably a known
palladium complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine,
tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl may
be preferably added, for example, in order to make the reaction
efficiently proceed. A preferable result may be achieved in the
presence of a base. The base used is not particularly limited
insofar as the base is used in a coupling reaction similar to this
reaction. Preferable examples of the base include triethylamine,
N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine and
tetrabutylammonium chloride. The solvent used varies according to
the starting material and the transition metal catalyst used, and
is not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C., for
example. This reaction is performed preferably in an inert gas
atmosphere, and more preferably in a nitrogen or argon atmosphere,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0270] In Suzuki-Miyaura reaction, a compound (33), wherein
L.sub.7' represents a boronic acid or boronate group, and 0.5 to
5.0 equivalents of a compound (34a) or compound (34b), wherein
L.sub.7 represents a chlorine atom, a bromine atom, an iodine atom
or a sulfonate group such as a trifluoromethanesulfonate group,
with respect to the compound (33) are stirred in a solvent in the
presence of 0.01 to 1.0 equivalent of a transition metal catalyst
with respect to the compound (33), for example. The transition
metal catalyst used is preferably a known palladium complex, for
example, and more preferably a known palladium complex such as
palladium (II) acetate, dichlorobis(triphenylphosphine)palladium
(II), tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine
or tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. A good result may
be achieved when appropriately adding a quaternary ammonium salt,
preferably tetrabutylammonium chloride or tetrabutylammonium
bromide, for example. In this reaction, a preferable result may be
achieved in the presence of a base. The base used at this time
varies according to the starting material, the solvent used and the
like, and is not particularly limited. Preferable examples of the
base include sodium hydroxide, barium hydroxide, potassium
fluoride, cesium fluoride, sodium carbonate, potassium carbonate,
cesium carbonate and potassium phosphate. The solvent used varies
according to the starting material and the transition metal
catalyst used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include acetonitrile, tetrahydrofuran,
1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone, N,N-dimethylformamide, water and a mixed
solvent thereof. The reaction temperature must be a temperature
that can complete the coupling reaction, and is preferably room
temperature to 200.degree. C., for example. This reaction is
performed preferably in an inert gas atmosphere, and more
preferably in a nitrogen or argon atmosphere, for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization. The desired compound of the general formula (I-4)
or general formula (I-5) can also be obtained from a combination of
the compound (33), wherein L.sub.7' represents a chlorine atom, a
bromine atom, an iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, with the compound (34a) or
compound (34b), wherein L.sub.7 represents a boronic acid or
boronate group, by the same method as above.
[0271] In Sonogashira reaction, an alkyne compound (33), wherein
L.sub.7' represents a hydrogen atom, and X.sub.1 represents an
alkynyl group, and 0.5 to 5 equivalents of a compound (34a) or
compound (34b), wherein L.sub.7 represents a chlorine atom, a
bromine atom, an iodine atom or a sulfonate group such as a
trifluoromethanesulfonate group, with respect to the compound (33)
are stirred in a solvent in the presence of 0.01 to 1.0 equivalent
of a transition metal with respect to the compound (33), for
example. The transition metal catalyst used is preferably a known
palladium complex, for example, and more preferably a known
palladium complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine or
tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. In the reaction, a
good result may be achieved when adding a metal halide or a
quaternary ammonium salt such as preferably copper (I) iodide,
lithium chloride, tetrabutylammonium fluoride or silver (I) oxide,
for example. A preferable result may be achieved in the presence of
a base. The base used here is not particularly limited insofar as
the base is used in a coupling reaction similar to this reaction.
Preferable examples of the base include diethylamine,
triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
Preferable examples of the solvent used include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide,
dimethyl sulfoxide and a mixture thereof. More preferable examples
of the solvent include tetrahydrofuran, 1,4-dioxane,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C., for
example. This reaction is performed preferably in an inert gas
atmosphere, and more preferably in a nitrogen or argon atmosphere,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0272] In Stille coupling reaction, a compound (33), wherein
L.sub.7' represents a chlorine atom, a bromine atom, an iodine atom
or a trifluoromethanesulfonate group, and 0.5 to 5 equivalents of a
compound (34a) or compound (34b), wherein L.sub.7 represents an
alkyltin group, with respect to the compound (33) are stirred in a
solvent in the presence of 0.01 to 1.0 equivalent of a transition
metal catalyst with respect to the compound (33), for example. The
transition metal catalyst used is preferably a known palladium
complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0), for example, and more
preferably tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0), for example. In order to
make the reaction efficiently proceed, 0.1 to 5.0 equivalents of
copper (I) halide or/and lithium chloride may be appropriately
used. Preferable examples of the solvent used include toluene,
xylene, N,N-dimethylformamide, N,N-dimethylacetamide,
1-methyl-2-pyrrolidone, dimethyl sulfoxide and a mixture thereof.
The reaction temperature must be a temperature that can complete
the coupling reaction, and is preferably room temperature to
150.degree. C., for example. This reaction is performed preferably
in an inert gas atmosphere, and more preferably in a nitrogen or
argon atmosphere, for example. Under preferable reaction
conditions, the reaction is completed in 1 to 24 hours, and the
progress of the reaction can be monitored by a known chromatography
technique. An undesirable by-product can be removed by a technique
known to a person skilled in the art such as a conventional
chromatography technique, extraction or/and crystallization. The
desired compound of the general formula (I-4) or general formula
(I-5) can also be obtained from a combination of the compound (33),
wherein L.sub.7' represents a trialkyltin group, with the compound
(34a) or compound (35b), wherein L.sub.7 represents a chlorine
atom, a bromine atom, an iodine atom or a trifluoromethanesulfonate
group, by the same method as above.
[Preparation of Compound (34a) and Compound (34b)]
[0273] The compound (34a) or compound (34b) can be prepared by the
same method as in the case of the compound (31).
[Preparation of Compound (33)]
[0274] The compound (33) can be prepared from a compound (13) or
compound (15) by the same method as in Step 2-7 or Step 2-9.
[0275] The compound of the general formula (I-7) or the general
formula (I-8) can be prepared from the compound (34a) or compound
(34b), wherein two of R.sup.10, R.sup.11 and R.sup.12 form a ring,
as a starting material by the same method as above.
[General Preparation Method 5]
[0276] Typically used General Preparation Method 5 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00042##
[0277] In the formula, the following partial structure (formula
III-4, III-5, III-7 or III-8):
##STR00043##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10,
Y.sub.11, R.sub.1, R.sub.2, R.sup.10, R.sup.11, R.sup.12, L.sub.2,
Pr, nd, ne, ni and nj are as defined above; and L.sub.8 represents
a phosphite group such as a diethylphosphonyl group, a phosphonium
salt such as triphenylphosphonium bromide or a silyl group such as
a trimethylsilyl group.
[0278] The above General Preparation Method 5 is an example of a
method of condensing a compound (35) with a heterocyclic compound
(36a) in Step 8-1 to prepare a compound of the general formula
(I-4), the general formula (I-7) or the general formula (I-8); or a
method of reacting a compound (35) with a heterocyclic compound
(36b) having a protecting group in Step 8-2 to once convert the
compound (35) into a compound of the general formula (I-5) having a
protecting group and then deprotecting the protecting group of the
compound of the general formula (I-5) and subsequently reacting the
compound with a compound (2b) in Step 5-3 to prepare a compound of
the general formula (I-4), the general formula (I-7) or the general
formula (I-8).
[Preparation of Compound of General Formula (I-4) and Compound of
General Formula (I-5)]
[0279] The compound of the general formula (I-4) or the compound of
the general formula (I-5) can be prepared by reacting a compound
(35) with a compound (36a) or (36b) according to Step 8-1 or Step
8-2. Specifically, Step 8-1 or Step 8-2 varies according to the
starting material and is not particularly limited insofar as the
conditions are similar to those in this reaction. A known method
described in many documents such as Wittig reaction, Horner-Emmons
reaction or Peterson reaction (see Shin Jikken Kagaku Koza (new
Courses in Experimental Chemistry), vol. 19, Yuki Gosei (Organic
Synthesis) [I], edited by The Chemical Society of Japan, Maruzen
Co., Ltd., June 1992, p. 57-85, for example) may be used.
[0280] In Wittig reaction, a compound (35), wherein L.sub.8
represents a phosphonium salt, and 0.5 to 2.0 equivalents of a
carbonyl compound (36a) or a compound (36b) with respect to the
compound (35) are stirred in a solvent in the presence of 1.0 to
5.0 equivalents of a base with respect to the compound (35), for
example. This reaction may be a method of first reacting a compound
(35) with a base to form a phosphorus ylide and then adding a
carbonyl compound (36a) or a compound (36b) to the ylide; or a
method of adding a base in the presence of a compound (35) and a
carbonyl compound (36a) or a compound (36b). The base used varies
according to the starting material and the solvent and is not
particularly limited. Preferable examples of the base include
alkali metal hydroxides such as sodium hydroxide and lithium
hydroxide; alkali metal carbonates such as sodium carbonate; alkali
metal salts of alcohols such as sodium methoxide and potassium
tert-butoxide; organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; and alkali metal hydrides such as sodium
hydride. The solvent used varies according to the starting material
and the base used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent used include polar solvents such as
nitromethane, acetonitrile, 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; halogenated solvents such as chloroform
and methylene chloride; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0281] In Horner-Emmons reaction, a compound (35), wherein L.sub.8
represents a phosphite group, is reacted with 0.5 to 2.0
equivalents of a carbonyl compound (36a) or a compound (36b) with
respect to the compound (35) in a solvent in the presence of 1.0 to
5.0 equivalents of a base with respect to the compound (35), for
example. This reaction may be a method of first treating a compound
(35) and a base to form a carbanion and then adding a carbonyl
compound (36a) or a compound (36b) to the carbanion; or a method of
adding a base in the presence of a compound (35) and a carbonyl
compound (36a) or a compound (36b). The base used varies according
to the starting material and the solvent and is not particularly
limited. Preferable examples of the base include alkali metal
hydroxides such as sodium hydroxide and lithium hydroxide; alkali
metal carbonates such as sodium carbonate; alkali metal salts of
alcohols such as sodium methoxide and potassium tert-butoxide;
organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; alkali metal hydrides such as sodium
hydride; and alkali metal ammonium salts such as sodium amide. The
solvent used varies according to the starting material and the base
used, and is not particularly limited insofar as the solvent does
not inhibit the reaction and allows the starting material to be
dissolved therein to a certain extent. Preferable examples of the
solvent include polar solvents such as 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0282] In Peterson reaction, a compound (35), wherein L.sub.8
represents a silyl group, is reacted with 0.5 to 2.0 equivalents of
a carbonyl compound (36a) or a compound (36b) with respect to the
compound (35) in a solvent in the presence of 1.0 to 5.0
equivalents of a base with respect to the compound (35), for
example. This reaction may be a method of first treating a compound
(35) and a base to form a carbanion and then adding a carbonyl
compound (36a) or a compound (36b) to the carbanion; or a method of
adding a base in the presence of a compound (35) and a carbonyl
compound (36a) or a compound (36b). The base used varies according
to the starting material and the solvent and is not particularly
limited. Preferable examples of the base include alkali metal
hydroxides such as sodium hydroxide and lithium hydroxide; alkali
metal carbonates such as sodium carbonate; alkali metal salts of
alcohols such as sodium methoxide and potassium tert-butoxide;
organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; alkali metal hydrides such as sodium
hydride; and alkali metal ammonium salts such as sodium amide. The
solvent used varies according to the starting material and the base
used, and is not particularly limited insofar as the solvent does
not inhibit the reaction and allows the starting material to be
dissolved therein to a certain extent. Preferable examples of the
solvent include polar solvents such as 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[Preparation of Compound (36a) and Compound (36b)]
[0283] The compound (36a) and the compound (36b) are commercially
available or can be prepared by a technique known to a person
skilled in the art. If not commercially available, the compounds
can be prepared by acylation of a compound (31), for example (see
Shin Jikken Kagaku Koza (New Courses in Experimental Chemistry),
vol. 21, Yuki Gosei (Organic Synthesis) [III], edited by The
Chemical Society of Japan, Maruzen Co., Ltd., February 1991, p.
184-194, for example).
[Preparation of Compound (35)]
[0284] The compound (35) can be prepared from a compound (6) or
compound (17) as a starting material by a known method described in
many documents. Preferably, for example, i) the compound (35) as a
Wittig reagent, wherein L.sub.8 represents a phosphonium salt, can
be prepared by halogenating a corresponding alcohol compound by a
method known to a person skilled in the art (see Shin Jikken Kagaku
Koza (New Courses in Experimental Chemistry), vol. 19, Yuki Gosei
(Organic Synthesis) [I], edited by The Chemical Society of Japan,
Maruzen Co., Ltd., June 1992, p. 430-438, for example), and then
reacting the compound with an organophosphorus compound such as
triphenylphosphine (see Organic Reaction, 1965, vol. 14, p. 270,
for example). ii) The compound (35) as a Horner-Emmons reagent,
wherein L.sub.8 represents a phosphite, can be prepared by
halogenating a corresponding alcohol compound by a method known to
a person skilled in the art (see Shin Jikken Kagaku Koza (New
Courses in Experimental Chemistry), vol. 19, Yuki Gosei (Organic
Synthesis) [I], edited by The Chemical Society of Japan, Maruzen
Co., Ltd., June 1992, p. 430-438, for example), and then reacting
the compound with an alkyl phosphinite by Arbuzov reaction (see
Chemical Review, 1981, vol. 81, p. 415, for example) or with a
metal phosphonite by Becker reaction (see Journal of the American
Chemical Society, 1945, vol. 67, p. 1180, for example).
Alternatively, the Horner-Emmons reagent can be prepared from a
corresponding carbonyl compound and a chlorophosphate in the
presence of a base (see The Journal of Organic Chemistry, 1989,
vol. 54, p. 4750, for example). iii) The compound (35) as a
Peterson reagent, wherein L.sub.9 represents a silyl group, can be
prepared from a corresponding halogen compound and a trialkylsilyl
chloride in the presence of a base (see Journal of Organometallic
Chemistry, 1983, vol. 248, p. 51, for example).
[0285] The compound of the general formula (I-7) or the compound of
the general formula (I-8) can be prepared from the compound (36a)
or compound (36b), wherein two of R.sup.10, R.sup.11 and R.sup.12
form a ring, as a starting material by the same method as
above.
[General Preparation Method 6]
[0286] Typically used General Preparation Method 6 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00044##
[0287] In the formula, the following partial structure (formula
III-4, III-5, III-7 or III-8):
##STR00045##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10,
Y.sub.11, R.sub.1, R.sub.2, R.sup.10, R.sup.11, R.sup.12, L.sub.2,
L.sub.8, Pr, nd, ne, ni and nj are as defined above.
[0288] The above General Preparation Method 6 is an example of a
method of condensing a compound (6) with a heterocyclic compound
(38a) in Step 9-1 to prepare a compound of the general formula
(I-4), the general formula (I-7) or the general formula (I-8); or a
method of condensing a compound (6) with a heterocyclic compound
(36b) having a protecting group in Step 8-2 to once convert the
compound (6) into a compound of the general formula (I-5) having a
protecting group and then deprotecting the protecting group of the
compound of the general formula (I-5) and subsequently reacting the
compound with a compound (2b) in Step 5-3 to prepare a compound of
the general formula (I-4), the general formula (I-7) or the general
formula (I-8).
[Preparation of Compound of General Formula (I-4) and Compound of
General Formula (I-5)]
[0289] The compound of the general formula (I-4) or general formula
(I-5) can be prepared by reacting a compound (6) with a compound
(38a) or compound (36b) according to Step 9-1 or Step 9-2.
Specifically, Step 9-1 or Step 9-2 varies according to the starting
material and is not particularly limited insofar as the conditions
are similar to those in this reaction. A known method described in
many documents such as Wittig reaction, Horner-Emmons reaction or
Peterson reaction may be used for the reaction (see Jikken Kagaku
Koza (Courses in Experimental Chemistry), vol. 19, Yuki Gosei
(Organic Synthesis) [I], edited by The Chemical Society of Japan,
Maruzen Co., Ltd., June 1992, p. 57-85, for example).
[0290] In Wittig reaction, a carbonyl compound (6) and 0.5 to 2.0
equivalents of a compound (38a) or compound (38b), wherein L.sub.8
represents a phosphonium salt, with respect to the carbonyl
compound (6) are stirred in a solvent in the presence of 1.0 to 5.0
equivalents of a base with respect to the carbonyl compound (6),
for example. This reaction may be a method of first reacting a
compound (38a) or compound (38b) with a base to form a phosphorus
ylide and then adding a carbonyl compound (6) to the ylide; or a
method of adding a base in the presence of a carbonyl compound (6)
and a compound (38a) or compound (38b). The base used varies
according to the starting material and the solvent and is not
particularly limited. Preferable examples of the base include
alkali metal hydroxides such as sodium hydroxide and lithium
hydroxide; alkali metal carbonates such as sodium carbonate; alkali
metal salts of alcohols such as sodium methoxide and potassium
tert-butoxide; organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; and alkali metal hydrides such as sodium
hydride. The solvent used varies according to the starting material
and the base used, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent used include polar solvents such as
nitromethane, acetonitrile, 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; halogenated solvents such as chloroform
and methylene chloride; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0291] In Horner-Emmons reaction, a carbonyl compound (6) and 0.5
to 2.0 equivalents of a compound (38a) or compound (38b), wherein
L.sub.8 represents a phosphite group, with respect to the carbonyl
compound (6) are stirred in a solvent in the presence of 1.0 to 5.0
equivalents of a base with respect to the carbonyl compound (6),
for example. This reaction may be a method of first treating a
compound (38a) or compound (38b) and a base to form a carbanion and
then adding a carbonyl compound (6) to the carbanion; or a method
of adding a base in the presence of a carbonyl compound (6) and a
compound (38a) or compound (38b). The base used varies according to
the starting material and the solvent and is not particularly
limited. Preferable examples of the base include alkali metal
hydroxides such as sodium hydroxide and lithium hydroxide; alkali
metal carbonates such as sodium carbonate; alkali metal salts of
alcohols such as sodium methoxide and potassium tert-butoxide;
organic bases such as triethylamine, pyridine and
diazabicyclononene; organic metals such as butyl lithium and
lithium diisobutylamide; alkali metal hydrides such as sodium
hydride; and alkali metal ammonium salts such as sodium amide. The
solvent used varies according to the starting material and the base
used, and is not particularly limited insofar as the solvent does
not inhibit the reaction and allows the starting material to be
dissolved therein to a certain extent. Preferable examples of the
solvent include polar solvents such as 1-methyl-2-pyrrolidone,
N,N-dimethylformamide and dimethyl sulfoxide; ether solvents such
as tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; nonpolar
solvents such as benzene, toluene and xylene; alcohol solvents such
as ethanol and methanol; water; and a mixed solvent thereof. The
reaction temperature must be a temperature that can complete the
reaction without promoting formation of an undesirable by-product,
and is preferably -78 to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0292] In Peterson reaction, a carbonyl compound (6) and 0.5 to 2.0
equivalents of a compound (38a) or compound (38b), wherein L.sub.8
represents a silyl group, with respect to the carbonyl compound (6)
are stirred in a solvent in the presence of 1.0 to 5.0 equivalents
of a base with respect to the carbonyl compound (6), for example.
This reaction may be a method of first treating a compound (38a) or
compound (38b) and a base to form a carbanion and then adding a
carbonyl compound (6) to the carbanion; or a method of adding a
base in the presence of a carbonyl compound (6) and a compound
(38a) or compound (38b). The base used varies according to the
starting material and the solvent and is not particularly limited.
Preferable examples of the base include alkali metal hydroxides
such as sodium hydroxide and lithium hydroxide; alkali metal
carbonates such as sodium carbonate; alkali metal salts of alcohols
such as sodium methoxide and potassium tert-butoxide; organic bases
such as triethylamine, pyridine and diazabicyclononene; organic
metals such as butyl lithium and lithium diisobutylamide; alkali
metal hydrides such as sodium hydride; and alkali metal ammonium
salts such as sodium amide. The solvent used varies according to
the starting material and the base used, and is not particularly
limited insofar as the solvent does not inhibit the reaction and
allows the starting material to be dissolved therein to a certain
extent. Preferable examples of the solvent include polar solvents
such as 1-methyl-2-pyrrolidone, N,N-dimethylformamide and dimethyl
sulfoxide; ether solvents such as tetrahydrofuran, 1,4-dioxane and
1,2-dimethoxyethane; nonpolar solvents such as benzene, toluene and
xylene; alcohol solvents such as ethanol and methanol; water; and a
mixed solvent thereof. The reaction temperature must be a
temperature that can complete the reaction without promoting
formation of an undesirable by-product, and is preferably -78 to
150.degree. C., for example. Under preferable reaction conditions,
the reaction is completed in 1 to 24 hours, and the progress of the
reaction can be monitored by a known chromatography technique. An
undesirable by-product can be removed by a technique known to a
person skilled in the art such as a conventional chromatography
technique, extraction or/and crystallization.
[Preparation of Compound (38a) and Compound (38b)]
[0293] The compound (38a) and the compound (38b) are commercially
available or prepared by a technique known to a person skilled in
the art. If not commercially available, for example, i) the
compound (38a) or compound (38b) as a Wittig reagent, wherein
L.sub.8 represents a phosphonium salt, can be prepared by
halogenating a corresponding alcohol compound by a method known to
a person skilled in the art (see Shin Jikken Kagaku Koza (New
Courses in Experimental Chemistry), vol. 19, Yuki Gosei (Organic
Synthesis) [I], edited by The Chemical Society of Japan, Maruzen
Co., Ltd., June 1992, p. 430-438, for example), and then reacting
the compound with an organophosphorus compound such as
triphenylphosphine (see Organic Reaction, 1965, vol. 14, p. 270,
for example). ii) The compound (38a) or compound (38b) as a
Horner-Emmons reagent, wherein L.sub.8 represents a phosphite, can
be prepared by halogenating a corresponding alcohol compound by a
method known to a person skilled in the art (see Shin Jikken Kagaku
Koza (New Courses in Experimental Chemistry), vol. 19, Yuki Gosei
(Organic Synthesis) [I], edited by The Chemical Society of Japan,
Maruzen Co., Ltd., June 1992, p. 430-438, for example), and then
reacting the compound with an alkyl phosphinite by Arbuzov reaction
(see Chemical Review, 1981, vol. 81, p. 415, for example) or with a
metal phosphonite by Becker reaction (see Journal of the American
Chemical Society, 1945, vol. 67, p. 1180, for example).
Alternatively, the compound can be prepared from a corresponding
carbonyl compound and a chlorophosphate in the presence of a base
(see Journal of Organic Chemistry, 1989, vol. 54, p. 4750, for
example). iii) The compound (38a) or compound (38b) as a Peterson
reagent, wherein L.sub.9 represents a silyl group, can be prepared
from a corresponding halogen compound and a trialkylsilyl chloride
(see Journal of Organometallic Chemistry, 1983, vol. 248, p. 51,
for example).
[0294] The compound of the general formula (I-7) or the compound of
the general formula (I-8) can be prepared from the compound (38a)
or compound (38b), wherein two of R.sup.10, R.sup.11 and R.sup.12
form a ring, as a starting material by the same method as
above.
[General Preparation Method 7]
[0295] Typically used General Preparation Method 7 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00046##
[0296] In the formula, the following partial structure (formula
III-4, III-7 or III-8):
##STR00047##
is a partial structure corresponding to the above-described Het,
Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10, Y.sub.11,
R.sup.10, R.sup.11, R.sup.12, L.sub.7, L.sub.7', nd, ne, ni and nj
are as defined above; and R.sup.111 is as defined for R.sup.11.
[0297] The above General Preparation Method 7 is an example of a
method of condensing a compound (39) with a compound (40) in Step
10 to prepare a compound of the general formula (I-4), the general
formula (I-7) or the general formula (I-8).
[Preparation of Compound of General Formula (I-4)]
[0298] The compound of the general formula (I-4) can be prepared by
reacting a compound (39) with a compound (40) according to Step 10.
Specifically, Step 10 varies according to the starting material and
is not particularly limited insofar as the conditions are similar
to those in this reaction. A known method described in many
documents such as Mizoroki-Heck reaction (see R. F. Heck, "Org.
Reactions.", 1982, vol. 27, p. 345, for example), Suzuki-Miyaura
reaction (see A. Suzuki, "Chem. Rev.", 1995, vol. 95, p. 2457, for
example), Sonogashira reaction (see K. Sonogashira, "Comprehensive
Organic Synthesis", 1991, vol. 3, p. 521) or Stille coupling
reaction (see J. K. Stille, "Angew. Chem. Int. Ed. Engl.", 1986,
vol. 25, p. 508, for example) may be used for the reaction.
[0299] In Mizoroki-Heck reaction, a compound (39), wherein L.sub.7'
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 5.0 equivalents of an alkene compound (40), wherein L.sub.7
represents a hydrogen atom and R.sup.111 represents a C1-6 alkenyl
group which may be substituted with 1 to 3 substituents selected
from the above Substituent Group A1, with respect to the compound
(39) are stirred in a solvent in the presence of 0.01 to 0.2
equivalent of a transition metal catalyst with respect to the
compound (39), for example. The transition metal catalyst used is
preferably a palladium complex, for example, and more preferably a
known palladium complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine,
tri-tert-butylphosphine or 2-(di-tert-butylphosphino)biphenyl may
be preferably added, for example, in order to make the reaction
efficiently proceed. A preferable result may be obtained in the
presence of a base, and the base used is not particularly limited
insofar as the base is used in a coupling reaction the same as this
reaction. Preferable examples of the base include triethylamine,
N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine and
tetrabutylammonium chloride. The solvent used varies according to
the starting material and the transition metal catalyst used, and
is not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
include acetonitrile, tetrahydrofuran, 1,4-dioxane,
1,2-dimethoxyethane, benzene, toluene, xylene,
1-methyl-2-pyrrolidone and N,N-dimethylformamide. The reaction
temperature must be a temperature that can complete the coupling
reaction, and is preferably room temperature to 150.degree. C., for
example. This reaction is performed preferably in an inert gas
atmosphere, and more preferably in a nitrogen or argon atmosphere,
for example. Under preferable reaction conditions, the reaction is
completed in 1 to 24 hours, and the progress of the reaction can be
monitored by a known chromatography technique. An undesirable
by-product can be removed by a technique known to a person skilled
in the art such as a conventional chromatography technique,
extraction or/and crystallization.
[0300] In Suzuki-Miyaura reaction, a compound (39), wherein
L.sub.7' represents a chlorine atom, a bromine atom, an iodine atom
or a sulfonate group such as a trifluoromethanesulfonate group, and
1.0 to 10.0 equivalents of a compound (40), wherein L.sub.7
represents a boronic acid group or a boronate group, with respect
to the compound (39) are stirred in a solvent in the presence of
0.01 to 0.5 equivalent of a transition metal catalyst with respect
to the compound (39), for example. The transition metal catalyst
used is preferably a known palladium complex, and more preferably a
known palladium complex such as palladium (II) acetate,
dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine, tricyclohexylphosphine
or tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. A quaternary
ammonium salt, preferably tetrabutylammonium chloride or
tetrabutylammonium bromide, for example, may also be added in order
to make the reaction efficiently proceed. In this reaction, a
preferable result may be achieved in the presence of a base. The
base used at this time varies according to the starting material,
the solvent used and the like, and is not particularly limited.
Preferable examples of the base include sodium hydroxide, barium
hydroxide, potassium fluoride, cesium fluoride, sodium carbonate,
potassium carbonate, cesium carbonate and potassium phosphate. The
solvent used varies according to the starting material and the
transition metal catalyst used, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide,
water and a mixed solvent thereof. The reaction temperature must be
a temperature that can complete the coupling reaction, and is
preferably room temperature to 200.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere, for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization. The desired compound of the general formula (I-4)
can also be obtained from a combination of the compound (39),
wherein L.sub.7' represents a boronic acid group or a boronate
group, with the compound (40), wherein L.sub.7 represents a
chlorine atom, a bromine atom, an iodine atom or a sulfonate group
such as a trifluoromethanesulfonate group, by the same method as
above.
[0301] In Sonogashira reaction, a compound (39), wherein L.sub.7'
represents a chlorine atom, a bromine atom, an iodine atom or a
sulfonate group such as a trifluoromethanesulfonate group, and 1.0
to 10 equivalents of an alkyne compound (40), wherein L.sub.7
represents a hydrogen atom and R.sup.111 represents a C1-6 alkynyl
group which may be substituted with 1 to 3 substituents selected
from the above Substituent Group A1, with respect to the compound
(39) are stirred in a solvent in the presence of 0.01 to 0.5
equivalent of a transition metal catalyst with respect to the
compound (39), for example. The transition metal catalyst used is
preferably a known palladium complex, for example, and more
preferably a known palladium complex such as palladium (II)
acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). A phosphorus ligand such
as triphenylphosphine, tri-o-tolylphosphine or
tri-tert-butylphosphine may be preferably added, for example, in
order to make the reaction efficiently proceed. In the reaction, a
good result may be achieved when adding a metal halide or a
quaternary ammonium salt, preferably copper (I) iodide, lithium
chloride, tetrabutylammonium fluoride or silver (I) oxide, for
example. A preferable result may be obtained in the presence of a
base, and the base used here is not particularly limited insofar as
the base is used in a coupling reaction the same as this reaction.
Preferable examples of the base include diethylamine,
triethylamine, N,N-diisopropylethylamine, piperidine and pyridine.
Preferable examples of the solvent used include acetonitrile,
tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene,
toluene, xylene, 1-methyl-2-pyrrolidone, N,N-dimethylformamide and
dimethyl sulfoxide. More preferable examples of the solvent include
tetrahydrofuran, 1,4-dioxane, 1-methyl-2-pyrrolidone and
N,N-dimethylformamide. The reaction temperature must be a
temperature that can complete the coupling reaction, and is
preferably room temperature to 150.degree. C., for example. This
reaction is performed preferably in an inert gas atmosphere, and
more preferably in a nitrogen or argon atmosphere, for example.
Under preferable reaction conditions, the reaction is completed in
1 to 24 hours, and the progress of the reaction can be monitored by
a known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique, extraction or/and
crystallization.
[0302] In Stille coupling reaction, a compound (39), wherein
L.sub.7' represents a chlorine atom, a bromine atom, an iodine atom
or a trifluoromethanesulfonate group, and 1.0 equivalent or more of
a compound (40), wherein L.sub.7 represents a trialkyltin group,
with respect to the compound (39) are stirred in a solvent in the
presence of 0.01 to 0.2 equivalent of a transition metal catalyst
with respect to the compound (39), for example. The transition
metal catalyst used is preferably a palladium complex, for example,
and more preferably a known palladium complex such as palladium
(II) acetate, dichlorobis(triphenylphosphine)palladium (II),
tetrakis(triphenylphosphine)palladium (0) or
tris(dibenzylideneacetone)dipalladium (0). In order to make the
reaction efficiently proceed, 0.1 to 5.0 equivalents of copper (I)
halide or/and lithium chloride may be added. Preferable examples of
the solvent used include toluene, xylene, N,N-dimethylformamide,
N,N-dimethylacetamide, 1-methyl-2-pyrrolidone and dimethyl
sulfoxide. The reaction temperature must be a temperature that can
complete the coupling reaction, and is preferably room temperature
to 150.degree. C., for example. This reaction is performed
preferably in an inert gas atmosphere, and more preferably in a
nitrogen or argon atmosphere, for example. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization. The desired compound of the general formula (I-4)
can also be obtained from a combination of the compound (39),
wherein L.sub.7' represents a trialkyltin group, with the compound
(40), wherein L.sub.7 represents a chlorine atom, a bromine atom,
an iodine atom or a trifluoromethanesulfonate group, by the same
method as above. The compound (40) is commercially available or can
be prepared by a method known to a person skilled in the art.
[Preparation of Compound (39)]
[0303] The compound (39) can be prepared by a method in the above
General Preparation Methods 1 to 6.
[0304] The compound of the general formula (I-7) or the general
formula (I-8) can be prepared by the same method as above using, as
a starting material, the compound (39), wherein R.sup.10 and
R.sup.12 each represent an alkyl group substituted with an alkenyl
group or an alkynyl group or an alkenyl group, an alkynyl group or
an alkyl group substituted with a halogen atom and L.sub.7'
represents a chlorine atom, a bromine atom, an iodine atom, a
sulfonate group such as a trifluoromethanesulfonate group, or a
trialkyltin group, without use of the compound (40).
[General Preparation Method 8]
[0305] Typically used General Preparation Method 8 for the compound
of the general formula (I) of the present invention will be
described below.
##STR00048##
[0306] In the formula, the following partial structure (formula
III-4, III-7 or III-8):
##STR00049##
is a partial structure corresponding to the above-described Het,
wherein Ar.sub.1, Ar.sub.2, X.sub.1, X.sub.5, X.sub.6, Y.sub.10,
Y.sub.11, R.sup.10, R.sup.11, R.sup.12, L.sub.3, nd, ne, ni and nj
are as defined above.
[0307] The above General Preparation Method 8 is an example of a
method of condensing a compound (41) with a compound (42) in Step
12 to prepare a compound of the general formula (I-4), the general
formula (I-7) or the general formula (I-8).
[Preparation of Compound of General Formula (I-4)]
[0308] The compound of the general formula (I-4) can be prepared by
condensing a compound (41) with a compound (42) according to Step
12. Specifically, Step 12 varies according to the starting material
and is not particularly limited insofar as the conditions are
similar to those in this reaction. For example, a known method
described in many documents such as coupling reaction using a
copper compound of an arylboronic acid derivative (see The Journal
of Organic Chemistry, 2001, vol. 66, p. 7892, for example), Ullmann
reaction (see Journal of Medicinal Chemistry, 1981, vol. 24, p.
1139, for example) or nucleophilic substitution reaction (see
Journal of Medicinal Chemistry, 1991, vol. 39, p. 2671-2677, for
example) may be used for the reaction.
[0309] The coupling reaction of an arylboronic acid derivative
using a copper compound is, for example, a method of stirring a
compound (41), wherein L.sub.3 represents a boronic acid group or a
boronate group, and 1.0 to 10.0 equivalents of a compound (42) with
respect to the compound (41) in a solvent in the presence of 0.01
to 1.0 equivalent of a copper reagent such as copper, copper
bromide or copper iodide with respect to the compound (41) by
addition of 1.0 to 10.0 equivalents of a base with respect to the
compound (41). The base used varies according to the starting
material, the solvent used and the like, and is not particularly
limited insofar as the base does not inhibit the reaction.
Preferable examples of the base include organic bases such as
triethylamine, pyridine and tetramethylethylenediamine; alkali
metal salts such as potassium carbonate, sodium carbonate,
potassium acetate, sodium acetate and cesium carbonate; and metal
alkoxides such as sodium methoxide and potassium tert-butoxide. The
copper reagent used varies according to the starting material and
is not particularly limited. Preferable examples of the copper
reagent include copper acetate and
di-.mu.-hydroxo-bis[(N,N,N,N-tetramethylethylenediamine)copper
(II)] chloride. The solvent used varies according to the starting
material, the reagent and the like, and is not particularly limited
insofar as the solvent does not inhibit the reaction and allows the
starting material to be dissolved therein to a certain extent.
Preferable examples of the solvent include ether solvents such as
tetrahydrofuran, 1,4-dioxane and diethyl ether; halogenated
solvents such as methylene chloride, 1,2-dichloroethane and
chloroform; polar solvents such as ethyl acetate,
N,N-dimethylformamide and N-methylpyrrolidone; nonpolar solvents
such as toluene, benzene and dichlorobenzene; and a mixture
thereof. The reaction temperature must be a temperature that can
complete the reaction without promoting formation of an undesirable
by-product, and is preferably room temperature to 200.degree. C.,
for example. Good results such as reduction in the reaction time
and improvement of the yield may be achieved when the reaction is
performed in an oxygen atmosphere or air stream. Under preferable
reaction conditions, the reaction is completed in 1 to 24 hours,
and the progress of the reaction can be monitored by a known
chromatography technique. An undesirable by-product can be removed
by a technique known to a person skilled in the art such as a
conventional chromatography technique, extraction or/and
crystallization.
[0310] In Ullmann reaction, a compound (41), wherein L.sub.3
represents a halogen atom such as a chlorine atom, a bromine atom
or an iodine atom, and 1.0 to 10.0 equivalents of a compound (42)
with respect to the compound (41) are stirred in a solvent in the
presence of 0.01 to 1.0 equivalent of a copper reagent such as
copper, copper bromide or copper iodide with respect to the
compound (41) by addition of 1.0 to 10.0 equivalents of a base with
respect to the compound (41), for example. The base used varies
according to the starting material and is not particularly limited.
Preferable examples of the base include alkali metal salts such as
potassium carbonate, sodium carbonate, potassium acetate, sodium
acetate and cesium carbonate; and metal alkoxides such as sodium
methoxide and potassium tert-butoxide. The solvent used varies
according to the starting material, the reagent and the like, and
is not particularly limited insofar as the solvent does not inhibit
the reaction and allows the starting material to be dissolved
therein to a certain extent. Preferable examples of the solvent
that can be used include ether solvents such as tetrahydrofuran,
1,4-dioxane and diethyl ether; halogenated solvents such as
methylene chloride, 1,2-dichloroethane and chloroform; alcohol
solvents such as amyl alcohol and isopropyl alcohol; polar solvents
such as N,N-dimethylformamide and N-methylpyrrolidone; nonpolar
solvents such as toluene, benzene and dichlorobenzene; and a
mixture thereof. The reaction temperature must be a temperature
that can complete the reaction without promoting formation of an
undesirable by-product, and is preferably room temperature to
200.degree. C., for example. Under preferable reaction conditions,
the reaction is completed in 1 to 24 hours, and the progress of the
reaction can be monitored by a known chromatography technique. An
undesirable by-product can be removed by a technique known to a
person skilled in the art such as a conventional chromatography
technique, extraction or/and crystallization.
[0311] In nucleophilic substitution reaction, a compound (41),
wherein L.sub.3 represents a halogen atom such as a chlorine atom,
a bromine atom or an iodine atom or a sulfonate group such as a
methanesulfonate group, a p-toluenesulfonate group or a
trifluoromethanesulfonate group, and 2.0 to 5.0 equivalents of a
compound (42) with respect to the compound (41) are stirred in a
solvent in the presence or absence of 1.0 to 5.0 equivalents of a
base with respect to the compound (41), for example. The base used
varies according to the starting material and is not particularly
limited. Preferable examples of the base include sodium hydride,
sodium hydroxide, potassium hydroxide, potassium carbonate, sodium
carbonate, cesium carbonate, barium carbonate, pyridine, lutidine
and triethylamine. The solvent used varies according to the
starting material, and is not particularly limited insofar as the
solvent does not inhibit the reaction and allows the starting
material to be dissolved therein to a certain extent. Preferable
examples of the solvent include acetonitrile, tetrahydrofuran,
dimethyl sulfoxide, N,N-dimethylformamide and N-methylpyrrolidine.
The base may optionally be used as a solvent. The reaction
temperature must be a temperature that can complete the reaction
without promoting formation of an undesirable by-product, and is
preferably room temperature to 150.degree. C., for example. Under
preferable reaction conditions, the reaction is completed in 1 to
24 hours, and the progress of the reaction can be monitored by a
known chromatography technique. An undesirable by-product can be
removed by a technique known to a person skilled in the art such as
a conventional chromatography technique or/and crystallization.
[Preparation of Compound (41)]
[0312] The compound (41) is prepared by the same method as in the
above General Preparation Methods 1 to 7.
[Preparation of Compound (42)]
[0313] The compound (42) is commercially available or prepared by a
method known to a person skilled in the art.
[0314] The compound of the general formula (I-7) or the general
formula (I-8) can be prepared from the compound (41), wherein two
of R.sup.10, R.sup.11 and R.sup.12 form a ring, as a starting
material by the same method as above.
[0315] General Preparation Methods 1 to 8 for the compound of the
present invention described above in detail are methods for
preparing a compound represented by the general formula (I-9), the
general formula (I-4), the general formula (I-5), the general
formula (I-6), the general formula (I-7) or the general formula
(I-8), wherein Het falls within a part of the definition of Het in
the general formula (I). However, the compound of the general
formula (I), wherein Het falls within another part of the
definition of Het, can be prepared almost in the same manner as in
the above General Preparation Methods 1 to 8, or can be prepared by
another method itself known to a person skilled in the art. The
examples described later will provide reference to these
Preparation Methods, and the compound of the general formula (I)
can be easily prepared by a method itself known to a person skilled
in the art based on these examples.
[0316] The compound of the general formula (I) or pharmacologically
acceptable salt thereof according to the present invention is
effective for prevention or treatment of a disease caused by
A.beta. and is excellent in terms of pharmacokinetics, toxicity,
stability, absorption and the like.
[0317] A prophylactic or therapeutic agent for a disease caused by
A.beta. comprising the compound of the formula (I) or
pharmacologically acceptable salt thereof according to the present
invention as an active ingredient can be prepared by a conventional
method. Preferable examples of the dosage form include tablets,
powders, fine granules, granules, coated tablets, capsules, syrups,
troches, inhalants, suppositories, injections, ointments,
ophthalmic solutions, ophthalmic ointments, nasal drops, ear drops,
cataplasms and lotions. The prophylactic or therapeutic agent can
be prepared by using ingredients typically used such as an
excipient, a binder, a lubricant, a colorant and a corrective, and
ingredients used where necessary such as a stabilizer, an
emulsifier, an absorbefacient, a surfactant, a pH adjuster, a
preservative and an antioxidant, and can be prepared by blending
ingredients generally used as materials for a pharmaceutical
preparation. Examples of such ingredients include animal and
vegetable oils such as soybean oil, beef tallow and synthetic
glyceride; hydrocarbons such as liquid paraffin, squalane and solid
paraffin; ester oils such as octyldodecyl myristate and isopropyl
myristate; higher alcohols such as cetostearyl alcohol and behenyl
alcohol; a silicone resin; silicone oil; surfactants such as
polyoxyethylene fatty acid ester, sorbitan fatty acid ester,
glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid
ester, polyoxyethylene hydrogenated castor oil and a
polyoxyethylene-polyoxypropylene block copolymer; water-soluble
polymers such as hydroxyethylcellulose, polyacrytic acid, a
carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone and
methylcellulose; lower alcohols such as ethanol and isopropanol;
polyhydric alcohols such as glycerin, propylene glycol, dipropylene
glycol and sorbitol; sugars such as glucose and sucrose; inorganic
powders such as silicic anhydride, magnesium aluminum silicate and
aluminum silicate; and purified water. Examples of the excipient
used include lactose, corn starch, saccharose, glucose, mannitol,
sorbitol, crystalline cellulose and silicon dioxide. Examples of
the binder used include polyvinyl alcohol, polyvinyl ether,
methylcellulose, ethylcellulose, gum arabic, tragacanth, gelatin,
shellac, hydroxypropylmethylcellulose, hydroxypropylcellulose,
polyvinylpyrrolidone, a polypropylene glycol-polyoxyethylene block
copolymer and meglumine Examples of the disintegrator used include
starch, agar, gelatin powder, crystalline cellulose, calcium
carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin and
carboxymethylcellulose calcium. Examples of the lubricant used
include magnesium stearate, talc, polyethylene glycol, silica and
hydrogenated vegetable oil. Examples of the colorant used include
those permitted to be added to pharmaceuticals. Examples of the
corrective used include cocoa powder, menthol, empasm, mentha oil,
borneol and cinnamon powder.
[0318] For example, an oral preparation is prepared by adding an
active ingredient compound or a salt thereof or a hydrate of the
compound or salt, an excipient, and, where necessary, a binder, a
disintegrant, a lubricant, a colorant and a corrective, for
example, and then forming the mixture into powder, fine granules,
granules, tablets, coated tablets or capsules, for example, by a
conventional method. It is obvious that tablets or granules may be
appropriately coated, for example, sugar coated, where necessary. A
syrup or an injection preparation is prepared by adding a pH
adjuster, a solubilizer and an isotonizing agent, for example, and
a solubilizing agent, a stabilizer and the like where necessary by
a conventional method. An external preparation may be prepared by
any conventional method without specific limitations. As a base
material, any of various materials usually used for a
pharmaceutical, a quasi drug, a cosmetic or the like may be used.
Examples of the base material include materials such as animal and
vegetable oils, mineral oils, ester oils, waxes, higher alcohols,
fatty acids, silicone oils, surfactants, phospholipids, alcohols,
polyhydric alcohols, water-soluble polymers, clay minerals and
purified water. A pH adjuster, an antioxidant, a chelator, a
preservative and fungicide, a colorant, a flavor or the like may be
added where necessary. Further, an ingredient having a
differentiation inducing effect such as a blood flow enhancer, a
bactericide, an antiphlogistic, a cell activator, vitamin, amino
acid, a humectant or a keratolytic agent may be blended where
necessary.
[0319] The dose of the therapeutic or prophylactic agent of the
present invention varies according to the degree of symptoms, age,
sex, body weight, mode of administration, type of salt and specific
type of disease, for example. Typically, the compound of the
formula (I) or pharmacologically acceptable salt thereof is orally
administered to an adult at about 30 .mu.g to 10 g, preferably 100
.mu.g to 5 g, and more preferably 100 .mu.g to 100 mg per day, or
is administered to an adult by injection at about 30 .mu.g to 1 g,
preferably 100 .mu.g to 500 mg, and more preferably 100 .mu.g to 30
mg per day, in a single dose or several divided doses,
respectively.
[0320] For prevention or treatment of a disease caused by A.beta.
such as Alzheimer's disease, senile dementia, Down's disease and
amyloidosis, the compound represented by the formula (I) or a
pharmacologically acceptable salt thereof according to the present
invention may be used in combination with for compounds having
mechanisms as described below.
[0321] For example, such compounds include cholinesterase
inhibitors (e.g., donepezil, huperzine A, tacrine, rivastigmine,
galantamine); AMPA receptor antagonists (e.g., 1,2-dihydropyridine
compounds such as
3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one);
NMDA receptor antagonists (e.g., memantine); acetylcholine
releasing stimulants (e.g., pramiracetam; aniracetam); calcium
channel agonists (e.g., nefiracetam); free radical scavengers
(e.g., EGb 761); platelet activating factor antagonists (e.g., EGb
761); platelet aggregation antagonists (e.g., EGb 761, triflusal);
insulin sensitizers (e.g., rosiglitazone); peroxisome
proliferator-activated receptor agonists (e.g., rosiglitazone);
peroxisome proliferator-activated receptor gamma agonists (e.g.,
rosiglitazone); monoamine oxidase B inhibitors (e.g., rasagiline,
selegiline, procaine); carnitine acetyltransferase stimulants
(e.g., levacecamine); NSAIDs (e.g., triflusal, cyclooxygenase-2
inhibitors, such as celecoxib); nerve growth factor agonists (e.g.,
xaliproden, FPF 1070); beta-amyloid inhibitors (e.g., tarenflurbil,
tramiprosate, leuprorelin-D); immunomodulators (e.g., tarenflurbil,
immune globulin, icosapentethyl ester); NF-kappa B inhibitors
(e.g., tarenflurbil); thyrotropin releasing hormone agonists (e.g.,
taltirelin); dopamine D2 receptor antagonists (e.g., risperidone);
serotonin 2 receptor antagonists (e.g., risperidone); muscarinic M1
receptor agonists (e.g., cevimeline); alpha 1 adrenoceptor agonists
(e.g., modafinil); serotonin 3 receptor antagonists (e.g.,
alosetron); dopamine D2 receptor agonists (e.g., aripiprazole);
dopamine D2 receptor antagonists (e.g., aripiprazole); serotonin 1A
receptor agonists (e.g., aripiprazole); serotonin 2A receptor
antagonists (e.g., aripiprazole); glucocorticoid antagonists (e.g.,
mifepristone); progesterone antagonists (e.g., mifepristone);
HMG-CoA reductase inhibitors (e.g., atorvastatin, simvastatin);
adenosine uptake inhibitors (e.g., propentofylline);
phosphodiesterase inhibitors (e.g., propentofylline); acetylcholine
receptor agonists (e.g., choline alfoscerate); membrane
permeability enhancers (e.g., choline alfoscerate); cannabinoid 1
receptor antagonists (e.g., rimonabant); cannabinoid receptor
agonists (e.g., dronabinol); angiogenesis inhibitors (e.g.,
paclitaxel); immunosuppressants (e.g., paclitaxel); tubulin
antagonists (e.g., paclitaxel); thromboxane A2 synthase inhibitors
(e.g., triflusal); antioxidants (e.g., idebenone); alpha
adrenoreceptor antagonists (e.g., nicergoline); estrogen agonists
(e.g., conjugated estrogens, trilostane); 3-beta hydroxysteroid
dehydrogenase inhibitors (e.g., trilostane); signal transduction
pathway inhibitors (e.g., trilostane); melatonin receptor agonists
(e.g., ramelteon); immunostimulants (e.g., immune globulin,
icosapentethyl ester, procaine); HIV entry inhibitors (e.g.,
procaine); sodium channel antagonists (e.g., procaine); microtubule
inhibitor (e.g., CPH 82); glycine NMDA agonists (e.g.,
cycloserine); adenosine A1 receptor antagonists (e.g., KW 3902);
ATP ase stimulants (e.g., triacetyluridine); mitochondrial function
enhancers (e.g, triacetyluridine); growth hormone releasing factor
agonists (e.g., tesamorelin); butylcholine esterase inhibitor
(e.g., bisnorcymserine); alpha adrenergic receptor antagonists
(e.g., nicergoline); NO synthase type II inhibitors (e.g., arundic
acid); chelating agents (e.g., PBT 2); amyloid fibrillogenesis
inhibitors (e.g., TTP488, PF 449-4700); serotonin 4 receptor
agonists (e.g., PRX 03140); serotonin 6 receptor antagonists (e.g.,
SB 742457); benzodiazepine receptor inverse agonists (e.g.,
radequinil); Ca channel antagonists (e.g., safinamide); nicotinic
receptor agonists (e.g., ispronicline); and ACE inhibitor (e.g.,
CTS 21166).
[0322] Further, the above compounds include, for example, huperzine
A, tacrine, rivastigmine, galantamine, pramiracetam, aniracetam,
nefiracetam, EGb 761, rosiglitazone, rasagiline, levacecamine,
celecoxib,
3-(2-cyanophenyl)-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridin-2-one,
talampanel, becampanel, memantine, xaliproden, tarenflurbil,
tramiprosate, leuprorelin-D, taltirelin, risperidone, cevimeline,
modafinil, alosetron, aripiprazole, mifepristone, atorvastatin,
propentofylline, choline alfoscerate, FPF 1070 (CAS Number
143637-01-8), rimonabant, dronabinol, docosahexaenoic acid,
paclitaxel, triflusal, idebenone, nicergoline, conjugated
estrogens, trilostane, simvastatin, selegiline, ramelteon, immune
globulin, icosapentethyl ester, procaine, CPH 82, cycloserine, KW
3902 (CAS Number 136199-02-5), triacetyluridine, estrogen dementia
therapeutics (e.g., MIGENIX, Vancouver, Canada), tesamorelin,
bisnorcymserine, nicergoline, arundic acid, PBT 2, TTP488, PF
449-4700, PRX 03140, SB 742457, radequinil, safinamide,
ispronicline, CTS 21166, Bapineuzumab, NP 031112,
(2S,3aS,7aS)-1{[(R,R)-2-Phenylcyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)-
carbonyl]octahydro-1H-indole, citalopram, venlafaxine, levprorelin,
prasterone, peptide T (CAS Number 53-43-0), besipiridine,
lexipafant, stacofylline, SGS 742 (CAS Number 123690-78-8), T 588
(CAS Number 142935-03-3), nerispiridine, dexanabinol, sabcomeline,
GTS 21 (CAS Number 156223-05-1), CX 516 (CAS Number 154235-83-3),
ABT 089 (CAS Number 161417-03-4), anapsos, tesofensine, SIB 1553A
(i.e., 4-[[2-(1-methyl-yl-2-pyrrolidinyl)ethyl]thia]phenol),
ladostigil, radequinil, GPI 1485, ispronicline, arundic acid, MEM
1003 (i.e., 3-Isopropyl 5-(2-methoxyethyl)
4-(2-chloro-3-cyanophenyl)-2,6-dimethylpyridine-3,5-dicarboxylate),
V 3381 (i.e., 2-(2,3-Dihydro-1H-inden-3-ylamino)acetamide
hydrochloride), farampator, paliroden, prasterone-paladin,
urocortin, DP b99 (i.e.,
2,2'-(Ethylenedioxy)bis(2,1-phenylene)bis[N-[2-[2-(octyloxy)ethoxy]-2-oxo-
ethyl]imino]bis(acetic acid)), capserod, DU 125530, bapineuzumab,
AL 108 (i.e.,
L-Asparaginyl-L-alanyl-L-prolyl-L-valyl-L-seryl-L-isoleucyl-L-prol-
yl-L-glutamine), DAS 431, DEBIO 9902, DAR 100, mitoquinone, IPL
455903 (i.e.,
5(S)-[3-(Cyclopentyloxy)-4-methoxyphenyl]-3(S)-(3-methylbenzyl)pip-
eridin-2-one), E2CDS, PYM 50028, PBT 2, lecozotan, SB 742457, CX
717, AVE 1625 (i.e.,
1-(bis(4-chlorophenyl)methyl)-3-((3,5-difluorophenyl)(methylsulfonyl)meth-
ylene)azetidine), LY 450139 (i.e.,
N2-[2(s)-Hydroxy-3-methylbutyryl]-N-1-[3-methyl-2-oxo-2,3,4,5-tetrahydro--
1H-3-benzazepin-1(S)-yl]-L-alaninamide), EM 1421 (i.e.,
4,4'-[(2R,3S)-2,3-Dimethylbutane-1,4-diyl]bis(1,2-dimethoxybenzene),
SRN 001, TTP 488, PRX 03140, dimebolin, glycine-proline-glutamate,
C105, AL 208, MEM 3454, AC 1202, L 830982, LY 451395 (i.e.,
(R)--N-[2-[4'-(methylsulfonamidomethyl)biphenyl-4-yl]propyl]propane-2-sul-
fonamide), MK 0249, LY 2062430, diethylnorspermine, neboglamine,
S18986, SA 4503 (CAS Number 165377-44-6), GRI 1, S 17092 (i.e.,
(2S,3aS,7aS)-1{[(R,R)-2-Phenylcyclopropyl]carbonyl}-2-[(thiazolidin-3-yl)-
carbonyl]octahydro-1H-indole), SL 251188, EUK 189, R 1450,
6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzot-
hiophen-4(5H)-one, CERE 110, dexefaroxan, CAD 106, HF 0220, HF
0420, EHT 0202, VP 025, MEM 1414, BGC 201259 (i.e.,
N,N-Dimethylcarbamic acid,
4-[1(S)-(methylamino)-3-(4-nitrophenoxy)propyl]phenyl ester), EN
100, ABT 834, ABT 239 (i.e.,
4-[2-[2-[(2R)-2-Methylpyrrolidinyl]ethyl]-benzofuran-5-yl]benzonitrile),
SGS 518, R 1500, C 9138, SSR 180711, alfatradiol, R 1577, T 817MA
(i.e.,
1-[3-[2-(1-Benzothien-5-yl)ethoxy]propyl]azetidin-3-olmaleate), CNP
1061 (i.e., 4-Methyl-5-(2-nitrooxyethyl)thiazole), KTX 0101 (i.e.,
sodium beta-hydroxybutyrate), GSK 189254 (i.e.,
6-[3-Cyclobutyl-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yloxy]-N-methylnic-
otinamide), AZD 1080, ACC 001, PRX 07034, midazolam, R-phenserine,
AZD 103 (CAS Number 488-59-5), SN 522, NGX 267 (CAS Number
503431-81-0), N-PEP-12, RN 1219, FGLL, AVE 8112, EVT 101, NP
031112, MK 0752, MK 0952, LX 6171, PAZ 417, AV 965, PF 3084014, SYN
114, GSI 953, SAM 315, SAM 531, D-serine, leteprinim potassium, BR
16A (CAS Number 149175-77-9), RPR 107393 (CAS Number 190841-57-7),
NXD 2858, REN 1654, CDD 0102, NC 1900 (CAS Number 132925-74-7),
ciclosporin, NCX 2216 (i.e., (E)-4-(Nitrooxy)butyl
3-[4-[2-(2-fluorobiphenyl-4-yl)propanoyloxy]-3-methoxyphenyl]acrylate),
NXD 3109, NXD 1191, ZSET 845 (i.e.,
3,3-diphenylimidazo[1,2-a]pyridin-2-(3H)-one), ET 002, NT 13, RO
638695 (i.e., [1,6-(1,6-dioxohexyl)]dipyrrolidine-(2R)-carboxylic
acid), bisnorcymserine, BA 1016, XD 4241, EUK 207 (i.e.,
(SP-5-.beta.)-(acetato-.kappa.O)[13,16,19,22-tetraoxa-3,6-diazatricyclo[2-
1.3.18,12]octacosa-1(27),2,6,8,10,12(28),23,25-octaene-27,28-diolato(2-)-.-
kappa.N3, .kappa.N6,.kappa.O27,.kappa.O28]manganese), LG 617
inhibitors, ZSET 1446, PAN 811, F 14413 (i.e.,
2-[5-fluoro-2(S)-methoxy-2,3-dihydro-1,4-benzodioxin-2-yl]-4,5-dihydro-1H-
-imidazole), FP 7832 (i.e.,
N-[2-(5-methoxy-1-nitroso-1H-indol-3-yl)ethyl]acetamide), ARA
014418 (i.e.,
N-(4-methoxybenzyl)-N'-(5-nitro-1,3-thiazol-2-yl)urea), AZD 3102,
KP 544 (i.e.,
2-amino-5-(4-chlorophenylethynyl)-4-(4-trans-hydroxycyclohexylamino)pyrim-
idine), DP 155,
5-chloro-N-[3-[2-(dimethylamino)ethyl]-1H-indol-5-yl]naphthalene-2-sulfon-
amide, TAK 070, huperzine,
N-[2-(3,5-dimethyladamant-1-yl)ethyl]acetamidine hydrochloride,
6-[4-[(dimethylamino)methyl]-5-ethyl-2-methoxyphenyl]pyridin-2-amine,
4,6-diphenyl-3-(4-(pyrimidin-2-yl)piperazin-1-yl)pyridazine,
N-[(1S,2R)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(5S,6R)-5-methyl-6-(neopen-
tyloxy)morpholin-3-yl]propan-2-yl]acetamide hydrochloride,
N-[(1R,2S)-3-(3,5-difluorophenyl)-1-hydroxy-1-[(2R,4R)-4-phenoxypyrrolidi-
n-2-yl]propan-2-yl]-3-[(R)-2-(methoxymethyl)pyrrolidine-1-carbonyl]-5-meth-
ylbenzamide, R 1589, midafotel, phenserine, coluracetam,
physostigmine, cipralisant, nitroflurbiprofen, PPI 1019 (i.e.,
(3.alpha.,5.beta.,7.alpha.,12.alpha.)-trihydroxycholan-24-oyl-L-leucyl-L--
valyl-L-phenylalanyl-L-phenylalanyl-L-alanine), dapsone, MDL 100453
(CAS Number 129938-34-7), NS 377, midaxifylline, propofol
phosphate, metrifonate, ceronapril, tenilsetam, sufoxazine,
seglitide, ebiratide, nebracetam, milacemide, iododoxorubicin, SM
10888 (CAS Number 129297-21-8), U 80816 (CAS Number 138554-11-7),
YM 954 (CAS Number 132041-85-1), SUT 8701 (CAS Number 123577-73-1),
apovincamine, FR 121196 (CAS Number 133920-65-7), LY 274614 (CAS
Number 136109-04-1), CL 275838 (CAS Number 115931-65-2), igmesine,
K 7259 (CAS Number 133667-88-6), vinconate, itasetron, CL 287663
(CAS Number 125109-98-0), WAY 100289 (CAS Number 136013-69-9), SR
46559A (CAS Number 137733-33-6), GYKI 46903 (CAS Number
142999-59-5), L 670548 (CAS Number 121564-89-4), Y 29794 (CAS
Number 129184-48-1), AF 125 (CAS Number 7631-86-9), KFM 19 (CAS
Number 133058-72-7), ST 796 (i.e.,
(S)-3-[3-(trifluoromethyl)benzoyl)amino]hexahydroazepin-2-one), RU
33965 (CAS Number 122321-05-5), SDZ 210086 (i.e.,
(-)-1',2(S)-Dimethylspiro[1,3-dioxolan-4,4'-piperidine]), L 689660
(CAS Number 144860-79-7), L 689560 (CAS Number 139051-78-8), ST 618
(i.e., 1-(6,7-Dimethoxy-1,2,3,4-tetrahydro-2-naphthyl)-4-hydroxy
pyrrolidin-2-one), U 74500A (CAS Number 110101-65-0), GEA 857 (CAS
Number 120493-42-7), BIBN 99 (CAS Number 145301-48-0), DX 9366, ONO
1603 (CAS Number 114668-76-7), MDL 102234 (CAS Number 137766-81-5),
P 9939 (CAS Number 157971-37-4), PD 140532 (CAS Number
157971-39-6), azetirelin, MR 16728 (CAS Number 147614-21-9),
dabelotine, MDL 102503 (i.e.,
8-[1(R)-methyl-2-phenylethyl]-1,3-dipropyl-7H-xanthine), PD 141606
(i.e.,
(.+-.)-(Z)-3-(3-Phenyl-2-propynyloxyimino)-1-azabicyclo[2.2.1]heptane),
SNK 882 (CAS Number 152221-12-0), L 696986 (CAS Number
141553-45-9), tazomeline, LY 235959 (CAS Number 137433-06-8),
2-(2-thiooxopyrrolidin-1-yl)acetamide, AK 30 NGF, ABT 418 (CAS
Number 147402-53-7), itameline, HUP 13, sibopirdine, KST 5452 (CAS
Number 157998-88-4), TJ 54, U 92798 (i.e.,
7-[4-[Bis(4-fluorophenyl)methyl]perhydro-1,4-diazepin-1-ylmethyl]-4-isopr-
opyl-2-methoxy-2,4,6-cycloheptatrien-1-one), U 92032 (CAS Number
142223-92-5), 3-(sulfamoyloxy)estra-1,3,5(10)-trien-17-one, P 11012
(CAS Number 164723-36-8), A 82695 (CAS Number 147388-86-1), FR
76659 (CAS Number 116904-25-7), apaxifylline, CX 417, 7 MEOTA (CAS
Number 5778-80-3), BU 4514N(CAS Number 151013-39-7), pregnenolone,
mexidol, ST 857 (CAS Number 154755-63-2), RU 49041 (CAS Number
123828-80-8), RU 35929 (CAS Number 111711-47-8), P 878184, P 128
(CAS Number 157716-52-4), eurystatin A, eurystatin B, LK 12, NBI
108, NBI 107, NBI 117, L 705106, bacoside A+B, clausenamide, SM 21
(CAS Number 155156-22-2), alaptide, RS 17017 (i.e.,
1-(4-Amino-5-chloro-2-methoxyphenyl)-5-(1-piperidinyl)-1-pentanone
hydrochloride), AF 150(S) (i.e.,
(S)-[1-Methyl-piperidine-4-spiro-(2'-methylthiazoline)]), RO 153505
(CAS Number 78771-.beta.-8), PV 113 (i.e.,
1,2,3,4-Tetrahydropyrrolo-[1,2-a]-pyrazine), arisugacin, A 98284
(i.e., 2(R)-(3-Methylisoxazol-5-yl) quinuclidine), AP 5 (CAS Number
136941-85-0), BD 1054, SDZ NDD 094 (i.e.,
bis-(2-(2-methylimidazol-1-yl]methyl)-pyridine-tris(hydrogen-fumarate),
AZ 36041 (CAS Number 173324-76-0), quilostigmine, A 84543 (i.e.,
3-[1-Methylpyrrolidin-2-(S)-ylmethoxy]pyridine fumarate), BTG 4247
(i.e.,
(2-[2-Chloroethoxy[4-(dimethylamino)phenyl]phosphoryl]-acetohydrazide),
CGP 50068 (CAS Number 158647-49-5), cerebrocrast,
desferri-nordanoxamine, isolichenan, MHP 133 (i.e.,
3-(N,N-dimethylcarbamoyloxy)-1-methyl-2-(4-phenyl-semicarbazonomethyl)pyr-
idinium chloride), FR 152558 (CAS Number 151098-08-7), GVS 111 (CAS
Number 157115-85-0), P 11149 (CAS Number 164724-79-2), PDC 008004,
KST 2818 (CAS Number 158623-26-8), KST 5410 (CAS Number
158623-27-9), RU 52583 (CAS Number 123829-33-4), PD 151832 (CAS
Number 149929-39-5), UCL 1199 (i.e.,
4-[2-[(5-Nitropyridin-2-ylsulfanyl)ethyl]-1H-imidazole),
isoyanihuperzine A, SIB 1765F (CAS Number 179120-52-6), JWS USC
751X (i.e.,
3-[[[2-[[(5-dimethylaminomethyl)-2-furanyl]methyl]thio]ethyl]amino]-4-nit-
ropyridazine), GR 175737 (i.e.,
3-(4-Chlorobenzyl)-5-[2-(1H-imidazol-4-yl)ethyl]-1,2,4-oxadiazole),
KS 505A (CAS Number 131774-53-3), ZTTA 1 (i.e.,
N-benzyloxycarbonyl-thioprolyl-thioprolynal-dimethylaceta 1), AGN
190837 (CAS Number 136527-40-7), P 10358 (188240-59-7), WAY 131256
(CAS Number 174001-71-9), DBO 83 (i.e.,
3-(6-chloropyridazin-3-yl)-diazabicyclo[3.2.1]octane
dihydrochloride monohydrate), FUB 181 (CAS Number 152029-80-6), RJR
2557, WSU 2088, LVV-haemorphin-7, M 40 (i.e.,
galanin[1-12]-Pro3-(Ala-Leu)-2-Ala-NH.sub.2), SIB 1757, SKF 74652
(i.e., [5-chloro-2-(4-methoxy
phenyl)-3-benzofuranyl][4-[3-(diethylamino)-propoxy]phenyl]methanone),
CGP 71982, SCH 57790 (i.e.,
4-cyclohexyl-alpha-[4-[[4-methoxyphenyl]sulfinyl]phenyl]-1-piperazineacet-
onitrile), Putrescine-D-YiAbeta11, DU 14 (i.e.,
p-O-(sulfamoyl)-N-tetradecanoyl tyramine), CLZ 4, SL 340026, PPRT
424, ciproxifan, UR 1827 (i.e.,
2-(1-benzylpiperidin-4-yl)-1-[4-(5-methylpyrimidin-4-ylamino)phenyl]-1-et-
hanone), caproctamine, TGS 20 (i.e., L-pyroglutamil-D-alanine
amide), PG 9 (i.e., alpha-tropanyl 2-[(4-bromo)phenyl]propionate),
TEI 3356 (i.e.,
(16S)-15-Deoxy-16-hydroxy-16-methyl-9-(O)-methano-DELTA6(9alpha)-prostagl-
andin II), LY 392098 (i.e., Thiophene,
3-[(2-methylethyl-2)sulphonylaminopropyl-2]phenyl-4-yl-), PG 1000,
DM 232, NEPP 11 (i.e.,
12-iso-15-Deoxy-18-(4-methyl)phenyl-13,14-dihydro-delta7-prostaglandinA1
methyl ester), VA 100 (i.e.,
(2,3-Dihydro-2-[[(4-fluorobenzoyl)amino]ethyl]-1-methyl-5-phenyl-1H-1,4-b-
enzodiazepine), VA 101 (i.e.,
(2,3-dihydro-2-[[(2-thienylcarbonyl)amino]ethyl]-1-methyl-5-phenyl-1H-1,4-
-benzodiazepine), NC 111585 (i.e.,
(3S)-1,3-Bis-[3-[(3-azabicylo[2.2.2]octanyl)-1,2,5-thiadiazol-4-yloxy]-1--
propyn-1-yl]benzene, 2L-(+)-tartate), IN 201, imoproxifan,
kanokodiol, picroside I, picroside II, DM 235 (i.e.,
1-(4-Benzoylpiperazin-1-yl)propan-1-one), monoclonal antibody 10D5,
JLK2, JLK 6, JLK 7, DAPT (i.e.,
N--[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl
ester), huperine X, SGS 111 (i.e., (S)-ethyl
2-[1-(2-phenylacetyl)pyrrolidine-2-carboxamido]acetate), NP 7557, C
9136, C 7617, R 1485, rofecoxib, velnacrine, montirelin,
lazabemide, ORG 2766 (CAS Number 50913-82-1), sabeluzole,
adafenoxate, CAS Number 9061-61-4, ipidacrine, bemesetron,
idazoxan, linopirdine, selfotel, suritozole, milameline,
xanomeline, TJ 960, fasoracetam, eptastigmine, ensaculin,
zanapezil, posatirelin, zacopride, RS 86 (CAS Number 3576-73-6),
ORG 5667 (CAS Number 37552-33-3), RX 77368 (CAS Number 76820-40-1),
BMS 181168 (CAS Number 123259-91-6), BY 1949 (CAS Number
90158-59-1), AWD 5239 (CAS Number 109002-93-9), YM 796
(171252-79-2), aloracetam, CI 933 (CAS Number 91829-95-7), ST 793
(CAS Number 99306-37-3), cebaracetam, zifrosilone, talsaclidine,
alvameline, JTP 2942 (148152-77-6), OPC 14117 (CAS Number
103233-65-4), elziverine, AP 521 (i.e.,
N-(1,3-Benzodioxol-5-ylmethyl)-1,2,3,4-tetrahydro[1]benzothieno[2,3-c]pyr-
idine-3(R)-carboxamide hydrochloride), S 8510 (CAS Number
151466-23-8), JTP 4819 (CAS Number 162203-65-8), icopezil, SC 110,
FK 960 (CAS Number 133920-70-4), DMP 543 (CAS Number 160588-45-4),
ganstigmine, CI 1017 (i.e.,
(R)-(-)-(Z)-1-Azabicyclo[2.2.1]heptan-3-one,
O-(3-(3'-methoxyphenyl)-2-propynyl)-oxime maleate), T 82 (i.e.,
2-[2-(1-Benzylpiperidin-4-yl)ethyl]-2,3-dihydro-9-methoxy-1H-pyrrolo[3,4--
b]quinolin-1-one hemifumarate), NGD 971, vaccine of
Aspartyl-alanyl-glutamyl-phenylalanyl-arginyl-histidyl-aspartyl-seryl-gly-
cyl-tyrosyl-glutamyl-valyl-histidyl-histidyl-glutaminyl-lysyl-leucyl-valyl-
-phenylalanyl-phenylalanyl-alanyl-glutamyl-aspartyl-valyl-glycyl-seryl-asp-
araginyl-lysyl-glycyl-alanyl-isoleucyl-isoleucyl-glycyl-leucyl-methionyl-v-
alyl-glycyl-glycyl-valyl-valyl-isoleucyl-alanine, PBT 1 (CAS Number
130-26-7), TCH 346, FK 962 (i.e.,
N-(1-acetylpiperidin-4-yl)-4-fluorobenzamide), voxergolide, KW 6055
(CAS Number 63233-46-5), thiopilocarpine, ZK 93426 (CAS Number
89592-45-0), SDZ NVI 085 (CAS Number 104195-17-7), CI 1002 (CAS
Number 149028-28-4), Z 321 (CAS Number 130849-58-0), mirisetron,
CHF 2060 (i.e., N-Heptylcarbamic acid
2,4a,9-trimethyl-2,3,4,4a,9,9a-hexahydro-1,2-oxazino[6,5-b]indol-6-yl
ester-L-tartrate), gedocarnil, terbequinil, HOE 065 (CAS Number
123060-44-6), SL 650102, GR 253035, ALE 26015, SB 271046 (i.e.,
5-Chloro-N-(4-methoxy-3-piperazin-1-yl-phenyl)-3-methyl-2-benzothiophenes-
ulfonamide), iAbeta5, SCH 211803 (i.e., Piperidine,
1-[1-(3-methyl-2-aminophenyl)carbonylpiperidin-4-yl]-4-[3-chlorophenyl)su-
lphonylphenyl-4]methyl-), EVT 301, alpha-Linolenic acid/linoleic
acid, Kamikihi-To, siagoside, FG 7142 (CAS Number 78538-74-6), RU
47067 (CAS Number 111711-92-3), RU 35963 (CAS Number 139886-03-6),
FG 7080 (CAS Number 100332-18-1), E 2030 (CAS Number 142007-70-3),
transforming growth factor beta-1, A 72055 (i.e.,
2',1-Dimethylspiro[piperidine-4,5'oxazolidine]-3'-carboxaldehyde),
NS 626, dimiracetam, GT 3001, GT 2501, GT 2342, GT 2016 (CAS Number
152241-24-2), ORG 20091 (CAS Number 141545-50-8), BCE 001 (CAS
Number 95678-81-2), CGP 35348 (CAS Number 123690-79-9), WAY 100635
(CAS Number 146714-97-8), E 4804 (CAS Number 162559-34-4), LIGA 20
(CAS Number 126586-85-4), NG 121 (i.e.,
2-[4,8-Dimethyl-3(E),7(E)-nonadienyl]-3,5-dihydroxy-2-methyl-3,4,7,9-tetr-
ahydro-2H-furo[3,4-h]-1-benzopyran-7-one), MF 247 (i.e.,
N-[10-(Diethylamino)decyl]carbamic acid
(3aS,8aR)-1,3a,8-trimethyl-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indol-5-y-
l ester), JTP 3399 (i.e.,
N-Benzyl-2(S)-[2(S)-(phenoxyacetyl)pyrrolidin-1-ylcarbonyl]pyrrolidine-1--
carboxamide), KF 17329, thioperamide, F 3796 (i.e.,
1-[2-(1-Benzylpiperidin-4-yl)ethyl]-3-[3,4-(methylene-dioxy)benzoyl]thiou-
rea), GT 4001, GT 4002, FPL 14995 (CAS Number 123319-03-9), RU
34332 (CAS
Number 137157-58-5), SR 96777A (CAS Number 115767-94-7), SIB T1980,
NS 649 (CAS Number 146828-02-6), PD 142505 (CAS Number
149929-08-8), GYKI 52466 (CAS Number 102771-26-6), RO 246173 (CAS
Number 159723-57-6), SCH 50911 (CAS Number 160415-07-6), Z 4105
(CAS Number 119737-52-9), RS 67333 (CAS Number 168986-60-5), NS
1546, ZM 241385 (CAS Number 139180-30-6), RO 249975 (i.e.,
[1S,3S(2'S),5R]-3-(1-Benzyl-5-oxopyrrolidin-2-ylmethyl)-5-(1H-imidazol-5--
ylmethyl)cyclohexane-1-acetamide), AF 185 (i.e.,
8-Methyl-3-(2-propynyl)-1,3,8-triazaspiro[4,5]decane-2,4-dione),
CEP 427, CX 423, CX 438, CX 480, CDP-ethanolamine, GT 4003, GT
4011, GT 5011, MS 430 (CAS Number 122113-44-4), MBF 379 (i.e.,
[3,3-Bis(hydroxymethyl)-8-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-5-yl][3',-
5'-dihydroxy-4'-(2-oxo-2-phenylethoxy)phenyl]methanone), NGD 187
(CAS Number 163565-48-8), DUP 856, MR 3066, MF 8615 (i.e.,
5-Amino-6-chloro-4-hydroxy-3,4-dihydro-1H-thiopyrano-[3,4-b]quinoline),
himbacine, ABS 300, RJR 2403 (CAS Number 538-79-4), MF 268 (CAS
Number 174721-00-7), RO 465934 (i.e., N,N-Dimethylcarbamic acid
3-(2-cyclohexylethyl)-2,3,3a,4,5,9b-hexahydro-1H-benz[e]indol-6-yl
ester), NS 393, RGH 2716 (CAS Number 134069-68-4), WIN 678702
(12,12-Bis(3-furyl)-6,11-dihydro-6,11-ethanobenzo[b]quinolizinium
chloride), RS 66252 (i.e.,
1-Butyl-2-[(2'-(2H-tetrazol-5-yl)-biphenyl-4-yl)methyl]-1H-indole-3-carbo-
xylic acid), AIT 034 (CAS Number 138117-48-3), NG 012 (CAS Number
131774-53-3), PD 142012 (CAS Number 5778-84-7), GT 4054, GT 4077,
GT 4035, P 26 (CAS Number 152191-74-7), RGH 5279 (i.e.,
(-)-(13aR,13bS)-13a-Ethyl-2,3,5,6,13a,13b-hexahydro-1H-indolo[3,2,1-de]py-
rido[3,2,1-ij][1,5]naphthyridine-12-carboxylic acid 2-acetoxyethyl
ester), AIT 083, CeNeS, estradiol (i.e.,
1,3,5(10)-Estratriene-3,17beta-diol), WAY 132983
((3R,4R)-3-(3-hexylsulfanylpyrazin-2-yloxy)-1-azabicyclo[2.2.1]heptane
hydrochloride), ABS 205, ABS 401, SX 3507 (i.e.,
3-(3-Propyl-1,2,4-oxadiazol-5-yl)quinoxaline-2(1H)-one), ARR 17779
(i.e., (-)-Spiro[1-azabicyclo[2.2.2]octane-3,5-oxazolidine]-2-one),
XE 991 (i.e., 10,10-bis(4-Pyridylmethyl)anthracen-10(9H)-one),
phenethylnorcymserine, RO 657199, RJR 1781 (i.e.,
R(+)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane), RJR 1782 (i.e.,
S(-)-2-(3-pyridyl)-1-azabicyclo[2.2.2.]octane), gilatide,
tolserine, TC 2559 (i.e.,
(E)-N-Methyl-4-[3-(5-ethoxypyridin)yl]-3-buten-1-amine), ER 127528
(i.e.,
1-(3-Fluorobenzyl)-4-[(2-fluoro-5,6-dimethoxy-1-indanone-2-yl)methyl]pipe-
ridine hydrochloride), thiatolserine, targacept, axonyx, cymserine,
thiacymserine, monoclonal antibody 266, Apan-CH, DP 103, SPI 339
(i.e.,
4-[3-(4-Oxo-4,5,6,7-tetrahydroindol-1-yl)propionylamino]benzoic
acid ethyl ester), S 37245 (i.e.,
4-(1,4-Benzodioxan-5-yl)-1-[3(S)-hydroxy-5-nitro-indan-2-yl]-piperazine),
LLG 88, AZD 2858, trometamol, AN 240, NG 002 (i.e.,
5-Hydroxy-5-(2-hydroxy-1-methylethyl)-4-methoxyfuran-2(5H)-one),
UCB 29427 (i.e.,
2-Cyclopropyl-4-(cyclopropylamino)-6-(morpholino)-1,3,5-triazine),
TRH-SR, RO 401641 (CAS Number 122199-02-4), MPV 1743AIII (CAS
Number 150586-64-4), IDRA 21 (CAS Number 22503-72-6), CEP 431, ACPD
(CAS Number 67684-64-4), CT 3577 (i.e.,
3,7-Dimethyl-1-[11-(3,4,5-trimethoxybenzylamino)-11-oxoundecyl]xanthine),
CT 2583, NXD 9062, Desferri-nordanoxamine, DP b99, PBT 1, T 817MA,
Alfatradiol (CAS No. 57-91-0), AL 108, SL 650102, RS 67333 (CAS No.
168986-60-5), RS 17017, SGS 518, SYN 114, SB 271046, RO 657199, PRX
07034, Suritozole (CAS No. 110623-33-19), Terbequinil (CAS No.
113079-82-6), FG 7142 (CAS No. 78538-74-6). RU 34332 (CAS No.
137157-58-5), SX 3507, RO 153505 (CAS No. 78771-.beta.-8), RU 33965
(CAS No. 122321-05-5), S 8510 (CAS No. 151466-23-8), Sabeluzole
(CAS No. 104383-17-7), Cerebrocrast (CAS No. 118790-71-9), NS 626,
NS 649 (CAS No. 146828-02-6), U 92032 (CAS No. 142223-92-5), MEM
1003, U 92798, RGH 2716 (CAS No. 134069-68-4), Safinamide (CAS No.
133865-89-1), AZD 0328, MEM 63908, ABT 418 (CAS No. 147402-53-7),
ARR 17779, RJR 2403 (CAS No. 538-79-4), TC 2559, A 82695 (CAS No.
147388-86-1), A 84543, A 98284, DBO 83, RJR 2557, SIB 1765F (CAS
No. 179120-52-6), GTS 21 (CAS No. 156223-05-1), MEM 3454, SIB
1553A, EVP 6124, SSR 180711, ABT 089 (CAS No. 161417-03-4), ABT
107, ABT 560, TC 5619, TAK 070,
N-[(1S,2R)-3-(3,5-Difluorophenyl)-1-hydroxy-1-[(5S,6R)-5-methyl-6-(neopen-
tyloxy)morpholin-3-yl]propan-2-yl]acetamide hydroCl,
6-Fluoro-5-(2-fluoro-5-methylphenyl)-3,4-dihydropyridine,
2-Amino-6-[2-(3'-methoxybiphenyl-3-yl)ethyl]-3,6-dimethyl-5,6-dihydropyri-
midin-4(3H)-one, AZD 1080, ARA 014418, XD 4241, Z 321 (CAS No.
130849-58-0), ONO 1603 (CAS No. 114668-76-7), JTP 3399, Eurystatin
A (CAS No. 137563-63-4), Eurystatin B (CAS No. 137563-64-5), P 128
(CAS No. 157716-52-4), Y 29794(CAS No. 129184-48-1), ZTTA 1, JTP
4819 (CAS No. 162203-65-8), Monoclonal antibody 266, duloxetine,
escitalopram oxalate, fluoxetine, fluvoxamine maleate, paroxetine,
sertraline, dapoxetine, desvenlafaxine, sibutramine, nefazodone,
milnacipran, desipramine, duloxetine, and bicifadine.
DETAILED DESCRIPTION OF THE INVENTION
[0323] The present invention will now be described in detail with
reference to examples; however, the examples are provided only for
illustration purposes. The prophylactic or therapeutic agent for a
disease caused by A.beta. according to the present invention is not
limited to the following specific examples in any cases. A person
skilled in the art can fully implement the present invention by
making various modifications to not only the following reference
examples and examples but also the claims of the present
specification, and such modifications are within the scope of the
claims of the present specification.
[0324] When the compound in the Examples include stereoisomers, and
the absolute configuration has not been determined, there are the
cases that the name of the compounds with optical rotating power
and its chemical structural formula are not described
correspondingly in the following Examples.
[0325] The following abbreviations are used in the following
examples.
[0326] DMF: N,N-Dimethylformamide
[0327] THF: Tetrahydrofuran
[0328] EDC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride
[0329] HOBT: 1-Hydroxybenzotriazole
[0330] IPEA: Diisopropylethylamine
[0331] IPA: 2-Propanol
[0332] DMAP: 4-(Dimethylamino)pyridine
[0333] TEA: Triethylamine
[0334] CDI: Carbonyldiimidazole
[0335] TBAF: Tetrabutylammonium fluoride
[0336] DBU: 1,8-Diazabicyclo[5.4.0]undec-7-ene
[0337] t: Tertiary
[0338] BOPCl: Bis(2-oxo-3-oxazolidinyl)phosphonic chloride
[0339] DIBAL-H: Diisobutylaluminum hydride
[0340] DAST: Diethylaminosulfur trifluoride
[0341] BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-binaphthyl
[0342] Chromatography was performed using BW-300 manufactured by
Fuji Silysia Chemical Ltd. as a carrier unless otherwise
specified.
[0343] LC-MS: High performance liquid chromatography for
preparative isolation of a target compound using mass spectroscopy.
As an elution solvent, a 10% to 99% linear gradient system of water
containing 0.1% trifluoroacetic acid and acetonitrile containing
0.1% trifluoroacetic acid was used.
Reference Examples 1 and 2
Synthesis of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vin-
yl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
##STR00050##
[0344] Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic
acid
N'-{(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acryloyl}h-
ydrazide
[0345] IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution
of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide
hydrochloride (83 mg) and
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (CAS No. 870837-77-7, 68 mg) in methylene chloride (5 mL), and
the reaction solution was stirred at room temperature for 18 hours.
Ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to obtain 112 mg of the
title compound. The property value of the compound is as
follows.
[0346] ESI-MS; m/z 522 [M.sup.++H].
Synthesis of
5-{(E)-2-{5-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-[1,3,4]oxadiazol-2--
yl}vinyl}-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine
[0347] A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic
acid
N'-{(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acryloyl}h-
ydrazide (112 mg) in phosphorus oxychloride (2 mL) was stirred at
120.degree. C. for 3.5 hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure to obtain 108 mg of the title compound. The property value
of the compound is as follows.
[0348] ESI-MS; m/z 504 [M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vin-
yl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
[0349] A solution of
5-{(E)-2-{5-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-[1,3,4]oxadiazol-2--
yl}vinyl}-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine (495 mg)
in acetic acid (2 mL) was stirred at 150.degree. C. for 25 hours.
The reaction solution was left to cool to room temperature. Then,
ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate)
to obtain a racemate of the title compound. The resulting racemate
was separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol) to
obtain the title optically active compound with a retention time of
20 minutes and positive optical rotation (11 mg, >99% ee) and
the title optically active compound with a retention time of 25
minutes and negative optical rotation (12 mg, >99% ee).
[0350] The property values of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0351] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.97-2.06 (m, 1H),
2.07-2.25 (m, 2H), 2.29 (s, 3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H),
4.23-4.30 (m, 3H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 7.08 (d, J=16.0
Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.49 (d, J=16.0 Hz, 1H), 7.52
(brs, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (brs, 1H).
[0352] The property values of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0353] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.97-2.06 (m, 1H),
2.07-2.25 (m, 2H), 2.29 (s, 3H), 2.34-2.42 (m, 1H), 3.97 (s, 3H),
4.23-4.30 (m, 3H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 7.08 (d, J=16.0
Hz, 1H), 7.46 (d, J=2.0 Hz, 1H), 7.49 (d, J=16.0 Hz, 1H), 7.52
(brs, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (brs, 1H).
Reference Examples 3 and 4
Synthesis of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin--
8-ol and
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl-
]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]-
pyridin-8-ol
##STR00051##
[0355] Sodium hydride (containing 40% of mineral oil, 4 mg) was
added to a solution of
2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3-
,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
synthesized by the method in Reference Examples 1 and 2 (21 mg) in
DMF (2 mL), and the reaction solution was stirred at room
temperature for 30 minutes while bubbling with oxygen gas. Ethyl
acetate and saturated aqueous ammonium chloride were added to the
reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The resulting racemic
crude product of the title compound was separated by CHIRALPAK.TM.
AD-H manufactured by Daicel Chemical Industries, Ltd. (2
cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with a retention time of 7 minutes
and negative optical rotation (3.7 mg, >99% ee) and the title
optically active compound with a retention time of 10 minutes and
positive optical rotation (3.2 mg, >99% ee).
[0356] The property values of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin--
8-ol are as follows.
[0357] ESI-MS; m/z 483 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.16 (m, 2H), 2.28 (s, 3H), 2.30-2.39 (m, 1H),
2.40-2.53 (m, 1H), 3.91 (s, 3H), 4.19-4.28 (m, 1H), 4.29-4.36 (m,
1H), 7.00-7.05 (m, 3H), 7.33 (d, J=1.6 Hz, 1H), 7.41 (d, J=16.8 Hz,
1H), 7.46 (brs, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.28 (brs, 1H).
[0358] The property values of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin--
8-ol are as follows.
[0359] ESI-MS; m/z 483 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.16 (m, 2H), 2.28 (s, 3H), 2.30-2.39 (m, 1H),
2.40-2.53 (m, 1H), 3.91 (s, 3H), 4.19-4.28 (m, 1H), 4.29-4.36 (m,
1H), 7.00-7.05 (m, 3H), 7.33 (d, J=1.6 Hz, 1H), 7.41 (d, J=16.8 Hz,
1H), 7.46 (brs, 1H), 8.02 (d, J=1.6 Hz, 1H), 8.28 (brs, 1H).
Examples 1 and 2
Synthesis of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00052##
[0360] Synthesis of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile
[0361] A lithium hydroxide monohydrate powder (2.23 g) was added to
a suspension of 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde
(CAS No. 870837-18-6, 10 g) and diethyl cyanomethylphosphonate (8.2
g) in THF (50 ml) under ice-cooling, and the reaction solution was
stirred at the same temperature for one hour. Ethyl acetate (200
mL) and water were added to the reaction solution, and the organic
layer was separated. The organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then filtered through a silica
gel pad (carrier: Chromatorex.TM. NH). The filtrate was
concentrated under reduced pressure. The resulting residue was
crystallized from ethyl acetate and hexane, and the crystals were
collected by filtration. The resulting crystals were dried under
reduced pressure to obtain 7.49 g of the title compound. The
property values of the compound are as follows.
[0362] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 3.91
(s, 3H), 5.90 (d, J=16.8 Hz, 1H), 6.93 (d, J=0.8 Hz, 1H), 7.06 (d,
J=1.6 Hz, 1H), 7.13 (dd, J=8.0, 1.6 Hz, 1H), 7.29 (d, J=8.0 Hz,
1H), 7.39 (d, J=16.8 Hz, 1H), 7.74 (d, J=0.8 Hz, 1H).
Synthesis of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride
[0363] A suspension of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylonitrile
(7.45 g) in ethanol (75 mL) was bubbled with hydrogen chloride gas
under ice-cooling for 10 minutes and at room temperature for 15
minutes, and then the reaction solution was stirred at room
temperature overnight. The reaction solution was concentrated under
reduced pressure. Then, ethanol and diethyl ether were added to the
residue, and the precipitated powder was collected by filtration.
The resulting powder was crystallized from ethanol and diethyl
ether to obtain 9.22 g of the title compound. The property values
of the compound are as follows. ESI-MS; m/z 286 [M.sup.++H-2HCl].
.sup.1H-NMR (DMSO-D.sub.6) .delta. (ppm): 1.46 (t, J=6.8 Hz, 3H),
2.35 (s, 3H), 3.93 (s, 3H), 4.54 (q, J=6.8 Hz, 2H), 7.18 (d, J=16.0
Hz, 1H), 7.50 (dd, J=8.0, 1.2 Hz, 1H), 7.68-7.77 (m, 3H), 8.01 (d,
J=16.0 Hz, 1H), 9.35 (s, 1H).
Synthesis of 5-chloro-2-(3-fluorophenyl)pentanoic acid
[0364] A solution of 3-fluorophenylacetic acid (500 mg) in THF (15
mL) was stirred at -78.degree. C. for 5 minutes. A 2.66 M solution
of n-butyl lithium in hexane (2.44 mL) was added, and the reaction
solution was stirred at -78.degree. C. for three hours. Thereafter,
the reaction solution was stirred at 0.degree. C. for one hour,
1-bromo-3-chloropropane was added, and the reaction solution was
stirred at room temperature for 17 hours. Thereafter, ethyl acetate
and 1 N aqueous hydrochloric acid were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to obtain 734 mg of the title
compound. The property values of the compound are as follows.
[0365] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.64-1.85 (m, 2H),
1.90-2.02 (m, 1H), 2.14-2.32 (m, 1H), 3.46-3.61 (m, 3H), 6.93-7.11
(m, 3H), 7.23-7.37 (m, 1H).
Synthesis of tert-butyl
N'-[5-chloro-2-(3-fluorophenyl)pentanoyl]hydrazinecarboxylate
[0366] IPEA (1.9 mL), HOBt (859 mg) and EDC (1.22 g) were added to
a solution of 5-chloro-2-(3-fluorophenyl)pentanoic acid (734 mg)
and tert-butyl carbazate (504 mg) in DMF (10 mL), and the reaction
solution was stirred at room temperature for seven hours. Ethyl
acetate and water were added to the reaction solution, and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 711 mg of the title compound. The property values of the
compound are as follows.
[0367] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.43 (s, 9H),
1.56-2.06 (m, 3H), 2.12-2.32 (m, 1H), 3.36-3.58 (m, 3H), 6.55 (brs,
1H), 6.90-7.16 (m, 3H), 7.20-7.34 (m, 1H), 7.67 (brs, 1H).
Synthesis of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0368] A solution of 4 N hydrochloric acid in ethyl acetate (12.1
mL) was added to tert-butyl
N'-[5-chloro-2-(3-fluorophenyl)pentanoyl]hydrazinecarboxylate (711
mg), and the reaction solution was stirred at room temperature for
two hours. The reaction solution was concentrated under reduced
pressure to obtain a crude product of
5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazide hydrochloride.
A solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (576 mg) and triethylamine (1.24 mL) in ethanol (10
mL) was added to a solution of the resulting crude product of
5-chloro-2-(3-fluorophenyl)pentanoic acid hydrazide hydrochloride
and triethylamine (1 mL) in ethanol (10 mL), and the reaction
solution was stirred at 80.degree. C. in a nitrogen atmosphere for
23 hours. The reaction solution was cooled to room temperature and
then the solvent was evaporated under reduced pressure. Ethyl
acetate and saturated sodium bicarbonate water were added to the
resulting residue, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (carrier: Chromatorex NH;
elution solvent: heptane:ethyl acetate=1:1->ethyl
acetate->ethyl acetate:methanol=9:1) and further purified by
silica gel column chromatography (elution solvent: ethyl
acetate->ethyl acetate:methanol=9:1) to obtain 306 mg of a
racemate of the title compound. The resulting racemate (152 mg) was
separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain a (+)-isomer of the title optically
active compound with a retention time of 14 minutes (60 mg; >99%
ee) and a (-)-isomer of the title optically active compound with a
retention time of 15.5 minutes (61 mg; 92% ee).
[0369] The property values of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are
as follows. ESI-MS; m/z 430 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.46 (m, 7H), 3.85 (s, 3H), 4.21-4.38 (m, 3H),
6.81-7.02 (m, 4H), 7.06 (d, J=16.0 Hz, 1H), 7.10-7.24 (m, 3H),
7.26-7.34 (m, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.69 (brs, 1H).
[0370] The property values of
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are
as follows. ESI-MS; m/z 430 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.46 (m, 7H), 3.85 (s, 3H), 4.21-4.38 (m, 3H),
6.81-7.02 (m, 4H), 7.06 (d, J=16.0 Hz, 1H), 7.10-7.24 (m, 3H),
7.26-7.34 (m, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.69 (brs, 1H).
Examples 3 and 4
Synthesis of
(-)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one
and
(+)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vin-
yl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-o-
ne
##STR00053##
[0372] 119 mg of a racemate of the title compound was obtained from
4-cyanophenylacetic acid (1 g) by the same method as in Examples 1
and 2. The racemate (60 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain a (-)-isomer of the title
optically active compound with a retention time of 18.5 minutes
(22.3 mg; 98% ee) and a (+)-isomer of the title optically active
compound with a retention time of 33 minutes (23 mg; 98% ee).
[0373] The property values of
(-)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one
are as follows.
[0374] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.95 (t, J=7.2 Hz, 3H), 1.34-1.46 (m, 2H), 1.66-1.76
(m, 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6 Hz, 2H), 3.85 (s, 3H),
4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs, 1H), 7.06 (d,
J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), 7.50 (d,
J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H).
[0375] The property values of
(+)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one
are as follows.
[0376] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.95 (t, J=7.2 Hz, 3H), 1.34-1.46 (m, 2H), 1.66-1.76
(m, 2H), 2.00-2.48 (m, 7H), 2.94 (t, J=7.6 Hz, 2H), 3.85 (s, 3H),
4.24-4.35 (m, 2H), 4.36-4.43 (m, 1H), 6.91 (brs, 1H), 7.06 (d,
J=16.4 Hz, 1H), 7.10-7.17 (m, 2H), 7.18-7.30 (m, 3H), 7.50 (d,
J=16.4 Hz, 1H), 7.73 (brs, 1H), 7.87-7.97 (m, 2H).
Examples 5 and 6
Synthesis of
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00054##
[0378] 242.4 mg of a racemate of the title compound was obtained
from 4-isopropylphenylacetic acid (1 g) by the same method as in
Examples 1 and 2. The racemate (100 mg) was separated by
CHIRALCEL.TM. OJ-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (-)-isomer of
the title optically active compound with a retention time of 8.5
minutes (40.7 mg; >99% ee) and a (+)-isomer of the title
optically active compound with a retention time of 15 minutes (39.1
mg; 96% ee).
[0379] The property values of
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0380] ESI-MS; m/z 454 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.8 Hz, 6H), 1.80-2.40 (m, 7H), 2.82-2.95
(m, 1H), 3.85 (s, 3H), 4.20-4.35 (m, 3H), 6.90 (brs, 1H), 6.98-7.24
(m, 8H), 7.51 (d, J=16.4 Hz, 1H), 7.67-7.72 (m, 1H).
[0381] The property values of
(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0382] ESI-MS; m/z 454 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.8 Hz, 6H), 1.80-2.40 (m, 7H), 2.82-2.95
(m, 1H), 3.85 (s, 3H), 4.20-4.35 (m, 3H), 6.90 (brs, 1H), 6.98-7.24
(m, 8H), 7.51 (d, J=16.4 Hz, 1H), 7.67-7.72 (m, 1H).
Examples 7 and 8
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00055##
[0384] 235.6 mg of a racemate of the title compound was obtained
from (4-methylsulfanylphenyl)acetic acid (500 mg) by the same
method as in Examples 1 and 2. The racemate (100 mg) was separated
by CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries,
Ltd. (2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain
a (-)-isomer of the title optically active compound with a
retention time of 21 minutes (49.2 mg; >99% ee) and a (+)-isomer
of the title optically active compound with a retention time of
29.5 minutes (49.6 mg; >99% ee).
[0385] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0386] ESI-MS; m/z 458 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.98-2.40 (m, 7H), 2.47 (s, 3H), 3.85 (s, 3H),
4.21-4.34 (m, 3H), 6.87-6.93 (m, 1H), 7.01-7.28 (m, 8H), 7.50 (d,
J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
[0387] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0388] ESI-MS; m/z 458 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.98-2.40 (m, 7H), 2.47 (s, 3H), 3.85 (s, 3H),
4.21-4.34 (m, 3H), 6.87-6.93 (m, 1H), 7.01-7.28 (m, 8H), 7.50 (d,
J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Example 9
Synthesis of
8-(4-methanesulfonylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00056##
[0390] mCPBA (6.83 mg) was added to a solution of
(-)-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4--
methylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
obtained in Example 7 (4.5 mg) in chloroform (1 mL), and the
reaction solution was stirred at room temperature for one hour.
Brine and ethyl acetate were added to the reaction solution and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (carrier: Chromatorex NH; elution solvent:
ethyl acetate->ethyl acetate:methanol=9:1) to obtain 0.44 mg of
the title compound.
[0391] The property values of
8-(4-methanesulfonylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0392] ESI-MS; m/z 490 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.96-2.48 (m, 7H), 3.05 (s, 3H), 3.85 (s, 3H), 4.31
(t, J=5.6 Hz, 2H), 4.42 (t, J=7.2 Hz, 1H), 6.91 (brs, 1H), 7.05 (d,
J=16.4 Hz, 1H), 7.10-7.30 (m, 3H), 7.38 (d, J=8.4 Hz, 2H), 7.49 (d,
J=16.4 Hz, 1H) 7.69 (d, J=0.8 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H).
Examples 10 and 11
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00057##
[0394] 258.6 mg of a racemate of the title compound was obtained
from thiophen-2-ylacetic acid (500 mg) by the same method as in
Examples 1 and 2. The racemate (106 mg) was separated by
CHIRALCEL.TM. OJ-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (-)-isomer of
the title optically active compound with a retention time of 11
minutes (51.5 mg; >99% ee) and a (+)-isomer of the title
optically active compound with a retention time of 19 minutes (52.1
mg; 98% ee).
[0395] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0396] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.03-2.48 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H),
4.63 (t, J=6.0 Hz, 1H), 6.88-6.98 (m, 3H), 7.07 (d, J=16.8 Hz, 1H),
7.12-7.24 (m, 4H), 7.54 (d, J=16.8 Hz, 1H), 7.69 (d, J=1.2 Hz,
1H).
[0397] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-2-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0398] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.03-2.48 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H),
4.63 (t, J=6.0 Hz, 1H), 6.88-6.98 (m, 3H), 7.07 (d, J=16.8 Hz, 1H),
7.12-7.24 (m, 4H), 7.54 (d, J=16.8 Hz, 1H), 7.69 (d, J=1.2 Hz,
1H).
Example 12
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-pheny-
lmethyl-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00058##
[0399] Synthesis of tert-butyl
5-chloro-2-[1-phenylmethyl-(E)-lidene]pentanoate
[0400] Ethanol (30 mL), benzaldehyde (3 mL) and lithium hydroxide
monohydrate (3.71 g) were added to a solution of a solution of
tert-butyl 5-chloro-2-(diethoxyphosphoryl)pentanoate (CAS No.
870843-25-7) (10.7 g) in THF (90 mL), and the reaction solution was
stirred at room temperature for 19.5 hours. Thereafter, ethyl
acetate and saturated sodium bicarbonate water were added to the
reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 6.57 g of the title
compound. The property values of the compound are as follows.
[0401] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.55 (S, 9H),
1.96-2.14 (m, 2H), 2.59-2.68 (m, 2H), 3.56 (t, J=6.8 Hz, 2H),
7.23-7.41 (m, 5H), 7.62 (brs, 1H).
Synthesis of 5-chloro-2-[1-phenylmethyl-(E)-lidene]pentanoic
acid
[0402] Anisole (1.16 mL) was added to tert-butyl
5-chloro-2-[1-phenylmethyl-(E)-lidene]pentanoate (1 g).
Trifluoroacetic acid (5 mL) was further added under ice-cooling,
and the reaction solution was stirred in a nitrogen atmosphere
under ice-cooling for four hours. Thereafter, the reaction solution
was concentrated under reduced pressure and the resulting residue
was dissolved in ethyl acetate at 80.degree. C. The solution was
left to stand at room temperature and the precipitated crystals
were collected by filtration. The crystals collected by filtration
was washed with ethyl acetate:heptane=1:1 to obtain 188.6 mg of the
title compound. The property values of the compound are as
follows.
[0403] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.02-2.22 (m, 2H),
2.67-2.77 (m, 2H), 3.60 (t, J=6.4 Hz, 2H), 7.32-7.47 (m, 5H), 7.86
(brs, 1H).
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-pheny-
lmethyl-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0404] IPEA (4 mL), HOBt (1.81 g) and EDC (2.56 g) were added to a
solution of 5-chloro-2-[1-phenylmethyl-(E)-lidene]pentanoic acid
(1.5 g) and tert-butyl carbazate (1.06 g) in DMF (20 mL), and the
reaction solution was stirred at room temperature for 2.5 hours.
Ethyl acetate and water were added to the reaction solution and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain an (E)/(Z) mixture of tert-butyl
N'-{5-chloro-2-[1-phenylmethylidene]pentanoyl}hydrazinecarboxylate
(1.97 g). A solution of 4 N hydrochloric acid in ethyl acetate
(12.1 mL) was added to the resulting (E)/(Z) mixture of tert-butyl
N'-{5-chloro-2-[1-phenylmethylidene]pentanoyl}hydrazinecarboxylate
(0.726 g), and the reaction solution was stirred at room
temperature for seven hours. The reaction solution was concentrated
under reduced pressure. A solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (0.576 g) and triethylamine (1.24 mL) in ethanol
(10 mL) was added to a solution of the resulting residue and
triethylamine (1 mL) in ethanol (10 mL). The reaction solution was
stirred at 80.degree. C. in a nitrogen atmosphere for 16 hours. The
reaction solution was cooled to room temperature and then the
solvent was evaporated under reduced pressure. Ethyl acetate and
saturated sodium bicarbonate water were added to the resulting
residue, and the organic layer was separated. The resulting organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane:ethyl acetate=1:1->ethyl acetate->ethyl
acetate:methanol=9:1) and further purified by silica gel column
chromatography (elution solvent: ethyl acetate->ethyl
acetate:methanol=9:1). Then, the purified product was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
compound with a retention time of 33 minutes (12.3 mg).
[0405] The property values of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-[1-pheny-
lmethyl-(E)-lidene]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0406] ESI-MS; m/z 424 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.11-2.21 (m, 2H), 2.30 (s, 3H), 2.93-3.01 (m, 2H),
3.89 (s, 3H), 4.29 (t, J=6.0 Hz, 2H), 6.92 (brs, 1H), 7.10 (d,
J=16.0 Hz, 1H), 7.16-7.46 (m, 8H), 7.62 (d, J=16.0 Hz, 1H), 7.70
(d, J=1.2 Hz, 1H), 7.79 (brs, 1H).
Examples 13 and 14
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00059##
[0408] 244.7 mg of a racemate of the title compound was obtained
from thiophen-3-ylacetic acid (500 mg) by the same method as in
Examples 1 and 2. The racemate (103 mg) was separated by
CHIRALCEL.TM. OJ-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (-)-isomer of
the title optically active compound with a retention time of 11
minutes (47.1 mg; >99% ee) and a (+)-isomer of the title
optically active compound with a retention time of 19.5 minutes
(45.9 mg).
[0409] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0410] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.42 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H),
4.45 (t, J=5.2 Hz, 1H), 6.91 (brs, 1H), 6.98-7.24 (m, 6H), 7.31
(dd, J=3.2, 5.2 Hz, 1H), 7.54 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2
Hz, 1H).
[0411] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-thio-
phen-3-yl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0412] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.42 (m, 7H), 3.86 (s, 3H), 4.16-4.32 (m, 2H),
4.45 (t, J=5.2 Hz, 1H), 6.91 (brs, 1H), 6.98-7.24 (m, 6H), 7.31
(dd, J=3.2, 5.2 Hz, 1H), 7.54 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2
Hz, 1H).
Examples 15 and 16
Synthesis of
(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00060##
[0413] Synthesis of tert-butyl
(3-benzyl-2-oxopiperidin-1-yl)carbamate
[0414] 10% palladium-carbon powder (50.36% aqueous, 1.92 g) was
added to a solution of the (E)/(Z) mixture of tert-butyl
N'-[5-chloro-2-(1-phenylmethylidene)pentanoyl]hydrazinecarboxylate
obtained in the process of Example 12 in ethanol (20 mL), and the
reaction solution was stirred in a hydrogen atmosphere at room
temperature for 10 days. Thereafter, the reaction solution was
filtered through celite and the solvent was evaporated under
reduced pressure. DBU (0.598 mL) was added to a solution of the
resulting residue in THF (50 mL) and the mixture was heated under
reflux for 44 hours. Thereafter, the solvent was evaporated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 727 mg of the title compound. The property values
of the compound are as follows.
[0415] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.36-1.60 (m, 10H),
1.70-1.98 (m, 3H), 2.60-2.78 (m, 2H), 3.36-3.48 (m, 1H), 3.50-3.66
(m, 2H), 6.69 (brs, 1H), 7.11-7.32 (m, 5H).
Synthesis of
(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0416] A solution of 4 N hydrochloric acid in ethyl acetate (13 mL)
was added to tert-butyl (3-benzyl-2-oxopiperidin-1-yl)carbamate
(727 mg), and the reaction solution was stirred at room temperature
for three hours. The reaction solution was concentrated under
reduced pressure. IPEA (2.45 mL), HOBT (646 mg) and EDC (916 mg)
were added to a solution of the resulting residue and
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(CAS No. 970839-41-1, 617 mg) in DMF (15 mL), and the reaction
solution was stirred at room temperature for 25 hours. Ethyl
acetate and water were added to the reaction solution and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. A solution of the resulting residue in phosphorus
oxychloride (20 mL) was heated under reflux for 1.5 hours. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. Acetic acid (12 mL) and
ammonium acetate (7.34 g) were added to the resulting residue, and
the reaction solution was stirred at 150.degree. C. for 2.5 hours.
The reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. Ethyl acetate and saturated
sodium bicarbonate water were added to the resulting residue, and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH; elution solvent:
heptane:ethyl acetate=1:1->ethyl acetate->ethyl
acetate:methanol=9:1) and further purified by silica gel column
chromatography (elution solvent: ethyl acetate->ethyl
acetate:methanol=9:1) to obtain 10.3 mg of a racemate of the title
compound. The resulting racemate (10.3 mg) was separated by
CHIRALCEL.TM. OD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain a
(+)-isomer of the title optically active compound with a retention
time of 8 minutes (2.83 mg, >99% ee) and a (-)-isomer of the
title optically active compound with a retention time of 13.5
minutes (3.27 mg, >99% ee).
[0417] The property values of
(+)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as follows.
ESI-MS; m/z 426 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3) .delta.
(ppm): 1.50-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.06-2.18 (m, 1H),
2.30 (s, 3H), 2.76 (dd, J=10.4, 13.2 Hz, 1H), 3.16-3.28 (m, 1H),
3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s, 3H), 4.03-4.13 (m, 1H),
4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d, J=16.4 Hz, 1H),
7.16-7.35 (m, 8H), 7.58 (d, J=16.4 Hz, 1H), 7.71 (d, J=1.2 Hz,
1H).
[0418] The property values of
(-)-8-benzyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0419] ESI-MS; m/z 426 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.50-1.76 (m, 1H), 1.86-2.02 (m, 2H), 2.06-2.18 (m,
1H), 2.30 (s, 3H), 2.76 (dd, J=10.4, 13.2 Hz, 1H), 3.16-3.28 (m,
1H), 3.65 (dd, J=3.6, 13.2 Hz, 1H), 3.89 (s, 3H), 4.03-4.13 (m,
1H), 4.14-4.24 (m, 1H), 6.92 (brs, 1H), 7.09 (d, J=16.4 Hz, 1H),
7.16-7.35 (m, 8H), 7.58 (d, J=16.4 Hz, 1H), 7.71 (d, J=1.2 Hz,
1H).
Examples 17 and 18
Synthesis of
(-)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00061##
[0421] 230 mg of a racemate of the title compound was obtained from
(2-chloropyridyl)-5-acetic acid (500 mg) by the same method as in
Examples 1 and 2. The racemate (104 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain a
(-)-isomer of the title optically active compound with a retention
time of 30 minutes (39 mg; >99% ee) and a (+)-isomer of the
title optically active compound with a retention time of 54 minutes
(38.7 mg; >99% ee).
[0422] The property values of
(-)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0423] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.94-2.34 (m, 6H), 2.36-2.46 (m, 1H), 3.86 (s, 3H),
4.23-4.37 (m, 3H), 6.91 (brs, 1H), 7.03 (d, J=16.4 Hz, 1H),
7.10-7.24 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.42-7.54 (m, 2H), 7.70
(d, J=1.2 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H).
[0424] The property values of
(+)-8-(6-chloropyridin-3-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0425] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.94-2.34 (m, 6H), 2.36-2.46 (m, 1H), 3.86 (s, 3H),
4.23-4.37 (m, 3H), 6.91 (brs, 1H), 7.03 (d, J=16.4 Hz, 1H),
7.10-7.24 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.42-7.54 (m, 2H), 7.70
(d, J=1.2 Hz, 1H), 8.30 (d, J=2.8 Hz, 1H).
Example 19
Synthesis of
1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,-
7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-ol
##STR00062##
[0427] Sodium tetrahydroborate (0.166 mg) was added to a solution
of
(-)-1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-one
obtained in Example 3 (2 mg) in methanol (0.5 mL), and the reaction
solution was stirred in a nitrogen atmosphere at room temperature
for one hour. Brine and ethyl acetate were added to the reaction
solution and the organic layer was separated. The resulting organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: ethyl acetate->ethyl acetate:methanol=9:1)
to obtain 1.19 mg of the title compound.
[0428] The property values of
1-{4-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,-
7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}pentan-1-ol
are as follows.
[0429] ESI-MS; m/z 498 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.89 (t, J=6.8 Hz, 3H), 1.10-2.40 (m, 13H), 3.85 (s,
3H), 4.16-4.38 (m, 3H), 4.60-4.70 (m, 1H), 6.90 (brs, 1H),
7.01-7.35 (m, 8H), 7.51 (d, J=16.0 Hz, 1H), 7.68 (d, J=1.2 Hz,
1H).
Examples 20 and 21
Synthesis of
(-)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(+)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00063##
[0430] Synthesis of 1-amino-3-(2-bromophenyl)piperidin-2-one
[0431] A solution of ethyl 4-bromophenylacetate (2.0 g) in DMF (5
mL) was added to a suspension of sodium hydride (containing 40% of
mineral oil, 362 mg) in DMF (20 mL) under ice-cooling. The reaction
solution was stirred for 10 minutes, further stirred at room
temperature for 30 minutes and then ice-cooled again. A solution of
1-chloro-3-iodopropane (1.85 g) in DMF (5 mL) was added to the
reaction mixture, and the reaction solution was stirred at room
temperature overnight. Water and ethyl acetate were added to the
reaction mixture and the organic layer was separated. The resulting
organic layer was washed with saturated aqueous sodium chloride,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. Hydrazine monohydrate (8 mL) was added to a
solution of the resulting residue in ethanol (20 mL), and the
reaction solution was stirred at room temperature for one day. The
reaction mixture was concentrated under reduced pressure. Saturated
sodium bicarbonate water and ethyl acetate and were added to the
residue, and the organic layer was separated. The resulting organic
layer was washed with saturated aqueous sodium chloride, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH; elution solvent:
heptane-ethyl acetate system) to obtain 898 mg of the title
compound. The property values of the compound are as follows.
.sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-2.00 (m, 3H),
2.08-2.15 (m, 1H), 2.14-3.67 (m, 3H), 4.62 (s, 2H), 7.06 (d, J=8.4
Hz, 2H), 7.42 (d, J=8.4 Hz, 2H).
Synthesis of
(E)-N-[3-(4-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)phenyl]acrylamide
[0432] BOPCl (1.18 g) was added to a suspension of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(800 mg), 1-amino-3-(4-bromophenyl)piperidin-2-one (898 mg) and TEA
(0.9 mL) in DMF (20 mL), and the reaction solution was stirred at
room temperature overnight. Water and ethyl acetate were added to
the reaction mixture and the organic layer was separated. The
resulting organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: ethyl acetate-methanol system) to obtain 1.484
g of the title compound. The property values of the compound are as
follows.
[0433] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.08 (m, 3H),
2.20-2.26 (m, 1H), 2.30 (s, 3H), 3.60-3.66 (m, 1H), 3.74-3.83 (m,
2H), 3.78 (s, 3H), 6.44 (d, J=15.6 Hz, 1H), 6.84-6.91 (m, 3H), 7.11
(d, J=8 Hz, 1H), 7.21 (d, J=8.4 Hz, 2H), 7.40-7.46 (m, 3H), 7.72
(d, J=1.6 Hz, 1H), 10.22 (s, 1H).
Synthesis of
(-)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(+)-8-(4-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0434] A solution of
(E)-N-[3-(4-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)phenyl]acrylamide (1.434 g) in phosphorus
oxychloride (6 mL) was heated under reflux for one hour. The
reaction mixture was left to cool to room temperature and then
concentrated under reduced pressure. Acetic acid (7 mL) and
ammonium acetate (4.8 g) were added to the residue, and the
reaction solution was stirred at 150.degree. C. for one hour. The
reaction mixture was left to cool to room temperature and then
concentrated under reduced pressure. Saturated sodium bicarbonate
water and ethyl acetate and were added to the residue, and the
organic layer was separated. The resulting organic layer was washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate
system) to obtain 770 mg of a racemate of the title compound. The
resulting racemate (73 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 17 minutes and
negative optical rotation (21 mg) and the title optically active
compound with a retention time of 20 minutes and positive optical
rotation (23 mg).
[0435] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[0436] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.26 (m, 3H),
2.30 (s, 3H), 2.32-2.39 (m, 1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H),
6.92 (s, 1H), 7.03-7.09 (m, 3H), 7.14-7.16 (m, 2H), 7.22 (d, J=7.6
Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.51 (d, J=16 Hz, 1H), 7.72 (s,
1H).
[0437] The property values of the title optically active compound
with a retention time of 20 minutes are as follows.
[0438] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.26 (m, 3H),
2.30 (s, 3H), 2.32-2.39 (m, 1H), 3.86 (s, 3H), 4.27-4.32 (m, 3H),
6.92 (s, 1H), 7.03-7.09 (m, 3H), 7.14-7.16 (m, 2H), 7.22 (d, J=7.6
Hz, 1H), 7.47 (d, J=8.4 Hz, 2H), 7.51 (d, J=16 Hz, 1H), 7.72 (s,
1H).
Examples 22 and 23
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-m-
ethoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-m-
ethoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00064##
[0439] Synthesis of
8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0440] 663 mg of the title compound was obtained from
(E)-N-[3-(2-bromophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)phenyl]acrylamide (1.130 g) using ethyl
2-bromophenylacetate as a starting material by the same method as
in Examples 20 and 21. The property values of the compound are as
follows.
[0441] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.20 (m, 3H),
2.30 (s, 3H), 2.35-2.42 (m, 1H), 3.86 (s, 3H), 4.25-4.35 (m, 2H),
4.76 (t, J=6.4 Hz, 1H), 6.86 (brd, J=7.6 Hz, 1H), 6.92 (s, 1H),
7.08 (d, J=16.4, 0.8 Hz, 1H), 7.13-7.17 (m, 3H), 7.21 (d, J=7.6 Hz,
1H), 7.26-7.27 (m, 2H), 7.51 (dd, J=7.6, 0.8 Hz, 1H), 7.69 (d,
J=0.8 Hz, 1H).
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-m-
ethoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-m-
ethoxymethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0442] Potassium methoxymethyl trifluoroborate (CAS No.
910251-11-5, 372 mg), palladium acetate (7 mg), BINAP (19 mg) and
cesium carbonate (1.2 g) were added to a mixed solution of
8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (150 mg)
in dioxane (7 mL) and water (0.7 mL). The reaction solution was
stirred in a nitrogen atmosphere at 100.degree. C. overnight. The
reaction mixture was left to cool to room temperature. Then, water
and ethyl acetate were added to the reaction mixture and the
organic layer was separated. The resulting organic layer was washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate
system) and further separated by CHIRALPAK.TM. AD-H manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 16 minutes and negative optical
rotation (6.2 mg) and the title optically active compound with a
retention time of 18 minutes and positive optical rotation (8
mg).
[0443] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0444] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.15 (m, 2H),
2.20-2.29 (m, 1H), 2.30 (s, 3H), 2.36-2.43 (m, 1H), 3.41 (s, 3H),
3.85 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz,
1H), 4.61 (t, J=6.4 Hz, 1H), 4.71 (dd, J=11.6 Hz, 1.6 Hz, 1H),
6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06 (dd, J=16 Hz, 1.6
Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, 1.6 Hz, 1H),
7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd, J=16 Hz, 1.6 Hz,
1H), 7.69 (t, J=1.6 Hz, 1H).
[0445] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[0446] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.15 (m, 2H),
2.20-2.29 (m, 1H), 2.30 (s, 3H), 2.36-2.43 (m, 1H), 3.41 (s, 3H),
3.85 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.46 (dd, J=11.6 Hz, 1.6 Hz,
1H), 4.61 (t, J=6.4 Hz, 1H), 4.71 (dd, J=11.6 Hz, 1.6 Hz, 1H),
6.85-6.88 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06 (dd, J=16 Hz, 1.6
Hz, 1H), 7.11-7.15 (m, 2H), 7.21 (dd, J=8 Hz, 1.6 Hz, 1H),
7.24-7.29 (m, 1H), 7.37-7.40 (m, 1H), 7.48 (dd, J=16 Hz, 1.6 Hz,
1H), 7.69 (t, J=1.6 Hz, 1H).
Examples 24 and 25
Synthesis of (-) and
(+)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine
##STR00065##
[0447] Synthesis of
8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0448] 559 mg of the title compound was obtained from
(E)-N-[3-(2-bromo-4-fluorophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4--
methyl-1H-imidazol-1-yl)phenyl]acrylamide (953 mg) using methyl
2-bromo-4-fluorophenylacetate as a starting material by the same
method as in Examples 20 and 21. The property values of the
compound are as follows.
[0449] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.20 (m, 3H),
2.30 (s, 3H), 2.35-2.42 (m, 1H), 3.86 (s, 3H), 4.28-4.31 (m, 2H),
4.71 (t, J=6.4 Hz, 1H), 6.87 (dd, J=8.4 Hz, 5.6 Hz, 1H), 6.92 (t,
J=1.2 Hz, 1H), 6.96-7.01 (m, 1H), 7.07 (d, J=16.4 Hz, 1H),
7.14-7.16 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.36 (dd, J=8.0, 2.8 Hz,
1H), 7.51 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
Synthesis of (-) and
(+)-8-(4-fluoro-2-methoxymethylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine
[0450] The title optically active compound with a retention time of
15 minutes in CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase:
hexane:ethanol=1:1, flow rate: 20 mL/min) and positive optical
rotation (1.1 mg) and the title optically active compound with a
retention time of 25 minutes in the CHIRALPAK.TM. IB and negative
optical rotation (0.4 mg) were obtained from
8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(40 mg) by the same method as in Examples 22 and 23.
[0451] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[0452] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.93-2.02 (m, 1H),
2.04-2.14 (m, 1H), 2.18-2.28 (m, 1H), 2.29 (s, 3H), 2.32-2.40 (m,
1H), 3.42 (s, 3H), 3.84 (s, 3H), 4.30 (t, J=6 Hz, 2H), 4.44 (d,
J=12 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 6.84
(dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H), 6.92-6.97 (m, 1H), 7.04
(d, J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.47
(d, J=16 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
[0453] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[0454] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.93-2.02 (m, 1H),
2.04-2.14 (m, 1H), 2.18-2.28 (m, 1H), 2.29 (s, 3H), 2.32-2.40 (m,
1H), 3.42 (s, 3H), 3.84 (s, 3H), 4.30 (t, J=6 Hz, 2H), 4.44 (d,
J=12 Hz, 1H), 4.50 (t, J=6 Hz, 1H), 4.65 (d, J=12 Hz, 1H), 6.84
(dd, J=8.4 Hz, 5.2 Hz, 1H), 6.90 (s, 1H), 6.92-6.97 (m, 1H), 7.04
(d, J=16 Hz, 1H), 7.11-7.14 (m, 3H), 7.20 (d, J=8.0 Hz, 1H), 7.47
(d, J=16 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Examples 26 and 27
Synthesis of
(-)-2-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile and
(+)-2-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile
##STR00066##
[0456] A suspension of
8-(2-bromophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (45 mg),
zinc cyanide (22 mg) and tetrakistriphenylphosphine palladium (11
mg) in DMF (2 mL) was subjected to microwave reaction in a nitrogen
atmosphere at 160.degree. C. for two hours. The reaction mixture
was left to cool to room temperature. Then, aqueous ammonia and
ethyl acetate were added to the reaction mixture and the organic
layer was separated. The resulting organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: heptane-ethyl acetate system) to
obtain 34 mg of a racemate of the title compound. The resulting
racemate (28 mg) was separated by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 17 minutes and negative optical
rotation (11.9 mg) and the title optically active compound with a
retention time of 19 minutes and positive optical rotation (13
mg).
[0457] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[0458] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.05-2.27 (m, 3H),
2.31 (s, 3H), 2.47-2.53 (m, 1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H),
4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H),
7.13-7.17 (m, 3H), 7.22 (d, J=8 Hz, 1H), 7.26-7.31 (m, 2H), 7.42
(dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.73 (s, 1H).
[0459] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[0460] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.05-2.27 (m, 3H),
2.31 (s, 3H), 2.47-2.53 (m, 1H), 3.86 (s, 3H), 4.30-4.37 (m, 2H),
4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H), 7.06 (d, J=16 Hz, 1H),
7.13-7.17 (m, 3H), 7.22 (d, J=8 Hz, 1H), 7.26-7.31 (m, 2H), 7.42
(dd, J=8 Hz, 2.8 Hz, 1H), 7.48 (d, J=16 Hz, 1H), 7.73 (s, 1H).
Examples 28 and 29
Synthesis of
5-fluoro-2-{(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]v-
inyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitrile
and
5-fluoro-2-{(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phen-
yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}benzonitri-
le
##STR00067##
[0462] The title optically active compound with a retention time of
17 minutes in CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase:
hexane:ethanol=9:1, flow rate: 20 mL/min) and negative optical
rotation (9.5 mg) and the title optically active compound with a
retention time of 23 minutes in the CHIRALPAK.TM. IB and positive
optical rotation (9.4 mg) were obtained from
8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(40 mg) by the same method as in Examples 26 and 27.
[0463] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[0464] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.09 (m, 1H),
2.16-2.27 (m, 2H), 2.30 (s, 3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H),
4.27-4.39 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H),
7.06 (d, J=16 Hz, 1H), 7.13-7.16 (m, 3H), 7.22 (d, J=7.6 Hz, 1H),
7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48
(d, J=16 Hz, 1H), 7.73 (s, 1H).
[0465] The property values of the title optically active compound
with a retention time of 23 minutes are as follows.
[0466] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.09 (m, 1H),
2.16-2.27 (m, 2H), 2.30 (s, 3H), 2.46-2.53 (m, 1H), 3.86 (s, 3H),
4.27-4.39 (m, 2H), 4.66 (dd, J=8.8 Hz, 6 Hz, 1H), 6.92 (s, 1H),
7.06 (d, J=16 Hz, 1H), 7.13-7.16 (m, 3H), 7.22 (d, J=7.6 Hz, 1H),
7.30 (dd, J=8 Hz, 2.8 Hz, 1H), 7.42 (dd, J=8 Hz, 2.8 Hz, 1H), 7.48
(d, J=16 Hz, 1H), 7.73 (s, 1H).
Examples 30 and 31
Synthesis of
(-)-8-(4-fluoro-2-pyridin-3-yl-phenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-
-imidazol-1-yl)-phenyl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine and
(+)-8-(4-fluoro-2-pyridin-3-yl-phenyl)-2-{(E)-2-[3-methoxy-4-(4-
-methyl-1H-imidazol-1-yl)-phenyl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00068##
[0468] Pyridine-3-borane acid (18.1 mg),
tetrakis(triphenylphosphine)palladium (5.7 mg) and a 2 M sodium
carbonate solution (197 .mu.l) in toluene (1.2 ml)/ethanol (0.3 ml)
were added to
8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(50 mg) as a starting material, and the reaction solution was
stirred at 100.degree. C. for two hours. Thereafter,
tetrakis(triphenylphosphine)palladium (17.0 mg) was added and the
reaction solution was stirred for 16 hours. The reaction solution
was diluted with ethyl acetate and the organic layer was washed
with brine. The resulting organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 15.4 mg of a
racemate of the title compound. The resulting racemate (15.4 mg)
was separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.cm, mobile phase: hexane:ethanol=3:7,
flow rate: 20 mL/min) to obtain the title optically active compound
with a retention time of 31 minutes and negative optical rotation
(5.0 mg) and the title optically active compound with a retention
time of 41 minutes and positive optical rotation (4.7 mg).
[0469] The property values of the title optically active compound
with a retention time of 31 minutes are as follows.
[0470] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-2.20 (m, 4H),
2.30 (s, 3H), 3.86 (s, 3H), 4.05-4.30 (m, 3H), 6.90 (s, 1H),
7.00-7.05 (m, 1H), 7.05 (d, J=16.0 Hz, 1H), 7.10-7.20 (m, 2H),
7.25-7.45 (m, 3H), 7.50 (d, J=16.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H),
7.71 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.70 (d, J=4.8 Hz, 1H), 8.80
(brd-s, 1H).
[0471] The property values of the title optically active compound
with a retention time of 41 minutes are as follows.
[0472] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-2.20 (m, 4H),
2.30 (s, 3H), 3.86 (s, 3H), 4.05-4.30 (m, 3H), 6.90 (s, 1H),
7.00-7.05 (m, 1H), 7.05 (d, J=16.0 Hz, 1H), 7.10-7.20 (m, 2H),
7.25-7.45 (m, 3H), 7.50 (d, J=16.0 Hz, 1H), 7.70 (d, J=8.4 Hz, 1H),
7.71 (s, 1H), 7.80 (d, J=8.4 Hz, 1H), 8.70 (d, J=4.8 Hz, 1H), 8.80
(brd-s, 1H).
Examples 32 and 33
Synthesis of
2-((-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine and
2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine
##STR00069##
[0473] Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-nitro-
phenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0474] The title compound (920 mg) was obtained from
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[3-(2-nitrophenyl-
)-2-oxopiperidin-1-yl]acrylamide (1.279 g) using methyl
2-nitrophenylacetate as a starting material by the same method as
in Examples 20 and 21. The property values of the compound are as
follows.
[0475] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.13-2.32 (m, 3H),
2.29 (s, 3H), 2.55-2.61 (m, 1H), 3.85 (s, 3H), 4.31-4.35 (m, 2H),
4.92-4.95 (m, 1H), 6.91-6.92 (m, 1H), 7.04 (d, J=16.4 Hz, 1H),
7.12-7.14 (m, 3H), 7.21 (d, J=7.6 Hz, 1H), 7.43-7.49 (m, 2H),
7.56-7.60 (m, 1H), 7.69 (d, J=1.6 Hz, 1H), 8.03 (dd, J=8.0, 1.6 Hz,
1H).
Synthesis of
2-((-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine and
2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine
[0476] A mixed solution of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-nitro-
phenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (178 mg)
and sodium dithionite (340 mg) in ethanol (10 mL) and water (2 mL)
was stirred at room temperature for one hour. Water and ethyl
acetate were added to the reaction mixture and the organic layer
was separated. The resulting organic layer was washed with
saturated aqueous sodium chloride, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: heptane-ethyl acetate system) to
obtain 70 mg of a racemate of the title compound. The resulting
racemate (30 mg) was separated by CHIRALPAK.TM. ADH manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 17 minutes and negative optical
rotation (12.7 mg) and the title optically active compound with a
retention time of 28 minutes and positive optical rotation (13.2
mg).
[0477] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[0478] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.10-2.18 (m, 1H),
2.24-2.34 (m, 3H), 2.30 (s, 3H), 3.87 (s, 3H), 4.03 (brs, 2H),
4.26-2.30 (m, 2H), 4.36 (t, J=5.6 Hz, 1H), 6.77-6.81 (m, 2H), 6.88
(dd, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6 Hz, 1H), 7.05 (d, J=16
Hz, 1H), 7.10-7.15 (m, 3H), 7.22 (d, J=7.6 Hz, 1H), 7.50 (d, J=16
Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
[0479] The property values of the title optically active compound
with a retention time of 28 minutes are as follows.
[0480] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.10-2.18 (m, 1H),
2.24-2.34 (m, 3H), 2.30 (s, 3H), 3.87 (s, 3H), 4.03 (brs, 2H),
4.26-2.30 (m, 2H), 4.36 (t, J=5.6 Hz, 1H), 6.77-6.81 (m, 2H), 6.88
(dd, J=7.6 Hz, 1.2 Hz, 1H), 6.92 (t, J=1.6 Hz, 1H), 7.05 (d, J=16
Hz, 1H), 7.10-7.15 (m, 3H), 7.22 (d, J=7.6 Hz, 1H), 7.50 (d, J=16
Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
Examples 34 and 35
Synthesis of
N-[2-((-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ylphenyl]acetamide
and
N-[2-((+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ylphenyl]acetamide
##STR00070##
[0482] Acetic anhydride (0.045 mL) was added to a solution of
2-((-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6-
,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenylamine (41
mg) in pyridine (2 mL), and the reaction solution was stirred at
50.degree. C. overnight. The reaction mixture was left to cool to
room temperature and then concentrated under reduced pressure. The
resulting residue was purified by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 11 minutes and negative optical
rotation (14.9 mg) and the title optically active compound with a
retention time of 14 minutes and positive optical rotation (15.1
mg).
[0483] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[0484] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.28 (m, 1H),
2.23 (s, 3H), 2.30 (s, 3H), 2.32-2.48 (m, 3H), 3.89 (s, 3H),
4.24-4.32 (m, 2H), 4.37 (t, J=6 Hz, 1H), 6.93 (t, J=1.2 Hz, 1H),
7.01 (d, J=16 Hz, 1H), 7.14-7.16 (m, 2H), 7.19-7.25 (m, 2H),
7.29-7.39 (m, 2H), 7.45 (d, J=16 Hz, 1H), 7.72-7.75 (m, 2H), 9.87
(s, 1H).
[0485] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[0486] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.28 (m, 1H),
2.23 (s, 3H), 2.30 (s, 3H), 2.32-2.48 (m, 3H), 3.89 (s, 3H),
4.24-4.32 (m, 2H), 4.37 (t, J=6 Hz, 1H), 6.93 (t, J=1.2 Hz, 1H),
7.01 (d, J=16 Hz, 1H), 7.14-7.16 (m, 2H), 7.19-7.25 (m, 2H),
7.29-7.39 (m, 2H), 7.45 (d, J=16 Hz, 1H), 7.72-7.75 (m, 2H), 9.87
(s, 1H).
Examples 36 and 37
Synthesis of
(-)-8-(3,4-dimethoxyphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(3,4-dimethoxyphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00071##
[0488] 559 mg of the title compound was obtained from
(E)-N-[3-(3,4-dimethoxyphenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-met-
hyl-1H-imidazol-1-yl)phenyl]acrylamide (401 mg) using ethyl
3,4-dimethoxyphenylacetate as a starting material by the same
method as in Examples 20 and 21. The resulting racemate (77 mg) was
separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow
rate: 10 mL/min) to obtain the title optically active compound with
a retention time of 24 minutes and negative optical rotation (17.8
mg) and the title optically active compound with a retention time
of 31 minutes and positive optical rotation (19.0 mg).
[0489] The property values of the title optically active compound
with a retention time of 24 minutes are as follows.
[0490] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.14 (m, 2H),
2.18-2.27 (m, 1H), 2.30 (s, 3H), 2.31-2.38 (m, 1H), 3.86 (s, 6H),
3.87 (s, 3H), 4.23-4.36 (m, 3H), 6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H),
6.71 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (q, J=1.2 Hz,
1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H), 7.13-7.16 (m, 2H), 7.22 (d,
J=8.4 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.70 (s, 1H).
[0491] The property values of the title optically active compound
with a retention time of 31 minutes are as follows.
[0492] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.14 (m, 2H),
2.18-2.27 (m, 1H), 2.30 (s, 3H), 2.31-2.38 (m, 1H), 3.86 (s, 6H),
3.87 (s, 3H), 4.23-4.36 (m, 3H), 6.64 (dd, J=8.4 Hz, 1.6 Hz, 1H),
6.71 (d, J=1.6 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.91 (q, J=1.2 Hz,
1H), 7.08 (dd, J=16.4 Hz, 0.8 Hz, 1H), 7.13-7.16 (m, 2H), 7.22 (d,
J=8.4 Hz, 1H), 7.53 (d, J=16.4 Hz, 1H), 7.70 (s, 1H).
Examples 38 and 39
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-O-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00072##
[0494] 208.5 mg of a racemate of the title compound was obtained
from methyl 2-pyridylacetate (6.76 g) by the same method as in
Examples 20 and 21. The racemate (100 mg) was separated by
CHIRALCEL.TM. OD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (-)-isomer of
the title optically active compound with a retention time of 17
minutes (43.6 mg; 79% ee) and a (+)-isomer of the title optically
active compound with a retention time of 24 minutes (47.7 mg; 87%
ee).
[0495] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0496] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.17 (m, 1H), 2.19-2.46 (m, 6H), 3.85 (s, 3H),
4.20-4.37 (m, 2H), 4.48 (t, J=6.4 Hz, 1H), 6.90 (t, J=1.2 Hz, 1H),
7.06 (d, J=16.4 Hz, 1H), 7.10-7.24 (m, 5H), 7.49 (d, J=16.4 Hz,
1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz, 1H).
[0497] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine are as
follows.
[0498] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.17 (m, 1H), 2.19-2.46 (m, 6H), 3.85 (s, 3H),
4.20-4.37 (m, 2H), 4.48 (t, J=6.4 Hz, 1H), 6.90 (t, J=1.2 Hz, 1H),
7.06 (d, J=16.4 Hz, 1H), 7.10-7.24 (m, 5H), 7.49 (d, J=16.4 Hz,
1H), 7.62-7.72 (m, 2H), 8.57 (dd, J=2.4, 5.6 Hz, 1H).
Examples 40 and 41
Synthesis of
(-)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00073##
[0499] Synthesis of ethyl (5-chlorothiophen-2-yl)acetate
[0500] Methyl methylsulfinylmethyl sulfide (5.53 g) and potassium
hydroxide (2 g) were added to a solution of
5-chloro-2-thiophenecarboxyaldehyde (6.21 g) in methanol (70 mL),
and the reaction solution was stirred with heating under reflux for
21 hours. After leaving to cool to room temperature, the solvent
was evaporated under reduced pressure. Methylene chloride was added
to the residue, the insoluble matter was removed by filtration, and
the solvent was evaporated under reduced pressure. Then, the
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 5.61 g of a
(E)/(Z) mixture of
2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene. A
saturated solution of hydrogen chloride in ethanol (10 mL) was
added to a solution of the resulting (E)/(Z) mixture of
2-chloro-5-(2-methanesulfinyl-2-methylsulfanylvinyl)thiophene (5.61
g) in ethanol (80 mL), and the reaction solution was stirred with
heating under reflux for 23 hours. After leaving to cool to room
temperature, the solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 3.31 g of the
title compound. The property values of the compound are as
follows.
[0501] ESI-MS; m/z 205 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.28 (t, J=7.2 Hz, 3H), 3.72 (d, J=0.8 Hz, 2H), 4.18
(q, J=7.2 Hz, 2H), 6.67-6.71 (m, 1H), 6.75 (d, J=3.6 Hz, 1H).
Synthesis of
(-)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0502] 5.2 mg of a racemate of the title compound was obtained from
ethyl (5-chlorothiophen-2-yl)acetate (3.31 g) by the same method as
in Examples 20 and 21. The racemate (5.2 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain a
(-)-isomer of the title optically active compound with a retention
time of 11.5 minutes (1.08 mg; >99% ee) and a (+)-isomer of the
title optically active compound with a retention time of 24 minutes
(0.74 mg; >99% ee).
[0503] The property values of
(-)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0504] ESI-MS; m/z 452 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.03-2.22 (m, 2H), 2.23-2.36 (m, 4H), 2.37-2.47 (m,
1H), 3.86 (s, 3H), 4.29 (t, J=5.6 Hz, 2H), 4.74 (t, J=7.6 Hz, 1H),
6.92 (brs, 1H), 6.94 (d, J=5.6 Hz, 1H), 7.07 (d, J=16.4 Hz, 1H),
7.12-7.24 (m, 4H), 7.53 (d, J=16.4 Hz, 1H), 7.71 (brs, 1H).
[0505] The property values of
(+)-8-(5-chlorothiophen-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
are as follows.
[0506] ESI-MS; m/z 452 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.03-2.22 (m, 2H), 2.23-2.36 (m, 4H), 2.37-2.47 (m,
1H), 3.86 (s, 3H), 4.29 (t, J=5.6 Hz, 2H), 4.74 (t, J=7.6 Hz, 1H),
6.92 (brs, 1H), 6.94 (d, J=5.6 Hz, 1H), 7.07 (d, J=16.4 Hz, 1H),
7.12-7.24 (m, 4H), 7.53 (d, J=16.4 Hz, 1H), 7.71 (brs, 1H).
[0507] The following compounds were obtained by the same method as
in Examples 20 and 21 (Table 1).
TABLE-US-00001 TABLE 1 ##STR00074## Ex- DATA: ample E.sub.1 E2 MS
m/z Note 42 ##STR00075## H M.sup.+ + H: 463 (ESI) Optically active
compound (separation conditions OD-H: retention time 36 min,
optical rotation (-)) 43 ##STR00076## H M.sup.+ + H: 463 (ESI)
Optically active compound (separation conditions OD-H: retention
time 46 min, optical rotation (+)) 44 ##STR00077## H M.sup.+ + H:
480 (ESI) Optically active compound (separation conditions AD-H:
retention time 33 min, optical rotation (+)) 45 ##STR00078## H
M.sup.+ + H: 480 (ESI) Optically active compound (separation
conditions AD-H: retention time 47 min, optical rotation (-)) 46
##STR00079## H M.sup.+ + H: 430 (ESI) Optically active compound
(separation conditions 80% ethanol-hexane: IB: retention time 15
min, optical rotation (+)) 47 ##STR00080## H M.sup.+ + H: 430 (ESI)
Optically active compound (separation conditions 80%
ethanol-hexane: IB: retention time 27 min, optical rotation (-)) 48
##STR00081## H M.sup.+ + H: 448 (ESI) 49 ##STR00082## H M.sup.+ +
H: 448 (ESI) 50 ##STR00083## H M.sup.+ + H: 464 (ESI) 51
##STR00084## H M.sup.+ + H: 466 (ESI) 52 ##STR00085## H M.sup.+ +
H: 466 (ESI)
Examples 53 and 54
Synthesis of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00086##
[0509] Sodium hydride (containing 40% of mineral oil, 21 mg) was
added to a solution of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyridin-
-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine synthesized
by the method in Example 38 and 39 (108 mg) in DMF (1.2 mL), and
the reaction solution was stirred at room temperature for three
hours under oxygen bubbling. Sodium thiosulfate pentahydride was
added to the reaction solution, and the reaction solution was
stirred at room temperature for several minutes. Ethyl acetate and
a saturated ammonium chloride solution were added to the reaction
solution and the organic layer was separated. The resulting organic
layer was dried over anhydrous magnesium sulfate and concentrated
under reduced pressure to obtain the racemic title compound.
[0510] The racemate of the title compound was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (+)-isomer of
the title optically active compound with a retention time of 11
minutes (49.3 mg, >99% ee) and a (-)-isomer of the title
optically active compound with a retention time of 13 minutes (44.6
mg, 94% ee).
[0511] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol are
as follows.
[0512] ESI-MS; m/z 429 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.11-2.37 (m, 6H), 2.50-2.64 (m, 1H), 3.81 (s, 3H),
4.22-4.32 (m, 1H), 4.35-4.44 (m, 1H), 6.88 (brs, 1H), 6.96-7.10 (m,
3H), 7.16 (d, J=8.0 Hz, 1H), 7.24-7.38 (m, 2H), 7.43 (d, J=16.4 Hz,
1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (dt, J=1.2, 8.0 Hz, 1H),
8.54-8.62 (m, 1H).
[0513] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyr-
idin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol are
as follows.
[0514] ESI-MS; m/z 429 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.11-2.37 (m, 6H), 2.50-2.64 (m, 1H), 3.81 (s, 3H),
4.22-4.32 (m, 1H), 4.35-4.44 (m, 1H), 6.88 (brs, 1H), 6.96-7.10 (m,
3H), 7.16 (d, J=8.0 Hz, 1H), 7.24-7.38 (m, 2H), 7.43 (d, J=16.4 Hz,
1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (dt, J=1.2, 8.0 Hz, 1H),
8.54-8.62 (m, 1H).
Examples 55 and 56
Synthesis of
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
and
(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00087##
[0516] A racemate of title compound (67.1 mg) was obtained from
8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
synthesized in Examples 5 and 6 (117.4 mg) by the same method as in
Examples 53 and 54. The racemate of the title compound was
separated by CHIRALPAK.TM. AD-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain a (-)-isomer of the title optically
active compound with a retention time of 13.5 minutes (20.7 mg;
>99% ee) and a (+)-isomer of the title optically active compound
with a retention time of 16.5 minutes (20.1 mg; 98% ee).
[0517] The property values of
(-)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
are as follows.
[0518] ESI-MS; m/z 470 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.8 Hz, 6H), 1.92-2.05 (m, 1H), 2.21-2.40
(m, 6H), 2.84-2.96 (m, 1H), 3.82 (s, 3H), 4.25 (t, J=5.6 Hz, 2H),
6.89 (brs, 1H), 7.02-7.13 (m, 3H), 7.14-7.24 (m, 5H), 7.49 (d,
J=16.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
[0519] The property values of
(+)-8-(4-isopropylphenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-y-
l)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
are as follows.
[0520] ESI-MS; m/z 470 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.8 Hz, 6H), 1.92-2.05 (m, 1H), 2.21-2.40
(m, 6H), 2.84-2.96 (m, 1H), 3.82 (s, 3H), 4.25 (t, J=5.6 Hz, 2H),
6.89 (brs, 1H), 7.02-7.13 (m, 3H), 7.14-7.24 (m, 5H), 7.49 (d,
J=16.4 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Examples 57 and 58
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00088##
[0521] Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5-
,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0522] 59 mg of the title compound was obtained from ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (650 mg) and 5-chloro-2-phenylpentanoic acid
hydrazide (436 mg) by the same method as in Example 1. The property
values of the compound are as follows.
[0523] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.06-2.12 (m, 2H),
2.16-2.24 (m, 1H), 2.29 (s, 3H), 2.33-2.40 (m, 1H), 3.85 (s, 3H),
4.21-4.37 (m, 3H), 6.91 (s, 1H), 7.07 (d, J=16.4 Hz, 1H), 7.13-7.15
(m, 3H), 7.21 (d, J=7.6 Hz, 1H), 7.26-7.29 (m, 2H), 7.32-7.36 (m,
2H), 7.52 (d, J=16.4 Hz, 1H), 7.69 (s, 1H).
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
[0524] The title optically active compound with a retention time of
14 minutes in CHIRALPAK.TM. ADH manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow
rate: 10 mL/min) and negative optical rotation (9.5 mg) and the
title optically active compound with a retention time of 16 minutes
in the CHIRALPAK.TM. ADH and positive optical rotation (9.4 mg)
were obtained from
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phenyl-5-
,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (59 mg) by the same
method as in Examples 53 and 54.
[0525] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[0526] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.95-2.03 (m, 1H),
2.21-2.27 (m, 1H), 2.28 (s, 3H), 2.31-2.38 (m, 2H), 3.81 (s, 3H),
4.25 (t, J=6 Hz, 2H), 6.88 (s, 1H), 7.00-7.07 (m, 3H), 7.16 (d, J=8
Hz, 1H), 7.29-7.35 (m, 5H), 7.46 (d, J=16.4 Hz, 1H), 7.71 (d, J=1.2
Hz, 1H).
[0527] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0528] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.95-2.03 (m, 1H),
2.21-2.27 (m, 1H), 2.28 (s, 3H), 2.31-2.38 (m, 2H), 3.81 (s, 3H),
4.25 (t, J=6 Hz, 2H), 6.88 (s, 1H), 7.00-7.07 (m, 3H), 7.16 (d, J=8
Hz, 1H), 7.29-7.35 (m, 5H), 7.46 (d, J=16.4 Hz, 1H), 7.71 (d, J=1.2
Hz, 1H).
Examples 59 and 60
Synthesis of
(-)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
and
(+)-8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00089##
[0529] Synthesis of
8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0530] 468 mg of the title compound was obtained from
(E)-N-[3-(2-fluorophenyl)-2-oxopiperidin-1-yl]-3-[3-methoxy-4-(4-methyl-1-
H-imidazol-1-yl)phenyl]acrylamide (761 mg) using methyl
2-fluorophenylacetate as a starting material by the same method as
in Examples 20 and 21. The property values of the compound are as
follows.
[0531] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.24 (m, 3H),
2.29 (s, 3H), 2.33-2.39 (m, 1H), 3.85 (s, 3H), 4.27-4.30 (m, 2H),
4.58-4.61 (m, 1H), 6.91-6.92 (m, 1H), 6.93-6.98 (m, 1H), 7.05-7.15
(m, 5H), 7.21 (d, J=7.6 Hz, 1H), 7.24-7.30 (m, 1H), 7.51 (d, J=16.4
Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-ol
[0532] The title optically active compound with a retention time of
12 minutes in CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow
rate: 10 mL/min) and positive optical rotation (20.6 mg) and the
title optically active compound with a retention time of 14 minutes
in the CHIRALPAK.TM. IA and negative optical rotation (17.2 mg)
were obtained from
8-(2-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine (50 mg)
by the same method as in Examples 53 and 54.
[0533] The property values of the title optically active compound
with a retention time of 12 minutes are as follows.
[0534] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.11 (m, 1H),
2.22-2.36 (m, 2H), 2.30 (s, 3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H),
4.29-4.35 (m, 1H), 6.85-6.99 (m, 4H), 7.09 (d, J=8 Hz, 2H),
7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34 (d, J=18.8 Hz, 1H), 7.65
(d, J=0.8 Hz, 1H), 7.83-7.88 (m, 1H).
[0535] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[0536] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.11 (m, 1H),
2.22-2.36 (m, 2H), 2.30 (s, 3H), 3.76 (s, 3H), 4.13-4.20 (m, 1H),
4.29-4.35 (m, 1H), 6.85-6.99 (m, 4H), 7.09 (d, J=8 Hz, 2H),
7.20-7.25 (m, 1H), 7.27-7.33 (m, 2H), 7.34 (d, J=18.8 Hz, 1H), 7.65
(d, J=0.8 Hz, 1H), 7.83-7.88 (m, 1H).
[0537] The following compounds were obtained by the same method as
in Examples 53 and 54 (Table 2).
TABLE-US-00002 TABLE 2 ##STR00090## Ex- DATA: ample E.sub.1 E2 MS
m/z Note 61 ##STR00091## OH M.sup.+ + H: 496 (ESI) Optically active
compound (separation conditions IA: retention time 21 min, optical
rotation (-)) 62 ##STR00092## OH M.sup.+ + H: 496 (ESI) Optically
active compound (separation conditions IA: retention time 29 min,
optical rotation (+)) 63 ##STR00093## OH M.sup.+ + H: 479 (ESI)
Optically active compound (separation conditions AD-H: retention
time 15 min, optical rotation (-)) 64 ##STR00094## OH M.sup.+ + H:
479 (ESI) Optically active compound (separation conditions AD-H:
retention time 21 min, optical rotation (+))
Examples 65 and 66
Synthesis of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le and
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-car-
bonitrile
##STR00095##
[0538] Synthesis of
(8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phen-
yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol
[0539] Paraformaldehyde (186 mg) and sodium hydride (containing 40%
of mineral oil, 28.7 mg) were added to a solution of
8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
synthesized by the method in Examples 1 and 2 (154 mg) in DMF (3
mL), and the reaction solution was stirred at room temperature for
30 minutes. Thereafter, ethyl acetate and saturated sodium
bicarbonate water were added to the reaction solution, and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to obtain 204 mg of the title compound. The property value
of the compound is as follows.
[0540] ESI-MS; m/z 460 [M.sup.++H].
Synthesis of
8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde
[0541] Dess-Martin periodinane (304 mg) was added to a solution of
(8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phen-
yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)methanol
(165 mg) in methylene chloride (10 mL), and the reaction solution
was stirred in a nitrogen atmosphere at room temperature for four
hours. Ethyl acetate and saturated sodium bicarbonate water were
added to the reaction solution, and the organic layer was
separated. The resulting organic layer was dried over anhydrous
magnesium sulfate and concentrated under reduced pressure to obtain
227 mg of the title compound. The property value of the compound is
as follows.
[0542] ESI-MS; m/z 458 [M.sup.++H].
Synthesis of
8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde
oxime
[0543] Sodium acetate (58.7 mg) and hydroxylammonium chloride (49.8
mg) were added to a solution of
8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde
(164 mg) in ethanol (10 mL), and the reaction solution was stirred
at room temperature for five hours. Ethyl acetate and saturated
sodium bicarbonate water were added to the reaction solution and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure to obtain 169 mg of the title compound. The
property value of the compound is as follows.
[0544] ESI-MS; m/z 473 [M.sup.++H].
Synthesis of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le and
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carb-
onitrile
[0545] 1,1'-Carbonylbis-1H-imidazole (290 mg) was added to a
solution of
8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbaldehyde
oxime (169 mg) in THF (15 mL), and the mixture was heated under
reflux for 2.5 hours. The reaction solution was cooled to room
temperature. Then, ethyl acetate and brine were added to the
reaction solution and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (carrier: Chromatorex NH;
elution solvent: heptane:ethyl acetate=1:1->ethyl
acetate->ethyl acetate:methanol=9:1) to obtain 84.6 mg of a
racemate of the title compound. The resulting racemate (84.6 mg)
was separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain a (+)-isomer of the title optically
active compound with a retention time of 14 minutes (26.5 mg;
>99% ee) and a (-)-isomer of the title optically active compound
with a retention time of 17 minutes (25.1 mg; 98% ee).
[0546] The property values of
(+)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le are as follows.
[0547] ESI-MS; m/z 455 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.12-2.25 (m, 1H), 2.26-2.51 (m, 5H), 2.67-2.77 (m,
1H), 3.87 (s, 3H), 4.26-4.42 (m, 2H), 6.92 (t, J=1.2 Hz, 1H),
6.99-7.27 (m, 7H), 7.37-7.44 (m, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.71
(d, J=1.6 Hz, 1H).
[0548] The property values of
(-)-8-(3-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le are as follows.
[0549] ESI-MS; m/z 455 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.12-2.25 (m, 1H), 2.26-2.51 (m, 5H), 2.67-2.77 (m,
1H), 3.87 (s, 3H), 4.26-4.42 (m, 2H), 6.92 (t, J=1.2 Hz, 1H),
6.99-7.27 (m, 7H), 7.37-7.44 (m, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.71
(d, J=1.6 Hz, 1H).
Examples 67 and 68
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-ca-
rbonitrile and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-ca-
rbonitrile
##STR00096##
[0551] 62 mg of a racemate of the title compound was obtained by
the same method as in Examples 65 and 66 from
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-methy-
lsulfanylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
obtained by the method in Examples 28 and 29 (135.6 mg). The
racemate (62 mg) was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain a (-)-isomer of the title optically
active compound with a retention time of 23 minutes (13.9 mg;
>99% ee) and a (+)-isomer of the title optically active compound
with a retention time of 32.5 minutes (15.3 mg; >99% ee).
[0552] The property values of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-c-
arbonitrile are as follows.
[0553] ESI-MS; m/z 483 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.12-2.24 (m, 1H), 2.28-2.54 (m, 8H), 2.64-2.74 (m,
1H), 3.86 (s, 3H), 4.26-4.40 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06
(d, J=16.0 Hz, 1H), 7.13-7.30 (m, 7H), 7.57 (d, J=16.0 Hz, 1H),
7.70 (d, J=1.2 Hz, 1H).
[0554] The property values of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(4-m-
ethylsulfanylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-c-
arbonitrile are as follows.
[0555] ESI-MS; m/z 483 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.12-2.24 (m, 1H), 2.28-2.54 (m, 8H), 2.64-2.74 (m,
1H), 3.86 (s, 3H), 4.26-4.40 (m, 2H), 6.91 (t, J=1.2 Hz, 1H), 7.06
(d, J=16.0 Hz, 1H), 7.13-7.30 (m, 7H), 7.57 (d, J=16.0 Hz, 1H),
7.70 (d, J=1.2 Hz, 1H).
Examples 69 and 70
Synthesis of
(-)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,-
4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}-
methanol and
(+)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,-
4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}-
methanol
##STR00097##
[0556] Synthesis of tert-butyl
N'-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
and tert-butyl
N'-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazine-
carboxylate
[0557] IPEA (1.7 mL), HOBT (851 mg) and EDC (1.2 g) were added to a
solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid (840
mg) synthesized according to the method described in Tetrahedron
Letters, 2003, vol. 44, p. 365 and tert-butyl carbazate (500 mg) in
DMF (5 mL), and the reaction solution was stirred at room
temperature for 23 hours. Ethyl acetate and saturated sodium
bicarbonate water were added to the reaction solution, and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane->heptane:ethyl
acetate=1:1) to obtain 718 mg of tert-butyl
N'-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
and 420 mg of tert-butyl
N'-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazine-
carboxylate.
[0558] The property values of tert-butyl
N'-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
are as follows.
[0559] ESI-MS; m/z 403 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.45 (s, 9H), 1.64-2.00 (m, 3H), 2.15-2.26 (m, 1H),
3.30 (t, J=7.2 Hz, 1H), 3.47-3.60 (m, 2H), 6.99 (dd, J=8.4, 6.4 Hz,
2H).
[0560] The property value of tert-butyl
N'-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazine-
carboxylate is as follows.
[0561] ESI-MS; m/z 480 [M.sup.++H].
Synthesis of tert-butyl
[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate
[0562] Sodium iodide (131 mg) and sodium hydride (containing 40% of
mineral oil, 70 mg) were added to a solution of tert-butyl
N'-[5-(benzotriazol-1-yloxy)-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazine-
carboxylate (420 mg) in DMF (3 mL), and the reaction solution was
stirred at 100.degree. C. for 19 hours. The reaction solution was
left to cool to room temperature. Ethyl acetate and saturated
sodium bicarbonate water were added to the reaction solution, and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane->ethyl acetate) to
obtain 134 mg of the title compound. The property values of the
compound are as follows.
[0563] .sup.1H-NMR (CD.sub.3 OD) .delta. (ppm): 1.50 (s, 9H),
1.90-2.05 (m, 3H), 2.15-2.23 (m, 1H), 3.61-3.80 (m, 3H), 6.70 (brs,
1H), 6.90 (t, J=8.0, 6.8 Hz, 2H).
Synthesis of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one
hydrochloride
[0564] A solution of 4 N hydrochloric acid in ethyl acetate (1 mL)
was added to a solution of
tert-butyl[2-oxo-3-(3,4,5-trifluorophenyl)piperidin-1-yl]carbamate
(134 mg) in chloroform (1 mL), and the reaction solution was
stirred at room temperature for three hours. The reaction solution
was concentrated under reduced pressure to obtain 109 mg of the
title compound. The property value of the compound is as
follows.
[0565] ESI-MS; m/z 245 [M.sup.++H].
Synthesis of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(3,4,5-t-
rifluorophenyl)piperidin-1-yl]acrylamide
[0566] IPEA (0.41 mL), HOBT (105 mg) and EDC (149 mg) were added to
a solution of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one
hydrochloride (109 mg) and
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(100 mg) in DMF (2 mL), and the reaction solution was stirred at
room temperature for three hours. Ethyl acetate and saturated
sodium bicarbonate water were added to the reaction solution, and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: ethyl acetate->ethyl
acetate:methanol=5:1) to obtain 95 mg of the title compound. The
property values of the compound are as follows.
[0567] ESI-MS; m/z 485 [M.sup.++H]. .sup.1H-NMR (CD.sub.3 OD)
.delta. (ppm): 1.94-2.10 (m, 3H), 2.22-2.30 (m, 1H), 2.31 (s, 3H),
3.64-3.72 (m, 1H), 3.78-3.82 (m, 2H), 3.84 (s, 3H), 6.41 (d, J=16.0
Hz, 1H), 6.88 (brd, J=8.0 Hz, 1H), 6.90 (brs, 1H), 6.93 (s, 1H),
7.00 (dd, J=6.8, 3.6 Hz, 2H), 7.14 (d, J=8.0 Hz, 1H), 7.44 (d,
J=16.0 Hz, 1H), 7.74 (d, J=1.2 Hz, 1H), 9.87 (brs, 1H).
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5-t-
rifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0568] A solution of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-(3,4,5-t-
rifluorophenyl)piperidin-1-yl]acrylamide (95 mg) in phosphorus
oxychloride (2 mL) was stirred at 120.degree. C. for one hour. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure Ammonium acetate (302 mg) was
added to a solution of the residue in acetic acid (1 mL), and the
reaction solution was stirred at 150.degree. C. for three hours.
The reaction solution was left to cool to room temperature. Then,
ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: heptane:ethyl acetate=1:1->ethyl acetate)
to obtain 50 mg of a racemate of the title compound. The property
values of the compound are as follows.
[0569] ESI-MS; m/z 466 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.97-2.25 (m, 3H), 2.30 (s, 3H), 2.32-2.42 (m, 1H),
3.86 (s, 3H), 4.24-4.30 (m, 3H), 6.82 (dd, J=8.0, 6.0 Hz, 2H), 6.91
(brs, 1H), 7.05 (d, J=16.8 Hz, 1H), 7.14 (dd, J=8.4, 1.6 Hz, 1H),
7.16 (s, 1H), 7.21 (d, J=8.4 Hz, 1H), 7.50 (d, J=16.8 Hz, 1H), 7.69
(d, J=1.2 Hz, 1H).
Synthesis of
(-)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,-
4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}-
methanol and
(+)-{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,-
4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}-
methanol
[0570] Sodium hydride (40% oil suspension, 31 mg) was added to a
solution of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,-
5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(180 mg) and paraformaldehyde (200 mg) in DMF (3 mL), and the
reaction solution was stirred at room temperature for 30 minutes.
Ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure to obtain 194 mg of a
racemic crude product. The resulting racemate (40 mg) was separated
by CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries,
Ltd. (2 cm.times.25 cm, mobile phase: hexane:ethanol=7:3) to obtain
the title optically active compound with a retention time of 9
minutes and negative optical rotation (10 mg) and the title
optically active compound with a retention time of 11 minutes and
positive optical rotation (10 mg).
[0571] The property values of the title optically active compound
with a retention time of 9 minutes are as follows.
[0572] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.84-1.97 (m, 1H),
2.05-2.16 (m, 2H), 2.21-2.29 (m, 1H), 2.30 (s, 3H), 3.89 (s, 3H),
3.89 (d, J=11.6 Hz, 1H), 4.08 (d, J=11.6 Hz, 1H), 4.10 (td, J=13.2,
6.0 Hz, 1H), 4.30 (dd, J=13.2, 6.0 Hz, 1H), 6.80 (dd, J=8.8, 6.4
Hz, 2H), 6.92 (brs, 1H), 7.07 (d, J=16.4 Hz, 1H), 7.16 (brs, 1H),
7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.57 (d,
J=16.4 Hz, 1H), 7.72 (brs, 1H).
[0573] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[0574] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.84-1.97 (m, 1H),
2.05-2.16 (m, 2H), 2.21-2.29 (m, 1H), 2.30 (s, 3H), 3.89 (s, 3H),
3.89 (d, J=11.6 Hz, 1H), 4.08 (d, J=11.6 Hz, 1H), 4.10 (td, J=13.2,
6.0 Hz, 1H), 4.30 (dd, J=13.2, 6.0 Hz, 1H), 6.80 (dd, J=8.8, 6.4
Hz, 2H), 6.92 (brs, 1H), 7.07 (d, J=16.4 Hz, 1H), 7.16 (brs, 1H),
7.18 (dd, J=8.0, 1.6 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.57 (d,
J=16.4 Hz, 1H), 7.72 (brs, 1H).
Examples 71 and 72
Synthesis of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4-
,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-car-
bonitrile and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4-
,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-car-
bonitrile
##STR00098##
[0576] Dess-Martin periodinane (190 mg) was added to a solution of
the crude product of
{2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(3,4,5--
trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl}meth-
anol obtained in Examples 69 and 70 (111 mg) in methylene chloride
(8 mL), and the reaction solution was stirred at room temperature
for 10 hours. Ethyl acetate and saturated sodium bicarbonate water
were added to the reaction solution, and the organic layer was
separated. The resulting organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure.
Sodium acetate (35 mg) and hydroxyamine hydrochloride (30 mg) were
added to a solution of the residue in ethanol (7 mL), and the
reaction solution was stirred at room temperature for four hours.
Ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. CDI (180 mg) was
added to a solution of the residue in THF (13 mL), and the reaction
solution was heated under reflux for one hour. The reaction
solution was left to cool to room temperature. Then, ethyl acetate
and brine were added to the reaction solution, and the organic
layer was separated. The resulting organic layer was dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The resulting racemic crude product was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with a retention time of 11 minutes
and negative optical rotation (38 mg) and the title optically
active compound with a retention time of 15 minutes and positive
optical rotation (40 mg).
[0577] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[0578] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.29 (m, 1H),
2.30 (s, 3H), 2.35-2.50 (m, 2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H),
4.26-4.34 (m, 1H), 4.36-4.44 (m, 1H), 6.92 (brs, 1H), 7.04 (d,
J=16.8 Hz, 1H), 7.05 (dd, J=7.6, 6.4 Hz, 2H), 7.16 (brs, 1H), 7.17
(brd, J=7.2 Hz, 1H), 7.24 (d, J=7.2 Hz, 1H), 7.56 (d, J=16.8 Hz,
1H), 7.70 (brs, 1H).
[0579] The property values of the title optically active compound
with a retention time of 15 minutes corresponded to the property
values of the title optically active compound with a retention time
of 11 minutes.
Examples 73 and 74
Synthesis of
(+)-8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carb-
onitrile
##STR00099##
[0581] A racemate of the title compound obtained from
8-(4-chlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (197 mg)
by the same method as in Examples 65 and 66 was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 16 minutes and
positive optical rotation (40 mg) and the title optically active
compound with a retention time of 18 minutes and negative optical
rotation (47 mg).
[0582] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0583] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.13-2.25 (m, 1H),
2.30 (s, 3H), 2.32-2.47 (m, 2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H),
4.28-4.42 (m, 2H), 6.93 (brs, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.17
(d, J=1.6 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 7.24 (d, J=8.4 Hz,
1H), 7.28 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.57 (d,
J=16.0 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).
[0584] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[0585] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.13-2.25 (m, 1H),
2.30 (s, 3H), 2.32-2.47 (m, 2H), 2.66-2.75 (m, 1H), 3.87 (s, 3H),
4.28-4.42 (m, 2H), 6.93 (brs, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.17
(d, J=1.6 Hz, 1H), 7.18 (dd, J=8.4, 1.6 Hz, 1H), 7.24 (d, J=8.4 Hz,
1H), 7.28 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 2H), 7.57 (d,
J=16.0 Hz, 1H), 7.71 (d, J=1.2 Hz, 1H).
Examples 75 and 76
Synthesis of
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbon-
itrile and
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-i-
midazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e-8-carbonitrile
##STR00100##
[0587] A racemate of the title compound obtained from
8-(3,4-dichlorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (132
mg) by the same method as in Examples 65 and 66 was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 13 minutes and
positive optical rotation (24 mg) and the title optically active
compound with a retention time of 16 minutes and negative optical
rotation (24 mg).
[0588] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[0589] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.16-2.27 (m, 1H),
2.30 (s, 3H), 2.36-2.47 (m, 2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H),
4.27-4.43 (m, 2H), 6.92 (brs, 1H), 7.05 (d, J=16.4 Hz, 1H),
7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d, J=16.4 Hz, 1H), 7.70
(brs, 1H).
[0590] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0591] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.16-2.27 (m, 1H),
2.30 (s, 3H), 2.36-2.47 (m, 2H), 2.68-2.75 (m, 1H), 3.87 (s, 3H),
4.27-4.43 (m, 2H), 6.92 (brs, 1H), 7.05 (d, J=16.4 Hz, 1H),
7.10-7.14 (m, 1H), 7.15-7.27 (m, 5H), 7.57 (d, J=16.4 Hz, 1H), 7.70
(brs, 1H).
Examples 77, 78, 79 and 80
Synthesis of
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbon-
itrile,
(+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imid-
azol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-
-carbonitrile,
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
and
(+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00101##
[0593]
8-(3,5-Difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carb-
onitrile (80 mg) was obtained from
8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (160
mg) by the same method as in Examples 65 and 66. At the same time,
8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
generated in the reaction step in the middle (80 mg) was
isolated.
[0594] The resulting
8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)p-
henyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbonitri-
le (80 mg) was optically resolved by CHIRALPAK.TM. ADH manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: 80% ethanol-hexane, flow rate: 10 mL/min) to obtain the
title optically active compound with a retention time of 15 minutes
and positive optical rotation
((+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-i-
midazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e-8-carbonitrile, 29.6 mg) and the title optically active compound
with a retention time of 18 minutes and negative optical rotation
((-)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-8-carbo-
nitrile, 35.1 mg).
[0595] The property values of the title optically active compound
with a retention time of 18 minutes and negative optical rotation
are as follows.
[0596] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.16-2.32 (m, 1H),
2.30 (s, 3H), 2.34-2.50 (m, 2H), 2.66-2.78 (m, 1H), 3.88 (s, 3H),
4.26-4.44 (m, 2H), 6.84-6.96 (m, 4H), 7.06 (d, J=16 Hz, 1H),
7.16-7.22 (m, 2H), 7.24 (d, J=8.4 Hz, 1H), 7.59 (d, J=16 Hz, 1H),
7.71 (d, J=0.80 Hz, 1H).
[0597] ESI-MS; m/z 473 [M.sup.++H].
[0598] The property values of the title optically active compound
with a retention time of 15 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
[0599]
8-(3,5-Difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
obtained in the same manner (80 mg) was optically resolved by
CHIRALPAK.TM. ADH manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: 50% ethanol-hexane, flow rate: 10
mL/min) to obtain the title optically active compound with a
retention time of 20 minutes and positive optical rotation
((+)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,
11.3 mg) and the title optically active compound with a retention
time of 22 minutes and negative optical rotation
((-)-8-(3,5-difluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol,
11.6 mg). The property values of the title optically active
compound with a retention time of 22 minutes and negative optical
rotation are as follows.
[0600] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.20 (m, 2H),
2.28 (s, 3H), 2.26-2.40 (m, 1H), 2.40-2.56 (m, 1H), 3.77 (s, 3H),
4.18-4.36 (m, 2H), 6.70-6.78 (m, 1H), 6.80-6.90 (m, 2H), 6.90-7.05
(m, 4H), 7.11 (d, J=8.0 Hz, 1H), 7.40 (d, J=16 Hz, 1H), 7.73 (s,
1H).
[0601] ESI-MS; m/z 464 [M.sup.++H].
[0602] The property values of the title optically active compound
with a retention time of 20 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
[0603] The following compounds were obtained by the same method as
in Examples 65 and 66 (Table 3).
TABLE-US-00003 TABLE 3 ##STR00102## Ex- DATA: ample E.sub.1 E2 MS
m/z Note 81 ##STR00103## CN M.sup.+ + H: 505 (ESI) Optically active
compound (separation conditions IA: retention time 27 min, optical
rotation (-)) 82 ##STR00104## CN M.sup.+ + H: 505 (ESI) Optically
active compound (separation conditions IA: retention time 28 min,
optical rotation (+)) 83 ##STR00105## CN M.sup.+ + H: 455 (ESI)
Optically active compound (separation conditions AD-H: ethanol:
retention time 15 min, optical rotation (+)) 84 ##STR00106## CN
M.sup.+ + H: 455 (ESI) Optically active compound (separation
conditions AD-H: ethanol: retention time 18 min, optical rotation
(-)) 85 ##STR00107## CN M.sup.+ + H: 473 (ESI) Optically active
compound (separation conditions IA: 80% ethanol-hexane: retention
time 15 min, optical rotation (+)) 86 ##STR00108## CN M.sup.+ + H:
473 (ESI) Optically active compound (separation conditions IA: 80%
ethanol-hexane: retention time 20 min, optical rotation (-)) 87
##STR00109## CN M.sup.+ + H: 491 (ESI) Optically active compound
(separation conditions IA: 70% ethanol-hexane: retention time 28
min, optical rotation (+)) 88 ##STR00110## CN M.sup.+ + H: 491
(ESI) Optically active compound (separation conditions IA: 70%
ethanol-hexane: retention time 33 min, optical rotation (-)) 89
##STR00111## CN M.sup.+ + H: 489 (ESI) Optically active compound
(separation conditions AD-H: ethanol: retention time 17 min,
optical rotation (-)) 90 ##STR00112## CN M.sup.+ + H: 489 (ESI)
Optically active compound (separation conditions AD-H: ethanol:
retention time 37 min, optical rotation (+))
Examples 91 and 92
Synthesis of
(-)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phen-
yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5--
a]pyridine
##STR00113##
[0604] Synthesis of
(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-
-(2,4,6-trifluorophenyl)piperidin-1-yl]acrylamide
[0605] BOPCl (221 mg) was added to a suspension of
(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic
acid (CAS No. 870838-71-4, 240 mg),
1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one (106 g) and IPEA
(0.45 mL) in DMF (5 mL), and the reaction solution was stirred at
room temperature for 16 hours. Saturated sodium bicarbonate water
and ethyl acetate were added to the reaction mixture and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (carrier: Chromatorex NH; elution solvent:
ethyl acetate) to obtain 110 mg of the title compound. The property
value of the compound is as follows.
[0606] ESI-MS; m/z 503 [M.sup.++H].
Synthesis of
(-)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phen-
yl]vinyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5--
a]pyridine
[0607] A solution of
(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-[2-oxo-3-
-(2,4,6-trifluorophenyl)piperidin-1-yl]acrylamide (110 mg) in
phosphorus oxychloride (2 mL) was heated under reflux for three
hours. The reaction mixture was left to cool to room temperature
and then concentrated under reduced pressure. Acetic acid (3 mL)
and ammonium acetate (506 mg) were added to the residue, and the
reaction solution was stirred at 150.degree. C. for two hours. The
reaction mixture was left to cool to room temperature and then
concentrated under reduced pressure. Saturated aqueous sodium
bicarbonate and ethyl acetate were added to the residue, and the
organic layer was separated. The resulting organic layer was washed
with saturated aqueous sodium chloride, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting residue was purified by silica gel column chromatography
(carrier: Chromatorex NH; elution solvent: heptane:ethyl
acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) to
obtain 42 mg of a racemate of the title compound. The resulting
racemate (22 mg) was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: hexane:ethanol=1:1) to obtain the title optically active
compound with a retention time of 10 minutes and negative optical
rotation (3.8 mg) and the title optically active compound with a
retention time of 13 minutes and positive optical rotation (4.4
mg).
[0608] The property values of the title optically active compound
with a retention time of 10 minutes are as follows.
[0609] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.24 (m, 3H),
2.29 (s, 3H), 2.30-2.39 (m, 1H), 3.85 (s, 3H), 4.21-4.30 (m, 1H),
4.37-4.45 (m, 1H), 4.52-4.59 (m, 1H), 6.65 (d, J=38.8 Hz, 1H), 6.70
(t, J=8.8 Hz, 2H), 6.92 (brs, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.24
(dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H), 7.72 (d, J=1.2 Hz,
1H).
[0610] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[0611] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.24 (m, 3H),
2.29 (s, 3H), 2.30-2.39 (m, 1H), 3.85 (s, 3H), 4.21-4.30 (m, 1H),
4.37-4.45 (m, 1H), 4.52-4.59 (m, 1H), 6.65 (d, J=38.8 Hz, 1H), 6.70
(t, J=8.8 Hz, 2H), 6.92 (brs, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.24
(dd, J=8.0, 1.6 Hz, 1H), 7.33 (brs, 1H), 7.72 (d, J=1.2 Hz,
1H).
Examples 93 and 94
Synthesis of
(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol and
(-)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol
##STR00114##
[0612] Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic
acid hydrazide hydrochloride
[0613] A solution of 4 N hydrochloric acid in ethyl acetate (2 mL)
was added to a solution of tert-butyl
N'-[5-chloro-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
(300 mg) in ethyl acetate (2 mL), and the reaction solution was
stirred at room temperature for one hour. The reaction solution was
concentrated under reduced pressure to obtain 250 mg of the title
compound. The property value of the compound is as follows.
[0614] ESI-MS; m/z 281 [M.sup.++H].
Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid
N'-{(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloy-
l}hydrazide
[0615] IPEA (0.14 mL) and BOPCl (100 mg) were added to a solution
of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide
hydrochloride (83 mg) and
(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic
acid (CAS No. 870838-71-4, 72 mg) in methylene chloride (5 mL), and
the reaction solution was stirred at room temperature for 13 hours.
Ethyl acetate and saturated sodium bicarbonate water were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (elution solvent:
heptane:ethyl acetate=1:1->ethyl acetate->ethyl
acetate:methanol=9:1) to obtain 84 mg of the title compound. The
property value of the compound is as follows.
[0616] ESI-MS; m/z 539 [M.sup.++H].
Synthesis of
2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy--
4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole
[0617] A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic
acid
N'-{(Z)-2-fluoro-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloy-
l}hydrazide (84 mg) in phosphorus oxychloride (1 mL) was stirred at
120.degree. C. for 7.5 hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure to obtain 81 mg of the title compound. The property value
of the compound is as follows.
[0618] ESI-MS; m/z 521 [M.sup.++H].
Synthesis of
2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-
-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0619] A solution of
2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(Z)-1-fluoro-2-[3-methoxy--
4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (81
mg) and ammonium acetate (358 mg) in acetic acid (2 mL) was stirred
at 150.degree. C. for three hours. The reaction solution was left
to cool to room temperature. Then, ethyl acetate and saturated
sodium bicarbonate water were added to the reaction solution, and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH; elution solvent:
heptane:ethyl acetate=1:1->ethyl acetate) to obtain 98 mg of the
title compound. The property values of the compound are as
follows.
[0620] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.99-2.08 (m, 1H),
2.09-2.28 (m, 2H), 2.31 (s, 3H), 2.35-2.44 (m, 1H), 3.87 (s, 3H),
4.28 (t, J=7.2 Hz, 1H), 4.34 (t, J=5.2 Hz, 2H), 6.74 (d, J=38.4 Hz,
1H), 6.82 (dd, J=8.0, 6.4 Hz, 2H), 6.94 (brs, 1H), 7.25 (d, J=8.4
Hz, 1H), 7.28 (dd, J=8.4, 1.6 Hz, 1H), 7.36 (brs, 1H), 7.73 (d,
J=0.8 Hz, 1H).
Synthesis of
(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol and
(-)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol
[0621] Sodium hydride (containing 40% of mineral oil, 16.2 mg) was
added to a solution of
2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-
-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(98 mg) in DMF (2 mL), and the reaction solution was stirred at
room temperature for 40 minutes. Ethyl acetate and a saturated
sodium thiosulfate solution were added to the reaction solution,
and the organic layer was separated. The resulting organic layer
was washed with saturated sodium bicarbonate water, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was separated by CHIRALCEL.TM. OD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain the title optically active
compound with a retention time of 9 minutes and positive optical
rotation (22 mg) and the title optically active compound with a
retention time of 11 minutes and negative optical rotation (23
mg).
[0622] The property values of
(+)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol are as follows.
[0623] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.16 (m, 2H),
2.28 (s, 3H), 2.31-2.39 (m, 1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H),
4.23-4.31 (m, 1H), 4.36-4.43 (m, 1H), 6.60 (d, J=37.6 Hz, 1H), 6.89
(brs, 1H), 6.98 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (dd, J=8.4, 6.4 Hz,
2H), 7.13 (d, J=8.4 Hz, 1H), 7.16 (brs, 1H), 7.72 (d, J=1.2 Hz,
1H).
[0624] The property values of
(-)-2-{(Z)-1-fluoro-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol are as follows.
[0625] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.03-2.16 (m, 2H),
2.28 (s, 3H), 2.31-2.39 (m, 1H), 2.46-2.58 (m, 1H), 3.77 (s, 3H),
4.23-4.31 (m, 1H), 4.36-4.43 (m, 1H), 6.60 (d, J=37.6 Hz, 1H), 6.89
(brs, 1H), 6.98 (dd, J=8.4, 1.6 Hz, 1H), 7.06 (dd, J=8.4, 6.4 Hz,
2H), 7.13 (d, J=8.4 Hz, 1H), 7.16 (brs, 1H), 7.72 (d, J=1.2 Hz,
1H).
Examples 95 and 96
Synthesis of
(+)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol and
(-)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol
##STR00115##
[0626] Synthesis of
(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic
acid
[0627] Lithium hydroxide monohydrate (240 mg) was added to a mixed
solution of
2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzaldehyde (CAS
No. 870851-52-8, 1.03 g) and triethyl phosphonoacetate (1.09 g) in
THF (4 mL)-ethanol (1 mL), and the reaction solution was stirred at
room temperature for five hours. A 2 N sodium hydroxide solution (4
mL) was added to the reaction solution, and the reaction solution
was stirred for 17 hours. 2 N aqueous hydrochloric acid (4 mL) was
added to the reaction solution, and the reaction solution was
stirred at room temperature for 30 minutes. The precipitated solid
was collected by filtration and washed with water and ether. The
resulting solid was air-dried to obtain 1.03 g of the title
compound. The property value of the compound is as follows.
[0628] ESI-MS; m/z 277 [M.sup.++H].
Synthesis of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid
N'-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloy-
l}hydrazide
[0629] IPEA (0.31 mL) and BOPCl (119 mg) were added to a solution
of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic acid hydrazide
hydrochloride (114 mg) and
(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic
acid (99 mg) in methylene chloride (5 mL), and the reaction
solution was stirred at room temperature for one hour. Ethyl
acetate and a saturated ammonium chloride solution were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to obtain 200 mg of the
title compound. The property value of the compound is as
follows.
[0630] ESI-MS; m/z 539 [M.sup.++H].
Synthesis of
2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(E)-2-[2-fluoro-5-methoxy--
4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole
[0631] A solution of 5-chloro-2-(3,4,5-trifluorophenyl)pentanoic
acid
N'-{(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloy-
l}hydrazide (200 mg) in phosphorus oxychloride (2 mL) was stirred
at 120.degree. C. for 5.5 hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure. Ethyl acetate and saturated sodium bicarbonate water were
added to the residue, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and concentrated under reduced pressure to obtain 180 mg of the
title compound. The property value of the compound is as
follows.
[0632] ESI-MS; m/z 521 [M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol and
(-)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyrid-
in-8-ol
[0633] A solution of
2-[4-chloro-1-(3,4,5-trifluorophenyl)butyl]-5-{(E)-2-[2-fluoro-5-methoxy--
4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-[1,3,4]oxadiazole (180
mg) and ammonium acetate (533 mg) in acetic acid (2 mL) was stirred
at 150.degree. C. for 24 hours. The reaction solution was left to
cool to room temperature. Then, ethyl acetate and saturated sodium
bicarbonate water were added to the reaction solution, and the
organic layer was separated. The resulting organic layer was dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane:ethyl
acetate=1:1->ethyl acetate->ethyl acetate:methanol=4:1) to
obtain a racemate of the title compound. Sodium hydride (40% oil
suspension, 22.2 mg) was added to a solution of the resulting
racemate (134 mg) in DMF (2 mL), and the reaction solution was
stirred at room temperature for one hour. Ethyl acetate and a
saturated sodium thiosulfate solution were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with saturated sodium bicarbonate water,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was separated by CHIRALPAK.TM. IA
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=1:1) to obtain the title optically
active compound with a retention time of 7 minutes (26 mg) and the
title optically active compound with a retention time of 8 minutes
(24 mg).
[0634] The property values of the title optically active compound
with a retention time of 7 minutes are as follows.
[0635] ESI-MS; m/z 500 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.14 (m, 2H), 2.26 (s, 3H), 2.28-2.36 (m, 1H),
2.45-2.57 (m, 1H), 3.74 (s, 3H), 4.17-4.25 (m, 1H), 4.28-4.37 (m,
1H), 6.83 (brs, 1H), 6.88 (d, J=10.4 Hz, 1H), 6.89 (d, J=6.4 Hz,
1H), 7.05 (d, J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4 Hz, 2H), 7.42
(d, J=16.4 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H).
[0636] The property values of the title optically active compound
with a retention time of 8 minutes are as follows.
[0637] ESI-MS; m/z 500 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.14 (m, 2H), 2.26 (s, 3H), 2.28-2.36 (m, 1H),
2.45-2.57 (m, 1H), 3.74 (s, 3H), 4.17-4.25 (m, 1H), 4.28-4.37 (m,
1H), 6.83 (brs, 1H), 6.88 (d, J=10.4 Hz, 1H), 6.89 (d, J=6.4 Hz,
1H), 7.05 (d, J=16.4 Hz, 1H), 7.06 (dd, J=8.8, 6.4 Hz, 2H), 7.42
(d, J=16.4 Hz, 1H), 7.67 (d, J=1.6 Hz, 1H).
Examples 97, 98, 99 and 100
Synthesis of
(6R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e,
(6R,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol--
1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine,
(6S,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1-imidazol-
-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine and
(6S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imi-
dazol-1-yl)phenyl]vinyl}-6-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a-
]pyridine
##STR00116##
[0639] 388 mg of a diastereomer mixture of the title compound was
obtained from
(E)-N-[3-(4-fluorophenyl)-5-methyl-2-oxopiperidin-1-yl]-3-[3-methoxy-
-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylamide (662 mg) using
methyl 4-fluorophenylacetate and 1-bromo-3-chloro-2-methylpropane
as starting materials by the same method as in Examples 20 and 21.
The resulting diastereomer mixture (388 mg) was separated by
CHIRALPAK.TM. OD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to
obtain the title optically active compound with a retention time of
10 minutes and negative optical rotation (67 mg), the title
optically active compound with a retention time of 13 minutes and
positive optical rotation (69 mg), the title optically active
compound with a retention time of 15 minutes and negative optical
rotation (93 mg) and the title optically active compound with a
retention time of 30 minutes and positive optical rotation (92
mg).
[0640] The property values of the title optically active compound
with a retention time of 10 minutes are as follows.
[0641] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.12 (d, J=6.8 Hz,
3H), 2.08-2.11 (m, 2H), 2.30 (s, 3H), 2.31-2.37 (m, 1H), 3.76 (dd,
J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s, 3H), 4.37 (dd, J=12.8 Hz, 5.2 Hz,
1H), 4.49 (t, J=4.4 Hz, 1H), 6.92 (t, J=0.8 Hz, 1H), 7.00-7.03 (m,
4H), 7.08 (d, J=16.4 Hz, 1H), 7.14-7.17 (m, 2H), 7.23 (d, J=8.0 Hz,
1H), 7.54 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H).
[0642] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[0643] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.12 (d, J=6.8 Hz,
3H), 2.08-2.11 (m, 2H), 2.30 (s, 3H), 2.31-2.37 (m, 1H), 3.76 (dd,
J=12.8 Hz, 9.6 Hz, 1H), 3.87 (s, 3H), 4.37 (dd, J=12.8 Hz, 5.2 Hz,
1H), 4.49 (t, J=4.4 Hz, 1H), 6.92 (t, J=0.8 Hz, 1H), 7.00-7.03 (m,
4H), 7.08 (d, J=16.4 Hz, 1H), 7.14-7.17 (m, 2H), 7.23 (d, J=8.0 Hz,
1H), 7.54 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz, 1H).
[0644] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[0645] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.20 (d, J=6.4 Hz,
3H), 1.66-1.76 (m, 1H), 2.29 (s, 3H), 2.30-2.42 (m, 2H), 3.76-3.83
(m, 1H), 3.85 (s, 3H), 4.19 (dd, J=11.6 Hz, 5.6 Hz, 1H), 4.36 (dd,
J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.02-7.07 (m, 3H),
7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), 7.48 (d, J=16.0 Hz, 1H), 7.69
(d, J=1.6 Hz, 1H).
[0646] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[0647] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.20 (d, J=6.4 Hz,
3H), 1.66-1.76 (m, 1H), 2.29 (s, 3H), 2.30-2.42 (m, 2H), 3.76-3.83
(m, 1H), 3.85 (s, 3H), 4.19 (dd, J=11.6 Hz, 5.6 Hz, 1H), 4.36 (dd,
J=11.6 Hz, 5.6 Hz, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.02-7.07 (m, 3H),
7.11-7.14 (m, 2H), 7.19-7.23 (m, 3H), 7.48 (d, J=16.0 Hz, 1H), 7.69
(d, J=1.6 Hz, 1H).
Examples 101 and 102
Synthesis of
(7S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(7R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidaz-
ol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00117##
[0648] Synthesis of 3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl
toluene-4-sulfonate
[0649] Triethylamine (4.64 mL), p-toluenesulfonyl chloride (4.66 g)
and DMAP (271 mg) were added to a solution of
4-(tert-butyldiphenylsilanyloxy)butan-2-ol (7.3 g; CAS
#114079-44-6) in 1,2-dichloroethane (80 mL) at 0.degree. C., and
the reaction solution was stirred at 60.degree. C. for three hours.
The reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. Ethyl acetate and brine were
added to the residue, and the organic layer was separated. The
resulting organic layer was dried over anhydrous sodium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (elution solvent: heptane-ethyl
acetate system) to obtain 6.4 g of the title compound. The property
value of the compound is as follows.
[0650] ESI-MS; m/z 505 [M.sup.++Na].
Synthesis of
5-(tert-butyldiphenylsilanyloxy-2-(4-fluorophenyl)-3-methylpentanoic
acid
[0651] n-Butyl lithium (4.89 mL; 2.66 M solution in hexane) was
added dropwise to a solution of 4-fluorophenylacetic acid (1 g) in
THF (30 mL) at -78.degree. C., and the reaction solution was
stirred for 20 minutes. The reaction solution was heated to
0.degree. C. and stirred for 30 minutes. Then, a solution of
3-(tert-butyldiphenylsilanyloxy)-1-methylpropyl toluene-4-sulfonate
(3.2 g) in THF (10 mL) was added dropwise to the reaction solution.
The reaction solution was heated to room temperature and stirred at
the same temperature for 12 hours. Then, 1 N hydrochloric acid and
ethyl acetate were added to the reaction solution, and the organic
layer was separated. The resulting organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 986 mg of the title compound. The property values
of the compound are as follows.
[0652] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 0.64 (d, J=6.8 Hz,
3H), 1.04 (s, 9H), 1.31-1.43 (m, 1H), 1.79-1.86 (m, 1H), 2.29-2.45
(m, 1H), 3.31 (d, J=10.0 Hz, 1H), 3.67-3.78 (m, 2H), 6.98 (t, J=8.8
Hz, 2H), 7.21-7.28 (m, 3H), 7.32-7.42 (m, 5H), 7.65 (d, J=7.6 Hz,
4H).
Synthesis of tert-butyl
N'-[5-(tert-butyldiphenylsilanyloxy)-2-(4-fluorophenyl)-3-methylpentanoyl-
]hydrazinecarboxylate
[0653] BOPCl (860 mg) and IPEA (0.552 mL) were added to a solution
of
5-(tert-butyldiphenylsilanyloxy-2-(4-fluorophenyl)-3-methylpentanoic
acid (980 mg) and tert-butyl carbazate (558 mg) in methylene
chloride (15 mL) at 0.degree. C. The reaction solution was stirred
at room temperature for 15 hours. Then, ethyl acetate and a
saturated ammonium chloride solution were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 1.04 g of the title
compound. The property value of the compound is as follows.
[0654] ESI-MS; m/z 601 [M.sup.++Na].
Synthesis of tert-butyl
N'-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate
[0655] TBAF (2.7 mL; 1 M solution in THF) was added to a solution
of tert-butyl
N'-[5-(tert-butyldiphenylsilanyloxy)-2-(4-fluorophenyl)-3-methylpentanoyl-
]hydrazinecarboxylate (1.04 g) in THF (20 mL). The reaction
solution was stirred at room temperature for 1 hours. Then, ethyl
acetate and a saturated ammonium chloride solution were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 525 mg of the
title compound. The property value of the compound is as
follows.
[0656] ESI-MS; m/z 363 [M.sup.++Na].
Synthesis of
5-(N'-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-p-
entyl toluene-4-sulfonate
[0657] p-Toluenesulfonyl chloride (321 mg) was added to a solution
of tert-butyl
N'-[2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarboxylate
(520 mg) in pyridine (6 mL). The reaction solution was stirred at
room temperature for 12 hours and then concentrated under reduced
pressure. Ethyl acetate and brine were added to the residue, and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 335 mg of the title compound. The property value of the
compound is as follows.
[0658] ESI-MS; m/z 517 [M.sup.++Na].
Synthesis of tert-butyl
N'-[5-chloro-2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarb-
oxylate
[0659] Lithium chloride (283 mg) was added to a solution of
5-(N'-tert-butoxycarbonylhydrazino)-4-(4-fluorophenyl)-3-methyl-5-oxo-1-p-
entyl toluene-4-sulfonate (330 mg) in DMF (5 mL). The reaction
solution was stirred at 80.degree. C. for three hours and then left
to cool to room temperature. Water and ethyl acetate were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine, and then dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 170 mg of the title compound. The property value of the
compound is as follows.
[0660] ESI-MS; m/z 381 [M.sup.++Na].
Synthesis of
(7S,8S)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(7R,8R)-8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidaz-
ol-1-yl)phenyl]vinyl}-7-methyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
[0661] A solution of 4 N hydrochloric acid in ethyl acetate (3 mL)
was added to tert-butyl
N'-[5-chloro-2-(4-fluorophenyl)-5-hydroxy-3-methylpentanoyl]hydrazinecarb-
oxylate (170 mg). The reaction solution was stirred at room
temperature for two hours and then concentrated under reduced
pressure. Subsequently, triethylamine (0.292 mL) was added to a
solution of the residue in ethanol (3 mL). A mixed solution of
ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (150 mg) and triethylamine (0.292 mL) in ethanol (3
mL) was added dropwise to the solution, and the reaction solution
was stirred at 80.degree. C. for 12 hours. The reaction solution
was left to cool to room temperature and then concentrated under
reduced pressure. Saturated sodium bicarbonate water and ethyl
acetate were added to the resulting residue, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: ethyl acetate-methanol system) to
obtain a racemate of the title compound. The resulting racemate was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with a retention time of 25 minutes (20.7 mg, >99% ee) and the
title optically active compound with a retention time of 36 minutes
(22.4 mg, >99% ee).
[0662] The property values of the title compound with a retention
time of 25 minutes are as follows.
[0663] ESI-MS; m/z 444 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.06 (d, J=6.4 Hz, 3H), 1.88-2.00 (m, 1H), 2.11-2.25
(m, 2H), 2.29 (s, 3H), 3.72 (d, J=9.2 Hz, 1H), 3.84 (s, 3H),
4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H), 7.19 (d, J=8.0
Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.69 (s, 1H).
[0664] The property values of the title compound with a retention
time of 36 minutes are as follows.
[0665] ESI-MS; m/z 444 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.06 (d, J=6.4 Hz, 3H), 1.88-2.00 (m, 1H), 2.11-2.25
(m, 2H), 2.29 (s, 3H), 3.72 (d, J=9.2 Hz, 1H), 3.84 (s, 3H),
4.26-4.37 (m, 2H), 6.90 (s, 1H), 7.00-7.12 (m, 7H), 7.19 (d, J=8.0
Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.69 (s, 1H).
Examples 103 and 104
Synthesis of
(7S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-
-ol and
(7R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-7-ol
##STR00118##
[0666] Synthesis of benzyl (3,4,5-trifluorophenyl)acetate
[0667] Triethylamine (0.808 mL) and benzyl chloroformate (0.752 mL)
were sequentially added dropwise to a solution of
3,4,5-trifluorophenylacetic acid (1 g) in methylene chloride (15
mL) at 0.degree. C., and the reaction solution was stirred at
0.degree. C. for five minutes. DMAP (64.4 mg) was added to the
reaction solution which was then stirred at 0.degree. C. for 30
minutes. Ethyl acetate and saturated sodium bicarbonate water were
added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 1.43 g of the title compound. The property values of the
compound are as follows.
[0668] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.59 (s, 2H), 5.14
(s, 2H), 6.90 (dd, J=8.0, 6.4 Hz, 2H), 7.29-7.38 (m, 5H), 3.83 (s,
3H), 3.89 (s, 3H), 6.44 (s, 1H), 6.95 (brs, 1H), 7.04 (d, J=1.6 Hz,
1H), 7.07 (dd, J=8.0, 1.6 Hz, 1H), 7.20 (t, J=8.8 Hz, 2H), 7.28 (d,
J=8.0 Hz, 1H), 7.78 (d, J=1.2 Hz, 1H), 7.83 (s, 1H), 8.09 (dd,
J=8.8, 5.2 Hz, 2H).
Synthesis of benzyl
(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate and benzyl
(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate
[0669] n-Butyl lithium (1.82 mL; 2.66 M solution in hexane) was
added dropwise to a solution of diisopropylamine (0.735 mL) in THF
(6 mL) at 0.degree. C. The reaction solution was stirred at
0.degree. C. for 20 minutes and then cooled to -78.degree. C.
Benzyl (3,4,5-trifluorophenyl)acetate (1.13 g) in THF (18 mL) was
added dropwise to the reaction solution, and the reaction solution
was stirred at -78.degree. C. for 15 minutes. Thereafter,
3-(tert-butyldiphenylsiloxy)propanol (CAS No. 112897-03-7, 1.26 g)
in THF (6 mL) was added dropwise to the reaction solution, and the
reaction solution was stirred at -78.degree. C. for 30 minutes. A
saturated ammonium chloride solution was added to the reaction
solution, and the reaction solution was returned to room
temperature. Ethyl acetate was added and the organic layer was
separated. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 840 mg of benzyl
(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate and 765 mg of benzyl
(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate.
[0670] The property values of benzyl
(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate are as follows.
[0671] ESI-MS; m/z 615 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.03 (s, 9H), 1.57-1.62 (m, 2H), 3.49 (d, J=2.4 Hz,
1H), 3.57 (d, J=6.8 Hz, 1H), 3.77-3.85 (m, 2H), 4.46 (m, 1H), 5.07
(d, J=12.4 Hz, 1H), 5.14 (d, J=12.4 Hz, 1H), 7.02 (dd, J=8.8, 6.4
Hz, 2H), 7.20-7.45 (m, 11H), 7.62 (d, J=8.0 Hz, 4H).
[0672] The property values of benzyl
(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate are as follows.
[0673] ESI-MS; m/z 615 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.03 (s, 9H), 1.45-1.51 (m, 2H), 3.54 (d, J=4.0 Hz,
1H), 3.57 (d, J=9.2 Hz, 1H), 3.73-3.81 (m, 2H), 4.38 (m, 1H), 5.13
(d, J=12.4 Hz, 1H), 5.19 (d, J=12.4 Hz, 1H), 6.91 (dd, J=8.8, 6.4
Hz, 2H), 7.24-7.44 (m, 11H), 7.57-7.62 (m, 4H).
Synthesis of benzyl
(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5-trif-
luorophenyl)pentanoate
[0674] IPEA (0.742 mL) and chloromethyl methyl ether (0.324 mL)
were added to a solution of benzyl
(2S,3R)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluorophen-
yl)pentanoate (840 mg) in 1,2-dichloroethane (20 mL) at 0.degree.
C. The reaction solution was stirred at 60.degree. C. for 4 hours
and then left to cool to room temperature and concentrated under
reduced pressure. Ethyl acetate and a saturated ammonium chloride
solution were added to the residue, and the organic layer was
separated. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 875 mg of the title compound. The property values of the
compound are as follows.
[0675] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.03 (s, 9H),
1.55-1.64 (m, 1H), 1.70-1.82 (m, 1H), 3.11 (s, 3H), 3.60-3.73 (m,
2H), 3.74 (d, J=6.0 Hz, 1H), 4.38-4.41 (m, 1H), 4.39 (d, J=6.4 Hz,
1H), 4.51 (d, J=6.4 Hz, 1H), 5.12 (s, 2H), 6.95 (dd, J=8.8, 6.8 Hz,
2H), 7.25-7.43 (m, 11H), 7.61 (d, J=8.0 Hz, 4H).
Synthesis of tert-butyl
N'-[(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5--
trifluorophenyl)pentanoyl]hydrazinecarboxylate
[0676] Palladium-carbon (258 mg; 10 wt %) was added to a solution
of benzyl
(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4-
,5-trifluorophenyl)pentanoate (770 mg) in methanol (10 mL). The
reaction solution was stirred in a hydrogen atmosphere for two
hours and then filtered through celite, and the filtrate was
concentrated under reduced pressure. Subsequently, BOPCl (493 mg)
and IPEA (0.316 mL) were added to a solution of the residue of
tert-butyl carbazate (320 mg) in methylene chloride (20 mL) at
0.degree. C. The reaction solution was stirred at room temperature
for 15 hours. Then, ethyl acetate and a saturated ammonium chloride
solution were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 603 mg of the title compound. The property value of the
compound is as follows.
[0677] ESI-MS; m/z 683 [M.sup.++Na].
Synthesis of tert-butyl
N'-[(2S*,3R*)-5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentano-
yl]hydrazinecarboxylate
[0678] TBAF (1.36 mL; 1 M solution in THF) was added to a solution
of tert-butyl
N'-[(2S*,3R*)-5-(tert-butyldiphenylsilanyloxy)-3-methoxymethoxy-2-(3,4,5--
trifluorophenyl)pentanoyl]hydrazinecarboxylate (600 mg) in THF (10
mL). The reaction solution was stirred at room temperature for one
hour. Then, ethyl acetate and a saturated ammonium chloride
solution were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 383 mg of the title compound. The property value of the
compound is as follows.
[0679] ESI-MS; m/z 445 [M.sup.++Na].
Synthesis of tert-butyl
N'-[(2S*,3R*)-5-chloro-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoy-
l]hydrazinecarboxylate
[0680] Triethylamine (0.209 mL) and methanesulfonyl chloride (58
uL) were added to a solution of tert-butyl
N'-[(2S*,3R*)-5-hydroxy-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentano-
yl]hydrazinecarboxylate (264 mg) in methylene chloride (10 mL) at
0.degree. C. The reaction solution was stirred at 0.degree. C. for
30 minutes. Then, ethyl acetate and saturated sodium bicarbonate
water were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. Subsequently, lithium chloride (265 mg) was added
to a solution of the residue in DMF (5 mL), and the reaction
solution was stirred at 80.degree. C. for three hours. The reaction
solution was left to cool to room temperature. Then, water and
ethyl acetate were added to the reaction solution, and the organic
layer was separated. The resulting organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 87.5 mg of the title compound. The property value
of the compound is as follows.
[0681] ESI-MS; m/z 463 [M.sup.++Na].
Synthesis of
(7S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-
-ol and
(7R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-7-ol
[0682] A solution of 4 N hydrochloric acid in ethyl acetate (2 mL)
was added to tert-butyl
N'-[(2S*,3R*)-5-chloro-3-methoxymethoxy-2-(3,4,5-trifluorophenyl)pentanoy-
l]hydrazinecarboxylate (100 mg). The reaction solution was stirred
at room temperature for two hours and then concentrated under
reduced pressure. Subsequently, triethylamine (0.156 mL) was added
to a solution of the residue in ethanol (2.5 mL). A mixed solution
of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (80 mg) and triethylamine (0.156 mL) in ethanol
(2.5 mL) was added dropwise to the solution, and the reaction
solution was stirred at 80.degree. C. for 12 hours. The reaction
solution was left to cool to room temperature and then concentrated
under reduced pressure. Saturated sodium bicarbonate water and
ethyl acetate were added to the resulting residue, and the organic
layer was separated. The resulting organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain a racemate of the title compound. The resulting
racemate was separated by CHIRALCEL.TM. OD-H manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=8:2) to obtain the title optically active compound
with a retention time of 11 minutes (8.2 mg, >99% ee) and the
title optically active compound with a retention time of 17 minutes
(7.4 mg, >99% ee).
[0683] The property values of the title compound with a retention
time of 11 minutes are as follows.
[0684] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.20-2.35 (m, 2H), 2.27 (s, 3H), 3.84 (s, 3H),
4.26-4.34 (m, 3H), 4.39-4.45 (m, 1H), 6.77 (dd, J=8.0, 6.8 Hz, 2H),
6.90 (d, J=1.2 Hz, 1H), 7.01 (d, J=16.4 Hz, 1H), 7.07 (d, J=8.4 Hz,
1H), 7.08 (s, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.45 (d, J=16.4 Hz, 1H),
7.56 (d, J=1.2 Hz, 1H).
[0685] The property values of the title compound with a retention
time of 17 minutes corresponded to the property values of the title
compound with a retention time of 11 minutes.
[0686] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.20-2.35 (m, 2H), 2.27 (s, 3H), 3.84 (s, 3H),
4.26-4.34 (m, 3H), 4.39-4.45 (m, 1H), 6.77 (dd, J=8.0, 6.8 Hz, 2H),
6.86 (d, J=7.2 Hz, 1H), 6.90 (d, J=2.0 Hz, 1H), 7.01 (d, J=16.4 Hz,
1H), 7.07 (d, J=8.4 Hz, 1H), 7.08 (d, J=2.0 Hz, 1H), 7.20 (d, J=8.4
Hz, 1H), 7.45 (d, J=16.4 Hz, 1H), 7.56 (d, J=1.2 Hz, 1H).
Examples 105 and 106
Synthesis of
(7R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-
-ol and
(7S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-7-ol
##STR00119##
[0687] (1) Synthesis of
(7R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-7-
-ol and
(7S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-7-ol
[0688] A racemate of the title compound (55.1 mg) was obtained from
benzyl
(2S*,3S*)-5-(tert-butyldiphenylsilanyloxy)-3-hydroxy-2-(3,4,5-trifluoroph-
enyl)pentanoate (1.01 g) by the same method as in Examples 103 and
104. The resulting racemate was separated by CHIRALPAK.TM. AD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain the title optically active
compound with a retention time of 6 minutes (11.0 mg, >99% ee)
and the title optically active compound with a retention time of 11
minutes (8.6 mg, >99% ee).
[0689] The property values of the title compound with a retention
time of 6 minutes are as follows.
[0690] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.20-2.40 (m, 2H), 2.28 (s, 3H), 3.85 (s, 3H),
4.20-4.34 (m, 3H), 4.40-4.47 (m, 1H), 6.79 (dd, J=8.0, 6.0 Hz, 2H),
6.90 (s, 1H), 7.01 (d, J=16.0 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.11
(s, 1H), 7.20 (d, J=8.8 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.59 (s,
1H).
[0691] The property values of the title compound with a retention
time of 11 minutes corresponded to the property values of the title
compound with a retention time of 6 minutes. ESI-MS; m/z 482
[M.sup.++H]. .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.20-2.40 (m,
2H), 2.28 (s, 3H), 3.85 (s, 3H), 4.20-4.34 (m, 3H), 4.40-4.47 (m,
1H), 6.79 (dd, J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 7.01 (d, J=16.0
Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 7.11 (s, 1H), 7.20 (d, J=8.8 Hz,
1H), 7.46 (d, J=16.0 Hz, 1H), 7.59 (s, 1H).
Examples 107, 108, 109 and 110
Synthesis of
(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol,
(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl-
}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
in-6-ol,
(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]v-
inyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridin-6-ol and
(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol
##STR00120##
[0692] Synthesis of 2-(3,4,5-trifluorophenyl)-4-pentenoic acid
[0693] n-Butyl lithium (7.89 mL; 2.66 M solution in hexane) was
added to a solution of 3,4,5-trifluorophenylacetic acid (2 g) in
THF (50 mL) at -78.degree. C. The reaction solution was stirred at
-78.degree. C. for 20 minutes. Then, the reaction solution was
heated to 0.degree. C. and further stirred for 30 minutes. Allyl
bromide (0.999 mL) was added dropwise to the reaction solution, and
the reaction solution was stirred at room temperature for three
hours. A 1 N sodium hydroxide solution and diethyl ether were added
to the reaction solution, and the aqueous layer was separated. 5 N
hydrochloric acid and ethyl acetate were added to the resulting
aqueous layer, and the organic layer was separated. The resulting
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 1.45 g of the title
compound. The property values of the compound are as follows.
[0694] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.44-2.52 (m, 1H),
2.72-2.81 (m, 1H), 3.58 (t, J=7.6 Hz, 1H), 5.03-5.10 (m, 2H),
5.60-5.71 (m, 1H), 6.90 (dd, J=8.4, 6.4 Hz, 2H).
Synthesis of tert-butyl
N'-[2-(3,4,5-trifluorophenyl)penten-4-oyl]hydrazinecarboxylate
[0695] BOPCl (2.57 g) and IPEA (1.65 mL) were added to a solution
of 2-(3,4,5-trifluorophenyl)-4-pentenoic acid (1.45 g) and
tert-butyl carbazate (1.94 g) in methylene chloride (30 mL) at
0.degree. C. The reaction solution was stirred at room temperature
for 15 hours. Then, ethyl acetate and a saturated ammonium chloride
solution were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 1.77 g of the title compound. The property value of the
compound is as follows.
[0696] ESI-MS; m/z 345 [M.sup.++H].
Synthesis of tert-butyl
N'-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
[0697] Osmium tetroxide (2.61 mL; 2.5 wt %) was added to a solution
of tert-butyl
N'-[2-(3,4,5-trifluorophenyl)penten-4-oyl]hydrazinecarboxylate
(1.77 g) and N-methylmorpholine N-oxide (1.81 g) in acetone (40 mL)
and water (40 mL). The reaction solution was stirred at room
temperature for 4 hours. Then, ethyl acetate and a saturated sodium
thiosulfate solution were added to the reaction solution, and the
organic layer was separated. The resulting organic layer was washed
with 1 N hydrochloric acid and brine, dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
ethyl acetate-methanol system) to obtain 1.09 g of the title
compound. The property value of the compound is as follows.
[0698] ESI-MS; m/z 401 [M.sup.++Na].
Synthesis of
5-(N'-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophe-
nyl)pentyl toluene-4-sulfonate
[0699] p-Toluenesulfonyl chloride (605 mg) was added to a solution
of tert-butyl
N'-[4,5-dihydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarboxylate
(1.09 g) in pyridine (11 mL) at room temperature. The reaction
solution was stirred at room temperature for 12 hours and then
concentrated under reduced pressure. Ethyl acetate was added to the
residue, and the organic layer was washed with brine, dried over
anhydrous sodium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 1.03 g of the title compound. The property value of the
compound is as follows.
[0700] ESI-MS; m/z 555 [M.sup.++H].
Synthesis of tert-butyl
N'-[5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarbox-
ylate
[0701] Lithium chloride (818 mg) was added to a solution of
5-(N'-tert-butoxycarbonylhydrazino)-2-hydroxy-5-oxo-4-(3,4,5-trifluorophe-
nyl)pentyl toluene-4-sulfonate (1.03 g) in DMF (8 mL). The reaction
solution was stirred at 80.degree. C. for three hours and then left
to cool to room temperature. Water and ethyl acetate were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 734 mg of the
title compound. The property value of the compound is as
follows.
[0702] ESI-MS; m/z 419 [M.sup.++Na].
Synthesis of tert-butyl
N'-[4-(tert-butyldiphenylsilanyloxy)-5-chloro-2-(3,4,5-trifluorophenyl)pe-
ntanoyl]hydrazinecarboxylate
[0703] tert-Butyldiphenylchlorosilane (0.889 mL), imidazole (233
mg) and DMAP (41.9 mg) were added to a solution of tert-butyl
N'-[5-chloro-4-hydroxy-2-(3,4,5-trifluorophenyl)pentanoyl]hydrazinecarbox-
ylate (680 mg) in DMF (5 mL). The reaction solution was stirred at
60.degree. C. for two hours and then left to cool to room
temperature. A saturated ammonium chloride solution and ethyl
acetate were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 831 mg of the title compound. The property value of the
compound is as follows.
[0704] ESI-MS; m/z 657 [M.sup.++Na].
Synthesis of
6-(tert-butyldiphenylsilanyloxy)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imida-
zol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4-
]triazolo[1,5-a]pyridine
[0705] TFA (5 mL) was added dropwise to a solution of tert-butyl
N'-[4-(tert-butyldiphenylsilanyloxy)-5-chloro-2-(3,4,5-trifluorophenyl)pe-
ntanoyl]hydrazinecarboxylate (830 mg) in methylene chloride (10 mL)
at 0.degree. C. The reaction solution was stirred at room
temperature for two hours. Then, saturated sodium bicarbonate water
and chloroform were added, and the organic layer was separated. The
aqueous layer was extracted with chloroform twice. The resulting
organic layers were combined, washed with brine, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. Subsequently, triethylamine (1.28 mL) was added to a
solution of the residue in ethanol (10 mL). A mixed solution of
ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (400 mg) in ethanol (10 mL) and triethylamine (1.28
mL) was added dropwise to the solution, and the reaction solution
was stirred at 80.degree. C. for 12 hours. The reaction solution
was left to cool to room temperature and then concentrated under
reduced pressure. Saturated sodium bicarbonate water and ethyl
acetate were added to the resulting residue, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 510 mg of the title compound. The property value of the
compound is as follows.
[0706] ESI-MS; m/z 720 [M.sup.++H].
Synthesis of
(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol,
(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl-
}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
in-6-ol,
(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]v-
inyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridin-6-ol and
(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol
[0707] TBAF (1.06 mL; 1 M solution in THF) was added to a solution
of
6-(tert-butyldiphenylsilanyloxy)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imida-
zol-1-yl)phenyl]vinyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4-
]triazolo[1,5-a]pyridine (510 mg) in THF (10 mL), and the reaction
solution was stirred at room temperature for one hour. Saturated
sodium bicarbonate water and ethyl acetate were added to the
reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: ethyl acetate-methanol system) to obtain a diastereomer
mixture of the title compound. The resulting mixture was separated
by CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries,
Ltd. (2 cm.times.25 cm; mobile phase: ethanol) to obtain
(6R,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol and
(6S,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-6-ol as an optically active compound with a retention time of
5.8 minutes (40.6 mg) and an optically active compound with a
retention time of 7.1 minutes (39.0 mg), respectively.
[0708] The property values of the compound with a retention time of
5.8 minutes are as follows.
[0709] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CD.sub.3 OD)
.delta. (ppm): 1.90-2.20 (m, 1H), 2.24 (s, 3H), 2.40-2.49 (m, 1H),
3.91 (s, 3H), 4.25 (d, J=13.2 Hz, 1H), 4.41-4.53 (m, 3H), 7.06 (d,
J=1.6 Hz, 1H), 7.08 (d, J=16.0 Hz, 1H), 7.14 (dd, J=8.8, 6.0 Hz,
1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.35 (d,
J=1.6 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 7.79 (s, 1H).
[0710] The property values of the compound with a retention time of
7.1 minutes are as follows.
[0711] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CD.sub.3 OD)
.delta. (ppm): 1.90-2.20 (m, 1H), 2.24 (s, 3H), 2.40-2.49 (m, 1H),
3.91 (s, 3H), 4.25 (d, J=13.2 Hz, 1H), 4.41-4.53 (m, 3H), 7.06 (d,
J=1.6 Hz, 1H), 7.08 (d, J=16.0 Hz, 1H), 7.14 (dd, J=8.8, 6.0 Hz,
1H), 7.23 (dd, J=8.0, 1.6 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H), 7.35 (d,
J=1.6 Hz, 1H), 7.48 (d, J=16.0 Hz, 1H), 7.79 (s, 1H).
[0712] The remaining diastereomers were separated by CHIRALPAK.TM.
AD-H manufactured by Daicel Chemical Industries, Ltd. (2
cm.times.25 cm; mobile phase: ethanol) to obtain
(6S,8S)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8--
(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-6-
-ol and
(6R,8R)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridin-6-ol as an optically active compound with a retention time of
6.2 minutes (10.2 mg) and an optically active compound with a
retention time of 8.2 minutes (7.4 mg), respectively.
[0713] The property values of the compound with a retention time of
6.2 minutes are as follows.
[0714] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CD.sub.3 OD)
.delta. (ppm): 2.06-2.15 (m, 1H), 2.23 (s, 3H), 2.49-2.55 (m, 1H),
3.90 (s, 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H), 4.35-4.48 (m, 3H),
7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22 (dd, J=8.0,
1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.46
(d, J=16.4 Hz, 1H), 7.79 (s, 1H).
[0715] The property values of the compound with a retention time of
8.2 minutes are as follows.
[0716] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CD.sub.3 OD)
.delta. (ppm): 2.06-2.15 (m, 1H), 2.23 (s, 3H), 2.49-2.55 (m, 1H),
3.90 (s, 3H), 4.06 (dd, J=12.0, 8.0 Hz, 1H), 4.35-4.48 (m, 3H),
7.03-7.12 (m, 2H), 7.15 (dd, J=8.8, 6.4 Hz, 2H), 7.22 (dd, J=8.0,
1.6 Hz, 1H), 7.32 (d, J=8.0 Hz, 1H), 7.33 (d, J=1.6 Hz, 1H), 7.46
(d, J=16.4 Hz, 1H), 7.79 (s, 1H).
Examples 111 and 112
Synthesis of (-) and
(+)-8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00121##
[0717] Synthesis of tert-butyl
N'-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazinecarboxylate
[0718] n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was
added dropwise to a solution of diisopropylamine (1.5 ml) in THF
(15 ml) at -30.degree. C., and the reaction solution was stirred at
the same temperature for 15 minutes. The reaction solution was
cooled to -78.degree. C. Then, a solution of cyclopropylacetic acid
(CAS No. 5239-82-7, 500 mg) in THF (3 ml) was added dropwise and
the reaction solution was further stirred at room temperature for
three hours. The reaction solution was cooled to 0.degree. C., and
then 1-bromo-3-chloropropane (CAS No. 109-70-6, 0.55 ml) was added
dropwise. The reaction solution was stirred at the same temperature
for 10 minutes and at room temperature for further one hour. Ice
water and diethyl ether were added to the reaction solution, and
the aqueous layer was separated. Then, 5 N hydrochloric acid (3 ml)
and ethyl acetate were added to the aqueous layer, and the organic
layer was separated. The resulting ethyl acetate layer was washed
with brine, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure to obtain crude
5-chloro-2-cyclopropyl-valeric acid (550 mg).
[0719] IPEA (1.6 ml) and BOPCl (1.2 g) were added to a solution of
the crude 5-chloro-2-cyclopropyl-valeric acid (550 mg) and
tert-butyl carbazate (CAS No. 870-46-2, 555 mg) in methylene
chloride (5 ml), and the reaction solution was stirred at room
temperature for three hours. Ethyl acetate and water were added to
the reaction solution, and the organic layer was separated. The
organic layer was sequentially washed with 1 N hydrochloric acid,
water, a saturated sodium bicarbonate solution and brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 210 mg of the title compound. The property value
of the compound is as follows.
[0720] ESI-MS; m/z 313 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.20-0.31 (m, 2H), 0.57-0.70 (m, 2H), 0.90-1.00 (m,
1H), 1.43-1.55 (m, 1H), 1.48 (s, 9H), 1.81-1.97 (m, 4H), 3.49-3.60
(m, 2H), 6.48 (brs, 1H), 7.38 (brs, 1H).
Synthesis of 5-chloro-2-cyclopropyl-valeric acid hydrazide
[0721] Trifluoroacetic acid (0.5 ml) was added to a solution of
tert-butyl
N'-(5-chloro-2-cyclopropyl-pentanoyl)-hydrazinecarboxylate (208 mg)
in methylene chloride (1 ml) under ice-cooling, and then the
reaction solution was stirred at room temperature for two hours. A
saturated sodium bicarbonate solution and ethyl acetate were added
to the reaction solution, and the organic layer was separated. The
organic layer was sequentially washed with a saturated sodium
bicarbonate solution and brine. The combined aqueous layers were
reextracted with ethyl acetate (twice). The combined organic layers
were dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure to obtain 127 mg of the title compound. The
property values of the compound are as follows.
[0722] ESI-MS; m/z 191 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.16-0.24 (m, 2H), 0.52-0.68 (m, 2H), 0.86-0.95 (m,
1H), 1.31-1.37 (m, 1H), 1.78-2.00 (m, 4H), 3.48-3.60 (m, 2H), 3.96
(brs, 2H), 6.88 (brs, 1H).
Synthesis of (-) and
(+)-8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0723] A solution of 5-chloro-2-cyclopropyl-valeric acid hydrazide
(125 mg) in ethanol (1.5 mL) was added to a solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (259 mg) and TEA (0.46 ml) in ethanol (3 ml), and
the reaction solution was stirred at 70.degree. C. for 22 hours.
The reaction solution was left to cool to room temperature. Then,
ethyl acetate and water were added to the reaction solution, and
the organic layer was separated. The organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (carrier: Chromatorex.TM. NH;
elution solvent: heptane-ethyl acetate system) and again purified
by silica gel column chromatography (elution solvent: ethyl
acetate-methanol system) to obtain 43 mg of racemic
8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vin-
yl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: 20%
ethanol-hexane) to obtain the title optically active compound with
a retention time of 28 minutes and negative optical rotation (16.4
mg; 100% ee) and the title optically active compound with a
retention time of 49 minutes and positive optical rotation (16.3
mg; 99% ee).
[0724] The property values of the title optically active compound
with a retention time of 28 minutes are as follows.
[0725] ESI-MS; m/z 376 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.31-0.39 (m, 1H), 0.52-0.65 (m, 2H), 0.73-0.81 (m,
1H), 0.99-1.09 (m, 1H), 1.83-1.93 (m, 1H), 1.97-2.17 (m, 2H),
2.21-2.32 (m, 1H), 2.30 (s, 3H), 2.33-2.40 (m, 1H), 3.88 (s, 3H),
4.16 (t, J=6.0 Hz, 2H), 6.91 (d, J=0.8 Hz, 1H), 7.08 (d, J=16.4 Hz,
1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d,
J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H).
[0726] The property values of the title optically active compound
with a retention time of 49 minutes are as follows.
[0727] ESI-MS; m/z 376 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.31-0.39 (m, 1H), 0.52-0.65 (m, 2H), 0.73-0.81 (m,
1H), 0.99-1.09 (m, 1H), 1.83-1.93 (m, 1H), 1.97-2.17 (m, 2H),
2.21-2.32 (m, 1H), 2.30 (s, 3H), 2.33-2.40 (m, 1H), 3.88 (s, 3H),
4.16 (t, J=6.0 Hz, 2H), 6.91 (d, J=0.8 Hz, 1H), 7.08 (d, J=16.4 Hz,
1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d,
J=8.0 Hz, 1H), 7.54 (d, J=16.4 Hz, 1H), 7.69 (d, J=0.8 Hz, 1H).
Examples 113 and 114
Synthesis of (+) and
(-)-8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-
vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00122##
[0728] Synthesis of methyl 5-chloro-2-cyclohexyl-valerate
[0729] n-Butyl lithium (2.64 M solution in hexane, 3.8 ml) was
added dropwise to a solution of diisopropylamine (1.55 ml) in THF
(15 ml) under ice-cooling, and the reaction solution was stirred at
the same temperature for 10 minutes. The reaction solution was
cooled to -78.degree. C. Then, a solution of methyl
cyclohexylacetate (CAS No. 14352-61-5, 500 mg) in THF (3 ml) was
added dropwise and the reaction solution was stirred at the same
temperature for 30 minutes. Then, 1-chloro-3-iodopropane (CAS No.
6940-76-7, 1.1 ml) was added dropwise to the reaction solution. The
reaction solution was stirred at the same temperature for 20
minutes and then gradually heated to room temperature. Water and
ethyl acetate were added to the reaction solution, and the organic
layer was separated. The organic layer was sequentially washed with
1 N hydrochloric acid, water, a saturated sodium bicarbonate
solution and brine, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (elution solvent:
hexane-diethyl ether system) to obtain 1.00 g of the title
compound. The property value of the compound is as follows.
[0730] ESI-MS; m/z 233 [M.sup.++H].
Synthesis of tert-butyl
N'-(5-chloro-2-cyclohexyl-pentanoyl)-hydrazinecarboxylate
[0731] A 5 N sodium hydroxide solution (2.5 ml) was added to a
solution of methyl 5-chloro-2-cyclohexyl-valerate (1.00 g) in THF
(3 ml)-methanol (6 ml). The reaction solution was stirred at room
temperature for six hours and at 60.degree. C. for further two
hours. After allowing the reaction solution to cool, water and
diethyl ether were added to the reaction solution, and the aqueous
layer was separated. 5 N hydrochloric acid (2.6 ml) and ethyl
acetate were added to the aqueous layer, and the organic layer was
separated. The ethyl acetate extraction layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (heptane-ethyl acetate system) to
obtain 5-chloro-2-cyclohexyl-valeric acid (287 mg).
[0732] IPEA (0.68 ml) and BOPCl (496 mg) were added to a solution
of 5-chloro-2-cyclohexyl-valeric acid (285 mg) and tert-butyl
carbazate (215 mg) in methylene chloride (2.5 ml), and the reaction
solution was stirred at room temperature for 5.5 hours. Ethyl
acetate and water were added to the reaction solution, and the
organic layer was separated. The organic layer was sequentially
washed with 1 N hydrochloric acid, water, a saturated sodium
bicarbonate solution and brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 156 mg of the
title compound. The property values of the compound are as
follows.
[0733] ESI-MS; m/z 355 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 0.90-1.32 (m, 6H), 1.47 (s, 9H), 1.50-1.94 (m, 10H),
3.46-3.61 (m, 2H), 6.46 (brs, 1H), 7.14 (brs, 1H).
Synthesis of 5-chloro-2-cyclohexyl-valeric acid hydrazide
hydrochloride
[0734] tert-Butyl
N'-(5-chloro-2-cyclohexyl-pentanoyl)-hydrazinecarboxylate (155 mg)
was dissolved in a solution of 4 N hydrogen chloride in dioxane (2
ml), and the reaction solution was stirred at room temperature for
one hour. The reaction solution was concentrated under reduced
pressure to obtain 144 mg of the title compound. The property value
of the compound is as follows.
[0735] ESI-MS; m/z 233 [M.sup.++H-HCl].
Synthesis of (+) and
(-)-8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-
vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0736] A solution of 5-chloro-2-cyclohexyl-valeric acid hydrazide
hydrochloride (144 mg) and TEA (0.32 ml) in ethanol (1 ml) was
added to a solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride obtained in Example 1 (167 mg) and TEA (0.32 ml) in
ethanol (1.6 ml), and the reaction solution was stirred at
70.degree. C. for two days. The reaction solution was left to cool
to room temperature. Then, ethyl acetate and water were added to
the reaction solution, and the organic layer was separated. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The resulting
residue was purified by silica gel column chromatography (carrier:
Chromatorex.TM. NH; elution solvent: heptane-ethyl acetate system)
and again purified by silica gel column chromatography (elution
solvent: ethyl acetate-methanol system) to obtain 27 mg of racemic
8-cyclohexyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: 20%
ethanol-hexane) to obtain the title optically active compound with
a retention time of 16 minutes and positive optical rotation (11.0
mg; 100% ee) and the title optically active compound with a
retention time of 39 minutes and negative optical rotation (10.2
mg; 100% ee).
[0737] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0738] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.07-1.54 (m, 7H), 1.66-1.85 (m, 4H), 1.90-2.06 (m,
2H), 2.13-2.25 (m, 2H), 2.30 (s, 3H), 2.84-2.92 (m, 1H), 3.88 (s,
3H), 4.01-4.11 (m, 1H), 4.16-4.24 (m, 1H), 6.91 (s, 1H), 7.06 (d,
J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.4 Hz, 1H), 7.69 (s,
1H).
[0739] The property values of the title optically active compound
with a retention time of 39 minutes are as follows.
[0740] ESI-MS; m/z 418 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.07-1.54 (m, 7H), 1.66-1.85 (m, 4H), 1.90-2.06 (m,
2H), 2.13-2.25 (m, 2H), 2.30 (s, 3H), 2.84-2.92 (m, 1H), 3.88 (s,
3H), 4.01-4.11 (m, 1H), 4.16-4.24 (m, 1H), 6.91 (s, 1H), 7.06 (d,
J=16.4 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.4 Hz, 1H), 7.69 (s,
1H).
Example 115
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-te-
trahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00123##
[0741] Synthesis of tert-butyl (2-oxopiperidin-1-yl)carbamate
[0742] A 4 N sodium hydroxide solution (4 ml) and 5-bromo-valeryl
chloride (CAS No. 4509-90-4, 1.06 ml) were added to a solution of
tert-butyl carbazate (CAS No. 870-46-2, 1 g) in methylene chloride
(10 ml) under ice-cooling. The reaction solution was stirred at the
same temperature for 40 minutes, and then the organic layer was
separated. The organic layer was sequentially washed with water and
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (carrier: Chromatorex.TM. NH;
elution solvent: ethyl acetate) to obtain 2.03 g of a carbazide
compound.
[0743] Potassium tert-butoxide (850 mg) was added to a solution of
the carbazide compound (2.03 g) in THF (30 ml) under ice-cooling.
The reaction solution was stirred at the same temperature for 30
minutes and at room temperature for further 1.5 hours. Ethyl
acetate and water were added to the reaction solution, and the
organic layer was separated. The organic layer was sequentially
washed with water and brine, dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The resulting residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 907 mg of the title
compound. The property values of the compound are as follows.
[0744] ESI-MS; m/z 237 [M.sup.+Na]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.48 (s, 9H), 1.78-1.96 (m, 4H), 2.47 (t, J=6.4 Hz,
2H), 3.58 (t, J=6.0 Hz, 2H), 6.66 (brs, 1H).
Synthesis of 1-aminopiperidin-2-one hydrochloride
[0745] tert-Butyl (2-oxopiperidin-1-yl)carbamate (129 mg) was
dissolved in a solution of 4 N hydrogen chloride in dioxane (2 ml),
and the reaction solution was stirred at room temperature for one
hour. The reaction solution was concentrated under reduced pressure
to obtain 92 mg of the title compound. The property values of the
compound are as follows.
[0746] .sup.1H-NMR (DMSO-D.sub.6) .delta. (ppm): 1.69-1.77 (m, 2H),
1.82-1.90 (m, 2H), 2.41 (t, J=6.4 Hz, 2H), 3.54 (t, J=6.0 Hz,
2H).
Synthesis of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxopiperidin-1-
-yl)acrylamide
[0747] IPEA (0.26 ml), HOBT (121 mg) and EDC (172 mg) were
sequentially added to a suspension of 1-aminopiperidin-2-one
hydrochloride (92 mg) and
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(CAS No. 870839-41-1, 150 mg) in DMF (4 ml), and the reaction
solution was stirred at room temperature overnight. Ethyl acetate
and water were added to the reaction solution, and the organic
layer was separated. The organic layer was sequentially washed with
a saturated sodium bicarbonate solution and brine. The combined
aqueous layers were reextracted with ethyl acetate (twice). The
combined organic layers were dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. The resulting residue was
triturated with ethyl acetate to obtain 97 mg of the title
compound. The property values of the compound are as follows.
[0748] ESI-MS; m/z 355 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.87-2.04 (m, 4H), 2.30 (s, 3H), 2.56 (t, J=6.4 Hz,
2H), 3.70 (t, J=6.0 Hz, 2H), 3.86 (s, 3H), 6.47 (d, J=16.0 Hz, 1H),
6.92 (s, 1H), 7.00 (s, 1H), 7.04 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0
Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.72 (s, 1H), 9.03 (brs, 1H).
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-te-
trahydro[1,2,4]triazolo[1,5-a]pyridine
[0749] A suspension of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-N-(2-oxopiperidin-1-
-yl)acrylamide (96 mg) in phosphorus oxychloride (1 ml) was stirred
at 150.degree. C. for 1.5 hours. Phosphorus oxychloride was
evaporated from the reaction solution under reduced pressure.
Glacial acetic acid (3 ml) and ammonium acetate (630 mg) were added
to the resulting residue, and the reaction solution was stirred at
130.degree. C. for three hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure. Ethyl acetate, water and a saturated sodium bicarbonate
solution were added to the resulting residue, and then the organic
layer was separated. The resulting organic layer was washed with
brine, dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The resulting residue was purified by
silica gel column chromatography (carrier: Chromatorex.TM. NH;
elution solvent: heptane-ethyl acetate system) to obtain 20 mg of
the title compound. The property values of the compound are as
follows.
[0750] ESI-MS; m/z 336 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.97-2.16 (m, 4H), 2.30 (s, 3H), 2.95 (t, J=6.4 Hz,
2H), 3.88 (s, 3H), 4.17 (t, J=6.0 Hz, 2H), 6.91 (s, 1H), 7.06 (d,
J=16.0 Hz, 1H), 7.14-7.20 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.52 (d,
J=16.0 Hz, 1H), 7.69 (s, 1H).
Examples 116 and 117
Synthesis of (-) and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tet-
rahydropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00124##
[0751] Synthesis of ethyl
5-chloro-2-(tetrahydropyran-4-yl)-valerate
[0752] 672 mg of the title compound was obtained from ethyl
(tetrahydropyran-4-yl)acetate (CAS No. 103260-44-2, 650 mg) and
1-chloro-3-iodopropane (0.61 ml) according to the method in Example
113. The property value of the compound is as follows.
[0753] ESI-MS; m/z 249 [M.sup.++H].
Synthesis of tert-butyl
N'-[5-chloro-2-(tetrahydropyran-4-yl)-pentanoyl]-hydrazinecarboxylate
[0754] A 5 N sodium hydroxide solution (1.6 ml) was added to a
solution of ethyl 5-chloro-2-(tetrahydropyran-4-yl)-valerate (672
mg) in THF (2.5 ml)-ethanol (7.5 ml), and the reaction solution was
stirred at room temperature for four days. Water and diethyl ether
were added to the reaction solution, and the aqueous layer was
separated. The aqueous layer was washed with diethyl ether again.
Then, 5 N hydrochloric acid (1.6 ml) and ethyl acetate were added
to the aqueous layer, and the organic layer was separated. The
ethyl acetate extraction layer was washed with brine, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure to obtain crude 5-chloro-2-(tetrahydropyran-4-yl)valeric
acid (442 mg).
[0755] IPEA (1.03 ml) and BOPCl (756 mg) were added to a solution
of the crude 5-chloro-2-(tetrahydropyran-4-yl)valeric acid (442 mg)
and tert-butyl carbazate (357 mg) in methylene chloride (7 ml), and
the reaction solution was stirred at room temperature overnight.
Ethyl acetate and water were added to the reaction solution, and
the organic layer was separated. The organic layer was sequentially
washed with 1 N hydrochloric acid, water, a saturated sodium
bicarbonate solution and brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The resulting
residue was triturated with ethyl acetate to obtain 250 mg of the
title compound. The property values of the compound are as follows.
ESI-MS; m/z 357 [M.sup.++Na]. .sup.1H-NMR (CDCl.sub.3) .delta.
(ppm): 1.28-1.44 (m, 2H), 1.44-1.54 (m, 1H), 1.45 (s, 9H),
1.60-1.83 (m, 7H), 3.30-3.41 (m, 2H), 3.46-3.60 (m, 2H), 3.91-4.03
(m, 2H), 6.43 (brs, 1H), 7.17 (brs, 1H).
Synthesis of 5-chloro-2-(tetrahydropyran-4-yl)-valeric acid
hydrazide hydrochloride
[0756] tert-Butyl
N'-[5-chloro-2-(tetrahydropyran-4-yl)-pentanoyl]-hydrazinecarboxylate
(250 mg) was dissolved in a solution of 4 N hydrogen chloride in
dioxane (2 ml), and the reaction solution was stirred at room
temperature for 2.5 hours. The reaction solution was concentrated
under reduced pressure to obtain 215 mg of the title compound. The
property value of the compound is as follows.
[0757] ESI-MS; m/z 235 [M.sup.++H-HCl].
Synthesis of (-) and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tet-
rahydropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0758] 70 mg of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(tetrahy-
dropyran-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine was
obtained according to the method in Example 113 from ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride obtained in Example 1 (300 mg) and
5-chloro-2-(tetrahydropyran-4-yl)-valeric acid hydrazide
hydrochloride (215 mg). Then, the racemate was separated by
CHIRALPAK.TM. AD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 29 minutes and
negative optical rotation (22.7 mg; 100% ee) and the title
optically active compound with a retention time of 41 minutes and
positive optical rotation (21.3 mg; 99% ee).
[0759] The property values of the title optically active compound
with a retention time of 29 minutes are as follows.
[0760] ESI-MS; m/z 420 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.40-1.1.48 (m, 1H), 1.52-1.83 (m, 4H), 1.95-2.10
(m, 2H), 2.18-2.28 (m, 1H), 2.30 (d, J=0.8 Hz, 3H), 2.33-2.46 (m,
1H), 2.87-2.95 (m, 1H), 3.42-3.53 (m, 2H), 3.88 (s, 3H), 3.97-4.12
(m, 3H), 4.17-4.26 (m, 1H), 6.92 (dd, J=1.2, 0.8 Hz, 1H), 7.06 (d,
J=16.4 Hz, 1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.53 (d,
J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
[0761] The property values of the title optically active compound
with a retention time of 41 minutes are as follows.
[0762] ESI-MS; m/z 420 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.40-1.1.48 (m, 1H), 1.52-1.83 (m, 4H), 1.95-2.10
(m, 2H), 2.18-2.28 (m, 1H), 2.30 (s, 3H), 2.33-2.46 (m, 1H),
2.87-2.95 (m, 1H), 3.42-3.53 (m, 2H), 3.88 (s, 3H), 3.97-4.12 (m,
3H), 4.17-4.26 (m, 1H), 6.92 (d, J=1.2 Hz, 1H), 7.06 (d, J=16.4 Hz,
1H), 7.15-7.20 (m, 2H), 7.23 (d, J=8.4 Hz, 1H), 7.53 (d, J=16.4 Hz,
1H), 7.70 (d, J=1.2 Hz, 1H).
Examples 118 and 119
Synthesis of (+) and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pip-
eridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00125##
[0763] Synthesis of tert-butyl
4-(4-chloro-1-ethoxycarbonyl-butan-1-yl)piperidine-1-carboxylate
[0764] 1.76 g of the title compound was obtained from tert-butyl
4-ethoxycarbonylmethyl-piperidine-1-carboxylate (CAS No.
142851-03-4, 1.95 g) and 1-chloro-3-iodopropane (1.16 ml) according
to the method in Example 113. The property value of the compound is
as follows.
[0765] ESI-MS; m/z 370 [M++Na].
Synthesis of tert-butyl
4-[1-(N'-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]piperidi-
ne-1-carboxylate
[0766] A 5 N sodium hydroxide solution (3 ml) was added to a
solution of tert-butyl
4-(4-chloro-1-ethoxycarbonyl-butan-1-yl)piperidine-1-carboxylate
(1.76 g) in THF (5 ml)-ethanol (15 ml), and the reaction solution
was stirred at room temperature for four days. Water and diethyl
ether were added to the reaction solution, and the aqueous layer
was separated. The aqueous layer was washed with diethyl ether
again. Then, 5 N hydrochloric acid (3 ml) and ethyl acetate were
added to the aqueous layer, and the organic layer was separated.
The ethyl acetate extraction layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure to obtain crude tert-butyl
4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate (1.25
g).
[0767] IPEA (2.0 ml) and BOPCl (1.55 g) were added to a solution of
the crude tert-butyl
4-(1-carboxy-4-chlorobutan-1-yl)piperidine-1-carboxylate (1.25 g)
and benzyl carbazate (CAS No. 5331-43-1, 883 mg) in methylene
chloride (15 ml), and the reaction solution was stirred at room
temperature overnight. Ethyl acetate and water were added to the
reaction solution, and the organic layer was separated. The organic
layer was sequentially washed with 1 N hydrochloric acid, water, a
saturated sodium bicarbonate solution and brine, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 928 mg of the title compound. The property value of the
compound is as follows.
[0768] ESI-MS; m/z 490 [M.sup.++Na].
Synthesis of tert-butyl
4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate
[0769] 10% palladium-carbon (50% wet, 200 mg) was added to a
solution of tert-butyl
4-[1-(N'-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]piperidi-
ne-1-carboxylate (928 mg) in methanol (15 ml), and the reaction
solution was hydrogenated at normal pressure at room temperature
for 4.5 hours. The catalyst is removed by filtration and the
filtrate is concentrated under reduced pressure to obtain 663 mg of
the title compound. The property value of the compound is as
follows.
[0770] ESI-MS; m/z 356[M.sup.++Na].
Synthesis of tert-butyl
4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-
-tetrahdro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate
[0771] A solution of tert-butyl
4-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]piperidine-1-carboxylate
(663 mg) in 1-propanol (4 mL) was added to a solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride obtained in Example 1 (792 mg) and TEA (1.7 mL) in
1-propanol (16 mL), and the reaction solution was stirred at
90.degree. C. overnight. The reaction solution was left to cool to
room temperature and then concentrated under reduced pressure.
Ethyl acetate, water and a saturated sodium bicarbonate solution
were added to the concentration residue, and the organic layer was
separated. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (carrier: Chromatorex.TM. NH; elution solvent:
heptane-ethyl acetate system) to obtain 361 mg of the title
compound. The property value of the compound is as follows.
[0772] ESI-MS; m/z 519[M.sup.++H].
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0773] Trifluoroacetic acid (1 ml) was added to a solution of
tert-butyl
4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-
-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidine-1-carboxylate
(361 mg) in methylene chloride (3 ml), and the mixture was stirred
at room temperature for two hours. A saturated sodium bicarbonate
solution and ethyl acetate were added to the reaction solution, and
the organic layer was separated. The organic layer was sequentially
washed with a saturated sodium bicarbonate solution and brine.
Since most of the target compound was present in the aqueous
layers, the combined aqueous layers were extracted with methylene
chloride three times. The methylene chloride extraction layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (carrier: Chromatorex.TM. NH; elution
solvent: chloroform-methanol system) to obtain 166 mg of the title
compound. The property values of the compound are as follows.
ESI-MS; m/z 419 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3) .delta.
(ppm): 1.34-1.56 (m, 3H), 1.72-1.83 (m, 2H), 1.93-2.09 (m, 2H),
2.16-2.36 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.63-2.75 (m, 2H),
2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88 (s, 3H), 4.02-4.12 (m,
1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.0 Hz,
1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz,
1H), 7.69 (d, J=1.2 Hz, 1H).
Synthesis of (+) and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pip-
eridin-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0774] Racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (5 mg)
was separated by CHIRALPAK.TM. OD-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: 50%
ethanol-hexane) to obtain the title optically active compound with
a retention time of 29 minutes and positive optical rotation (1.58
mg, 100% ee) and the title optically active compound with a
retention time of 55 minutes and negative optical rotation (1.40
mg, 99% ee).
[0775] The property values of the title optically active compound
with a retention time of 29 minutes are as follows.
[0776] ESI-MS; m/z 419 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.34-1.56 (m, 3H), 1.72-1.83 (m, 2H), 1.93-2.09 (m,
2H), 2.16-2.36 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.63-2.75 (m, 2H),
2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88 (s, 3H), 4.02-4.12 (m,
1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.0 Hz,
1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz,
1H), 7.69 (d, J=1.2 Hz, 1H).
[0777] The property values of the title optically active compound
with a retention time of 55 minutes are as follows.
[0778] ESI-MS; m/z 419 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.34-1.56 (m, 3H), 1.72-1.83 (m, 2H), 1.93-2.09 (m,
2H), 2.16-2.36 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.63-2.75 (m, 2H),
2.87-2.93 (m, 1H), 3.06-3.20 (m, 2H), 3.88 (s, 3H), 4.02-4.12 (m,
1H), 4.17-4.25 (m, 1H), 6.92 (t, J=1.2 Hz, 1H), 7.06 (d, J=16.0 Hz,
1H), 7.15-7.20 (m, 2H), 7.22 (d, J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz,
1H), 7.69 (d, J=1.2 Hz, 1H).
Examples 120 and 121
Synthesis of (+) and
(-)-1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethan-
one
##STR00126##
[0780] A 1 N sodium hydroxide solution (0.5 ml) and acetyl chloride
(14 ul) were added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 118 and 119 (25 mg) in methylene chloride (0.5 ml), and
the reaction solution was stirred at room temperature for 40
minutes. Chloroform was added to the reaction solution, and the
organic layer was separated. The aqueous layer was reextracted with
chloroform twice. The combined organic layers were dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to obtain 25 mg of racemic
1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,-
7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]ethanone.
Then, the racemate was separated by CHIRALPAK.TM. IA manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain the title optically active compound with
a retention time of 27 minutes and positive optical rotation (7.4
mg; 100% ee) and the title optically active compound with a
retention time of 34 minutes and negative optical rotation (6.7 mg;
97% ee).
[0781] The property values of the title optically active compound
with a retention time of 27 minutes are as follows.
[0782] ESI-MS; m/z 461 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.30-1.85 (m, 3H), 1.88-2.65 (m, 7H), 2.09 and 2.11
(each s, 3H), 2.30 (s, 3H), 2.88-3.01 (m, 1H), 3.05-3.16 (m, 1H),
3.80-3.95 (m, 1H), 3.88 (s, 3H), 4.01-4.13 (m, 1H), 4.18-4.28 (m,
1H), 4.66-4.80 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0 Hz, 1H),
7.15-7.20 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H),
7.70 (d, J=1.2 Hz, 1H).
[0783] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[0784] ESI-MS; m/z 461 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.30-1.85 (m, 3H), 1.88-2.65 (m, 7H), 2.09 and 2.11
(each s, 3H), 2.30 (s, 3H), 2.88-3.01 (m, 1H), 3.05-3.16 (m, 1H),
3.80-3.95 (m, 1H), 3.88 (s, 3H), 4.01-4.13 (m, 1H), 4.18-4.28 (m,
1H), 4.66-4.80 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0 Hz, 1H),
7.15-7.20 (m, 2H), 7.23 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H),
7.70 (d, J=1.2 Hz, 1H).
Examples 122 and 123
Synthesis of (+) and
(-)-8-(1-isopropylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imid-
azol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00127##
[0786] Acetone (16 .mu.l) and glacial acetic acid (17 .mu.l) were
added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 118 and 119 (30 mg) in THF (3 ml), and the reaction
solution was stirred at room temperature for 30 minutes. Sodium
triacetoxyhydroborate (46 mg) was added to the reaction solution,
and the reaction solution was stirred at room temperature for 1.5
hours. Acetone (80 .mu.A) and sodium triacetoxyhydroborate (184 mg)
were added to the reaction solution, and the reaction solution was
stirred at room temperature overnight. A saturated sodium
bicarbonate solution and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The organic layer
was sequentially washed with water and brine and dried over
anhydrous magnesium sulfate.
[0787] On the other hand, cesium carbonate (47 .mu.l) was added to
a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (20 mg)
and 2-iodopropane (15 .mu.A) in DMF (1 ml), and the reaction
solution was stirred at room temperature overnight. The reaction
solution was concentrated under reduced pressure. Water and ethyl
acetate were added to the residue, and the organic layer was
separated. The organic layer was washed with brine and dried over
anhydrous magnesium sulfate.
[0788] At this time, the organic layer was combined with the
after-treatment solution in the above experiment, and the layers
were concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (carrier:
Chromatorex.TM. NH; elution solvent: ethyl acetate) and again
purified by silica gel column chromatography (elution solvent:
ethyl acetate-methanol system) to obtain 21 mg of racemic
8-(1-isopropylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-
-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.
Then, the racemate was separated by CHIRALCEL.TM. OD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: 40% ethanol-hexane) to obtain the title optically active
compound with a retention time of 9 minutes and positive optical
rotation (4.61 mg; 100% ee) and the title optically active compound
with a retention time of 15 minutes and negative optical rotation
(4.83 mg; 99% ee).
[0789] The property values of the title optically active compound
with a retention time of 9 minutes are as follows.
[0790] ESI-MS; m/z 461 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.06 (s, 3H), 1.07 (s, 3H), 1.40-1.56 (m, 3H),
1.70-1.88 (m, 2H), 1.91-2.09 (m, 2H), 2.13-2.35 (m, 4H), 2.30 (s,
3H), 2.68-2.80 (m, 1H), 2.88-3.04 (m, 3H), 3.88 (s, 3H), 4.02-4.12
(m, 1H), 4.17-4.25 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0 Hz, 1H),
7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,
J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
[0791] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[0792] ESI-MS; m/z 461 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.06 (s, 3H), 1.07 (s, 3H), 1.40-1.56 (m, 3H),
1.70-1.88 (m, 2H), 1.91-2.09 (m, 2H), 2.13-2.35 (m, 4H), 2.30 (s,
3H), 2.68-2.80 (m, 1H), 2.88-3.04 (m, 3H), 3.88 (s, 3H), 4.02-4.12
(m, 1H), 4.17-4.25 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.0 Hz, 1H),
7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d,
J=8.0 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
Examples 124 and 125
Synthesis of (+) and
(-)-8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazo-
l-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00128##
[0794] Benzaldehyde (15 .mu.l) and glacial acetic acid (16 .mu.l)
were added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 118 and 119 (30 mg) in THF (2 ml), and the reaction
solution was stirred at room temperature for 30 minutes. Sodium
triacetoxyhydroborate (46 mg) was added to the reaction solution,
and the reaction solution was stirred at room temperature for four
hours. A saturated sodium bicarbonate solution and ethyl acetate
were added to the reaction solution, and the organic layer was
separated. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate and concentrated under reduced
pressure. The resulting residue was purified by silica gel column
chromatography (carrier: Chromatorex.TM. NH; elution solvent: ethyl
acetate) to obtain 27 mg of racemic
8-(1-benzylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine.
Then, the racemate was separated by CHIRALPAK.TM. IB manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: 50% ethanol-hexane) to obtain the title optically active
compound with a retention time of 14 minutes and positive optical
rotation (9.4 mg; >99% ee) and the title optically active
compound with a retention time of 20 minutes and negative optical
rotation (8.9 mg; 99% ee).
[0795] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[0796] ESI-MS; m/z 509 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.40-1.70 (m, 3H), 1.72-1.82 (m, 2H), 1.90-2.10 (m,
4H), 2.12-2.25 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.87-3.01 (m, 3H),
3.51 (d, J=13.2 Hz, 1H), 3.53 (d, J=13.2 Hz, 1H), 3.88 (s, 3H),
4.02-4.11 (m, 1H), 4.16-4.25 (m, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.05
(d, J=16.0 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.18 (d, J=1.6
Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.23-7.35 (m, 5H), 7.51 (d, J=16.0
Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
[0797] The property values of the title optically active compound
with a retention time of 20 minutes are as follows.
[0798] ESI-MS; m/z 509 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.40-1.70 (m, 3H), 1.72-1.82 (m, 2H), 1.90-2.10 (m,
4H), 2.12-2.25 (m, 2H), 2.30 (d, J=1.2 Hz, 3H), 2.87-3.01 (m, 3H),
3.51 (d, J=13.2 Hz, 1H), 3.53 (d, J=13.2 Hz, 1H), 3.88 (s, 3H),
4.02-4.11 (m, 1H), 4.16-4.25 (m, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.05
(d, J=16.0 Hz, 1H), 7.16 (dd, J=8.0, 1.6 Hz, 1H), 7.18 (d, J=1.6
Hz, 1H), 7.22 (d, J=8.0 Hz, 1H), 7.23-7.35 (m, 5H), 7.51 (d, J=16.0
Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Examples 126 and 127
Synthesis of (+) and
(-)-1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}--
5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenyl-
methanone
##STR00129##
[0800] A 1 N sodium hydroxide solution (0.5 ml) and benzoyl
chloride (11 ul) were added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and
the reaction solution was stirred under ice-cooling for four hours.
Methylene chloride was added to the reaction solution, and the
organic layer was separated. The aqueous layer was reextracted with
methylene chloride. The combined organic layers were dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to obtain 19 mg of racemic
1-[4-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,-
7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)piperidin-1-yl]phenylmeth-
anone. Then, the racemate was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: 50% ethanol-hexane) to obtain the title optically
active compound with a retention time of 16 minutes and positive
optical rotation (6.9 mg; 100% ee) and the title optically active
compound with a retention time of 22 minutes and negative optical
rotation (6.8 mg; >99% ee).
[0801] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0802] ESI-MS; m/z 523 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.30-2.14 (m, 6H), 2.17-2.28 (m, 2H), 2.30 (s, 3H),
2.33-2.58 (m, 1H), 2.70-3.15 (m, 3H), 3.73-3.95 (m, 1H), 3.88 (s,
3H), 4.00-4.16 (m, 1H), 4.18-4.28 (m, 1H), 4.70-4.95 (m, 1H), 6.92
(s, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.14-7.20 (m, 2H), 7.22 (d, J=8.0
Hz, 1H), 7.40 (s, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz,
1H).
[0803] The property values of the title optically active compound
with a retention time of 22 minutes are as follows.
[0804] ESI-MS; m/z 523 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.30-2.14 (m, 6H), 2.17-2.28 (m, 2H), 2.30 (s, 3H),
2.33-2.58 (m, 1H), 2.70-3.15 (m, 3H), 3.73-3.95 (m, 1H), 3.88 (s,
3H), 4.00-4.16 (m, 1H), 4.18-4.28 (m, 1H), 4.70-4.95 (m, 1H), 6.92
(s, 1H), 7.05 (d, J=16.4 Hz, 1H), 7.14-7.20 (m, 2H), 7.22 (d, J=8.0
Hz, 1H), 7.40 (s, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.2 Hz,
1H).
Examples 128 and 129
Synthesis of (+) and
(-)-8-(1-benzenesulfonylpiperidin-4-O-2-{(E)-2-[3-methoxy-4-(4-methyl-1H--
imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00130##
[0806] TEA (20 .mu.l) and benzenesulfonyl chloride (8 .mu.A) were
added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(piperid-
in-4-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 118 and 119 (20 mg) in methylene chloride (1 ml), and
the reaction solution was stirred at room temperature for 40
minutes. Water and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The organic layer
was sequentially washed with a saturated sodium bicarbonate
solution and brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure to obtain 24 mg of racemic
8-(1-benzenesulfonylpiperidin-4-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-im-
idazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine-
. Then, the racemate was separated by CHIRALCEL.TM. OD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain the title optically active
compound with a retention time of 24 minutes and positive optical
rotation (7.3 mg; 100% ee) and the title optically active compound
with a retention time of 29 minutes and negative optical rotation
(7.4 mg; >98% ee).
[0807] The property values of the title optically active compound
with a retention time of 24 minutes are as follows.
[0808] ESI-MS; m/z 559 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.50-1.76 (m, 3H), 1.82-2.37 (m, 8H), 2.30 (d, J=1.2
Hz, 3H), 2.87-2.95 (m, 1H), 3.80-3.96 (m, 2H), 3.87 (s, 3H),
4.00-4.10 (m, 1H), 4.17-4.27 (m, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.01
(d, J=16.0 Hz, 1H), 7.13 (dd, J=8.0, 1.2 Hz, 1H), 7.16 (d, J=1.2
Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.53 (td,
J=7.2, 1.2 Hz, 2H), 7.61 (tt, J=7.2, 1.2 Hz, 1H), 7.69 (d, J=1.2
Hz, 1H), 7.76 (dt, J=8.0, 1.2 Hz, 2H).
[0809] The property values of the title optically active compound
with a retention time of 29 minutes are as follows.
[0810] ESI-MS; m/z 559 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.50-1.76 (m, 3H), 1.82-2.37 (m, 8H), 2.30 (d, J=1.2
Hz, 3H), 2.87-2.95 (m, 1H), 3.80-3.96 (m, 2H), 3.87 (s, 3H),
4.00-4.10 (m, 1H), 4.17-4.27 (m, 1H), 6.91 (t, J=1.2 Hz, 1H), 7.01
(d, J=16.0 Hz, 1H), 7.13 (dd, J=8.0, 1.2 Hz, 1H), 7.16 (d, J=1.2
Hz, 1H), 7.21 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.53 (td,
J=7.2, 1.2 Hz, 2H), 7.61 (tt, J=7.2, 1.2 Hz, 1H), 7.69 (d, J=1.2
Hz, 1H), 7.76 (dt, J=8.0, 1.2 Hz, 2H).
Examples 130, 131, 132 and 133
Synthesis of (-), (+), (+) and
(-)-8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidaz-
ol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00131##
[0811] Synthesis of tert-butyl
2-methoxycarbonylmethyl-pyrrolidine-1-carboxylate
[0812] Trimethylsilyldiazomethane (2 M solution in hexane, 1.5 ml)
was added dropwise to a mixed solution of tert-butyl
2-carboxymethylpyrrolidine-1-carboxylate (CAS No. 194154-91-1, 500
mg) in methanol (1 ml)-toluene (1 ml) under ice-cooling, and the
reaction solution was stirred at the same temperature for three
hours. The reaction solution was concentrated. The resulting
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain 506 mg of the
title compound. The property values of the compound are as
follows.
[0813] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.46 (s, 9H),
1.67-1.90 (m, 3H), 1.98-2.12 (m, 1H), 2.30 (dd, J=15.2, 10.0 Hz,
1H), 2.75-3.02 (m, 1H), 3.26-3.45 (m, 2H), 3.67 (s, 3H), 4.04-4.25
(m, 1H)
Synthesis of tert-butyl
2-(4-chloro-1-methoxycarbonyl-butan-1-yl)pyrrolidine-1-carboxylate
[0814] 335 mg of the title compound was obtained from tert-butyl
2-methoxycarbonylmethyl-pyrrolidine-1-carboxylate (506 mg) and
1-chloro-3-iodopropane (335 .mu.l) according to the method in
Example 113. The property value of the compound is as follows.
[0815] ESI-MS; m/z 342 [M.sup.++Na].
Synthesis of tert-butyl
2-[1-(N'-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]pyrrolid-
ine-1-carboxylate
[0816] 142 mg of the title compound was obtained from tert-butyl
2-(4-chloro-1-methoxycarbonyl-butan-1-yl)pyrrolidine-1-carboxylate
(335 mg) according to the method in Example 118. The property value
of the compound is as follows.
[0817] ESI-MS; m/z 476 [M.sup.++Na].
Synthesis of tert-butyl
2-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]pyrrolidine-1-carboxylate
[0818] 107 mg of the title compound was obtained from tert-butyl
2-[1-(N'-benzyloxycarbonyl-hydrazinocarbonyl)-4-chlorobutan-1-yl]pyrrolid-
ine-1-carboxylate (142 mg) according to the method in Example 118.
The property value of the compound is as follows.
[0819] ESI-MS; m/z 342 [M.sup.++Na].
Synthesis of tert-butyl
2-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-
-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyrrolidine-1-carboxylate
[0820] 56 mg of the title compound was obtained from ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (125 mg) and tert-butyl
2-[4-chloro-1-hydrazinocarbonyl-butan-1-yl]pyrrolidine-1-carboxylate
(107 mg) according to the method in Example 118. The property value
of the compound is as follows.
[0821] ESI-MS; m/z 505 [M.sup.++H].
Synthesis of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrroli-
din-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0822] 24 mg of the title compound was obtained from tert-butyl
2-(2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-
-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)pyrrolidine-1-carboxylate
(56 mg) according to the method in Example 118. The property value
of the compound is as follows.
[0823] ESI-MS; m/z 405 [M.sup.++H].
Synthesis of (-), (+), (+) and
(-)-8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidaz-
ol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0824] 8 mg of a diastereomer mixture,
8-(1-benzylpyrrolidin-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine,
was obtained from
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrroli-
din-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (10 mg)
according to the method in Example 124. The diastereomer mixture
was separated by CHIRALPAK.TM. AD-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: 100% ethanol) to
obtain the title optically active compound with a retention time of
26 minutes and negative optical rotation (1.43 mg; >96% ee).
Then, the diastereomer mixture with a retention time of 19.5 to 23
minutes in the AD-H column was separated again by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: 50% ethanol-hexane) to obtain the title optically
active compound with a retention time of 7.5 minutes and positive
optical rotation (0.90 mg; >99% ee), the title optically active
compound with a retention time of 8 minutes and positive optical
rotation (1.75 mg; >99% ee) and the title optically active
compound with a retention time of 14 minutes and negative optical
rotation (8.9 mg; 99% ee).
[0825] The property values of the title optically active compound
with a retention time of 26 minutes in the AD-H column are as
follows.
[0826] ESI-MS; m/z 495 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.70-1.79 (m, 2H), 1.84-2.35 (m, 7H), 2.30 (s, 3H),
2.91-2.98 (m, 1H), 3.02-3.09 (m, 1H), 3.23 (d, J=13.2 Hz, 1H), 3.52
(d, J=13.2 Hz, 1H), 3.57-3.64 (m, 1H), 3.87 (s, 3H), 3.99-4.08 (m,
1H), 4.14-4.23 (m, 1H), 6.91 (s, 1H), 7.04 (d, J=16.0 Hz, 1H),
7.12-7.26 (m, 8H) 7.52 (d, J=16.0 Hz, 1H), 7.69 (d, J=0.8 Hz,
1H).
[0827] The property values of the title optically active compound
with a retention time of 7.5 minutes in the IB column are as
follows.
[0828] ESI-MS; m/z 495 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.25-1.40 (m, 1H), 1.55-2.02 (m, 5H), 2.16-2.37 (m,
3H), 2.30 (s, 3H), 2.95-3.03 (m, 1H), 3.22-3.30 (m, 1H), 3.37 (d,
J=13.2 Hz, 1H), 3.50-3.60 (m, 1H), 3.88 (s, 3H), 4.00-4.11 (m, 2H),
4.24-4.31 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.16 (dd,
J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),
7.25-7.40 (m, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz,
1H).
[0829] The property values of the title optically active compound
with a retention time of 8 minutes in the IB column are as
follows.
[0830] ESI-MS; m/z 495 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.70-1.79 (m, 2H), 1.84-2.35 (m, 7H), 2.30 (s, 3H),
2.91-2.98 (m, 1H), 3.02-3.09 (m, 1H), 3.23 (d, J=13.2 Hz, 1H), 3.52
(d, J=13.2 Hz, 1H), 3.57-3.64 (m, 1H), 3.87 (s, 3H), 3.99-4.08 (m,
1H), 4.14-4.23 (m, 1H), 6.91 (s, 1H), 7.04 (d, J=16.0 Hz, 1H),
7.12-7.26 (m, 8H) 7.52 (d, J=16.0 Hz, 1H), 7.69 (d, J=0.8 Hz,
1H).
[0831] The property values of the title optically active compound
with a retention time of 14 minutes in the IB column are as
follows.
[0832] ESI-MS; m/z 495 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.25-1.40 (m, 1H), 1.55-2.02 (m, 5H), 2.16-2.37 (m,
3H), 2.30 (s, 3H), 2.95-3.03 (m, 1H), 3.22-3.30 (m, 1H), 3.37 (d,
J=13.2 Hz, 1H), 3.50-3.60 (m, 1H), 3.88 (s, 3H), 4.00-4.11 (m, 2H),
4.24-4.31 (m, 1H), 6.92 (s, 1H), 7.06 (d, J=16.4 Hz, 1H), 7.16 (dd,
J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H),
7.25-7.40 (m, 5H), 7.52 (d, J=16.4 Hz, 1H), 7.70 (d, J=1.6 Hz,
1H).
Examples 134 and 135
Synthesis of erythro- and
threo-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(1-
-phenylpyrrolidin-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00132##
[0834] Bromobenzene (12 ul) was added to a solution of
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(pyrroli-
din-2-yl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine obtained
in Examples 130, 131, 132 and 133 (15 mg),
tris(dibenzylideneacetone)dipalladium (0) (7 mg),
bis(diphenylphosphino)-1,1-binaphthalene (10 mg) and sodium
tert-butoxide (13 mg) in toluene (3 ml)-dioxane (1 ml). The
reaction solution was stirred at an external temperature of
100.degree. C. overnight. Tris(dibenzylideneacetone)dipalladium (0)
(7 mg), bis(diphenylphosphino)-1,1-binaphthalene (10 mg), sodium
tert-butoxide (13 mg) and bromobenzene (12 ul) were added to the
reaction solution, and the reaction solution was heated for further
nine hours. After leaving the reaction solution to cool, ethyl
acetate and water were added to the reaction solution and the
organic layer was separated. The resulting organic layer was washed
with brine, dried over anhydrous magnesium sulfate and then
evaporated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (carrier:
Chromatorex.TM. NH; elution solvent: heptane-ethyl acetate system)
to obtain 10.3 mg of a diastereomer mixture of the title
compound.
[0835] The mixture was separated by LC-MS. A saturated sodium
bicarbonate solution and ethyl acetate were added to each of the
resulting diastereomers, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure to
obtain 0.35 mg of the title compound with a short retention time in
LC-MS and 0.25 mg of the title compound with a long retention time
in LC-MS.
[0836] The property value of the title diastereomer with a short
retention time in LC-MS is as follows.
[0837] ESI-MS; m/z 481 [M.sup.++H].
[0838] The property value of the title diastereomer with a long
retention time in LC-MS is as follows.
[0839] ESI-MS; m/z 481 [M.sup.++H].
Examples 136, 137, 138 and 139
Synthesis of (+), (+), (-) and
(-)-8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl--
1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine
##STR00133##
[0840] Synthesis of methyl
2-(6,6-dimethyltetrahydropyran-2-yl)acetate
[0841] Cerium chloride heptahydrate (812 mg) and sodium iodide (327
mg) were added to a solution of methyl
3-hydroxy-7-methyl-6-octenoate obtained by the method described in
Heterocycles, 34, 1107-1117 (1992) (4.06 g) in acetonitrile (10
ml), and the reaction solution was heated under reflux for 10
hours. The reaction solution was left to cool and then concentrated
under reduced pressure. Diethyl ether and 12 ml of 1 N hydrochloric
acid were added to the resulting residue, and the organic layer was
separated. Diethyl ether was added to the aqueous layer, and the
organic layer was separated. The combined organic layers were
sequentially washed with water, a saturated sodium bicarbonate
solution (pH=9), a 5% sodium thiosulfate solution, water and brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 2.65 g of the title compound. The property values
of the compound are as follows.
[0842] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.08-1.48 (m, 3H),
1.18 (s, 3H), 1.20 (s, 3H), 1.57-1.73 (m, 3H), 2.34 (dd, J=14.8,
6.0 Hz, 1H), 2.48 (dd, J=14.8, 7.2 Hz, 1H), 3.67 (s, 3H), 3.94-4.02
(m, 1H).
Synthesis of tert-butyl
N'-[5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)pentanoyl]hydrazinecarbo-
xylate
[0843] n-Butyl lithium (2.64 M solution in hexane, 1.1 ml) was
added dropwise to a solution of diisopropylamine (0.45 ml) in THF
(6 ml), and the reaction solution was stirred at -30.degree. C. for
15 minutes. The reaction solution was cooled to -78.degree. C.
Hexamethylphosphoramide (0.75 ml) and a solution of methyl
2-(6,6-dimethyltetrahydropyran-2-yl)acetate (500 mg) in THF (3 ml)
were sequentially added dropwise to the reaction solution, and the
reaction solution was stirred at the same temperature for 20
minutes. 1-Chloro-3-iodopropane (0.43 ml) was added dropwise to the
resulting reaction solution. The reaction solution was gradually
heated, and then a saturated ammonium chloride solution was added
to the reaction solution. Ethyl acetate and water were added to the
reaction solution, and the organic layer was separated. The
resulting organic layer was sequentially washed with 1 N
hydrochloric acid, water, a saturated sodium bicarbonate solution
and brine, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The resulting residue was
purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 278 mg of methyl
5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)valerate.
[0844] 39 mg of the title compound was obtained from 278 mg of
methyl 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)valerate
according to the method in Example 113. The property values of the
compound are as follows.
[0845] ESI-MS; m/z 385 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.15-1.33 (m, 1H), 1.21 (s, 3H), 1.23 (s, 3H),
1.36-1.57 (m, 3H), 1.47 (s, 9H), 1.58-1.98 (m, 6H), 2.26-2.33 (m,
1H), 3.48-3.62 (m, 2H), 3.63-3.76 (m, 1H), 6.39 (brs, 1H), 8.17 and
8.40 (each brs, 1H).
Synthesis of 5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric
acid hydrazide hydrochloride
[0846] 36 mg of the title compound was obtained from 39 mg of
tert-butyl
N'-[5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)pentanoyl]hydrazinecarbo-
xylate according to the method in Example 113. The property value
of the compound is as follows.
[0847] ESI-MS; m/z 263 [M.sup.+-HCl+H].
Synthesis of (+), (+), (-) and
(-)-8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl--
1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine
[0848] 5.2 mg of a diastereomer mixture,
8-(6,6-dimethyltetrahydropyran-2-yl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-i-
midazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e, was obtained according to the method in Example 113 from ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride obtained in Example 1 (47 mg) and
5-chloro-2-(6,6-dimethyltetrahydropyran-2-yl)-valeric acid
hydrazide hydrochloride (36 mg). The diastereomer mixture was
separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: 30%
ethanol-hexane) to obtain the title optically active compound with
a retention time of 13 minutes and positive optical rotation (0.75
mg), the title optically active compound with a retention time of
14 minutes and positive optical rotation (0.21 mg), the title
optically active compound with a retention time of 16 minutes and
negative optical rotation (0.13 mg) and the title optically active
compound with a retention time of 24 minutes and negative optical
rotation (0.54 mg).
[0849] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[0850] ESI-MS; m/z 448 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.12 (s, 3H), 1.14 (s, 3H), 1.30-1.50 (m, 3H),
1.60-1.76 (m, 2H), 1.73-2.00 (m, 3H), 2.12-2.35 (m, 2H), 2.30 (d,
J=0.8 Hz, 3H), 2.93 (dd, J=11.6, 6.0 Hz, 1H), 3.88 (s, 3H),
4.04-4.20 (m, 3H), 6.91 (brs, 1H), 7.07 (d, J=16.0 Hz, 1H), 7.16
(dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz,
1H), 7.51 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
[0851] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[0852] ESI-MS; m/z 448 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.15-1.80 (m, 6H), 1.19 (s, 3H), 1.28 (s, 3H),
1.81-2.05 (m, 2H), 2.10-2.40 (m, 2H), 2.30 (s, 3H), 3.12-3.20 (m,
1H), 3.88 (s, 3H), 4.02-4.40 (m, 3H), 6.92 (brs, 1H), 7.07 (d,
J=16.0 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.70 (s,
1H).
[0853] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0854] ESI-MS; m/z 448 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.15-1.80 (m, 6H), 1.19 (s, 3H), 1.28 (s, 3H),
1.81-2.05 (m, 2H), 2.10-2.40 (m, 2H), 2.30 (s, 3H), 3.12-3.20 (m,
1H), 3.88 (s, 3H), 4.02-4.40 (m, 3H), 6.92 (brs, 1H), 7.07 (d,
J=16.0 Hz, 1H), 7.17 (dd, J=8.0, 1.6 Hz, 1H), 7.21 (d, J=1.6 Hz,
1H), 7.22 (d, J=8.0 Hz, 1H), 7.52 (d, J=16.0 Hz, 1H), 7.70 (s,
1H).
[0855] The property values of the title optically active compound
with a retention time of 24 minutes are as follows.
[0856] ESI-MS; m/z 448 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.12 (s, 3H), 1.14 (s, 3H), 1.30-1.50 (m, 3H),
1.60-1.76 (m, 2H), 1.73-2.00 (m, 3H), 2.12-2.35 (m, 2H), 2.30 (d,
J=0.8 Hz, 3H), 2.93 (dd, J=11.6, 6.0 Hz, 1H), 3.88 (s, 3H),
4.04-4.20 (m, 3H), 6.91 (brs, 1H), 7.07 (d, J=16.0 Hz, 1H), 7.16
(dd, J=8.0, 1.6 Hz, 1H), 7.19 (d, J=1.6 Hz, 1H), 7.22 (d, J=8.0 Hz,
1H), 7.51 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz, 1H).
Examples 140 and 141
Synthesis of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00134##
[0857] Synthesis of 4-chloro-2-phenylbutyric acid
[0858] A 2.64 M solution of butyl lithium in hexane (28 mL) was
added to a solution of phenylacetic acid (5.07 g) in THF (150 mL)
in a nitrogen atmosphere at -78.degree. C., and the reaction
solution was stirred at -78.degree. C. for 20 minutes. The reaction
solution was further stirred at 0.degree. C. for one hour. Then,
1-bromo-2-chloroethane (3.1 mL) was added at 0.degree. C., and the
reaction solution was stirred at room temperature for 14 hours.
Ethyl acetate and 1 N hydrochloric acid were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with a saturated sodium chloride solution.
The resulting organic layer was dried over magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (elution solvent: heptane-ethyl
acetate system) to obtain 5.54 g of the title compound. The
property values of the compound are as follows.
[0859] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.19-2.28 (m, 1H),
2.47-2.57 (m, 1H), 3.32-3.40 (m, 1H), 3.52-3.58 (m, 1H), 3.92 (dd,
J=8.0, 7.2 Hz, 1H), 7.26-7.37 (m, 5H).
Synthesis of
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
[0860] Oxalyl chloride (1.56 mL) and DMF (1 drop) were added to a
solution of 4-chloro-2-phenylbutyric acid (2.28 g) in methylene
chloride (40 mL) at 0.degree. C., and the reaction solution was
stirred at room temperature for one hour. The reaction solution was
concentrated under reduced pressure to obtain
4-chloro-2-phenylbutyric acid chloride. A solution of
4-chloro-2-phenylbutyric acid chloride in THF (10 mL) was added to
a solution of tert-butyl carbazate (1.5 g) and triethylamine (7.8
mL) in THF (40 mL) at 0.degree. C., and the reaction solution was
stirred at room temperature for one hour. The reaction solution was
added to a saturated sodium bicarbonate solution, followed by
extraction with ethyl acetate. The resulting extract was dried over
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain tert-butyl
N'-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). A
solution of 4 N hydrogen chloride in ethyl acetate (50 mL) was
added to tert-butyl
N'-(4-chloro-2-phenylbutyryl)hydrazinecarboxylate (3.17 g). The
reaction solution was stirred at room temperature for one hour and
then concentrated under reduced pressure to obtain
4-chloro-2-phenylbutyric acid hydrazide hydrochloride (2.52 g). A
solution of 4-chloro-2-phenylbutyric acid hydrazide hydrochloride
(2.52 g) and triethylamine (5.7 mL) in ethanol (40 mL) was added to
a solution of ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (3.00 g) and triethylamine (6.0 mL) in ethanol (50
mL) at room temperature, and the reaction solution was stirred at
80.degree. C. for 24 hours. The reaction solution was left to cool
to room temperature and then concentrated under reduced pressure. A
saturated sodium bicarbonate solution was added to the resulting
residue, followed by extraction with chloroform. The resulting
extract was dried over magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (carrier: Chromatorex NH; elution solvent:
heptane-ethyl acetate system) to obtain 231 mg of the racemic title
compound. The property values of the compound are as follows.
[0861] ESI-MS; m/z 398 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.29 (d, J=0.4 Hz, 3H), 2.67-2.76 (m, 1H), 3.20-3.30
(m, 1H), 3.87 (s, 3H), 4.17-4.25 (m, 1H), 4.30-4.38 (m, 1H), 4.45
(dd, J=8.8, 6.0 Hz, 1H), 6.89-6.92 (m, 1H), 7.08 (d, J=16.0 Hz,
1H), 7.14-7.38 (m, 8H), 7.56 (d, J=16.0 Hz, 1H), 7.69 (d, J=1.2 Hz,
1H).
[0862] The racemic title compound (16 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=7:3) to obtain the
title optically active compound with a retention time of 32 minutes
and positive optical rotation (4 mg) and the title optically active
compound with a retention time of 39 minutes and negative optical
rotation (6 mg).
[0863] The following compounds were obtained by the same method as
in Examples 140 and 141 (Table 4).
TABLE-US-00004 TABLE 4 ##STR00135## Example E.sub.3 DATA: MS m/z
Note 142 ##STR00136## M.sup.+ + H: 432 (ESI) Optically active
compound (separation conditions IA: ethanol: retention time 22 min,
optical rotation (+)) 143 ##STR00137## M.sup.+ + H: 432 (ESI)
Optically active compound (separation conditions IA: ethanol:
retention time 27 min, optical rotation (-)) 144 ##STR00138##
M.sup.+ + H: 416 (ESI) Optically active compound (separation
conditions IA: ethanol: retention time 25 min, optical rotation
(+)) 145 ##STR00139## M.sup.+ + H: 416 (ESI) Optically active
compound (separation conditions IA: ethanol: retention time 28 min,
optical rotation (-))
[0864] The following compounds were obtained by the same method as
in Examples 53 and 54 (Table 5).
TABLE-US-00005 TABLE 5 ##STR00140## Example E.sub.3 DATA: MS m/z
Note 146 ##STR00141## M.sup.+ + H: 414 (ESI) Optically active
compound (separation conditions OJ-H, hexane:ethanol = 4:1,
retention time 20 min, optical rotation (-)) 147 ##STR00142##
M.sup.+ + H: 414 (ESI) Optically active compound (separation
conditions OJ-H, hexane:ethanol = 4:1, retention time 34 min,
optical rotation (+)) 148 ##STR00143## M.sup.+ + H: 432 (ESI)
Optically active compound (separation conditions IA, hexane:ethanol
= 4:1, retention time 31 min, optical rotation (-)) 149
##STR00144## M.sup.+ + H: 432 (ESI) Optically active compound
(separation conditions IA, hexane:ethanol = 4:1, retention time 47
min, optical rotation (+)) 150 ##STR00145## M.sup.+ + H: 448 (ESI)
Optically active compound (separation conditions IA, hexane:ethanol
= 4:1, retention time 35 min, optical rotation (-)) 151
##STR00146## M.sup.+ + H: 448 (ESI) Optically active compound
(separation conditions IA, hexane:ethanol = 4:1, retention time 39
min, optical rotation (+))
[0865] The following compounds were obtained by the same method as
in Examples 65 and 66 (Table 6).
TABLE-US-00006 TABLE 6 ##STR00147## Example E.sub.3 DATA: MS m/z
Note 152 ##STR00148## M.sup.+ + H: 423 (ESI) Optically active
compound (separation conditions IA, hexane:ethanol = 1:1, retention
time 15 min, optical rotation (+)) 153 ##STR00149## M.sup.+ + H:
423 (ESI) Optically active compound (separation conditions IA,
hexane:ethanol = 1:1, retention time 18 min, optical rotation (-))
154 ##STR00150## M.sup.+ + H: 441 (ESI) Optically active compound
(separation conditions IB, hexane:ethanol = 4:1, retention time 28
min, optical rotation (-)) 155 ##STR00151## M.sup.+ + H: 441 (ESI)
Optically active compound (separation conditions IB, hexane:ethanol
= 4:1, retention time 34 min, optical rotation (+)) 156
##STR00152## M.sup.+ + H: 457 (ESI) Optically active compound
(separation conditions IB, hexane:ethanol = 4:1, retention time 23
min, optical rotation (-)) 157 ##STR00153## M.sup.+ + H: 457 (ESI)
Optically active compound (separation conditions IB, hexane:ethanol
= 4:1, retention time 32 min, optical rotation (+)) 158
##STR00154## M.sup.+ + H: 477 (ESI) Optically active compound
(separation conditions IB, hexane:ethanol = 1:1, retention time 10
min, optical rotation (-)) 159 ##STR00155## M.sup.+ + H: 477 (ESI)
Optically active compound (separation conditions IB, hexane:
ethanol = 1:1, retention time 13 min, optical rotation (+))
Examples 160 and 161
Synthesis of
(-)-7-fluoro-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole and
(+)-7-fluoro-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00156##
[0867] DAST (0.11 mL) was added to a solution of racemic
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phenyl-6-
,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol synthesized in
Examples 146 and 147 (115 mg) in methylene chloride (5 mL) in a
nitrogen atmosphere at 0.degree. C., and the reaction solution was
stirred at 0.degree. C. for one hour. A saturated sodium
bicarbonate solution was added to the reaction solution, followed
by extraction with ethyl acetate. The resulting extract was dried
over magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH; elution solvent:
heptane-ethyl acetate system) to obtain 33 mg of the racemic title
compound. The property values of the compound are as follows.
[0868] ESI-MS; m/z 416 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 3.10-3.26 (m, 1H), 3.28-3.42 (m, 1H),
3.88 (s, 3H), 4.30-4.40 (m, 1H), 4.44-4.53 (m, 1H), 6.92 (brs, 1H),
7.11 (d, J=16.0 Hz, 1H), 7.15-7.26 (m, 3H), 7.39-7.48 (m, 3H),
7.54-7.59 (m, 2H), 7.64 (d, J=16.0 Hz, 1H), 7.70 (brs, 1H).
[0869] The racemic title compound (33 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=8:2) to obtain the
title optically active compound with a retention time of 32 minutes
and negative optical rotation (10 mg) and the title optically
active compound with a retention time of 36 minutes and positive
optical rotation (10 mg).
Example 162
Synthesis of
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-4H-[1,2,4]triazol-3-yl}amine
##STR00157##
[0870] Synthesis of tert-butyl
N'-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazi-
necarboxylate
[0871] HOBT (420 mg) and EDC (590 mg) were sequentially added to a
solution of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(530 mg), tert-butyl carbazate (271 mg) and IPEA (0.71 mL) in DMF
(10 mL), and the reaction solution was stirred at room temperature
for 15 hours. Ethyl acetate and saturated sodium bicarbonate water
were added to the reaction solution, and the organic layer was
separated. The resulting organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
resulting solid was recrystallized from a mixed solution of ethyl
acetate and ethanol to obtain 668 mg of the title compound. The
property values of the compound are as follows.
[0872] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.51 (s, 9H), 2.30
(s, 3H), 3.88 (s, 3H), 6.45 (d, J=15.6 Hz, 1H), 6.76 (brs, 1H),
6.93 (s, 1H), 7.09 (brs, 1H), 7.11 (brd, J=8.0 Hz, 1H), 7.25 (d,
J=8.0 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.73 (s, 1H), 8.80 (brs,
1H).
Synthesis of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
hydrazide dihydrochloride
[0873] A solution of 4 N hydrochloric acid in ethyl acetate (3 mL)
was added to a solution of tert-butyl
N'-{(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acryloyl}hydrazi-
necarboxylate (668 mg) in ethyl acetate (5 mL) and methanol (1 mL),
and the reaction solution was stirred at room temperature for two
hours. The solid precipitated in the reaction solution was
collected by filtration and washed with diethyl ether to obtain 658
mg of the title compound. The property value of the compound is as
follows.
[0874] ESI-MS; m/z 273 [M.sup.++H].
Synthesis of
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-[1,3,4]oxadiazol-2-yl}amine
[0875] TEA (1.25 mL) was added to a solution of
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
hydrazide dihydrochloride (771 mg) in DMF (15 mL) at room
temperature, and the reaction solution was stirred at room
temperature for 10 minutes. 4-Fluorophenyl isocyanate (0.26 mL) was
added to the reaction solution at room temperature, and the
reaction solution was stirred at room temperature for one hour. The
reaction solution was added to cold water. The generated solid was
separated by filtration, washed with water and diethyl ether and
then dried at 60.degree. C. for three hours. Phosphorus oxychloride
(15 mL) was added to the resulting solid at room temperature, and
the reaction solution was heated under reflux for three hours. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. A saturated sodium bicarbonate
solution was added to the residue. The generated solid was
separated by filtration, washed with diethyl ether and then dried
at 60.degree. C. for one hour to obtain 820 mg of the title
compound. The property value of the compound is as follows.
[0876] ESI-MS; m/z 392 [M.sup.++H].
Synthesis of
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-4H-[1,2,4]triazol-3-yl}amine
[0877] Acetic acid (10 mL) and ammonium acetate (6.8 g) were added
to
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-[1,3,4]oxadiazol-2-yl}amine (692 mg), and the reaction
solution was stirred at 150.degree. C. for 12 hours. The reaction
solution was left to cool to room temperature and then concentrated
under reduced pressure. A saturated sodium bicarbonate solution was
added to the resulting residue, followed by extraction with
chloroform. The insoluble matter generated during separation was
added to the resulting extract, and THF and ethanol were further
added to provide a mixed solution. The mixed solution was
concentrated under reduced pressure and solidified with ethyl
acetate and diethyl ether to obtain 372 mg of the title compound.
The property values of the compound are as follows.
[0878] ESI-MS; m/z 391 [M.sup.++H]. .sup.1H-NMR (DMSO-d.sub.6)
.delta. (ppm): 2.16 (s, 3H), 3.91 (s, 3H), 7.04-7.19 (m, 4H),
7.27-7.30 (m, 1H), 7.36-7.48 (m, 2H), 7.51 (s, 1H), 7.57-7.64 (m,
2H), 7.80 (s, 1H).
Example 163
Synthesis of
8-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrimidin-7-one
##STR00158##
[0879] Synthesis of
N-(4-fluorophenyl)-N-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-[1,3,4]oxadiazol-2-yl}acrylamide
[0880] TEA (0.07 mL) was added to a suspension of
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-[1,3,4]oxadiazol-2-yl}amine synthesized in Example 162 (100
mg) in methylene chloride (3 mL) and THF (2 mL) at room
temperature. Acrylic acid chloride (0.03 mL) was added to the
reaction solution at 0.degree. C., and the reaction solution was
stirred at room temperature for two hours. TEA (0.08 mL) and
acrylic acid chloride (0.04 mL) were added to the reaction solution
at room temperature, and the reaction solution was stirred at room
temperature for two hours. Further, DMF (0.5 mL), acetonitrile (0.5
mL), DMAP (2 mg), TEA (0.08 mL) and acrylic acid chloride (0.04 mL)
were added and the reaction solution was stirred at room
temperature for 12 hours. The reaction solution was concentrated
under reduced pressure. Ethyl acetate and a saturated sodium
bicarbonate solution were added to the residue, and the organic
layer was separated. The resulting organic layer was dried over
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system, then ethyl acetate-methanol
system) to obtain 22 mg of the title compound. The property value
of the compound is as follows.
[0881] ESI-MS; m/z 446 [M.sup.++H].
Synthesis of
8-(4-fluorophenyl)-3-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[4,3-a]pyrimidin-7-one
[0882] Acetic acid (1 mL) and ammonium acetate (0.11 g) were added
to
N-(4-fluorophenyl)-N-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)ph-
enyl]vinyl}-[1,3,4]oxadiazol-2-yl}acrylamide (22 mg), and the
reaction solution was stirred at 150.degree. C. for six hours. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. A saturated sodium bicarbonate
solution was added to the resulting residue, followed by extraction
with chloroform. The resulting extract was dried over magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: heptane-ethyl acetate system, then
ethyl acetate-methanol system) to obtain 1 mg of the title
compound. The property values of the compound are as follows.
[0883] ESI-MS; m/z 445 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 3.16 (t, J=6.8 Hz, 2H), 3.91 (s, 3H),
4.39 (t, J=6.8 Hz, 2H), 6.85 (d, J=16.0 Hz, 1H), 6.94 (s, 1H),
7.12-7.29 (m, 5H), 7.33-7.40 (m, 2H), 7.59 (d, J=16.0 Hz, 1H), 7.73
(d, J=1.2 Hz, 1H).
Example 164
Synthesis of
4-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-6,7-dihydro-4H-[1,2,4]triazolo[1,5-a]pyrimidin-5-one
##STR00159##
[0885] DMF (3 mL) and TEA (0.06 mL) were added to
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162 (44
mg), and the reaction solution was stirred at room temperature for
10 minutes. Acrylic acid chloride (0.01 mL) was added to the
reaction solution at room temperature, and the reaction solution
was stirred at room temperature for one hour and at 60.degree. C.
for two hours. TEA (0.03 mL) and acrylic acid chloride (0.01 mL)
were added to the reaction solution at 60.degree. C., and the
reaction solution was stirred at 60.degree. C. for four hours. The
reaction solution was left to cool to room temperature and then
diluted with ethyl acetate and washed with a saturated sodium
bicarbonate solution and a saturated sodium chloride solution. The
resulting organic layer was dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane-ethyl acetate system, then ethyl acetate-methanol
system) and further purified by silica gel column chromatography
(elution solvent: heptane-ethyl acetate system, then ethyl
acetate-methanol system) to obtain 6 mg of the title compound. The
property values of the compound are as follows.
[0886] ESI-MS; m/z 445 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.29 (d, J=0.8 Hz, 3H), 3.23 (t, J=7.2 Hz, 2H), 3.86
(s, 3H), 4.47 (t, J=7.2 Hz, 2H), 6.90-6.92 (m, 1H), 6.94 (d, J=16.0
Hz, 1H), 7.11-7.15 (m, 2H), 7.19-7.27 (m, 3H), 7.33-7.38 (m, 2H),
7.46 (d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
Example 165
Synthesis of
8-(4-fluorophenyl)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)pheny-
l]vinyl}-5,6,7,8-tetrahydro-4H-1,3,3a,8-tetraazaazulene
##STR00160##
[0888] 60% sodium hydride (10 mg) was added to a solution of
(4-fluorophenyl)-{5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl-
]vinyl}-4H-[1,2,4]triazol-3-yl}amine synthesized in Example 162
(47.5 mg) in DMF (3 mL) at room temperature, and the reaction
solution was stirred at room temperature for 10 minutes.
1,4-Dibromobutane (0.02 mL) was added to the reaction solution at
room temperature, and the reaction solution was stirred at room
temperature for two hours. 60% sodium hydride (5 mg) was added to
the reaction solution at room temperature, and the reaction
solution was stirred at room temperature for two hours. A saturated
ammonium chloride solution was added to the reaction solution at
0.degree. C., followed by extraction with ethyl acetate. The
resulting extract was washed with a saturated sodium bicarbonate
solution and a saturated sodium chloride solution. The resulting
organic layer was dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane-ethyl acetate system, then ethyl acetate-methanol
system), silica gel column chromatography (elution solvent:
heptane-ethyl acetate system, then ethyl acetate-methanol system)
and CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries,
Ltd. (2 cm.times.25 cm; mobile phase: ethanol) to obtain 14 mg of
the title compound. The property values of the compound are as
follows.
[0889] ESI-MS; m/z 445 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.94-2.06 (m, 4H), 2.29 (s, 3H), 3.69-3.76 (m, 2H),
3.85 (s, 3H), 4.23-4.30 (m, 2H), 6.89-6.95 (m, 2H), 7.00-7.06 (m,
2H), 7.10-7.22 (m, 5H), 7.40 (d, J=16.0 Hz, 1H), 7.68 (d, J=0.8 Hz,
1H).
Examples 166 and 167
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00161##
[0890] Synthesis of 5-hydroxy-3-phenylpentanoic acid hydrazide
[0891] Hydrazine monohydrate (1.6 mL) was added to a solution of
4-phenyl-tetrahydropyran-2-one (573 mg; CAS No. 61949-75-5) in
ethanol (3 mL) at room temperature, and the reaction solution was
heated under reflux for three hours. The reaction solution was left
to cool to room temperature and then concentrated under reduced
pressure. A saturated sodium bicarbonate solution was added to the
resulting residue, followed by extraction with chloroform. The
resulting extract was dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (elution solvent: ethyl
acetate-methanol system) to obtain 492 mg of the title compound.
The property value of the compound is as follows.
[0892] ESI-MS; m/z 209 [M.sup.++H].
Synthesis of and
2-(4-chloro-2-phenylbutyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-[1,3,4]oxadiazole
[0893] IPEA (2.0 mL),
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(600 mg) and BOPCl (0.71 g) were added to a solution of
5-hydroxy-3-phenylpentanoic acid hydrazide (492 mg) in methylene
chloride (20 mL) at room temperature, and the reaction solution was
stirred at room temperature for seven hours. Water was added to the
reaction solution, followed by extraction with chloroform. The
resulting extract was washed with a saturated sodium bicarbonate
solution. The resulting organic layer was dried over magnesium
sulfate and then concentrated under reduced pressure. Phosphorus
oxychloride (10 mL) was added to the resulting residue at room
temperature, and the reaction solution was heated under reflux for
1.5 hours. The reaction solution was left to cool to room
temperature and then concentrated under reduced pressure. A
saturated sodium bicarbonate solution was added to the residue,
followed by extraction with ethyl acetate. The resulting extract
was dried over magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH; elution solvent:
heptane-ethyl acetate system) to obtain 445 mg of the title
compound. The property value of the compound is as follows.
[0894] ESI-MS; m/z 449 [M.sup.++H].
Synthesis of
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(+)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-phen-
yl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0895] Acetic acid (5 mL) and ammonium acetate (1.2 g) were added
to
2-(4-chloro-2-phenylbutyl)-5-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1--
yl)phenyl]vinyl}-[1,3,4]oxadiazole (224 mg), and the reaction
solution was stirred at 150.degree. C. for 17 hours. The reaction
solution was left to cool to room temperature and then concentrated
under reduced pressure. A saturated sodium bicarbonate solution was
added to the resulting residue, followed by extraction with ethyl
acetate. The resulting extract was dried over magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (carrier: Chromatorex NH;
elution solvent: heptane-ethyl acetate system) to obtain 115 mg of
the racemic title compound. The property values of the compound are
as follows.
[0896] ESI-MS; m/z 412 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.27-2.44 (m, 2H), 2.30 (d, J=0.8 Hz, 3H), 3.00-3.11
(m, 1H), 3.25-3.37 (m, 2H), 3.88 (s, 3H), 4.17-4.26 (m, 1H),
4.27-4.35 (m, 1H), 6.91-6.94 (m, 1H), 7.08 (d, J=16.4 Hz, 1H),
7.15-7.32 (m, 6H), 7.35-7.40 (m, 2H), 7.55 (d, J=16.4 Hz, 1H), 7.70
(d, J=1.6 Hz, 1H).
[0897] The racemic title compound (26 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:IPA=1:4) to obtain the
title optically active compound with a retention time of 25 minutes
and negative optical rotation (10 mg) and the title optically
active compound with a retention time of 29 minutes and positive
optical rotation (6.6 mg).
Examples 168 and 169
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00162##
[0898] Synthesis of 6-chloro-2-methoxy-3-nitropyridine
[0899] Sodium methoxide (2.8 g) was added to a solution of
2,6-dichloro-3-nitropyridine (10 g) in THF (100 mL) at 0.degree.
C., and the reaction solution was stirred at room temperature for
13 hours. A saturated ammonium chloride solution and ethyl acetate
were added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 6.49 g of the title compound. The property value of the
compound is as follows.
[0900] ESI-MS; m/z 189 [M.sup.++H].
Synthesis of ethyl
(E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylate
[0901] Palladium acetate (386 mg),
2-(di-tert-butylphosphino)biphenyl (1.03 g), triethylamine (9.59
mL) and ethyl acrylate (18.6 mL) were added to a solution of
6-chloro-2-methoxy-3-nitropyridine (6.49 g) in DMF (100 mL). The
reaction solution was stirred in a nitrogen atmosphere at
120.degree. C. for two hours and then left to cool to room
temperature. The reaction solution was concentrated under reduced
pressure. Water and ethyl acetate were added to the resulting
residue, and the organic layer was separated. The resulting organic
layer was washed with water and brine, dried over anhydrous sodium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) and crystallized from heptane to
obtain 2.1 g of the title compound. The property values of the
compound are as follows.
[0902] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.37 (t, J=7.6 Hz,
3H), 4.15 (s, 3H), 4.30 (q, J=7.6 Hz, 2H), 7.00 (d, J=16.0 Hz, 1H),
7.09 (d, J=8.4 Hz, 1H), 7.56 (d, J=16.0 Hz, 1H), 8.28 (d, J=8.4 Hz,
1H).
Synthesis of ethyl
(E)-3-(5-amino-6-methoxypyridin-2-yl)acrylate
[0903] Iron (3.72 g) and ammonium chloride (7.13 g) were added to a
solution of ethyl (E)-3-(6-methoxy-5-nitropyridin-2-yl)acrylate
(2.1 g) in ethanol (100 mL) and water (20 mL). The reaction
solution was stirred at 100.degree. C. for one hour and then left
to cool to room temperature. The reaction solution was filtered
through celite. Ethyl acetate was added and the organic layer was
separated. The resulting organic layer was washed with saturated
sodium bicarbonate water and brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 1.85 g of the title
compound. The property values of the compound are as follows.
[0904] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.33 (t, J=7.2 Hz,
3H), 4.01 (s, 3H), 4.07 (brs, 2H), 4.25 (q, J=7.2 Hz, 2H), 6.71 (d,
J=15.6 Hz, 1H), 6.78 (d, J=7.6 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H),
7.51 (d, J=15.6 Hz, 1H).
Synthesis of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate
[0905] A mixed solution prepared from acetic anhydride (6.29 mL)
and formic acid (9.42 mL) was added dropwise to a solution of ethyl
(E)-3-(5-amino-6-methoxypyridin-2-yl)acrylate (1.85 g) in THF (30
mL) at 0.degree. C. The reaction solution was stirred at room
temperature for one hour and then added dropwise to ice water.
Ethyl acetate was added and the organic layer was separated. The
resulting organic layer was washed with saturated sodium
bicarbonate water and brine, dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. Subsequently, cesium
carbonate (4.87 g), potassium iodide (124 mg) and chloroacetone
(1.23 mL) were added to a solution of the residue in DMF (20 mL),
and the reaction solution was stirred at room temperature for 12
hours. Ice water and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with water and brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain a crude product.
Subsequently, ammonium acetate (2.88 g) was added to a solution of
the resulting compound in acetic acid (4.28 mL), and the reaction
solution was stirred at 130.degree. C. for one hour. The reaction
solution was left to cool to room temperature. Ice water and ethyl
acetate were added and the organic layer was separated. The
resulting organic layer was washed with saturated sodium
bicarbonate water and brine, dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 1.50 g of the title
compound. The property values of the compound are as follows.
[0906] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.36 (t, J=7.2 Hz,
3H), 2.30 (d, J=0.8 Hz, 3H), 4.07 (s, 3H), 4.29 (q, J=7.2 Hz, 2H),
6.95 (d, J=15.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz,
1H), 7.58 (d, J=15.6 Hz, 1H), 7.83 (d, J=0.8 Hz, 1H).
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid
[0907] A 5 N sodium hydroxide solution (4 mL) was added to a
solution of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate
(1.5 g) in methanol (10 mL) and THF (6 mL). The reaction solution
was stirred at room temperature for two hours, and then 5 N
hydrochloric acid (5 mL) was added to the reaction solution. The
generated precipitate was filtered and washed with THF to obtain
755 mg of the title compound. The property values of the compound
are as follows.
[0908] ESI-MS; m/z 260 [M.sup.++H]. .sup.1H-NMR (DMSO-d.sub.6)
.delta. (ppm): 2.16 (s, 3H), 3.99 (s, 3H), 6.81 (d, J=16.0 Hz, 1H),
7.27 (s, 1H), 7.42 (d, J=8.0 Hz, 1H), 7.57 (d, J=16.0 Hz, 1H), 7.89
(d, J=8.0 Hz, 1H), 7.94 (s, 1H).
Synthesis of 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one
[0909] 6.6 g of the title compound was obtained from
3,4,5-trifluorophenylacetic acid (11 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0910] ESI-MS; m/z 245 [M.sup.++H].
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3-
,4,5-trifluorophenyl)piperidin-1-yl]acrylamide
[0911] EDC (667 mg), HOBT (470 mg) and IPEA (1.01 mL) were added to
a suspension of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (300 mg) and 1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one
(368 mg) in DMF (10 mL). The reaction solution was stirred at room
temperature for 15 hours. Then, water and ethyl acetate were added
to the reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: ethyl acetate-methanol system) to obtain 508 mg of the
title compound. The property value of the compound is as
follows.
[0912] ESI-MS; m/z 486 [M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
[0913] Phosphorus oxychloride (5 mL) was added to
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3-
,4,5-trifluorophenyl)piperidin-1-yl]acrylamide (508 mg). The
reaction solution was stirred at 120.degree. C. for one hour and
then concentrated under reduced pressure. Subsequently, ammonium
acetate (2.43 g) was added to a solution of the residue in acetic
acid (5 mL), and the reaction solution was stirred at 150.degree.
C. for two hours. The reaction solution was left to cool to room
temperature and then concentrated under reduced pressure. Saturated
sodium bicarbonate water and ethyl acetate were added to the
resulting residue, and the organic layer was separated. The
resulting organic layer was washed with brine, dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (elution
solvent: heptane-ethyl acetate system) to obtain a racemate of the
title compound. The resulting racemate was separated by
CHIRALCEL.TM. OD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 6 minutes and
positive optical rotation (108.8 mg, >99% ee) and the title
optically active compound with a retention time of 8 minutes and
negative optical rotation (104.8 mg, >99% ee).
[0914] The property values of the title compound with a retention
time of 6 minutes are as follows.
[0915] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.06 (m, 1H), 2.11-2.22 (m, 2H), 2.29 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 4.05 (s, 3H), 4.25-4.31 (m, 3H),
4.39-4.45 (m, 1H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 6.94 (d, J=8.0 Hz,
1H), 6.95 (d, J=1.2 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.47 (d,
J=8.0 Hz, 1H), 7.64 (d, J=15.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).
[0916] The property values of the title compound with a retention
time of 8 minutes are as follows.
[0917] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.06 (m, 1H), 2.11-2.22 (m, 2H), 2.29 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 4.05 (s, 3H), 4.25-4.31 (m, 3H),
4.39-4.45 (m, 1H), 6.81 (dd, J=8.0, 6.4 Hz, 2H), 6.94 (d, J=8.0 Hz,
1H), 6.95 (d, J=1.2 Hz, 1H), 7.45 (d, J=15.2 Hz, 1H), 7.47 (d,
J=8.0 Hz, 1H), 7.64 (d, J=15.2 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).
Examples 170 and 171
Synthesis of (+) and
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00163##
[0919] 242 mg of the racemic title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (600 mg) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one
(471 mg) in the same manner as in Examples 168 and 169. The
property values of the compound are as follows.
[0920] ESI-MS; m/z 449 [M.sup.++H].
[0921] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.25 (m, 3H),
2.29 (s, 3H), 2.31-2.41 (m, 1H), 4.05 (s, 3H), 4.27-4.32 (m, 3H),
6.87-6.91 (m, 1H), 6.93-6.95 (m, 2H), 6.97-7.00 (m, 1H), 7.09-7.16
(m, 1H), 7.45 (d, J=15.6 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 7.64 (d,
J=15.6 Hz, 1H), 7.76 (d, J=1.6 Hz, 1H).
[0922] The racemic title compound was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain the title optically active
compound with a retention time of 13.5 minutes and positive optical
rotation (100 mg) and the title optically active compound with a
retention time of 20.0 minutes and negative optical rotation (94
mg).
Examples 172 and 173
Synthesis of
(+)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00164##
[0923] Synthesis of 1-amino-3-(4-fluorophenyl)piperidin-2-one
[0924] 3.6 g of the title compound was obtained from
4-fluorophenylacetic acid (6 g) according to the method in Examples
20 and 21. The property value of the compound is as follows.
[0925] ESI-MS; m/z 209 [M.sup.++H].
Synthesis of
(+)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0926] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (150 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (181
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with a retention time of 18 minutes and positive optical rotation
(6.2 mg, >99% ee) and the title optically active compound with a
retention time of 42 minutes and negative optical rotation (5.5 mg,
>99% ee).
[0927] The property values of the title compound with a retention
time of 18 minutes are as follows.
[0928] ESI-MS; m/z 431 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.27-4.35 (m, 3H), 6.93 (d, J=8.0
Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m, 2H), 7.08-7.12 (m, 2H), 7.45
(d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.6 Hz,
1H), 7.76 (s, 1H).
[0929] The property values of the title compound with a retention
time of 42 minutes are as follows.
[0930] ESI-MS; m/z 431 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.27-4.35 (m, 3H), 6.93 (d, J=8.0
Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m, 2H), 7.08-7.12 (m, 2H), 7.45
(d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.6 Hz,
1H), 7.76 (s, 1H).
Examples 174 and 175
Synthesis of
(-)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00165##
[0931] Synthesis of
1-amino-3-(3-chloro-4-fluorophenyl)piperidin-2-one
[0932] The title compound (2.8 g) was obtained from
3-chloro-4-fluorophenylacetic acid (5.0 g) according to the method
in Examples 20 and 21. The property value of the compound is as
follows.
[0933] ESI-MS; m/z 243 [M.sup.++H].
Synthesis of
(-)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-8-(3-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[0934] A racemate of the title compound (30 mg) was obtained from
1-amino-3-(3-chloro-4-fluorophenyl)piperidin-2-one (100 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (200 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: 80% ethanol-hexane, flow rate: 10 mL/min) to isolate the
title optically active compound with a retention time of 19 minutes
and positive optical rotation (13.6 mg) and the title optically
active compound with a retention time of 23 minutes and negative
optical rotation (13.6 mg). The property values of the title
optically active compound with a retention time of 23 minutes are
as follows.
[0935] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.96-2.26 (m, 3H),
2.26-2.44 (m, 1H), 2.29 (s, 3H), 4.05 (s, 3H), 4.30 (t, J=6.0 Hz,
3H), 6.95 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 7.00-7.06 (m, 1H), 7.12
(t, J=8.0 Hz, 1H), 7.20 (dd, J=2.4, 6.8 Hz, 1H), 7.46 (d, J=16 Hz,
1H), 7.47 (d, J=8.0 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.77 (d, J=1.6
Hz, 1H).
[0936] ESI-MS; m/z 465 [M.sup.++H].
[0937] The property values of the title optically active compound
with a retention time of 19 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 176 and 177
Synthesis of
(-)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00166##
[0938] Synthesis of
1-amino-3-(4-chloro-3-fluorophenyl)piperidin-2-one
[0939] The title compound (940 mg) was obtained from
4-chloro-3-fluorobenzaldehyde (5.0 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0940] ESI-MS; m/z 243 [M.sup.++H].
Synthesis of
(-)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-8-(4-chloro-3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[0941] A racemate of the title compound (300 mg) was obtained from
1-amino-3-(4-chloro-3-fluorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (477 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to isolate the title optically
active compound with a retention time of 15 minutes and positive
optical rotation (91 mg) and the title optically active compound
with a retention time of 23 minutes and negative optical rotation
(82 mg). The property values of the title optically active compound
with a retention time of 23 minutes are as follows.
[0942] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.96-2.32 (m, 3H),
2.29 (s, 3H), 2.32-2.44 (m, 1H), 4.05 (s, 3H), 4.24-4.36 (m, 3H),
6.88-7.00 (m, 4H), 7.37 (t, J=7.2 Hz, 1H), 7.46 (d, J=15.6 Hz, 1H),
7.47 (d, J=7.2 Hz, 1H), 7.65 (d, J=15.6 Hz, 1H), 7.70 (s, 1H).
[0943] ESI-MS; m/z 465 [M.sup.++H].
[0944] The property values of the title optically active compound
with a retention time of 15 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 178 and 179
Synthesis of
(-)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imid-
azol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
##STR00167##
[0945] Synthesis of
1-amino-3-(2,4,5-trifluorophenyl)piperidin-2-one
[0946] The title compound (2.4 g) was obtained from
2,4,5-trifluorophenylacetic acid (5.0 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0947] ESI-MS; m/z 245 [M.sup.++H].
Synthesis of
(-)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,4,5-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imid-
azol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
[0948] A racemate of the title compound (19 mg) was obtained from
1-amino-3-(2,4,5-trifluorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (439 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: 80% ethanol-hexane, flow rate: 10 mL/min) to isolate the
title optically active compound with a retention time of 17 minutes
and positive optical rotation (6.6 mg) and the title optically
active compound with a retention time of 26 minutes and negative
optical rotation (6.6 mg). The property values of the title
optically active compound with a retention time of 26 minutes are
as follows.
[0949] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.96-2.32 (m, 3H),
2.94 (s, 3H), 2.32-2.46 (m, 1H), 4.05 (s, 3H), 4.26-4.38 (m, 2H),
4.50-4.56 (m, 1H), 6.78-6.88 (m, 1H), 6.92-7.02 (m, 3H), 7.45 (d,
J=16 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.65 (d, J=16 Hz, 1H), 7.78
(d, J=1.2 Hz, 1H).
[0950] ESI-MS; m/z 467 [M.sup.++H].
[0951] The property values of the title optically active compound
with a retention time of 17 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 180 and 181
Synthesis of
(-)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imid-
azol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
##STR00168##
[0952] Synthesis of
1-amino-3-(2,3,6-trifluorophenyl)piperidin-2-one
[0953] The title compound (820 mg) was obtained from
2,3,6-trifluorophenylacetic acid (2.0 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0954] ESI-MS; m/z 245 [M.sup.++H].
Synthesis of
(-)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,3,6-trifluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imid-
azol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyri-
dine
[0955] A racemate of the title compound (120 mg) was obtained from
1-amino-3-(2,3,6-trifluorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (439 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to isolate the title optically
active compound with a retention time of 11 minutes and positive
optical rotation (54 mg) and the title optically active compound
with a retention time of 16 minutes and negative optical rotation
(55 mg). The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[0956] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.44 (m, 4H),
2.29 (s, 3H), 4.04 (s, 3H), 4.20-4.32 (m, 1H), 4.32-4.44 (m, 1H),
4.60-4.70 (m, 1H), 6.80-6.90 (m, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.95
(s, 1H), 7.04-7.16 (m, 1H), 7.41 (d, J=15.6 Hz, 1H), 7.46 (d, J=7.6
Hz, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.76 (s, 1H).
[0957] ESI-MS; m/z 467 [M.sup.++H].
[0958] The property values of the title optically active compound
with a retention time of 11 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 182 and 183
Synthesis of
(-)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e
##STR00169##
[0959] Synthesis of
1-amino-3-(2,5-difluorophenyl)piperidin-2-one
[0960] The title compound (790 mg) was obtained from
2,5-difluorophenylacetic acid (930 mg) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0961] ESI-MS; m/z 227 [M.sup.++H].
Synthesis of
(-)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e
[0962] A racemate of the title compound (170 mg) was obtained from
1-amino-3-(2,5-difluorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (477 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 11 minutes and positive optical
rotation (48 mg) and the title optically active compound with a
retention time of 22 minutes and negative optical rotation (51 mg).
The property values of the title optically active compound with a
retention time of 22 minutes are as follows.
[0963] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.32 (m, 3H),
2.29 (s, 3H), 2.32-2.46 (m, 1H), 4.05 (s, 3H), 4.31 (t, J=5.6 Hz,
2H), 4.57 (t, J=5.6 Hz, 1H), 6.64-6.73 (m, 1H), 6.90-7.00 (m, 3H),
7.00-7.10 (m, 1H), 7.46 (d, J=16 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H),
7.66 (d, J=16 Hz, 1H), 7.77 (s, 1H). ESI-MS; m/z 449
[M.sup.++H].
[0964] The property values of the title optically active compound
with a retention time of 11 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 184 and 185
Synthesis of (+) and
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00170##
[0965] Synthesis of
1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one
[0966] The title compound (2.6 g) was obtained using
2-bromo-4-fluorophenylacetic acid (3 g) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[0967] ESI-MS; m/z 289 [M.sup.++H].
Synthesis of (+) and
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
[0968] A racemate of the title compound (149 mg) was obtained using
1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (300 mg) as a
starting material according to the method in Examples 168 and 169.
The resulting racemate (149 mg) was separated by CHIRALPAK.TM. OD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 23 minutes and
positive optical rotation (44 mg) and the title optically active
compound with a retention time of 31 minutes and negative optical
rotation (45 mg).
[0969] The property values of the title optically active compound
with a retention time of 23 minutes are as follows.
[0970] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.20 (m, 3H),
2.29 (s, 3H), 2.35-2.45 (m, 1H), 4.05 (s, 3H), 4.29-4.32 (m, 2H),
4.72 (dd, J=6.8, 6.8 Hz, 1H), 6.84-7.00 (m, 4H), 7.36 (dd, J=8.0,
2.8 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.47 (d, J=4.8 Hz, 1H), 7.65
(d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
[0971] The property values of the title optically active compound
with a retention time of 31 minutes are as follows.
[0972] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.20 (m, 3H),
2.29 (s, 3H), 2.35-2.45 (m, 1H), 4.05 (s, 3H), 4.29-4.32 (m, 2H),
4.72 (dd, J=6.8, 6.8 Hz, 1H), 6.84-7.00 (m, 4H), 7.36 (dd, J=8.0,
2.8 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.47 (d, J=4.8 Hz, 1H), 7.65
(d, J=16.0 Hz, 1H), 7.70 (d, J=1.2 Hz, 1H).
Examples 186 and 187
Synthesis of
(+)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00171##
[0973] Synthesis of
1-amino-3-(2-chloro-4-fluorophenyl)piperidin-2-one
[0974] 2.9 g of the title compound was obtained using methyl
2-chloro-4-fluorophenylacetate (3 g) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[0975] ESI-MS; m/z 243 [M.sup.++H].
Synthesis of
(+)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(2-chloro-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[0976] A racemate of the title compound (174 mg) was obtained using
1-amino-3-(2-chloro-4-fluorophenyl)piperidin-2-one (300 mg) as a
starting material according to the method in Examples 168 and 169.
The resulting racemate (174 mg) was separated by CHIRALPAK.TM. OD-H
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 22 minutes and
positive optical rotation (68 mg) and the title optically active
compound with a retention time of 30 minutes and negative optical
rotation (69 mg).
[0977] The property values of the title optically active compound
with a retention time of 22 minutes are as follows.
[0978] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.99-2.41 (m, 7H),
4.05 (s, 3H), 4.27-4.34 (m, 2H), 4.72 (dd, J=6.0, 6.0 Hz, 1H),
6.85-6.95 (m, 4H), 7.18 (dd, J=8.6, 2.8 Hz, 1H), 7.43-7.48 (m, 2H),
7.66 (d, J=16 Hz, 1H), 7.70 (s, 1H).
[0979] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[0980] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.99-2.41 (m, 7H),
4.05 (s, 3H), 4.27-4.34 (m, 2H), 4.72 (dd, J=6.0, 6.0 Hz, 1H),
6.85-6.95 (m, 4H), 7.18 (dd, J=8.6, 2.8 Hz, 1H), 7.43-7.48 (m, 2H),
7.66 (d, J=16 Hz, 1H), 7.70 (s, 1H).
Examples 188 and 189
Synthesis of
(-)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00172##
[0981] Synthesis of 1-amino-3-(3-fluorophenyl)piperidin-2-one
[0982] The title compound (3.0 g) was obtained from
3-fluorophenylacetic acid (5.0 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0983] ESI-MS; m/z 209 [M.sup.++H].
Synthesis of
(-)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(3-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[0984] A racemate of the title compound (110 mg) was obtained from
1-amino-3-(3-fluorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (439 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with a retention time of 13 minutes and positive optical
rotation (29 mg) and the title optically active compound with a
retention time of 22 minutes and negative optical rotation (29 mg).
The property values of the title optically active compound with a
retention time of 22 minutes are as follows.
[0985] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.30 (m, 3H),
2.29 (s, 3H), 2.30-2.46 (m, 1H), 4.05 (s, 3H), 4.20-4.40 (m, 3H),
6.85 (d, J=10.4 Hz, 1H), 6.90-7.02 (m, 4H), 7.24-7.36 (m, 1H), 7.47
(d, J=7.6 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz,
1H), 7.77 (s, 1H).
[0986] ESI-MS; m/z 431 [M.sup.++H].
[0987] The property values of the title optically active compound
with a retention time of 13 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 190 and 191
Synthesis of
(-)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00173##
[0988] Synthesis of 1-amino-3-(3-chlorophenyl)piperidin-2-one
[0989] The title compound (3.5 g) was obtained from
3-chlorophenylacetic acid (5.0 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[0990] ESI-MS; m/z 225 [M.sup.++H].
Synthesis of
(-)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(3-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0991] A racemate of the title compound (160 mg) was obtained from
1-amino-3-(3-chlorophenyl)piperidin-2-one (200 mg) and
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (477 mg) according to the method in Examples 168 and 169. The
racemate was optically resolved by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 10 mL/min) to isolate the title optically
active compound with a retention time of 14 minutes and positive
optical rotation (68 mg) and the title optically active compound
with a retention time of 24 minutes and negative optical rotation
(67 mg). The property values of the title optically active compound
with a retention time of 24 minutes are as follows.
[0992] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.23 (m, 3H),
2.29 (s, 3H), 2.30-2.46 (m, 1H), 4.05 (s, 3H), 4.20-4.38 (m, 3H),
6.92-6.98 (m, 2H), 7.00-7.06 (m, 1H), 7.14 (s, 1H), 7.22-7.32 (m,
2H), 7.47 (d, J=7.6 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H), 7.66 (d,
J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
[0993] ESI-MS; m/z 447 [M.sup.++H].
[0994] The property values of the title optically active compound
with a retention time of 14 minutes and positive optical rotation
corresponded to the values of the (-)-isomer.
Examples 192 and 193
Synthesis of
(+)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00174##
[0995] Synthesis of 1-amino-3-(2-chlorophenyl)piperidin-2-one
[0996] The title compound (831 mg) was obtained using
2-chlorophenylacetic acid (1 g) as a starting material according to
the method in Examples 20 and 21. The property value of the
compound is as follows.
[0997] ESI-MS; m/z 225 [M.sup.++H].
Synthesis of
(+)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(2-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[0998] A racemate of the title compound (192 mg) was obtained from
1-amino-3-(2-chlorophenyl)piperidin-2-one (250 mg) according to the
method in Examples 168 and 169. The resulting racemate (192 mg) was
separated by CHIRALPAK.TM. OJ-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase:
hexane:ethanol=8:2, flow rate: 11 mL/min) to obtain the title
optically active compound with a retention time of 34 minutes and
positive optical rotation (37 mg) and the title optically active
compound with a retention time of 40 minutes and negative optical
rotation (31 mg).
[0999] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[1000] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.41 (m, 7H),
4.04 (s, 3H), 4.25-4.34 (m, 2H), 4.76-4.79 (m, 1H), 6.85-6.95 (m,
3H), 7.18-7.26 (m, 2H), 7.40-7.48 (m, 3H), 7.66 (d, J=16 Hz, 1H),
7.76 (s, 1H).
[1001] The property values of the title optically active compound
with a retention time of 40 minutes are as follows.
[1002] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.41 (m, 7H),
4.04 (s, 3H), 4.25-4.34 (m, 2H), 4.76-4.79 (m, 1H), 6.85-6.95 (m,
3H), 7.18-7.26 (m, 2H), 7.40-7.48 (m, 3H), 7.66 (d, J=16 Hz, 1H),
7.76 (s, 1H).
Examples 194 and 195
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-
vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00175##
[1003] Synthesis of
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one
[1004] Thionyl chloride (2.72 mL) was added to a solution of
2-trifluoromethylphenylacetic acid (1.9 g) in methanol (38 mL), and
the reaction solution was stirred at room temperature for three
hours. The reaction solution was concentrated under reduced
pressure. The resulting residue was diluted with DMF. Sodium
hydride (containing 40% of mineral oil, 410 mg) was added under
ice-cooling, and the reaction solution was stirred for 10 minutes.
The reaction solution was further stirred at room temperature for
30 minutes and then ice-cooled again. 1-Chloro-3-iodopropane (1.02
mL) was added to the reaction mixture, and the reaction solution
was stirred at room temperature overnight. Water and ethyl acetate
were added to the reaction mixture and the organic layer was
separated. The resulting organic layer was washed with saturated
aqueous sodium chloride, dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The resulting residue was
diluted with ethanol (26.6 mL). Hydrazine monohydrate (7.6 mL) was
added, and the reaction solution was stirred at room temperature
for two hours and then at 60.degree. C. for further three hours.
The reaction mixture was concentrated under reduced pressure.
Saturated aqueous sodium bicarbonate and ethyl acetate and were
added to the residue, and the organic layer was separated. The
resulting organic layer was washed with saturated aqueous sodium
chloride, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane-ethyl acetate system) to obtain 1.68 g of the
title compound. The property values of the compound are as
follows.
[1005] ESI-MS; m/z 259 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.82-2.10 (m, 3H), 2.18-2.26 (m, 1H), 3.58-3.76 (m,
2H), 4.07 (dd, J=10.0, 5.6 Hz, 1H), 4.60 (s, 2H), 7.24 (d, J=7.6
Hz, 1H), 7.35 (t, J=7.6 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.66 (d,
J=7.6 Hz, 1H).
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-
-trifluoromethylphenyl)piperidin-1-yl]acrylamide
[1006] EDC (834 mg), HOBT (588 mg) and IPEA (2.03 mL) were added to
a suspension of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid trifluoroacetate (1.42 g) and
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (750 mg) in DMF
(30 mL). The reaction mixture was stirred at room temperature for
14 hours. Then, saturated aqueous sodium bicarbonate and ethyl
acetate were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was dried over anhydrous
magnesium sulfate and then concentrated under reduced pressure. The
residue was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: ethyl acetate-methanol system) to
obtain 1.23 g of the title compound. The property value of the
compound is as follows.
[1007] ESI-MS; m/z 500 [M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-
vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[1008] Phosphorus oxychloride (24.2 mL) was added to
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-
-trifluoromethylphenyl)piperidin-1-yl]acrylamide (1.2 g). The
reaction solution was stirred at 100.degree. C. for one hour and
then concentrated under reduced pressure. Subsequently, the residue
was diluted with acetic acid (24.2 mL). Then, ammonium acetate (1.9
g) was added and the reaction solution was stirred at 150.degree.
C. for two hours. The reaction solution was left to cool to room
temperature and then concentrated under reduced pressure. Saturated
aqueous sodium bicarbonate and ethyl acetate were added to the
resulting residue, and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: heptane-ethyl acetate system) to obtain a
racemate of the title compound (750 mg). The resulting racemate
(410 mg) was separated by CHIRALPAK.TM. IA manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase;
hexane:ethanol=8:2, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 28 minutes and
positive optical rotation (174 mg), and the title optically active
compound with a retention time of 33 minutes and negative optical
rotation (170 mg).
[1009] The property values of the title optically active compound
with a retention time of 28 minutes are as follows.
[1010] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.01 (m, 1H),
2.10-2.35 (m, 2H), 2.29 (d, J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03
(s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J=8.4, 6.0 Hz, 1H), 6.92 (d,
J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.39
(t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.72 (d, J=7.6 Hz,
1H), 7.76 (d, J=1.2 Hz, 1H).
[1011] The property values of the title optically active compound
with a retention time of 33 minutes are as follows.
[1012] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.01 (m, 1H),
2.10-2.35 (m, 2H), 2.29 (d, J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03
(s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J=8.4, 6.0 Hz, 1H), 6.92 (d,
J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.39
(t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.72 (d, J=7.6 Hz,
1H), 7.76 (d, J=1.2 Hz, 1H).
Examples 196 and 197
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl-
}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-
-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00176##
[1013] Synthesis of
1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one
[1014] 1.0 g of the title compound was obtained using
4-(trifluoromethyl)phenylacetic acid as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1015] ESI-MS; m/z 259 [M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl-
}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-
-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
[1016] A racemate of the title compound (13.2 mg) was obtained
using 1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one (203 mg)
as a starting material according to the method in Examples 168 and
169. Here, the compounds of Examples 200 and 201 described below
(149 mg) were generated at the same time. The resulting racemate
(13.2 mg) was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol,
flow rate: 12 mL/min) to obtain the title optically active compound
with a retention time of 10 minutes and positive optical rotation
(2.8 mg) and the title optically active compound with a retention
time of 15 minutes and negative optical rotation (3.0 mg).
[1017] The property values of the title optically active compound
with a retention time of 10 minutes are as follows.
[1018] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.30 (s, 3H), 2.36-2.48 (m, 1H), 4.05 (s, 3H), 4.28-4.36 (m, 2H),
4.41 (t, J=7.3 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.95-6.97 (m, 1H),
7.26-7.30 (m, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.46 (d, J=16.1 Hz, 1H),
7.59-7.63 (m, 2H), 7.65 (d, J=16.1 Hz, 1H), 7.77 (d, J=1.5 Hz,
1H).
[1019] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[1020] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.30 (s, 3H), 2.36-2.48 (m, 1H), 4.05 (s, 3H), 4.28-4.36 (m, 2H),
4.41 (t, J=7.3 Hz, 1H), 6.94 (d, J=8.1 Hz, 1H), 6.95-6.97 (m, 1H),
7.26-7.30 (m, 2H), 7.45 (d, J=8.1 Hz, 1H), 7.46 (d, J=16.1 Hz, 1H),
7.59-7.63 (m, 2H), 7.65 (d, J=16.1 Hz, 1H), 7.77 (d, J=1.5 Hz,
1H).
Examples 198 and 199
Synthesis of
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00177##
[1021] Synthesis of 1-amino-3-(naphthalen-1-yl)piperidin-2-one
[1022] 858 mg of the title compound was obtained using
1-naphthylacetic acid as a starting material according to the
method in Examples 20 and 21. The property value of the compound is
as follows.
[1023] ESI-MS; m/z 241 [M.sup.++H].
Synthesis of
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(naphthalen-1-yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1024] A racemate of the title compound (173 mg) was obtained from
1-amino-3-(naphthalen-1-yl)piperidin-2-one (254 mg) as a starting
material according to the method in Examples 168 and 169. The
resulting racemate (173 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 12 mL/min) to obtain the title
optically active compound with a retention time of 11 minutes and
negative optical rotation (74 mg) and the title optically active
compound with a retention time of 30 minutes and positive optical
rotation (52 mg).
[1025] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[1026] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.02-2.32 (m, 3H),
2.29 (s, 3H), 2.40-2.50 (m, 1H), 4.05 (s, 3H), 4.29 (ddd, J=13.2,
8.8, 5.9 Hz, 1H), 4.43 (ddd, J=13.2, 5.1, 5.1 Hz, 1H), 5.22 (t,
J=5.5 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H),
6.94-6.97 (m, 1H), 7.35-7.40 (m, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.48
(d, J=15.7 Hz, 1H), 7.50-7.60 (m, 2H), 7.69 (d, J=15.7 Hz, 1H),
7.77 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.89-7.92 (m, 1H),
8.01 (d, J=8.4 Hz, 1H).
[1027] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[1028] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.02-2.32 (m, 3H),
2.29 (s, 3H), 2.40-2.50 (m, 1H), 4.05 (s, 3H), 4.29 (ddd, J=13.2,
8.8, 5.9 Hz, 1H), 4.43 (ddd, J=13.2, 5.1, 5.1 Hz, 1H), 5.22 (t,
J=5.5 Hz, 1H), 6.86 (d, J=7.3 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H),
6.94-6.97 (m, 1H), 7.35-7.40 (m, 1H), 7.45 (d, J=7.7 Hz, 1H), 7.48
(d, J=15.7 Hz, 1H), 7.50-7.60 (m, 2H), 7.69 (d, J=15.7 Hz, 1H),
7.77 (d, J=1.1 Hz, 1H), 7.78 (d, J=8.4 Hz, 1H), 7.89-7.92 (m, 1H),
8.01 (d, J=8.4 Hz, 1H).
Examples 200 and 201
Synthesis of
(+)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phenyl)--
5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol
and
(-)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phen-
yl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-
-ol
##STR00178##
[1030] A racemate of the title compound (149 mg) was obtained from
1-amino-6-(4-trifluoromethyl-phenyl)-piperidin-2-one (203 mg)
according to the method in Examples 168 and 169. The resulting
racemate (149 mg) was separated by CHIRALPAK.TM. IA manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
ethanol, flow rate: 12 mL/min) to obtain the title optically active
compound with a retention time of 19 minutes and positive optical
rotation (39 mg) and the title optically active compound with a
retention time of 39 minutes and negative optical rotation (41
mg).
[1031] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1032] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.28 (s, 3H), 2.37-2.44 (m, 1H), 4.30-4.37 (m, 2H), 4.40 (t, J=7.0
Hz, 1H), 6.35 (d, J=7.7 Hz, 1H), 7.18 (d, J=16.5 Hz, 1H), 7.20 (3.6
Hz, 1H), 7.24-7.28 (m, 2H), 7.39 (d, J=16.5 Hz, 1H), 7.40 (d, J=7.3
Hz, 1H), 7.62-7.56 (m, 2H), 8.18 (brd-s, 1H).
[1033] The property values of the title optically active compound
with a retention time of 39 minutes are as follows.
[1034] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.28 (s, 3H), 2.37-2.44 (m, 1H), 4.30-4.37 (m, 2H), 4.40 (t, J=7.0
Hz, 1H), 6.35 (d, J=7.7 Hz, 1H), 7.18 (d, J=16.5 Hz, 1H), 7.20 (3.6
Hz, 1H), 7.24-7.28 (m, 2H), 7.39 (d, J=16.5 Hz, 1H), 7.40 (d, J=7.3
Hz, 1H), 7.62-7.56 (m, 2H), 8.18 (brd-s, 1H).
Examples 202 and 203
Synthesis of
(+)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-fluorophenyl)-5,6,7,8-te-
trahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol and
(-)-3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-fluorophenyl)-5,6,7,8-te-
trahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol
##STR00179##
[1036] A racemate of the title compound (30 mg) was obtained from
1-amino-6-(4-fluorophenyl)-piperidin-2-one (500 mg) according to
the method in Examples 168 and 169. The resulting racemate (30 mg)
was separated by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow
rate: 10 mL/min) to obtain the title optically active compound with
a retention time of 41 minutes and positive optical rotation (8.2
mg) and the title optically active compound with a retention time
of 51 minutes and negative optical rotation (8.2 mg).
[1037] The property values of the title optically active compound
with a retention time of 51 minutes are as follows.
[1038] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.44 (m, 4H),
2.28 (s, 3H), 4.26-4.38 (m, 3H), 6.35 (d, J=7.6 Hz, 1H), 6.98-7.07
(m, 2H), 7.07-7.14 (m, 2H), 7.16-7.22 (m, 2H), 7.24-7.38 (m, 1H),
7.39 (d, J=7.6 Hz, 1H), 8.14 (d, J=1.6 Hz, 1H).
[1039] The property values of the title optically active compound
with a retention time of 41 minutes corresponded to those of the
title optically active compound with a retention time of 51
minutes.
Examples 204 and 205
Synthesis of
(+)-2-{(E)-2-[6-ethoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-
-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyr-
idine and
(-)-2-{(E)-2-[6-ethoxy-5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-y-
l]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[-
1,5-a]pyridine
##STR00180##
[1041] Cesium carbonate (22.6 mg) and methyl iodide (6.5 .mu.l)
were added to racemic
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(4-trifluoromethyl-phenyl)-5,6,-
7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}-pyridin-2-ol
(26.9 mg) as a starting material in DMF (0.6 ml), and the reaction
solution was stirred at room temperature for four hours. Water and
ethyl acetate were added to the reaction solution, and the organic
layer was separated. The organic layer was washed with brine. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 13.6 mg of a racemate of
the title compound. The resulting racemate (13.6 mg) was separated
by CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries,
Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow rate: 12
mL/min) to obtain the title optically active compound with a
retention time of 11 minutes and positive optical rotation (35 mg)
and the title optically active compound with a retention time of 16
minutes and negative optical rotation (41 mg).
[1042] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[1043] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.41 (t, J=7.3 Hz,
3H), 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.36-2.45 (m, 1H), 4.29-4.34
(m, 2H), 4.42 (t, J=7.0 Hz, 1H), 4.57 (q, J=7.3 Hz, 2H), 6.91 (d,
J=7.7 Hz, 1H), 6.95-6.98 (m, 1H), 7.25-7.31 (m, 2H), 7.45 (d,
J=15.7 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.58-7.63 (m, 2H), 7.62 (d,
J=15.7 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H).
[1044] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1045] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.41 (t, J=7.3 Hz,
3H), 2.00-2.26 (m, 3H), 2.29 (s, 3H), 2.36-2.45 (m, 1H), 4.29-4.34
(m, 2H), 4.42 (t, J=7.0 Hz, 1H), 4.57 (q, J=7.3 Hz, 2H), 6.91 (d,
J=7.7 Hz, 1H), 6.95-6.98 (m, 1H), 7.25-7.31 (m, 2H), 7.45 (d,
J=15.7 Hz, 1H), 7.46 (d, J=7.7 Hz, 1H), 7.58-7.63 (m, 2H), 7.62 (d,
J=15.7 Hz, 1H), 7.83 (d, J=1.1 Hz, 1H).
Examples 206 and 207
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00181##
[1047] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (150 mg) and 1-amino-3-phenylpiperidin-2-one (120 mg)
according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with a retention time of 18 minutes and positive optical rotation
(45.1 mg, >99% ee) and the title optically active compound with
a retention time of 42 minutes and negative optical rotation (46.5
mg, >99% ee).
[1048] The property values of the title compound with a retention
time of 18 minutes are as follows.
[1049] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.10 (m, 2H), 2.16-2.21 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.26-4.38 (m, 3H), 6.92
(d, J=8.0 Hz, 1H), 6.94 (s, 1H), 7.11-7.13 (m, 2H), 7.26-7.35 (m,
3H), 7.45 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.65 (d,
J=16.0 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H).
[1050] The property values of the title compound with a retention
time of 42 minutes are as follows.
[1051] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.10 (m, 2H), 2.16-2.21 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.26-4.38 (m, 3H), 6.92
(d, J=8.0 Hz, 1H), 6.94 (s, 1H), 7.11-7.13 (m, 2H), 7.26-7.35 (m,
3H), 7.45 (d, J=8.0 Hz, 1H), 7.46 (d, J=16.0 Hz, 1H), 7.65 (d,
J=16.0 Hz, 1H), 7.75 (d, J=1.2 Hz, 1H).
Examples 208 and 209
Synthesis of
(+)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00182##
[1052] Synthesis of 1-amino-3-(4-chlorophenyl)piperidin-2-one
[1053] 1.69 g of the title compound was obtained from methyl
4-chlorophenylacetate (5 g) according to the method in Examples 20
and 21. The property value of the compound is as follows.
[1054] ESI-MS; m/z 225 [M.sup.++H].
Synthesis of
(+)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-
-1-yl)pyridin-2-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[1055] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (150 mg) and 1-amino-3-(4-chlorophenyl)piperidin-2-one (143
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. IA manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=8:2) to obtain the title optically active compound
with a retention time of 20 minutes and positive optical rotation
(45.3 mg, >99% ee) and the title optically active compound with
a retention time of 24 minutes and negative optical rotation (45.9
mg, >99% ee).
[1056] The property values of the title compound with a retention
time of 20 minutes are as follows.
[1057] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.12 (m, 2H), 2.16-2.19 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.31-2.41 (m, 1H), 4.04 (s, 3H), 4.27-4.34 (m, 3H), 6.93
(d, J=8.0 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H), 7.05-7.09 (m, 2H),
7.28-7.32 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H),
7.64 (d, J=15.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).
[1058] The property values of the title compound with a retention
time of 24 minutes are as follows.
[1059] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.12 (m, 2H), 2.16-2.19 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.31-2.41 (m, 1H), 4.04 (s, 3H), 4.27-4.34 (m, 3H), 6.93
(d, J=8.0 Hz, 1H), 6.94 (d, J=1.2 Hz, 1H), 7.05-7.09 (m, 2H),
7.28-7.32 (m, 2H), 7.44 (d, J=8.0 Hz, 1H), 7.45 (d, J=15.6 Hz, 1H),
7.64 (d, J=15.6 Hz, 1H), 7.76 (d, J=1.2 Hz, 1H).
Examples 210 and 211
Synthesis of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00183##
[1060] Synthesis of 1-amino-3-phenylpiperidin-2-one
[1061] 2.83 g of the title compound was obtained from methyl
phenylacetate (5 g) according to the method in Examples 20 and 21.
The property value of the compound is as follows. ESI-MS; m/z 191
[M.sup.++H].
Synthesis of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1062] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (CAS No. 870837-77-7, 300 mg) and
1-amino-3-phenylpiperidin-2-one (110 mg) according to the method in
Examples 168 and 169. The resulting racemate was separated by
CHIRALPAK.TM. AD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 5 minutes and
negative optical rotation (33.8 mg, >99% ee) and the title
optically active compound with a retention time of 8 minutes and
positive optical rotation (34.5 mg, >99% ee).
[1063] The property values of the title compound with a retention
time of 5 minutes are as follows.
[1064] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.11 (m, 2H), 2.16-2.24 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 3.97 (s, 3H), 4.25-4.37 (m, 3H), 7.10
(d, J=16.4 Hz, 1H), 7.12 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.26-7.37
(m, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.52 (d,
J=16.4 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).
[1065] The property values of the title compound with a retention
time of 8 minutes are as follows.
[1066] ESI-MS; m/z 413 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.11 (m, 2H), 2.16-2.24 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 3.97 (s, 3H), 4.25-4.37 (m, 3H), 7.10
(d, J=16.4 Hz, 1H), 7.12 (s, 1H), 7.13 (d, J=8.0 Hz, 1H), 7.26-7.37
(m, 3H), 7.46 (d, J=1.2 Hz, 1H), 7.51 (d, J=8.0 Hz, 1H), 7.52 (d,
J=16.4 Hz, 1H), 8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).
Examples 212 and 213
Synthesis of
(+)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00184##
[1068] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (300 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (133
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. AD-H manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol)
to obtain the title optically active compound with a retention time
of 5.6 minutes and negative optical rotation (48.1 mg, >99% ee)
and the title optically active compound with a retention time of 8
minutes and positive optical rotation (46.2 mg, >99% ee).
[1069] The property values of the title compound with a retention
time of 5.6 minutes are as follows.
[1070] ESI-MS; m/z 431 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.27-4.35 (m, 3H), 6.93 (d, J=8.0
Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m, 2H), 7.08-7.12 (m, 2H), 7.45
(d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.6 Hz,
1H), 7.76 (s, 1H).
[1071] The property values of the title compound with a retention
time of 8 minutes are as follows.
[1072] ESI-MS; m/z 431 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.10 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.33-2.38 (m, 1H), 4.04 (s, 3H), 4.27-4.35 (m, 3H), 6.93 (d, J=8.0
Hz, 1H), 6.94 (s, 1H), 6.99-7.05 (m, 2H), 7.08-7.12 (m, 2H), 7.45
(d, J=15.6 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.64 (d, J=15.6 Hz,
1H), 7.76 (s, 1H).
Examples 214 and 215
Synthesis of
(+)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-
-1-yl)pyridin-3-yl]vinyl}-8-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00185##
[1074] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (300 mg) and 1-amino-3-(4-fluorophenyl)piperidin-2-one (143
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. IA manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=65:35) to obtain the title optically active compound
with a retention time of 26 minutes and positive optical rotation
(26.2 mg, >99% ee) and the title optically active compound with
a retention time of 31 minutes and negative optical rotation (20.7
mg, >99% ee).
[1075] The property values of the title compound with a retention
time of 26 minutes are as follows.
[1076] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.13 (m, 2H), 2.17-2.22 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.33-2.38 (m, 1H), 3.96 (s, 3H), 4.26-4.32 (m, 3H),
7.05-7.10 (m, 3H), 7.29-7.32 (m, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.48
(d, J=7.6 Hz, 1H), 7.49 (d, J=16.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H),
8.33 (d, J=1.2 Hz, 1H).
[1077] The property values of the title compound with a retention
time of 31 minutes are as follows.
[1078] ESI-MS; m/z 447 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.13 (m, 2H), 2.17-2.22 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.33-2.38 (m, 1H), 3.96 (s, 3H), 4.26-4.32 (m, 3H),
7.05-7.10 (m, 3H), 7.29-7.32 (m, 2H), 7.46 (d, J=7.6 Hz, 1H), 7.48
(d, J=7.6 Hz, 1H), 7.49 (d, J=16.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H),
8.33 (d, J=1.2 Hz, 1H).
Examples 216 and 217
Synthesis of
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-pyridin-3-yl]-vinyl-
}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)-pyridin-3-
-yl]-vinyl}-8-(4-trifluoromethyl-phenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00186##
[1080] A racemate of the title compound (28.5 mg) was obtained
using 1-amino-6-(4-trifluoromethylphenyl)-piperidin-2-one (203 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (28.5 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 12 mL/min) to
obtain the title optically active compound with a retention time of
13 minutes and positive optical rotation (12 mg) and the title
optically active compound with a retention time of 16 minutes and
negative optical rotation (15 mg).
[1081] The property values of the title optically active compound
with positive optical rotation are as follows.
[1082] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.29 (s, 3H), 2.36-2.46 (m, 1H), 3.96 (s, 3H), 4.27-4.34 (m, 2H),
4.38 (t, J=6.9 Hz, 1H), 7.04 (d, J=16.4 Hz, 1H), 7.25-7.30 (m, 2H),
7.45 (d, J=1.8 Hz, 1H), 7.48 (d, J=16.4 Hz, 1H), 7.51 (d, J=1.1 Hz,
1H), 7.58-7.63 (m, 2H), 8.13 (d, J=1.8 Hz, 1H), 8.33 (d, J=1.8 Hz,
1H).
[1083] The property values of the title optically active compound
with negative optical rotation are as follows.
[1084] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.26 (m, 3H),
2.29 (s, 3H), 2.36-2.46 (m, 1H), 3.96 (s, 3H), 4.27-4.34 (m, 2H),
4.38 (t, J=6.9 Hz, 1H), 7.04 (d, J=16.4 Hz, 1H), 7.25-7.30 (m, 2H),
7.45 (d, J=1.8 Hz, 1H), 7.48 (d, J=16.4 Hz, 1H), 7.51 (d, J=1.1 Hz,
1H), 7.58-7.63 (m, 2H), 8.13 (d, J=1.8 Hz, 1H), 8.33 (d, J=1.8 Hz,
1H).
Examples 218 and 219
Synthesis of
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazo-
l-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00187##
[1086] 601 mg of the racemic title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (1.25 g) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one
(547 mg) according to the method in Examples 168 and 169. The
property values of the compound are as follows.
[1087] ESI-MS; m/z 449 [M.sup.++H].
[1088] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.01-2.25 (m, 3H),
2.29 (s, 3H), 2.31-2.40 (m, 1H), 3.96 (s, 3H), 4.26-4.31 (m, 3H),
6.87-6.91 (m, 1H), 6.95-7.00 (m, 1H), 7.08 (d, J=16.4 Hz, 1H),
7.10-7.17 (m, 1H), 7.26-7.51 (m, 3H), 8.13 (d, J=1.6 Hz, 1H), 8.33
(d, J=1.2 Hz, 1H).
[1089] The racemic title compound (60 mg) was separated by
CHIRALPAK.TM. AD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 21.7 minutes and
negative optical rotation (13.6 mg) and the title optically active
compound with a retention time of 28.8 minutes and positive optical
rotation (14.8 mg).
Examples 220 and 221
Synthesis of
(R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00188##
[1090] Synthesis of
4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid
diisopropylamide
[1091] 4-Methyl-1H-imidazole (680 mg), copper iodide (78.8 mg),
trans-1,2-bis(methylamino)cyclohexane (0.265 mL) and potassium
carbonate (2.52 g) were added to a solution of
5-iodo-4-methoxypyridine-2-carboxylic acid diisopropylamide
synthesized according to the method in Organic Letters, 2002, vol.
4, p. 2385 (3 g) in DMF (10 mL). The reaction solution was stirred
in a sealed tube at 110.degree. C. for 20 hours. The reaction
solution was left to cool to room temperature, and ethyl acetate
was added. The insoluble matter was removed by filtration through
celite. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 881 mg of the title compound. The property value of the
compound is as follows.
[1092] ESI-MS; m/z 317 [M.sup.++H].
Synthesis of ethyl
(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate
[1093] DIBAL-H (1.39 mL; 1.02 M solution in hexane) was added
dropwise to a solution of
4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carboxylic acid
diisopropylamide (150 mg) in THF (5 mL) at -78.degree. C. The
reaction solution was stirred at -78.degree. C. for 15 minutes, and
then heated to room temperature and stirred for 45 minutes. A
saturated ammonium chloride solution and ethyl acetate were added
to the reaction solution. A saturated Rochelle salt solution was
further added and the reaction solution was vigorously stirred for
one hour. The resulting organic layer was washed with saturated
sodium bicarbonate water and brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. Subsequently,
ethyl diethylphosphonoacetate (0.142 mL) and lithium hydroxide
(18.2 mg) were added to a solution of the resulting residue in THF
(3 mL), and the reaction solution was stirred at room temperature
for 12 hours. Water and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with brine, dried over anhydrous magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 53 mg of the title
compound. The property value of the compound is as follows.
[1094] ESI-MS; m/z 288 [M.sup.++H].
Synthesis of
(R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
[1095] A 5 N sodium hydroxide solution (0.5 mL) was added to a
mixed solution of ethyl
(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate
(90 mg) in THF (2 mL) and methanol (1 mL). The reaction solution
was stirred at room temperature for two hours. Then, 5 N
hydrochloric acid (0.5 mL) was added, and the reaction solution was
concentrated under reduced pressure. Subsequently,
1-amino-3-(3,4,5-trifluorophenyl)piperidin-2-one (115 mg), EDC (180
mg), HOBT (127 mg) and IPEA (0.327 mL) were added to a solution of
the resulting residue in DMF (3 mL). The reaction solution was
stirred at room temperature for 15 hours. Then, water and ethyl
acetate were added to the reaction solution, and the organic layer
was separated. The resulting organic layer was washed with brine,
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: ethyl acetate-methanol system) to
obtain a crude coupled compound. Subsequently, phosphorous
oxychloride (3 mL) was added to the compound. The reaction solution
was stirred at 120.degree. C. for one hour and then concentrated
under reduced pressure. Subsequently, ammonium acetate (727 mg) was
added to a solution of the residue in acetic acid (2 mL), and the
reaction solution was stirred at 150.degree. C. for two hours. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. Saturated sodium bicarbonate
water and ethyl acetate were added to the resulting residue, and
the organic layer was separated. The resulting organic layer was
washed with brine, dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (elution solvent: heptane-ethyl
acetate system) to obtain a racemate of the title compound. The
resulting racemate was separated by CHIRALPAK.TM. IA manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain the title optically active compound with
a retention time of 7 minutes (5.7 mg, >99% ee) and the title
optically active compound with a retention time of 9 minutes (5.6
mg, >99% ee).
[1096] The property values of the title compound with a retention
time of 7 minutes are as follows.
[1097] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.97-2.22 (m, 1H), 2.11-2.22 (m, 2H), 2.30 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 3.91 (s, 3H), 4.24-4.30 (m, 3H), 6.82
(dd, J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 6.99 (s, 1H), 7.52 (d,
J=16.0 Hz, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H),
8.41 (s, 1H).
[1098] The property values of the title compound with a retention
time of 9 minutes are as follows.
[1099] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.97-2.22 (m, 1H), 2.11-2.22 (m, 2H), 2.30 (d, J=1.2
Hz, 3H), 2.34-2.40 (m, 1H), 3.91 (s, 3H), 4.24-4.30 (m, 3H), 6.82
(dd, J=8.0, 6.0 Hz, 2H), 6.90 (s, 1H), 6.99 (s, 1H), 7.52 (d,
J=16.0 Hz, 1H), 7.58 (d, J=16.0 Hz, 1H), 7.67 (d, J=1.2 Hz, 1H),
8.41 (s, 1H).
Examples 222 and 223
Synthesis of (+) and
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]-1-methylvinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine
##STR00189##
[1100] Synthesis of N-(6-chloro-2-methoxypyridin-3-yl)formamide
[1101] Iron (11.9 g) and ammonium chloride (22.7 g) were added to a
solution of 6-chloro-2-methoxy-3-nitropyridine (10.0 g, CAS:
40851-91-0) in ethanol (130 mL) and water (52 mL). The reaction
solution was stirred at 80 to 90.degree. C. for one hour and 20
minutes and then left to cool to room temperature. The reaction
solution was filtered through celite and washed with ethanol. Then,
the filtrate was concentrated under reduced pressure. The residue
was diluted with ethyl acetate and water, and the organic layer was
separated. The resulting organic layer was washed with brine, dried
over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was diluted with THF (26 mL). The THF
solution was added dropwise to a mixed solution of formic acid
(20.1 mL) and acetic anhydride (20.1 mL) at room temperature. Then,
the reaction solution was stirred for one hour. Ice water (120 mL)
was added to the reaction solution, and the precipitated crystals
were collected by filtration. The crystals were washed with water
and then air-dried to obtain 5.85 g of the title compound. The
property value of the compound is as follows.
[1102] ESI-MS; m/z 187 [M.sup.++H].
Synthesis of
N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide
[1103] Cesium carbonate (20.5 g), potassium iodide (521 mg) and
chloroacetone (5.0 mL) were added to a solution of
N-(6-chloro-2-methoxypyridin-3-yl)formamide (5.85 g) in DMF (34.3
mL), and the reaction solution was stirred at 100.degree. C. for
one hour. Ice water and chloroform were added to the reaction
solution, and the organic layer was separated. The organic layer
was dried over anhydrous magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 4.71 g of the title compound. The property value
of the compound is as follows.
[1104] ESI-MS; m/z 243 [M.sup.++H].
Synthesis of
6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine
[1105] A mixture of
N-(6-chloro-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (4.71
g), acetic acid (11.1 mL) and ammonium acetate (7.48 g) was stirred
at 130.degree. C. for one hour. The reaction solution was left to
cool to room temperature. Ice water, ethyl acetate and aqueous
ammonia were added and the organic layer was separated. The organic
layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (elution solvent: heptane-ethyl
acetate system) to obtain 2.42 g of the title compound. The
property values of the compound are as follows.
[1106] ESI-MS; m/z 224 [M.sup.++H].
[1107] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 4.02
(s, 3H), 6.91 (brs, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz,
1H), 7.71 (brs, 1H).
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacryl-
ic acid
[1108] A mixture of
6-chloro-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (400 mg),
an allylpalladium chloride dimer (32.8 mg), tri-o-tolylphosphine
(54.4 mg), sodium acetate (441 mg), dimethylacetamide (0.640 mL),
tert-butyl methacrylate (0.724 mL) and toluene (2 mL) was stirred
in a nitrogen atmosphere at 120.degree. C. for 3.5 hours. The
reaction solution was left to cool to room temperature. Then, a
silica gel was added and the reaction solution was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 313 mg of tert-butyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacryl-
ate. The ester was diluted with trifluoroacetic acid (2.48 mL) and
methylene chloride (2.48 mL), and the reaction solution was stirred
at room temperature for 3.5 hours. The reaction solution was
concentrated under reduced pressure to obtain 260 mg of the title
compound. The property value of the compound is as follows.
[1109] ESI-MS; m/z 274 [M.sup.++H].
Synthesis of (+) and
(-)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]-1-methylvinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yridine
[1110] 74.6 mg of the racemic title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-methylacryl-
ic acid (260 mg) and 1-amino-3-(3,4-difluorophenyl)piperidin-2-one
(172 mg) according to the method in Examples 168 and 169. The
racemic title compound was separated by CHIRALPAK.TM. IA
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol:hexane=1:1) to obtain the title optically
active compound with a retention time of 7.4 minutes and positive
optical rotation (11.9 mg) and the title optically active compound
with a retention time of 9.8 minutes and negative optical rotation
(12.2 mg).
[1111] The property values of the title optically active compound
with negative optical rotation are as follows.
[1112] ESI-MS; m/z 463 [M.sup.++H].
[1113] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.21 (m, 3H),
2.30 (s, 3H), 2.30-2.37 (m, 1H), 2.75 (s, 3H), 4.06 (s, 3H),
4.23-4.36 (m, 3H), 6.86-6.90 (m, 1H), 6.94-7.02 (m, 3H), 7.10-7.17
(m, 1H), 7.47-7.49 (m, 2H), 7.79 (d, J=1.2 Hz, 1H).
[1114] The property values of the title optically active compound
with positive optical rotation corresponded to the property values
of the title optically active compound with negative optical
rotation.
Example 224
Synthesis of
8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00190##
[1116] 10.1 mg of the racemic title compound was obtained according
to the method in Example 53 from
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
obtained in Example 170 (20 mg). The property values of the
compound are as follows.
[1117] ESI-MS; m/z 465 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.98-2.08 (m, 1H), 2.16 (ddd, J=13.6, 10.0, 3.2 Hz,
1H), 2.29 (s, 3H), 2.35 (ddd, J=13.6, 8.0, 2.4 Hz, 1H), 2.36-2.50
(m, 1H), 4.00 (s, 3H), 4.23-4.40 (m, 2H), 5.23 (brs, 1H), 6.78 (d,
J=5.2 Hz, 1H), 6.94 (s, 1H), 7.01-7.07 (m, 1H), 7.13 (q, J=8.4 Hz,
1H) 7.25-7.32 (m, 1H), 7.39 (d, J=15.6 Hz, 1H), 7.41 (d, J=5.2 Hz,
1H), 7.62 (d, J=15.6 Hz, 1H), 7.80 (d, J=1.2 Hz, 1H).
Example 225
Synthesis of
8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-ol
##STR00191##
[1119] 7.2 mg of the title compound was obtained according to the
method in Example 53 from
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
obtained in Example 219 (10.2 mg). The property values of the
compound are as follows.
[1120] ESI-MS; m/z 465 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.97-2.08 (m, 1H), 2.16 (ddd, J=13.6, 10.4, 3.2 Hz,
1H), 2.28 (s, 3H), 2.35 (ddd, J=13.6, 8.4, 3.2 Hz, 1H), 2.34-2.48
(m, 1H), 3.92 (s, 3H), 4.21-4.37 (m, 2H), 4.80 (brs, 1H), 6.98-7.04
(m, 1H), 7.06 (d, J=16.0 Hz, 1H), 7.12 (q, J=8.4 Hz, 1H) 7.20-7.28
(m, 1H), 7.36 (d, J=1.6 Hz, 1H), 7.43 (d, J=16.0 Hz, 1H), 7.48 (s,
1H), 8.06 (d, J=1.6 Hz, 1H), 8.30 (s, 1H).
Examples 226 and 227
Synthesis of (-) and
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-
-carbonitrile
##STR00192##
[1122] 70.6 mg of the racemic title compound was obtained from
8-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
(100 mg) in the same manner as in Example 65. The property values
of the compound are as follows.
[1123] ESI-MS; m/z 474 [M.sup.++H].
[1124] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.15-2.26 (m, 1H),
2.30 (s, 3H), 2.35-2.48 (m, 2H), 2.68-2.76 (m, 1H), 4.07 (s, 3H),
4.29-4.45 (m, 2H), 6.97 (d, J=1.2 Hz, 1H), 6.98 (d, J=7.6 Hz, 1H),
7.10-7.28 (m, 3H), 7.50 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H),
7.64 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).
[1125] The racemic title compound was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=7:3) to obtain the title optically
active compound with a retention time of 12.8 minutes and negative
optical rotation (18.5 mg) and the title optically active compound
with a retention time of 16.8 minutes and positive optical rotation
(19.8 mg).
Examples 228 and 229
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(3,4,5-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e-8-carbonitrile
##STR00193##
[1127] 308 mg of the racemic title compound was obtained from
2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-8-(3-
,4,5-trifluorophenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(255 mg) in the same manner as in Example 65. The property values
of the compound are as follows.
[1128] ESI-MS; m/z 492 [M.sup.++H].
[1129] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.22-2.29 (m, 1H),
2.29 (s, 3H), 2.36-2.50 (m, 2H), 2.69-2.75 (m, 1H), 3.98 (s, 3H),
4.27-4.42 (m, 2H), 7.02-7.06 (m, 2H), 7.07 (d, J=16.4 Hz, 1H), 7.46
(d, J=2.0 Hz, 1H), 7.53 (s, 1H), 7.56 (d, J=16.4 Hz, 1H), 8.17 (d,
J=2.0 Hz, 1H), 8.36 (s, 1H).
[1130] The racemic title compound (48 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with a retention time of 12.9 minutes and
positive optical rotation (8.35 mg) and the title optically active
compound with a retention time of 14.6 minutes and negative optical
rotation (9.62 mg).
Examples 230 and 231
Synthesis of (-) and
(+)-8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine-8-
-carbonitrile
##STR00194##
[1132] 174 mg of the racemic title compound was obtained as a crude
product from
8-(3,4-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
(100 mg) in the same manner as in Example 65. The crude product was
separated by CHIRALPAK.TM. AD-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol) to
obtain the title optically active compound with a retention time of
14.3 minutes and negative optical rotation (22.4 m) and the title
optically active compound with a retention time of 18.2 minutes and
positive optical rotation (9.26 mg).
[1133] The property values of the title optically active compound
with negative optical rotation are as follows.
[1134] ESI-MS; m/z 474 [M.sup.++H].
[1135] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.18-2.28 (m, 1H),
2.30 (d, J=1.2 Hz, 3H), 2.36-2.48 (m, 2H), 2.69-2.74 (m, 1H), 3.99
(s, 3H), 4.28-4.44 (m, 2H), 7.08-7.25 (m, 4H), 7.48 (d, J=2.0 Hz,
1H), 7.55-7.59 (m, 2H), 8.18 (d, J=2.0 Hz, 1H), 8.39 (d, J=1.2 Hz,
1H).
[1136] The property values of the title optically active compound
with positive optical rotation corresponded to those of the title
optically active compound with negative optical rotation.
Example 232
Synthesis of
4-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyrid-
in-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00195##
[1137] Synthesis of 3-(4-chlorophenylamino)propan-1-ol
[1138] 4-Chloroaniline (4.39 g) and lithium tetrafluoroborate (3.32
g) were added to a solution of oxetane (1.00 g) in acetonitrile (20
mL) at room temperature, and the reaction solution was stirred at
room temperature for 52 hours. A saturated sodium bicarbonate
solution was added to the reaction solution, followed by extraction
with chloroform. The resulting extract was dried over magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 2.17 g of the title
compound. The property values of the compound are as follows.
[1139] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.88 (tt, J=6.4, 6.0
Hz, 2H), 3.25 (t, J=6.4 Hz, 2H), 3.81 (brt, J=6.0 Hz, 2H), 3.90
(brs, 1H), 6.52-6.56 (m, 2H), 7.08-7.13 (m, 2H).
Synthesis of
1-amino-3-(4-chlorophenyl)tetrahydropyrimidin-2-one
[1140] Thionyl chloride (4.4 mL) was added to a solution of
3-(4-chlorophenylamino)propan-1-ol (2.17 g) in toluene (30 mL) at
room temperature, and the reaction solution was stirred at
60.degree. C. for five hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure. Ice and a saturated sodium bicarbonate solution were
added, followed by extraction with ethyl acetate (200 mL). Heptane
(100 mL) was added to the resulting extract to prepare a mixed
solution. The solution was purified by silica gel column
chromatography (elution solvent: heptane:ethyl acetate=2:1) to
obtain (4-chlorophenyl)-(3-chloropropyl)amine
(4-Chlorophenyl)-(3-chloropropyl)amine was dissolved in THF (45
mL). Triethylamine (4.9 mL) and phenyl chlorocarbonate (1.8 mL)
were added at 0.degree. C., and the reaction solution was stirred
at room temperature for 15 hours. Water was added to the reaction
solution, followed by extraction with ethyl acetate. The resulting
extract was dried over magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate
(3.70 g). Phenyl (4-chlorophenyl)-(3-chloropropyl)carbamate (3.70
g) was dissolved in ethanol (60 mL). Hydrazine monohydrate (5.65
mL) was added at room temperature, and the reaction solution was
heated under reflux for 17 hours. The reaction solution was left to
cool to room temperature and then concentrated under reduced
pressure. A saturated sodium bicarbonate solution was added,
followed by extraction with chloroform. The resulting extract was
dried over magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system, then
ethyl acetate-methanol system) to obtain 2.19 g of the title
compound. The property values of the compound are as follows.
[1141] ESI-MS; m/z 226 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.15 (tt, J=6.4, 5.6 Hz, 2H), 3.62 (t, J=6.4 Hz,
2H), 3.65 (t, J=5.6 Hz, 2H), 4.31 (brs, 2H), 7.17-7.22 (m, 2H),
7.26-7.31 (m, 2H).
Synthesis of
(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5--
(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
[1142] IPEA (0.65 mL),
1-amino-3-(4-chlorophenyl)tetrahydropyrimidin-2-one (139 mg), EDC
(177 mg) and HOBT (125 mg) were added to a solution of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (300 mg) in DMF (6 mL) at room temperature. The reaction
solution was stirred at room temperature for 24 hours. The reaction
solution was diluted with ethyl acetate and washed with a saturated
sodium bicarbonate solution and a saturated sodium chloride
solution. The resulting organic layer was dried over magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: heptane-ethyl acetate system, then
ethyl acetate-methanol system) to obtain 287 mg of the title
compound. The property value of the compound is as follows.
[1143] ESI-MS; m/z 467 [M.sup.++H].
Synthesis of
4-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyrid-
in-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
[1144] Phosphorus oxychloride (5 mL) was added to
(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5--
(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (287 mg), and
the reaction mixture was heated under reflux for one hour. The
reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. Acetic acid (5 mL) and
ammonium acetate (2.4 g) were added to the resulting residue, and
the reaction solution was stirred at 150.degree. C. for two hours.
The reaction solution was left to cool to room temperature and then
concentrated under reduced pressure. A saturated sodium bicarbonate
solution was added to the resulting residue, followed by extraction
with chloroform. The resulting extract was dried over magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (carrier:
Chromatorex NH; elution solvent: heptane-ethyl acetate system) and
further solidified with a mixed solvent of ethyl acetate, diethyl
ether and heptane to obtain 117 mg of the title compound. The
property values of the compound are as follows. ESI-MS; m/z 448
[M.sup.++H]. .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=1.2
Hz, 3H), 2.35-2.42 (m, 2H), 3.84 (brt, J=5.6 Hz, 2H), 4.05 (s, 3H),
4.23 (t, J=6.0 Hz, 2H), 6.93-6.97 (m, 2H), 7.33-7.41 (m, 3H), 7.46
(d, J=7.6 Hz, 1H), 7.49-7.55 (m, 3H), 7.76 (d, J=1.2 Hz, 1H).
Example 233
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-ph-
enyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00196##
[1146] 120 mg of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-(2-oxo-3-ph-
enyl-tetrahydropyrimidin-1-yl)acrylamide (259 mg) by the same
method as in Example 232. The property values of the compound are
as follows.
[1147] ESI-MS; m/z 414 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.29 (s, 3H), 2.34-2.41 (m, 2H), 3.88 (brt, J=5.6
Hz, 2H), 4.05 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.93-6.96 (m, 2H),
7.12-7.27 (m, 1H), 7.36-7.43 (m, 3H), 7.45 (d, J=7.6 Hz, 1H),
7.51-7.57 (m, 3H), 7.75 (brs, 1H).
Example 234
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(3-
,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00197##
[1149] 175 mg of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(3-
,4,5-trifluorophenyl)-tetrahydropyrimidin-1-yl]acrylamide (298 mg)
by the same method as in Example 232. The property values of the
compound are as follows.
[1150] ESI-MS; m/z 468 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.35-2.44 (m, 2H), 3.81 (t, J=5.6 Hz,
2H), 4.06 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.95-7.01 (m, 2H),
7.31-7.37 (m, 2H), 7.41 (d, J=16.0 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H),
7.53 (d, J=16.0 Hz, 1H), 7.77 (s, 1H).
Examples 235 and 236
Synthesis of
(R)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrim-
idine and
(S)-4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyrimidine
##STR00198##
[1152] 178 mg of the racemic title compound was obtained from
(E)-N-[3-(4-fluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-m-
ethoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (378
mg) by the same method as in Example 232. The racemic title
compound (178 mg) was separated by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with a retention time of 31 minutes (75 mg) and the title optically
active compound with a retention time of 39 minutes (75 mg).
[1153] The property values of the title optically active compound
with a retention time of 31 minutes are as follows (Example
235).
[1154] ESI-MS; m/z 446 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.29 (d, J=6.4 Hz, 3H), 2.10-2.18 (m, 1H), 2.29 (d,
J=0.8 Hz, 3H), 2.37-2.48 (m, 1H), 4.03 (s, 3H), 4.08-4.17 (m, 1H),
4.19-4.32 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H),
7.07-7.13 (m, 2H), 7.33 (d, J=15.6 Hz, 1H), 7.39-7.44 (m, 2H), 7.44
(d, J=7.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.75 (d, J=0.8 Hz,
1H).
[1155] The property values of the title optically active compound
with a retention time of 39 minutes are as follows (Example
236).
[1156] ESI-MS; m/z 446 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.29 (d, J=6.4 Hz, 3H), 2.10-2.18 (m, 1H), 2.29 (d,
J=0.8 Hz, 3H), 2.37-2.48 (m, 1H), 4.03 (s, 3H), 4.08-4.17 (m, 1H),
4.19-4.32 (m, 2H), 6.91 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H),
7.07-7.13 (m, 2H), 7.33 (d, J=15.6 Hz, 1H), 7.39-7.44 (m, 2H), 7.44
(d, J=7.6 Hz, 1H), 7.51 (d, J=15.6 Hz, 1H), 7.75 (d, J=0.8 Hz,
1H).
Example 237
Synthesis of
2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-ph-
enyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00199##
[1157] Synthesis of
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-(2-oxo-3-ph-
enyl-tetrahydropyrimidin-1-yl)acrylamide
[1158] 1-Amino-3-phenyl-tetrahydropyrimidin-2-one synthesized by
the same method as in Example 232 at room temperature (111 mg;
ESI-MS; m/z 192 [M.sup.++H]), IPEA (0.41 mL), EDC (166 mg) and HOBT
(117 mg) were added to a solution of
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (300 mg) in DMF (6 mL). The reaction solution was stirred at
room temperature for 24 hours. The reaction solution was diluted
with ethyl acetate and washed with a saturated sodium bicarbonate
solution and a saturated sodium chloride solution. The resulting
organic layer was dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane-ethyl acetate system, then ethyl acetate-methanol
system) to obtain 250 mg of the title compound. The property value
of the compound is as follows.
[1159] ESI-MS; m/z 433 [M.sup.++H].
Synthesis of
2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-ph-
enyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
[1160] Phosphorus oxychloride (4 mL) was added to
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-(2-oxo-3-ph-
enyl-tetrahydropyrimidin-1-yl)acrylamide (250 mg), and the reaction
solution was heated under reflux for one hour. The reaction
solution was left to cool to room temperature and then concentrated
under reduced pressure. Acetic acid (3 mL) and ammonium acetate
(2.3 g) were added to the resulting residue, and the reaction
solution was stirred at 150.degree. C. for two hours. The reaction
solution was left to cool to room temperature and then concentrated
under reduced pressure. A saturated sodium bicarbonate solution was
added to the resulting residue, followed by extraction with
chloroform. The resulting extract was dried over magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH; elution solvent: heptane-ethyl acetate system) and further
solidified with a mixed solvent of ethyl acetate, diethyl ether and
heptane to obtain 123 mg of the title compound. The property values
of the compound are as follows.
[1161] ESI-MS; m/z 414 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.35-2.42 (m, 2H), 3.88 (t,
J=6.0 Hz, 2H), 3.97 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.99 (d,
J=16.0 Hz, 1H), 7.14-7.19 (m, 1H), 7.39-7.58 (m, 7H), 8.15 (d,
J=1.6 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).
Example 238
Synthesis of
4-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyrid-
in-3-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00200##
[1163] 199 mg of the racemic title compound was obtained from
(E)-N-[3-(4-chlorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[5-methoxy-6--
(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylamide (270 mg) by the
same method as in Example 237. The property values of the compound
are as follows.
[1164] ESI-MS; m/z 448 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.35-2.42 (m, 2H), 3.85
(brt, J=5.6 Hz, 2H), 3.98 (s, 3H), 4.23 (t, J=6.4 Hz, 2H), 6.98 (d,
J=16.4 Hz, 1H), 7.35-7.39 (m, 2H), 7.44 (d, J=16.4 Hz, 1H), 7.47
(d, J=2.0 Hz, 1H), 7.49-7.54 (m, 3H), 8.16 (d, J=2.0 Hz, 1H), 8.34
(d, J=1.2 Hz, 1H).
Example 239
Synthesis of
2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}-4-(3-
,4,5-trifluorophenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00201##
[1166] 180 mg of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]-N-[2-oxo-3-(3-
,4,5-trifluorophenyl)-tetrahydropyrimidin-1-yl]acrylamide (280 mg)
by the same method as in Example 237. The property values of the
compound are as follows.
[1167] ESI-MS; m/z 468 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.37-2.43 (m, 2H), 3.82
(brt, J=5.6 Hz, 2H), 4.00 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.99 (d,
J=16.4 Hz, 1H), 7.31-7.37 (m, 2H), 7.44-7.55 (m, 3H), 8.20 (d,
J=1.6 Hz, 1H), 8.35 (d, J=1.2 Hz, 1H).
Examples 240 and 241
Synthesis of
(R)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrim-
idine and
(S)-4-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyrimidine
##STR00202##
[1169] 245 mg of the racemic title compound was obtained from
(E)-N-[3-(4-fluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3-[5-m-
ethoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylamide (445
mg) by the same method as in Example 237. The racemic title
compound (180 mg) was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: hexane:ethanol=1:1) to obtain the title optically active
compound with a retention time of 22 minutes (80 mg) and the title
optically active compound with a retention time of 28 minutes (70
mg).
[1170] The property values of the title optically active compound
with a retention time of 22 minutes are as follows (Example
240).
[1171] ESI-MS; m/z 446 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.29 (d, J=6.8 Hz, 3H), 2.11-2.19 (m, 1H), 2.29 (d,
J=1.2 Hz, 3H), 2.38-2.48 (m, 1H), 3.96 (s, 3H), 4.08-4.17 (m, 1H),
4.20-4.31 (m, 2H), 6.96 (d, J=16.4 Hz, 1H), 7.08-7.15 (m, 2H),
7.35-7.46 (m, 4H), 7.51 (brs, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.33 (d,
J=1.2 Hz, 1H).
[1172] The property values of the title optically active compound
with a retention time of 28 minutes are as follows (Example
241).
[1173] ESI-MS; m/z 446 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.29 (d, J=6.8 Hz, 3H), 2.11-2.19 (m, 1H), 2.29 (d,
J=1.2 Hz, 3H), 2.38-2.48 (m, 1H), 3.96 (s, 3H), 4.08-4.17 (m, 1H),
4.20-4.31 (m, 2H), 6.96 (d, J=16.4 Hz, 1H), 7.08-7.15 (m, 2H),
7.35-7.46 (m, 4H), 7.51 (brs, 1H), 8.13 (d, J=2.0 Hz, 1H), 8.33 (d,
J=1.2 Hz, 1H).
[1174] The following compounds were obtained using
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
by the same method as in Example 232 (Table 7).
TABLE-US-00007 TABLE 7 ##STR00203## Example E.sub.3 DATA: MS m/z
Note 242 ##STR00204## M.sup.+ + H: 413 (ESI) 243 ##STR00205##
M.sup.+ + H: 447 (ESI) 244 ##STR00206## M.sup.+ + H: 467 (ESI) 245
##STR00207## M.sup.+ + H: 427 (ESI) Optically active compound
(separation conditions IA, hexane:ethanol = 1:1, retention time 18
min) 246 ##STR00208## M.sup.+ + H: 427 (ESI) Optically active
compound (separation conditions IA, hexane:ethanol = 1:1, retention
time 23 min) 247 ##STR00209## M.sup.+ + H: 463 (ESI) Optically
active compound (separation conditions IB, hexane:ethanol = 1:1,
retention time 30 min) 248 ##STR00210## M.sup.+ + H: 463 (ESI)
Optically active compound (separation conditions IB, hexane:ethanol
= l:1, retention time 36 min) 249 ##STR00211## M.sup.+ + H: 445
(ESI) Optically active compound (separation conditions IA, IPA,
retention time 20 min) 250 ##STR00212## M.sup.+ + H: 445 (ESI)
Optically active compound (separation conditions IA, IPA, retention
time 25 min) 251 ##STR00213## M.sup.+ + H: 399 (ESI) 252
##STR00214## M.sup.+ + H: 419 (ESI)
Example 253 and 254
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00215##
[1175] Synthesis of 4-chloro-2-(3,4,5-trifluorophenyl)butyric
acid
[1176] A 2.66 M solution of butyl lithium in hexane (20 mL) was
added to a solution of 3,4,5-trifluorophenylacetic acid (5.00 g) in
THF (150 mL) in a nitrogen atmosphere at -78.degree. C., and the
reaction solution was stirred at -78.degree. C. for 20 minutes. The
reaction solution was further stirred at 0.degree. C. for one hour.
Then, 1-bromo-2-chloroethane (2.2 mL) was added at 0.degree. C.,
and the reaction solution was stirred at room temperature for 14
hours. Ethyl acetate and 1 N hydrochloric acid were added to the
reaction solution, and the organic layer was separated. The
resulting organic layer was washed with a saturated sodium chloride
solution. The resulting organic layer was dried over magnesium
sulfate and then concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 4.54 g of the title
compound. The property values of the compound are as follows.
[1177] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.13-2.22 (m, 1H),
2.45-2.54 (m, 1H), 3.36 (ddd, J=11.6, 8.4, 4.8 Hz, 1H), 3.58 (ddd,
J=11.6, 6.4, 5.2 Hz, 1H), 3.89 (dd, J=7.6, 7.6 Hz, 1H), 6.94-7.02
(m, 2H).
Synthesis of tert-butyl
N'-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate
[1178] oxalyl chloride (0.63 mL) and DMF (1 drop) were added to a
solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid (1.17 g)
in methylene chloride (30 mL) at 0.degree. C., and the reaction
solution was stirred at room temperature for one hour. The reaction
solution was concentrated under reduced pressure to obtain
4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride. A solution
of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid chloride in THF
(5 mL) was added to a solution of tert-butyl carboxylate (600 mg)
and triethylamine (3.1 mL) in THF (20 mL) at 0.degree. C., and the
reaction solution was stirred at room temperature for one hour. The
reaction solution was added to a saturated sodium bicarbonate
solution, followed by extraction with ethyl acetate. The resulting
extract was dried over magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain 1.35 g of the title compound. The property value
of the compound is as follows.
[1179] ESI-MS; m/z 389 [M.sup.++Na]
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
[1180] Isopropyl chloroformate (3.99 mL) was added dropwise to a
solution of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (5.2 g) and N,N-diisopropylethylamine (7.44 mL) in DMF (52 mL)
under ice-cooling, and the reaction solution was stirred for 20
minutes. Aqueous ammonic (5.2 mL) was added to the reaction
solution, and the reaction solution was stirred at room temperature
for 30 minutes. Similarly, ethyl chloroformate (3.76 mL) was added
dropwise to a solution of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (4.8 g) and N,N-diisopropylethylamine (6.87 mL) in DMF (48 mL)
under ice-cooling, and the reaction solution was stirred for 10
minutes. Then, aqueous ammonia (5.2 mL) was added to the reaction
solution, and the reaction solution was stirred at room temperature
for 30 minutes. The reaction solutions were mixed and diluted with
water and chloroform, and then the organic layer was separated. The
aqueous layer was extracted with chloroform five times. The organic
layers were combined, dried over anhydrous magnesium sulfate and
then concentrated under reduced pressure. The residue was purified
by silica gel column chromatography (chloroform-2-propanol system)
to obtain 3.54 g of the title compound. The property value of the
compound is as follows. ESI-MS; m/z 259 [M.sup.++H].
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile
[1181] A mixture of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
(3.54 g) and phosphorus oxychloride (12 ml) was stirred at
90.degree. C. for one hour. The reaction solution was concentrated
under reduced pressure and then diluted with ice water, chloroform
and aqueous ammonia, and the organic layer was separated. The
organic layer was dried over anhydrous magnesium sulfate and then
concentrated under reduced pressure. The residue was diluted with
ether and the precipitated crystals were collected by filtration.
The crystals were washed with ether and then air-dried to obtain
2.27 g of the title compound. The property value of the compound is
as follows.
[1182] ESI-MS; m/z 241 [M.sup.++H].
[1183]
(E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acryloni-
trile is also synthesized by the following synthesis method.
Synthesis of N-(6-bromo-2-methoxypyridin-3-yl)formaldehyde
[1184] Acetic anhydride (203 ml) was added dropwise to formic acid
(204 ml) under ice-cooling, and the reaction solution was stirred
at the same temperature for 25 minutes.
6-Bromo-2-methoxypyridine-3-amine powder (CAS No. 89466-18-2, 146
g) was put into the reaction mixture over 10 minutes, and then the
reaction solution was stirred at the same temperature for 30
minutes. The water bath was removed. tert-Butyl methyl ether (300
ml) and n-heptane (500 ml) were sequentially added dropwise to the
reaction solution, and then the reaction solution was stirred for
30 minutes. The precipitated powder was collected by filtration.
The resulting powder was crushed with a mortar, washed with
tert-butyl methyl ether and then dried under reduced pressure to
obtain 137.4 g of the title compound.
[1185] Then, the combined filtrate and washing solution were
concentrated under reduced pressure. The residue was triturated
with tert-butyl methyl ether and dried under reduced pressure to
obtain 21.9 g of the title compound.
[1186] The property values of the compound are as follows.
[1187] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 4.03 (s, 3H), 7.08
(d, J=8.0 Hz, 1H), 7.61 (brs, 1H), 8.47-8.51 (m, 2H).
Synthesis of
N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide
[1188] Chloroacetone (82 ml) was added dropwise to a suspension of
N-(6-bromo-2-methoxypyridin-3-yl)formamide (159.3 g), cesium
carbonate (359 g) and potassium iodide (11.4 g) in
N,N-dimethylformamide (800 ml) over seven minutes. Then, the
reaction solution was stirred at room temperature for one hour and
20 minutes.
[1189] The reaction solution was concentrated under reduced
pressure. Ethyl acetate and water were added to the resulting
residue, and the organic layer was separated. The resulting organic
layer was washed with brine, dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure to obtain 215.2 g of
the title compound. The property values of the compound are as
follows.
[1190] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.17 (s, 3H), 4.00
(s, 3H), 4.47 (s, 2H), 7.13 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz,
1H), 8.22 (s, 1H).
Synthesis of
6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine
[1191] A suspension of ammonium acetate (267 g) and
N-(6-bromo-2-methoxypyridin-3-yl)-N-(2-oxopropyl)formamide (199 g)
in glacial acetic acid (400 ml) was stirred at 130.degree. C. for
one hour and 10 minutes. The reaction solution was returned to room
temperature. Ethyl acetate and ice water were added to the reaction
solution, and the reaction solution was ice-cooled. Then,
concentrated aqueous ammonia (500 ml) was added dropwise and then
the organic layer was separated. The resulting organic layer was
sequentially washed with water and brine and dried over anhydrous
magnesium sulfate. Then, the organic layer was purified by short
silica gel column chromatography (carrier: Wakogel C-200; elution
solvent: ethyl acetate). The eluted fraction was concentrated. The
resulting residue was triturated with ethyl acetate and tert-butyl
methyl ether and dried under reduced pressure to obtain 107.7 g of
the title compound.
[1192] Then, the trituration mother liquor was concentrated. The
resulting residue was purified by silica gel column chromatography
(carrier: Wakogel C-200; elution solvent: toluene-ethyl acetate
system). The target fraction was concentrated. The resulting
residue was triturated with tert-butyl methyl ether and dried under
reduced pressure to obtain 12.9 g of the title compound.
[1193] The property values of the compound are as follows.
[1194] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=0.8 Hz,
3H), 4.03 (s, 3H), 6.92 (dd, J=1.2, 0.8 Hz, 1H), 7.16 (d, J=8.0 Hz,
1H), 7.40 (d, J=8.0 Hz, 1H), 7.73 (d, J=1.2 Hz, 1H).
[1195] ESI-MS; m/z 268 [M.sup.++H].
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
[1196] Triethylamine (52 ml) was added to a suspension of
6-bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (49.8 g),
tris(dibenzylideneacetone)dipalladium (0) (5.11 g),
tri-o-tolylphosphine (3.41 g) and acrylamide (14.5 g) in
N,N-dimethyl formamide (260 ml). The reaction solution was stirred
at 100.degree. C. for 50 minutes. The reaction solution was
returned to room temperature and then filtered through celite. The
filter cake was sequentially washed with N,N-dimethylformamide,
methanol, a 50% N,N-dimethylformamide solution and
N,N-dimethylformamide. The resulting filtrate was filtered through
celite again, and the filtrate was concentrated under reduced
pressure. Toluene was added to the residue, and the reaction
solution was concentrated again. Toluene and a saturated sodium
bicarbonate solution were added to the resulting residue, and the
insoluble matter was collected by filtration. The resulting powder
was dried under reduced pressure to obtain 42.96 g of the title
compound. The property values of the compound are as follows.
[1197] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (d, J=0.8 Hz,
3H), 4.07 (s, 3H), 5.57 (brs, 1H), 5.68 (brs, 1H), 6.98 (brs, 1H),
7.00 (d, J=15.2 Hz, 1H), 7.06 (d, J=7.6 Hz, 1H), 7.54 (d, J=7.6 Hz,
1H), 7.56 (d, J=15.2 Hz, 1H), 7.82 (d, J=1.2 Hz, 1H).
[1198] ESI-MS; m/z 259 [M.sup.++H].
Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile
[1199] Methyl dichlorophosphate (33 ml) was added dropwise to a
suspension of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
(42.96 g) and 1,8-diazabicyclo[5,4,0]-7-undecene (112 ml) in
methylene chloride (400 ml) under ice-cooling over 20 minutes. The
reaction solution was stirred at the same temperature for 10
minutes and at room temperature for further 35 minutes. Then, a
saturated sodium bicarbonate solution (200 ml) was added to the
reaction solution, and the reaction solution was stirred at room
temperature for 10 minutes. Water was added to the reaction
solution. Then, the reaction solution was filtered and the organic
layer in the filtrate was separated. The aqueous layer was
reextracted with methylene chloride (twice). The combined organic
layers were dried over anhydrous magnesium sulfate and purified by
short silica gel column chromatography (carrier: Chromatorex NH;
elution solvent: methylene chloride). The eluted fraction was
concentrated. The resulting residue was triturated with ethyl
acetate and tert-butyl methyl ether and dried under reduced
pressure overnight to obtain 34.28 g of the title compound.
[1200] Then, the trituration mother liquor was concentrated. The
resulting residue was triturated with acetone and dried under
reduced pressure to obtain 0.56 g of the title compound.
[1201] The property values of the compound are as follows.
[1202] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 4.07
(s, 3H), 6.54 (d, J=16.0 Hz, 1H), 7.00 (brs, 1H), 7.02 (d, J=7.6
Hz, 1H), 7.32 (d, J=16.0 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.84 (d,
J=1.2 Hz, 1H).
[1203] ESI-MS; m/z 241 [M.sup.++H].
Synthesis of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride
[1204] A suspension of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylonitrile
(2.27 g) in ethanol (45 mL) was bubbled with hydrogen chloride gas
under ice-cooling for 20 minutes, and the reaction solution was
stirred at room temperature for 4.5 hours. The reaction solution
was concentrated under reduced pressure. Then, ethyl acetate was
added to the residue, and the precipitated powder was collected by
filtration. The resulting powder was washed with ethyl acetate
containing 50% of ethanol and then dried under reduced pressure to
obtain 1.83 g of the title compound. The property values of the
compound are as follows.
[1205] ESI-MS; m/z 287 [M.sup.++H-2HCl].
[1206] 1H-NMR (DMSO-D.sub.6) .delta. (ppm): 1.47 (t, J=6.8 Hz, 3H),
2.35 (s, 3H), 4.06 (s, 3H), 4.53 (q, J=6.8 Hz, 2H), 7.45 (d, J=15.6
Hz, 1H), 7.64 (d, J=8.4 Hz, 1H), 7.80 (brs, 1H), 7.92 (d, J=15.6
Hz, 1H), 8.18 (d, J=8.4 Hz, 1H), 9.33 (brs, 1H).
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
[1207] A solution of 4 N hydrogen chloride in ethyl acetate (120
mL) was added to tert-butyl
N'-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate
(6.6 g). The reaction solution was stirred at room temperature for
one hour and then concentrated under reduced pressure to obtain
4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide
hydrochloride (6.03 g). A solution of
4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide
hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10
mL) was added to a solution of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10
mL) at room temperature. The reaction solution was stirred at
80.degree. C. for 25 hours. The reaction solution was left to cool
to room temperature and then concentrated under reduced pressure. A
saturated sodium bicarbonate solution was added to the resulting
residue, followed by extraction with chloroform. The resulting
extract was dried over magnesium sulfate and then concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography (carrier: Chromatorex NH; elution solvent:
heptane-ethyl acetate system) to obtain 150 mg of the racemic title
compound. The racemic title compound (150 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with a retention time of 13 minutes
and positive optical rotation (54 mg) and the title optically
active compound with a retention time of 34 minutes and negative
optical rotation (51 mg).
[1208] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[1209] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.62-2.72 (m, 1H), 3.22-3.32
(m, 1H), 4.08 (s, 3H), 4.19-4.27 (m, 1H), 4.31-4.45 (m, 2H),
6.93-7.02 (m, 4H), 7.50 (d, J=8.0 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H),
7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).
[1210] The property values of the title optically active compound
with a retention time of 13 minutes corresponded to the property
values of the title optically active compound with a retention time
of 34 minutes.
Examples 255 and 256
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00216##
[1211] Synthesis of N-(5-bromo-3-methoxypyridin-2-yl)formamide
[1212] Iron (67.3 g) and ammonium chloride (129 g) were added to a
solution of 5-bromo-3-methoxy-2-nitropyridine (56.0 g, CAS:
152684-26-9) in ethanol (500 mL) and water (200 mL). The reaction
solution was stirred at 80 to 90.degree. C. for one hour and then
left to cool to room temperature. The reaction solution was
filtered through celite and washed with ethanol. Then, the filtrate
was concentrated under reduced pressure. The residue was diluted
with ethyl acetate and water, and the organic layer was separated.
The resulting organic layer was washed with brine, dried over
anhydrous magnesium sulfate and then concentrated under reduced
pressure. The residue was diluted with THF (84 mL). The THF
solution was added dropwise to a mixed solution of formic acid
(78.1 mL) and acetic anhydride (78.3 mL) at room temperature. Then,
the reaction solution was stirred for one hour. Ice water (500 mL)
was added to the reaction solution, and the precipitated crystals
were collected by filtration. The crystals were washed with water
and then air-dried. The crystals were recrystallized from toluene
to obtain 34.1 g of the title compound. The property value of the
compound is as follows.
[1213] ESI-MS; m/z 231 [M.sup.++H].
Synthesis of
N-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)formamide
[1214] Cesium carbonate (96 g), potassium iodide (2.45 g) and
chloroacetone (23.5 mL) were added to a solution of
N-(5-chloro-3-methoxypyridin-2-yl)formamide (34.1 g) in DMF (200
mL), and the reaction solution was stirred at 80.degree. C. for 45
minutes. Ice water and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The organic layer
was washed with brine and then dried over anhydrous magnesium
sulfate and concentrated under reduced pressure to obtain 52.8 g of
the crude title compound. The property value of the compound is as
follows.
[1215] ESI-MS; m/z 287 [M.sup.++H].
Synthesis of
5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine
[1216] A mixture of the crude
N-(5-bromo-3-methoxypyridin-2-yl)-N-(2-oxopropyl)formamide obtained
above (26.4 g), acetic acid (52.8 mL) and ammonium acetate (35.5 g)
was stirred at 130.degree. C. for one hour. The reaction solution
was left to cool to room temperature and concentrated under reduced
pressure. The residue diluted with ice water, ethyl acetate and
aqueous ammonia, and the organic layer was separated. The organic
layer was washed with brine and then dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 5.69 g of the title
compound. The property values of the compound are as follows.
[1217] ESI-MS; m/z 268 [M.sup.++H].
[1218] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 3.97
(s, 3H), 7.48 (brs, 1H), 7.49 (d, J=2.0 Hz, 1H), 8.12 (d, J=2.0 Hz,
1H), 8.30 (brs, 1H).
Synthesis of
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylonitrile
[1219] A mixture of
5-bromo-3-methoxy-2-(4-methyl-1H-imidazol-1-yl)pyridine (3.8 g),
tris(dibenzylideneacetone)dipalladium (650 mg),
tri-o-tolylphosphine (433 mg), N,N-diisopropylethylamine (4.86 mL),
DMF (14.1 mL) and acrylonitrile (2.82 mL) was stirred in a nitrogen
atmosphere at 110.degree. C. for five hours. The reaction solution
was left to cool to room temperature and then concentrated under
reduced pressure. The residue was diluted with ethyl acetate and
then filtered through celite, and the filtrate was washed with
water. The organic layer was concentrated under reduced pressure,
and the precipitated crystals were hot dissolved in ethyl acetate.
After leaving to cool to room temperature, the precipitated
crystals were collected by filtration and air-dried to obtain 1.79
g of the title compound. The filtrate was concentrated under
reduced pressure. Then, the residue was purified by silica gel
column chromatography (heptane-ethyl acetate system) and then
recrystallized from ethyl acetate to obtain 0.312 g of the title
compound. The property value of the compound is as follows.
[1220] ESI-MS; m/z 241 [M.sup.++H].
Synthesis of ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate
dihydrochloride
[1221] A suspension of
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylonitrile
(2.1 g) in ethanol (40 mL) was bubbled with hydrogen chloride gas
under ice-cooling for one hour, and the reaction solution was
stirred at room temperature overnight. The reaction solution was
concentrated under reduced pressure. Then, ethyl acetate was added
to the residue, and the precipitated powder was collected by
filtration. The resulting powder was washed with ethyl acetate
containing 50% of ethanol and then dried under reduced pressure to
obtain 1.82 g of the title compound. The property values of the
compound are as follows.
[1222] ESI-MS; m/z 287 [M.sup.++H-2HCl].
[1223] .sup.1H-NMR (DMSO-D.sub.6) .delta. (ppm): 1.47 (t, J=6.8 Hz,
3H), 2.36 (s, 3H), 4.06 (s, 3H), 4.55 (q, J=6.8 Hz, 2H), 7.26 (d,
J=16.4 Hz, 1H), 8.04 (brs, 1H), 8.05 (d, J=16.4 Hz, 1H), 8.21 (d,
J=1.6 Hz, 1H), 8.50 (d, J=1.6 Hz, 1H), 9.61 (brs, 1H).
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
[1224] A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid
hydrazide hydrochloride synthesized in Examples 253 and 254 (565
mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a
solution of ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimi-
date dihydrochloride (500 mg) and triethylamine (0.95 mL) in
ethanol (10 mL) at room temperature. The reaction solution was
stirred at 80.degree. C. for 25 hours. The reaction solution was
left to cool to room temperature and then concentrated under
reduced pressure. A saturated sodium bicarbonate solution was added
to the resulting residue, followed by extraction with chloroform.
The resulting extract was dried over magnesium sulfate and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography (carrier: Chromatorex NH; elution
solvent: heptane-ethyl acetate system) to obtain 154 mg of the
racemic title compound. The racemic title compound (154 mg) was
purified by CHIRALPAK.TM. IA manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) and then separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=7:3) to obtain the title optically
active compound with a retention time of 17 minutes and positive
optical rotation (40 mg) and the title optically active compound
with a retention time of 23 minutes and negative optical rotation
(37 mg).
[1225] The property values of the title optically active compound
with a retention time of 23 minutes are as follows.
[1226] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.62-2.72 (m, 1H), 3.22-3.32
(m, 1H), 4.00 (s, 3H), 4.19-4.26 (m, 1H), 4.31-4.45 (m, 2H),
6.93-7.02 (m, 2H), 7.11 (d, J=16.4 Hz, 1H), 7.49 (d, J=2.0 Hz, 1H),
7.53-7.55 (m, 1H), 7.58 (d, J=16.4 Hz, 1H), 8.18 (d, J=2.0 Hz, 1H),
8.36 (d, J=1.2 Hz, 1H).
[1227] The property values of the title optically active compound
with a retention time of 17 minutes corresponded to the property
values of the title optically active compound with a retention time
of 23 minutes.
Examples 257 and 258
Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine
##STR00217##
[1228] Synthesis of
1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene
[1229] A solution containing 4-fluorobenzaldehyde (5 g),
2-chloroethanol (13.5 mL) and p-toluenesulfonic acid (767 mg) in
ethanol (100 mL) was heated under reflux for 15 hours while
dehydrating with a Dean-Stalk trap for 15 hours. The reaction
solution was concentrated. Ethyl acetate and saturated sodium
bicarbonate water were added to the residue, and the organic layer
was separated. The organic layer was washed with brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH, elution solvent:
heptane/ethyl acetate) to obtain the title compound (5.43 g). The
property values of the compound are as follows.
[1230] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.67 (t, J=5.6 Hz,
4H), 3.74-3.83 (m, 4H), 7.06 (dd, J=8.8, 8.8 Hz, 2H), 7.45 (dd,
J=8.8, 5.6 Hz, 2H).
Synthesis of (2-chloroethoxy)-(4-fluorophenyl)acetonitrile
[1231] A solution containing
1-[bis-(2-chloroethoxy)methyl]-4-fluorobenzene (5.43 g),
trimethylsilyl cyanide (4.06 mL) and tetracyanoethylene (520 mg) in
acetonitrile (100 mL) was heated under reflux for four hours. The
reaction solution was returned to room temperature and the solvent
was evaporated under reduced pressure. Ethyl acetate and brine were
added to the residue, and the organic layer was separated. The
organic layer was dried over anhydrous magnesium sulfate. The
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex,
elution solvent: heptane/ethyl acetate) to obtain the title
compound (4.3 g). The property values of the compound are as
follows.
[1232] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.70 (t, J=5.2 Hz,
2H), 3.82-3.87 (m, 1H), 3.96-4.01 (m, 1H), 5.36 (s, 1H), 7.13 (dd,
J=8.4, 8.4 Hz, 2H), 7.48-7.52 (m, 2H).
Synthesis of (2-chloroethoxy)-(4-fluorophenyl)acetic acid
[1233] A mixture of (2-chloroethoxy)-(4-fluorophenyl)acetonitrile
(3 g) and 5 N hydrochloric acid was heated under reflux for 15
hours. After returning to room temperature, the reaction solution
was made basic with 5 N sodium hydroxide and washed with ether. The
aqueous layer was made acidic with 5 N hydrochloric acid. Ethyl
acetate was added, and the organic layer was separated. The organic
layer was dried over anhydrous magnesium sulfate, and the solvent
was evaporated under reduced pressure to obtain the title compound
(2.8 g). The property values of the compound are as follows.
[1234] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.68 (t, J=6.0 Hz,
2H), 3.73-3.79 (m, 1H), 3.80-3.86 (m, 1H), 4.97 (s, 1H), 7.09 (dd,
J=8.4, 8.4 Hz, 2H), 7.45 (dd, J=8.8, 5.2 Hz, 2H).
Synthesis of tert-butyl
N'-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate
[1235] Bis(2-oxo-3-oxazolidinyl)phosphinic acid chloride (4.38 g)
was added to a solution of (2-chloroethoxy)-(4-fluorophenyl)acetic
acid (2 g), tert-butyl carbazate (2.27 g) and triethylamine (3.58
mL) in tetrahydrofuran (20 mL), and the reaction solution was
stirred at room temperature for 16 hours. Saturated aqueous
ammonium chloride and ethyl acetate were added to the reaction
solution, and the organic layer was separated. The organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex,
elution solvent: heptane/ethyl acetate) to obtain the title
compound (2.8 g). The property values of the compound are as
follows.
[1236] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.46 (s, 9H), 3.68
(t, J=6.0 Hz, 2H), 3.74-3.81 (m, 2H), 4.90 (s, 1H), 7.03 (brs, 1H),
7.03-7.09 (m, 2H), 7.41-7.45 (m, 2H), 8.40 (brs, 1H).
Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-3-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine
[1237] A solution of 4 N hydrochloric acid in ethyl acetate (5 mL)
was added to a solution of tert-butyl
N'-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate
(363 mg) in ethyl acetate (5 mL). The reaction solution was stirred
at room temperature for 1.5 hours, and then the solvent was
evaporated under reduced pressure. Ethanol (5 mL) and triethylamine
(0.58 mL) were added to the residue. A solution of ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate
hydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5
mL) was added dropwise to the mixture. The reaction solution was
heated under reflux for 14 hours. The reaction solution was
returned to room temperature and the solvent was evaporated under
reduced pressure. Ethyl acetate and sodium bicarbonate water were
added. The organic layer was separated and washed with brine. The
organic layer was dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH, elution solvent: heptane/ethyl acetate->ethyl acetate) to
obtain a racemate of the title compound (180 mg). The resulting
racemate (180 mg) was optically resolved by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
elution solvent: 50% solution of hexane in ethanol) to obtain the
title optically active compound with positive optical rotation and
a retention time of 33 minutes (60 mg) and the title optically
active compound with negative optical rotation and a retention time
of 42 minutes (53 mg).
[1238] The property values of the title optically active compound
with a retention time of 33 minutes are as follows.
[1239] ESI-MS; m/z 433 [M.sup.++H].
[1240] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 3.98
(s, 3H), 4.14-4.19 (m, 1H), 4.31-4.42 (m, 3H), 5.92 (s, 1H),
7.08-7.13 (m, 3H), 7.43-7.48 (m, 3H), 7.52-7.56 (m, 2H), 8.16 (s,
1H), 8.36 (s, 1H).
[1241] The property values of the title optically active compound
with a retention time of 42 minutes are as follows.
[1242] ESI-MS; m/z 433 [M.sup.++H].
[1243] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 3.98
(s, 3H), 4.14-4.19 (m, 1H), 4.31-4.42 (m, 3H), 5.92 (s, 1H),
7.08-7.13 (m, 3H), 7.43-7.48 (m, 3H), 7.52-7.56 (m, 2H), 8.16 (s,
1H), 8.36 (s, 1H).
Examples 259 and 260
Synthesis of (+) and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-1-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine
##STR00218##
[1244] Synthesis of tert-butyl
N'-[2-(2-chloroethoxy)-2-(4-chlorophenyl)acetyl]-hydrazinecarboxylate
[1245] The title compound (2.24 g) was obtained from
4-chlorobenzaldehyde (5 g) by the same method as in Examples 257
and 258. The property values of the compound are as follows.
[1246] ESI-MS; m/z 385 [M.sup.++Na].
[1247] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.45 (s, 9H), 3.68
(d, J=5.6 Hz, 2H), 3.75-3.82 (m, 2H), 4.90 (s, 1H), 6.36 (brs, 1H),
7.33-7.41 (m, 4H), 8.39 (s, 1H).
Synthesis of 4-chlorobenzoic acid hydrazide hydrochloride
[1248] 4 N hydrochloric acid-ethyl acetate (10 mL) was added to a
solution of tert-butyl
N'-[2-(2-chloroethoxy)-2-(4-chlorophenyl)acetyl]-hydrazinecarboxylate
(2.24 g) in ethyl acetate (10 mL), and the reaction solution was
stirred at room temperature for six hours. The solvent was
evaporated under reduced pressure to obtain the title compound (1.8
g).
[1249] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.50-3.67 (m, 4H),
4.91 (s, 1H), 7.25-7.32 (m, 4H).
Synthesis of (+) and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)p-
yridin-1-yl]vinyl}-hexahydro-[1,2,4]triazolo[5,1-c][1,4]oxazine
[1250] A solution of 4-chlorobenzoic acid hydrazide hydrochloride
(250 mg) and triethylamine (0.58 mL) in ethanol (5 mL) was added
dropwise to a solution of ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate
hydrochloride (250 mg) and triethylamine (0.58 mL) in ethanol (5
mL). The reaction solution was heated under reflux for 14 hours.
The reaction solution was returned to room temperature and the
solvent was evaporated under reduced pressure. Ethyl acetate and
sodium bicarbonate water were added. The organic layer was
separated and washed with brine. The organic layer was dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH, elution solvent:
heptane/ethyl acetate->ethyl acetate) to obtain a racemate of
the title compound (145 mg). The resulting racemate (145 mg) was
optically resolved by CHIRALPAK.TM. IA manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm, elution solvent: 50%
solution of hexane in ethanol, flow rate: 10 mL/min) to obtain the
title optically active compound with positive optical rotation and
a retention time of 14.7 minutes (analysis conditions:
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(0.46 cm.times.25 cm, elution solvent: 50% solution of hexane in
ethanol, flow rate: 1 mL/min) (40 mg) and the title optically
active compound with negative optical rotation and a retention time
of 16.4 minutes (analysis conditions: CHIRALPAK.TM. IA manufactured
by Daicel Chemical Industries, Ltd. (0.46 cm.times.25 cm, elution
solvent: 50% solution of hexane in ethanol, flow rate: 1 mL/min)
(54 mg).
[1251] The property values of the title optically active compound
with a retention time of 14.7 minutes are as follows.
[1252] ESI-MS; m/z 449 [M.sup.++H].
[1253] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=1.2 Hz,
3H), 3.98 (s, 3H), 4.14-4.31 (m, 1H), 4.29-4.40 (m, 3H), 5.90 (s,
1H), 7.08 (d, J=16.0 Hz, 1H), 7.37-7.43 (m, 4H), 7.46 (d, J=2.0 Hz,
1H), 7.52 (s, 1H), 7.52 (d, J=16.0 Hz, 1H), 8.15 (d, J=1.6 Hz, 1H),
8.34 (d, J=1.2 Hz, 1H).
[1254] The property values of the title optically active compound
with a retention time of 16.4 minutes are as follows.
[1255] ESI-MS; m/z 449 [M.sup.++H].
[1256] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=1.2 Hz,
3H), 3.98 (s, 3H), 4.14-4.31 (m, 1H), 4.29-4.40 (m, 3H), 5.90 (s,
1H), 7.08 (d, J=16.0 Hz, 1H), 7.37-7.43 (m, 4H), 7.46 (d, J=2.0 Hz,
1H), 7.52 (s, 1H), 7.52 (d, J=16.0 Hz, 1H), 8.15 (d, J=2.0 Hz, 1H),
8.34 (d, J=1.2 Hz, 1H).
Examples 261 and 262
Synthesis of (+) and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine
##STR00219##
[1257] Synthesis of (+) and
(-)-8-(4-chlorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine
[1258] A solution of 4-chlorobenzoic acid hydrazide hydrochloride
(250 mg) and triethylamine (0.58 mL) in ethanol (5 mL) was added
dropwise to a solution of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
hydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5
mL). The reaction solution was heated under reflux for 14 hours.
The reaction solution was returned to room temperature and the
solvent was evaporated under reduced pressure. Ethyl acetate and
sodium bicarbonate water were added. The organic layer was
separated and washed with brine. The organic layer was dried over
anhydrous magnesium sulfate, and the solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography (carrier: Chromatorex NH, elution solvent:
heptane/ethyl acetate->ethyl acetate) to obtain a racemate of
the title compound (170 mg). The resulting racemate (170 mg) was
optically resolved by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm, elution solvent:
ethanol, flow rate: 10 mL/min) to obtain the title optically active
compound with positive optical rotation and a retention time of 16
minutes (68 mg) and the title optically active compound with
negative optical rotation and a retention time of 25 minutes (63
mg).
[1259] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1260] ESI-MS; m/z 449 [M.sup.++H].
[1261] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=1.2 Hz,
3H), 4.06 (s, 3H), 4.11-4.20 (m, 1H), 4.28-4.42 (m, 3H), 5.92 (s,
1H), 6.96 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 7.38-7.44 (m, 4H), 7.47
(d, J=7.6 Hz, 1H), 7.50 (d, J=16.0 Hz, 1H), 7.65 (d, J=16.0 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
[1262] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[1263] ESI-MS; m/z 449 [M.sup.++H].
[1264] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (d, J=1.2 Hz,
3H), 4.06 (s, 3H), 4.11-4.20 (m, 1H), 4.28-4.42 (m, 3H), 5.92 (s,
1H), 6.96 (s, 1H), 6.96 (d, J=7.6 Hz, 1H), 7.38-7.44 (m, 4H), 7.47
(d, J=7.6 Hz, 1H), 7.50 (d, J=16.0 Hz, 1H), 7.65 (d, J=16.0 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
[1265] The following compounds were obtained using ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride by the same method as in Examples 257 and 258
(Table 8).
TABLE-US-00008 TABLE 8 ##STR00220## Example E.sub.3 DATA: MS m/z
Note 263 ##STR00221## M.sup.+ + H: 432 (ESI) Optically active
compound (separation conditions IB: retention time 22 min, optical
rotation (+)) 264 ##STR00222## M.sup.+ + H: 432 (ESI) Optically
active compound (separation conditions IB: retention time 27 min,
optical rotation (-)) 265 ##STR00223## M.sup.+ + H: 448 (ESI)
Optically active compound (separation conditions IA: retention time
31 min, optical rotation (+)) 266 ##STR00224## M.sup.+ + H: 448
(ESI) Optically active compound (separation conditions IA:
retention time 35 min, optical rotation (-)) 267 ##STR00225##
M.sup.+ + H: 482 (ESI) Optically active compound (separation
conditions IA: retention time 19 min, optical rotation (+)) 268
##STR00226## M.sup.+ + H: 482 (ESI) Optically active compound
(separation conditions IA: retention time 25 min, optical rotation
(-)) 269 ##STR00227## M.sup.+ + H: 457 (ESI) Optically active
compound (separation conditions OJ-H: retention time 11 min,
optical rotation (-)) 270 ##STR00228## M.sup.+ + H: 457 (ESI)
Optically active compound (separation conditions OJ-H: retention
time 27 min, optical rotation (+)) 271 ##STR00229## M.sup.+ + H:
414 (ESI) Optically active compound (separation conditions AD-H:
retention time 10 min, optical rotation (-)) 272 ##STR00230##
M.sup.+ + H: 414 (ESI) Optically active compound (separation
conditions AD-H: retention time 12 min, optical rotation (+)) 273
##STR00231## M.sup.+ + H: 446 (ESI) Optically active compound
(separation conditions AD-H: ethanol: retention time 30 min,
optical rotation (-)) 274 ##STR00232## M.sup.+ + H: 446 (ESI)
Optically active compound (separation conditions AD-H: ethanol:
retention time 36 min, optical rotation (+))
Examples 275 and 276
Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine
##STR00233##
[1266] Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxazine
[1267] A solution of 4 N hydrochloric acid in ethyl acetate (5 mL)
was added to a solution of tert-butyl
N'-[2-(2-chloroethoxy)-2-(4-fluorophenyl)acetyl]-hydrazinecarboxylate
(363 mg) in ethyl acetate (5 mL). The reaction solution was stirred
at room temperature for 1.5 hours, and then the solvent was
evaporated under reduced pressure. Ethanol (5 mL) and triethylamine
(0.58 mL) were added to the residue. A solution of ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
hydrochloride (300 mg) and triethylamine (0.58 mL) in ethanol (5
mL) was added dropwise to the mixture. Then, the reaction solution
was heated under reflux for 14 hours. The reaction solution was
returned to room temperature and the solvent was evaporated under
reduced pressure. Ethyl acetate and sodium bicarbonate water were
added. The organic layer was separated and washed with brine. The
organic layer was dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
purified by silica gel column chromatography (carrier: Chromatorex
NH, elution solvent: heptane/ethyl acetate->ethyl acetate) to
obtain a racemate of the title compound (130 mg). The resulting
racemate (130 mg) was optically resolved by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
elution solvent: ethanol) to obtain the title optically active
compound with positive optical rotation and a retention time of 17
minutes (28 mg) and the title optically active compound with
negative optical rotation and a retention time of 26 minutes (35
mg).
[1268] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[1269] ESI-MS; m/z 433 [M.sup.++H].
[1270] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 4.06
(s, 3H), 4.13-4.20 (m, 1H), 4.29-4.41 (m, 3H), 5.93 (s, 1H), 6.96
(d, J=8.0 Hz, 1H), 6.97 (s, 1H), 7.11 (dd, J=8.8, 8.4 Hz, 2H), 7.45
(dd, J=8.8, 5.2 Hz, 2H), 7.48 (d, J=15.6 Hz, 1H), 7.48 (d, J=8.0
Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78 (s, 1H).
[1271] The property values of the title optically active compound
with a retention time of 26 minutes are as follows.
[1272] ESI-MS; m/z 433 [M.sup.++H].
[1273] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 4.06
(s, 3H), 4.13-4.20 (m, 1H), 4.29-4.41 (m, 3H), 5.93 (s, 1H), 6.96
(d, J=8.0 Hz, 1H), 6.97 (s, 1H), 7.11 (dd, J=8.8, 8.4 Hz, 2H), 7.45
(dd, J=8.8, 5.2 Hz, 2H), 7.48 (d, J=15.6 Hz, 1H), 7.48 (d, J=8.0
Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.78 (s, 1H).
Examples 277 and 278
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vi-
nyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00234##
[1275] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (300 mg) and 1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one
(180 mg) according to the method in Examples 168 and 169. The
resulting racemate was separated by CHIRALPAK.TM. IB manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: hexane:ethanol=80:20) to obtain the title optically active
compound with a retention time of 8.9 minutes and positive optical
rotation (79.9 mg, >99% ee) and the title optically active
compound with a retention time of 19.8 minutes and negative optical
rotation (73.0 mg, >99% ee).
[1276] The property values of the title compound with positive
optical rotation are as follows.
[1277] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.07-2.19 (m, 2H), 2.29 (s, 3H), 2.29-2.36 (m, 2H),
4.03 (s, 3H), 4.23-4.28 (m, 1H), 4.35-4.39 (m, 1H), 4.54-4.59 (m,
1H), 6.66-6.72 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.40
(d, J=16.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=16.0 Hz,
1H), 7.76 (s, 1H).
[1278] The property values of the title compound with negative
optical rotation are as follows.
[1279] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.07-2.19 (m, 2H), 2.29 (s, 3H), 2.29-2.36 (m, 2H),
4.03 (s, 3H), 4.23-4.28 (m, 1H), 4.35-4.39 (m, 1H), 4.54-4.59 (m,
1H), 6.66-6.72 (m, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.40
(d, J=16.0 Hz, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.62 (d, J=16.0 Hz,
1H), 7.76 (s, 1H).
Examples 279 and 280
Synthesis of
(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00235##
[1281] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (300 mg) and 1-amino-3-(2,4,6-trifluorophenyl)piperidin-2-one
(160 mg) according to the method in Examples 168 and 169. The
resulting racemate was separated by CHIRALPAK.TM. IB manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain the title optically active compound with
a retention time of 3.5 minutes and positive optical rotation (53.8
mg, >99% ee) and the title optically active compound with a
retention time of 4.3 minutes and negative optical rotation (54.2
mg, >99% ee).
[1282] The property values of the title compound with positive
optical rotation are as follows.
[1283] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.24 (m, 3H), 2.29 (s, 3H), 2.37-2.43 (m, 1H),
4.05 (s, 3H), 4.31 (t, J=6.0 Hz, 2H), 4.62 (t, J=6.4 Hz, 1H), 6.73
(t, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 7.01-7.14
(m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.65 (d,
J=15.6 Hz, 1H), 7.77 (s, 1H).
[1284] The property values of the title compound with negative
optical rotation are as follows.
[1285] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.24 (m, 3H), 2.29 (s, 3H), 2.37-2.43 (m, 1H),
4.05 (s, 3H), 4.31 (t, J=6.0 Hz, 2H), 4.62 (t, J=6.4 Hz, 1H), 6.73
(t, J=6.8 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 7.01-7.14
(m, 2H), 7.45 (d, J=15.6 Hz, 1H), 7.47 (d, J=8.0 Hz, 1H), 7.65 (d,
J=15.6 Hz, 1H), 7.77 (s, 1H).
Examples 281 and 282
Synthesis of
(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
##STR00236##
[1287] A racemate of the title compound (44.5 mg) was obtained
using 1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one (150 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (44.5 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 12 mL/min) to
obtain the title optically active compound with a retention time of
13 minutes and positive optical rotation (17 mg) and the title
optically active compound with a retention time of 19 minutes and
negative optical rotation (15 mg).
[1288] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1289] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.12-2.24 (m, 3H),
2.28 (s, 3H), 2.29 (s, 3H), 2.32-2.40 (m, 1H), 4.04 (s, 3H),
4.23-4.36 (m, 2H), 4.59 (dd, J=6.6, 6.6 Hz, 1H), 6.72-6.78 (m, 1H),
6.93 (d, J=7.7 Hz, 1H), 6.94-6.96 (m, 1H), 6.99 (d, J=7.7 Hz, 1H),
7.09-7.14 (m, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H),
7.65 (d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).
[1290] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1291] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.12-2.24 (m, 3H),
2.28 (s, 3H), 2.29 (s, 3H), 2.32-2.40 (m, 1H), 4.04 (s, 3H),
4.23-4.36 (m, 2H), 4.59 (dd, J=6.6, 6.6 Hz, 1H), 6.72-6.78 (m, 1H),
6.93 (d, J=7.7 Hz, 1H), 6.94-6.96 (m, 1H), 6.99 (d, J=7.7 Hz, 1H),
7.09-7.14 (m, 1H), 7.46 (d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H),
7.65 (d, J=15.7 Hz, 1H), 7.77 (d, J=1.1 Hz, 1H).
Examples 283 and 284
Synthesis of
(-)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imida-
zol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine and
(+)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
##STR00237##
[1292] Synthesis of
1-amino-3-(2-trifluoromethoxyphenyl)piperidin-2-one
[1293] 520 mg of the title compound was obtained using
2-trifluoromethoxyphenylacetic acid (1 g) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1294] ESI-MS; m/z 275 [M.sup.++H].
Synthesis of
(-)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imida-
zol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine and
(+)-8-(2-trifluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
[1295] A racemate of the title compound (146 mg) was obtained from
1-amino-3-(2-trifluoromethoxyphenyl)piperidin-2-one (300 mg)
according to the method in Examples 168 and 169. The resulting
racemate (146 mg) was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: hexane:ethanol=8:2, flow rate: 11 mL/min) to obtain the
title optically active compound with a retention time of 32 minutes
and negative optical rotation (49.9 mg) and the title optically
active compound with a retention time of 46 minutes and positive
optical rotation (47.2 mg).
[1296] The property values of the title optically active compound
with a retention time of 32 minutes are as follows.
[1297] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.41 (m, 7H),
4.04 (s, 3H), 4.28-4.32 (m, 2H), 4.64 (m, 1H), 6.92-6.99 (m, 3H),
7.19-7.35 (m, 3H), 7.44 (d, J=15.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H),
7.65 (d, J=16.0 Hz, 1H), 7.76 (s, 1H).
[1298] The property values of the title optically active compound
with a retention time of 46 minutes are as follows.
[1299] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.00-2.41 (m, 7H),
4.04 (s, 3H), 4.28-4.32 (m, 2H), 4.64 (m, 1H), 6.92-6.99 (m, 3H),
7.19-7.35 (m, 3H), 7.44 (d, J=15.2 Hz, 1H), 7.46 (d, J=8.2 Hz, 1H),
7.65 (d, J=16.0 Hz, 1H), 7.76 (s, 1H).
Examples 285 and 286
Synthesis of
(+)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
##STR00238##
[1300] Synthesis of
1-amino-3-(2-trifluoromethyl-4-fluorophenyl)piperidin-2-one
[1301] 364 mg of the title compound was obtained using
2-trifluoromethyl-4-fluorophenylacetic acid (1 g) as a starting
material according to the method in Examples 194 and 195. The
property value of the compound is as follows.
[1302] ESI-MS; m/z 277 [M.sup.++H].
Synthesis of
(+)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(2-trifluoromethyl-4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
[1303] A racemate of the title compound (190 mg) was obtained using
1-amino-3-(2-trifluoromethyl-4-fluorophenyl)piperidin-2-one (360
mg) as a starting material according to the method in Examples 168
and 169. The resulting racemate (149 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=8:2, flow rate: 11
mL/min) to obtain the title optically active compound with a
retention time of 25 minutes and positive optical rotation (83.6
mg) and the title optically active compound with a retention time
of 30 minutes and negative optical rotation (82.8 mg).
[1304] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[1305] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.86-2.48 (m, 7H),
4.03 (s, 3H), 4.27-4.40 (m, 2H), 4.64 (dd, J=8.8, 6.0 Hz, 1H),
6.92-7.04 (m, 3H), 7.19 (t, J=8.0 Hz, 1H), 7.40-7.47 (m, 3H), 7.62
(d, J=15.6 Hz, 1H), 7.76 (s, 1H).
[1306] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[1307] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.86-2.48 (m, 7H),
4.03 (s, 3H), 4.27-4.40 (m, 2H), 4.64 (dd, J=8.8, 6.0 Hz, 1H),
6.92-7.04 (m, 3H), 7.19 (t, J=8.0 Hz, 1H), 7.40-7.47 (m, 3H), 7.62
(d, J=15.6 Hz, 1H), 7.76 (s, 1H).
Examples 287 and 288
Synthesis of
(-)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-octahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-octahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00239##
[1308] Synthesis of (2-difluoromethoxyphenyl)acetonitrile
[1309] A solution of p-toluenesulfonylmethyl isocyanide (2.4 g) in
dimethoxyethane (10 mL) was added to a solution of potassium
tert-butoxide (2.68 g) in dimethoxyethane (30 mL) at -35.degree.
C., and the reaction solution was stirred at the same temperature
for 10 minutes. The reaction solution was cooled to -55.degree. C.
A solution of difluoromethoxybenzaldehyde (2 g) in dimethoxyethane
(5 mL) was added dropwise, and the reaction solution was stirred at
the same temperature for two hours. 10 mL of methanol was added to
the reaction solution, and the reaction solution was heated under
reflux for 15 minutes. The reaction solution was left to cool to
room temperature. Then, water and dichloromethane were added and
the organic layer was separated. The resulting organic layer was
dried over anhydrous magnesium sulfate and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (elution solvent: heptane-ethyl acetate system) to
obtain 1.45 g of the title compound. The property values of the
compound are as follows.
[1310] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.78 (s, 2H), 6.58
(t, J=73.2 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.26 (t, J=7.0 Hz, 1H),
7.36 (t, J=8.0 Hz, 1H), 7.51 (d, J=7.6 Hz, 1H).
Synthesis of ethyl (2-difluoromethoxyphenyl)acetate
[1311] (2-Difluoromethoxyphenyl)acetonitrile (1.45 g) was added
dropwise to a solution of chlorotrimethylsilane (2.23 mL) in
ethanol (2.0 mL), and the reaction solution was stirred at
50.degree. C. for five hours. The reaction solution was left to
cool to room temperature. Then, potassium carbonate, water and
ethyl acetate were added and the organic layer was separated. The
resulting organic layer was dried over anhydrous magnesium sulfate
and then concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (elution solvent:
heptane-ethyl acetate system) to obtain 620 mg of the title
compound. The property values of the compound are as follows.
[1312] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.26 (t, J=7.2 Hz,
3H), 3.68 (s, 2H), 4.16 (q, 7.2 Hz, 2H), 6.48 (t, J=74.4 Hz, 1H),
7.13-7.32 (m, 4H).
Synthesis of 1-amino-3-(2-difluoromethoxyphenyl)piperidin-2-one
[1313] 395 mg of the title compound was obtained using ethyl
2-difluoromethoxyphenylacetate (630 mg) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1314] ESI-MS; m/z 257 [M.sup.++H].
Synthesis of
(-)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine and
(+)-8-(2-difluoromethoxyphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-
-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5--
a]pyridine
[1315] A racemate of the title compound (105 mg) was obtained from
1-amino-3-(2-difluoromethoxyphenyl)piperidin-2-one (395 mg)
according to the method in Examples 168 and 169. The resulting
racemate (105 mg) was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile
phase: hexane:ethanol=8:2, flow rate: 13 mL/min) to obtain the
title optically active compound with a retention time of 45 minutes
and negative optical rotation (48.1 mg) and the title optically
active compound with a retention time of 69 minutes and positive
optical rotation (41 mg).
[1316] The property values of the title optically active compound
with a retention time of 45 minutes are as follows.
[1317] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.05-2.37 (m, 7H),
4.04 (s, 3H), 4.24-4.35 (m, 2H), 4.55 (m, 1H), 6.43 (t, J=74.0 Hz,
1H), 6.92 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.04-7.20 (m, 3H), 7.31
(t, J=7.8 Hz, 1H), 7.41 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.63 (d, J=16.0 Hz, 1H), 7.60 (s, 1H).
[1318] The property values of the title optically active compound
with a retention time of 69 minutes are as follows.
[1319] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.05-2.37 (m, 7H),
4.04 (s, 3H), 4.24-4.35 (m, 2H), 4.55 (m, 1H), 6.43 (t, J=74.0 Hz,
1H), 6.92 (d, J=8.0 Hz, 1H), 6.95 (s, 1H), 7.04-7.20 (m, 3H), 7.31
(t, J=7.8 Hz, 1H), 7.41 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.63 (d, J=16.0 Hz, 1H), 7.60 (s, 1H).
Examples 289 and 290
Synthesis of
(+)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00240##
[1320] Synthesis of 1-amino-3-(2-bromophenyl)piperidin-2-one
[1321] 820 mg of the title compound was obtained using
2-bromophenylacetic acid (1 g) as a starting material according to
the method in Examples 20 and 21. The property value of the
compound is as follows.
[1322] ESI-MS; m/z 269 [M.sup.++H].
Synthesis of
(+)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-8-(2-bromophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)py-
ridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1323] A racemate of the title compound (210 mg) was obtained from
1-amino-3-(2-bromophenyl)piperidin-2-one (300 mg) according to the
method in Examples 168 and 169. The resulting racemate (210 mg) was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm, mobile phase: ethanol, flow
rate: 13 mL/min) to obtain the title optically active compound with
a retention time of 14.5 minutes and positive optical rotation
(78.6 mg) and the title optically active compound with a retention
time of 19.2 minutes and negative optical rotation (68 mg).
[1324] The property values of the title optically active compound
with a retention time of 14.5 minutes are as follows.
[1325] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.42 (m, 7H),
4.04 (s, 3H), 4.24-4.36 (m, 2H), 4.76 (m, 1H), 6.84 (d, J=7.6 Hz,
1H), 6.93 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.13 (d, J=7.6 Hz, 1H),
7.23 (d, J=7.6 Hz, 1H), 7.45 (d, J=16.0 Hz, 1H), 7.46 (d, J=7.6 Hz,
1H), 7.59 (d, J=7.6 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.76 (s,
1H).
[1326] The property values of the title optically active compound
with a retention time of 19.2 minutes are as follows.
[1327] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.42 (m, 7H),
4.04 (s, 3H), 4.24-4.36 (m, 2H), 4.76 (m, 1H), 6.84 (d, J=7.6 Hz,
1H), 6.93 (d, J=7.6 Hz, 1H), 6.95 (s, 1H), 7.13 (d, J=7.6 Hz, 1H),
7.23 (d, J=7.6 Hz, 1H), 7.45 (d, J=16.0 Hz, 1H), 7.46 (d, J=7.6 Hz,
1H), 7.59 (d, J=7.6 Hz, 1H), 7.65 (d, J=16.0 Hz, 1H), 7.76 (s,
1H).
Examples 291 and 292
Synthesis of
(+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00241##
[1329] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (300 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (163
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol)
to obtain the title optically active compound with a retention time
of 4.1 minutes and positive optical rotation (76.4 mg, >99% ee)
and the title optically active compound with a retention time of
4.7 minutes and negative optical rotation (78.2 mg, >99%
ee).
[1330] The property values of the title compound with positive
optical rotation are as follows.
[1331] ESI-MS; m/z 443 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.09 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.29-2.37 (m, 1H), 3.80 (s, 3H), 4.05 (s, 3H), 4.24-4.33 (m, 3H),
6.87 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 7.06
(d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H),
7.66 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).
[1332] The property values of the title compound with negative
optical rotation are as follows.
[1333] ESI-MS; m/z 443 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.09 (m, 2H), 2.16-2.22 (m, 1H), 2.29 (s, 3H),
2.29-2.37 (m, 1H), 3.80 (s, 3H), 4.05 (s, 3H), 4.24-4.33 (m, 3H),
6.87 (d, J=8.8 Hz, 2H), 6.93 (d, J=8.0 Hz, 1H), 6.96 (s, 1H), 7.06
(d, J=8.8 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.47 (d, J=15.6 Hz, 1H),
7.66 (d, J=15.6 Hz, 1H), 7.77 (s, 1H).
Examples 293 and 294
Synthesis of
(+)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine
##STR00242##
[1334] Synthesis of
1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one
[1335] 521 mg of the title compound was obtained according to the
method in Examples 20 and 21 through ethyl
3-fluoro-2-methylphenylacetate as an intermediate from
3-fluoro-2-methylbenzaldehyde (1.5 g) as a starting material
according to the method in Examples 40 and 41. The property value
of the compound is as follows.
[1336] ESI-MS; m/z 223 [M.sup.++H].
Synthesis of
(+)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine
[1337] A racemate of the title compound (34.8 mg) was obtained
using 1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one (171 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (34.8 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol:hexane=3:7, flow rate: 20
mL/min) to obtain the title optically active compound with a
retention time of 9 minutes and positive optical rotation (12 mg)
and the title optically active compound with a retention time of 15
minutes and negative optical rotation (15 mg).
[1338] The property values of the title optically active compound
with a retention time of 9 minutes are as follows.
[1339] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.94-2.03 (m, 1H),
2.04-2.15 (m, 1H), 2.16-2.38 (m, 2H), 2.29 (s, 3H), 2.30 (s, 3H),
3.97 (s, 3H), 4.29 (ddd, J=12.5, 12.5, 5.8 Hz, 1H), 4.33 (ddd,
J=12.5, 12.5, 5.5 Hz, 1H), 4.54 (t, J=6.2 Hz, 1H), 6.54 (d, J=7.7
Hz, 1H), 6.93-7.00 (m, 1H), 7.06-7.13 (m, 1H), 7.09 (d, J=16.1 Hz,
1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52 (d,
J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).
[1340] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[1341] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.94-2.03 (m, 1H),
2.04-2.15 (m, 1H), 2.16-2.38 (m, 2H), 2.29 (s, 3H), 2.30 (s, 3H),
3.97 (s, 3H), 4.29 (ddd, J=12.5, 12.5, 5.8 Hz, 1H), 4.33 (ddd,
J=12.5, 12.5, 5.5 Hz, 1H), 4.54 (t, J=6.2 Hz, 1H), 6.54 (d, J=7.7
Hz, 1H), 6.93-7.00 (m, 1H), 7.06-7.13 (m, 1H), 7.09 (d, J=16.1 Hz,
1H), 7.46 (d, J=1.8 Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52 (d,
J=1.1 Hz, 1H), 8.14 (d, J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).
Examples 295 and 296
Synthesis of
(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine
##STR00243##
[1342] Synthesis of ethyl (2-fluoro-3-methylphenyl)acetate
[1343] A mixture of 2-fluoro-3-methylbenzyl bromide (2.0 g), sodium
cyanide (2.41 g), sodium iodide (148 mg) and DMSO (10 ml) was
stirred at 60.degree. C. for two hours. Water and ethyl acetate
were added to the reaction solution, and the organic layer was
separated. The organic layer was washed with brine. The resulting
organic layer was dried over anhydrous magnesium sulfate. The
organic layer was concentrated under reduced pressure. 5 N
hydrochloric acid (15 ml) was added to the residue, and the
reaction solution was heated at 110.degree. C. for 22 hours. The
reaction solution was brought to room temperature. Chloroform was
added and the organic layer was separated. The organic layer was
concentrated under reduced pressure. Saturated hydrogen
chloride-ethanol (15 ml) was added to the residue, and the reaction
solution was stirred at 85.degree. C. for four hours. The reaction
solution was concentrated under reduced pressure, and then diluted
with ethyl acetate and washed with saturated sodium bicarbonate
water and then with brine. The resulting organic layer was dried
over anhydrous magnesium sulfate and concentrated under reduced
pressure to obtain the title compound (1.1 g). The property values
of the compound are as follows.
[1344] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.24 (t, J=6.9 Hz,
3H), 2.27 (s, 3H), 3.65 (s, 2H), 4.15 (q, J=6.9 Hz, 2H), 6.96-7.01
(m, 1H), 7.05-7.13 (m, 2H).
Synthesis of 1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one
[1345] 766 mg of the title compound was obtained using ethyl
(2-fluoro-3-methylphenyl)acetate (1.1 g) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1346] ESI-MS; m/z 223 [M.sup.++H].
Synthesis of
(+)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine and
(-)-8-(2-fluoro-3-methylphenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-3-yl]vinyl}-8-(4-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
-[1,2,4]triazolo[1,5-a]pyridine
[1347] A racemate of the title compound (161.8 mg) was obtained
using 1-amino-3-(2-fluoro-3-methylphenyl)piperidin-2-one (250 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (34.8 mg) was separated by
CHIRALPAK.TM. AD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 12 mL/min) to
obtain the title optically active compound with a retention time of
18 minutes and negative optical rotation (75 mg) and the title
optically active compound with a retention time of 28 minutes and
positive optical rotation (70 mg).
[1348] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[1349] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.10-2.40 (m, 4H),
2.28 (s, 3H), 2.29 (s, 3H), 3.96 (s, 3H), 4.23-4.26 (m, 2H), 4.57
(dd, J=7.0, 5.7 Hz, 1H), 6.73-6.77 (m, 1H), 6.98 (dd, J=7.3, 7.3
Hz, 1H), 7.10 (d, J=16.1 Hz, 1H), 7.09-7.14 (m, 1H), 7.46 (d, J=1.8
Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 8.14 (d,
J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).
[1350] The property values of the title optically active compound
with a retention time of 15 minutes are as follows.
[1351] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.10-2.40 (m, 4H),
2.28 (s, 3H), 2.29 (s, 3H), 3.96 (s, 3H), 4.23-4.26 (m, 2H), 4.57
(dd, J=7.0, 5.7 Hz, 1H), 6.73-6.77 (m, 1H), 6.98 (dd, J=7.3, 7.3
Hz, 1H), 7.10 (d, J=16.1 Hz, 1H), 7.09-7.14 (m, 1H), 7.46 (d, J=1.8
Hz, 1H), 7.51 (d, J=16.1 Hz, 1H), 7.52 (d, J=1.1 Hz, 1H), 8.14 (d,
J=1.8 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H).
Examples 297 and 298
Synthesis of
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazo-
l-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00244##
[1352] Synthesis of
1-amino-3-(2,3-difluorophenyl)piperidin-2-one
[1353] 2.06 g of the title compound was obtained from methyl
2,3-difluorophenylacetate (5.63 g) according to the method in
Examples 20 and 21. The property value of the compound is as
follows.
[1354] ESI-MS; m/z 227 [M.sup.++H].
Synthesis of
(-)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1--
yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-8-(2,3-difluorophenyl)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazo-
l-1-yl)pyridin-3-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridi-
ne
[1355] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (250 mg) and 1-amino-3-(2,3-difluorophenyl)piperidin-2-one
(167 mg) according to the method in Examples 168 and 169. The
resulting racemate was separated by CHIRALPAK.TM. AD-H manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain the title optically active compound with
a retention time of 7.9 minutes and negative optical rotation (27.3
mg, >99% ee) and the title optically active compound with a
retention time of 12 minutes and positive optical rotation (27.1
mg, >99% ee).
[1356] The property values of the title compound with negative
optical rotation are as follows.
[1357] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.28 (m, 3H), 2.29 (s, 3H), 2.36-2.43 (m, 1H),
3.97 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.60 (t, J=6.0 Hz, 1H), 6.75
(dd, J=8.0, 6.0 Hz, 1H), 7.00-7.15 (m, 3H), 7.45 (s, 1H), 7.49 (d,
J=15.6 Hz, 1H), 7.52 (s, 1H), 8.15 (s, 1H), 8.34 (s, 1H).
[1358] The property values of the title compound with positive
optical rotation are as follows.
[1359] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.28 (m, 3H), 2.29 (s, 3H), 2.36-2.43 (m, 1H),
3.97 (s, 3H), 4.31 (t, J=5.6 Hz, 2H), 4.60 (t, J=6.0 Hz, 1H), 6.75
(dd, J=8.0, 6.0 Hz, 1H), 7.00-7.15 (m, 3H), 7.45 (s, 1H), 7.49 (d,
J=15.6 Hz, 1H), 7.52 (s, 1H), 8.15 (s, 1H), 8.34 (s, 1H).
Examples 299 and 300
Synthesis of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00245##
[1360] Synthesis of 1-amino-3-(4-methoxyphenyl)piperidin-2-one
[1361] 0.910 g of the title compound was obtained from methyl
4-methoxyphenylacetate (5 g) according to the method in Examples 20
and 21. The property value of the compound is as follows.
[1362] ESI-MS; m/z 221 [M.sup.++H].
Synthesis of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
and
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(4-methoxyphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1363] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (250 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (162
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. AD-H manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol)
to obtain the title optically active compound with a retention time
of 14 minutes and negative optical rotation (9.6 mg, >99% ee)
and the title optically active compound with a retention time of 20
minutes and positive optical rotation (10.4 mg, >99% ee).
[1364] The property values of the title compound with negative
optical rotation are as follows.
[1365] ESI-MS; m/z 443 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.17 (m, 2H), 2.18-2.28 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.30-2.39 (m, 1H), 3.80 (s, 3H), 3.97 (s, 3H), 4.25-4.32
(m, 3H), 6.85-6.90 (m, 2H), 7.04-7.07 (m, 2H), 7.10 (d, J=16.0 Hz,
1H), 7.46 (d, J=2.0 Hz, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.52 (s, 1H),
8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).
[1366] The property values of the title compound with positive
optical rotation are as follows.
[1367] ESI-MS; m/z 443 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.17 (m, 2H), 2.18-2.28 (m, 1H), 2.29 (d, J=1.2
Hz, 3H), 2.30-2.39 (m, 1H), 3.80 (s, 3H), 3.97 (s, 3H), 4.25-4.32
(m, 3H), 6.85-6.90 (m, 2H), 7.04-7.07 (m, 2H), 7.10 (d, J=16.0 Hz,
1H), 7.46 (d, J=2.0 Hz, 1H), 7.51 (d, J=16.0 Hz, 1H), 7.52 (s, 1H),
8.14 (d, J=2.0 Hz, 1H), 8.34 (d, J=1.2 Hz, 1H).
Examples 301 and 302
Synthesis of
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e and
(+)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vi-
nyl}-8-(2,4,6-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00246##
[1369] A racemate of the title compound was obtained from
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (250 mg) and 1-amino-3-(4-methoxyphenyl)piperidin-2-one (180
mg) according to the method in Examples 168 and 169. The resulting
racemate was separated by CHIRALPAK.TM. AD-H manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol)
to obtain the title optically active compound with a retention time
of 6.4 minutes and negative optical rotation (48.6 mg, >99% ee)
and the title optically active compound with a retention time of
8.1 minutes and positive optical rotation (47.7 mg, >99%
ee).
[1370] The property values of the title compound with negative
optical rotation are as follows.
[1371] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.20 (m, 3H), 2.29 (s, 3H), 2.29-2.37 (m, 1H),
3.96 (s, 3H), 4.19-4.27 (m, 1H), 4.34-4.40 (m, 1H), 4.54-4.58 (m,
1H), 6.70 (t, J=8.4 Hz, 2H), 7.06 (d, J=16.0 Hz, 1H), 7.45 (d,
J=16.0 Hz, 1H), 7.46 (s, 1H), 7.52 (s, 1H), 8.13 (s, 1H), 8.34 (s,
1H).
[1372] The property values of the title compound with positive
optical rotation are as follows.
[1373] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.04-2.20 (m, 3H), 2.29 (s, 3H), 2.29-2.37 (m, 1H),
3.96 (s, 3H), 4.19-4.27 (m, 1H), 4.34-4.40 (m, 1H), 4.54-4.58 (m,
1H), 6.70 (t, J=8.4 Hz, 2H), 7.06 (d, J=16.0 Hz, 1H), 7.45 (d,
J=16.0 Hz, 1H), 7.46 (s, 1H), 7.52 (s, 1H), 8.13 (s, 1H), 8.34 (s,
1H).
Examples 303 and 304
Synthesis of
(+)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[4-methoxy-5-(4-methyl-1H-imidazo-
l-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e and
(-)-8-(2-bromo-4-fluorophenyl)-2-{(E)-2-[4-methoxy-5-(4-methyl-1H-im-
idazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]py-
ridine
##STR00247##
[1375] A racemate of the title compound was obtained from
(E)-3-[4-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (63.2 mg) and
1-amino-3-(2-bromo-4-fluorophenyl)piperidin-2-one (91.1 mg)
according to the method in Examples 220 and 221. The resulting
racemate was separated by CHIRALPAK.TM. IB manufactured by Daicel
Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol)
to obtain the title optically active compound with a retention time
of 6.4 minutes and negative optical rotation (6.2 mg, >99% ee)
and the title optically active compound with a retention time of
7.6 minutes and positive optical rotation (5.5 mg, >99% ee).
[1376] The property values of the title compound with negative
optical rotation are as follows.
[1377] ESI-MS; m/z 509 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.95-2.05 (m, 1H), 2.06-2.12 (m, 2H), 2.30 (d, J=0.8
Hz, 3H), 2.35-2.42 (m, 1H), 3.90 (s, 3H), 4.31 (t, J=6.0 Hz, 2H),
4.71 (t, J=6.8 Hz, 1H), 6.85-6.91 (m, 1H), 6.91 (d, J=0.8 Hz, 1H),
6.98 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 7.36 (dd,
J=8.0, 2.8 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.60 (d, J=16.0 Hz,
1H), 7.68 (d, J=1.2 Hz, 1H), 8.42 (s, 1H).
[1378] The property values of the title compound with positive
optical rotation are as follows.
[1379] ESI-MS; m/z 509 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.95-2.05 (m, 1H), 2.06-2.12 (m, 2H), 2.30 (d, J=0.8
Hz, 3H), 2.35-2.42 (m, 1H), 3.90 (s, 3H), 4.31 (t, J=6.0 Hz, 2H),
4.71 (t, J=6.8 Hz, 1H), 6.85-6.91 (m, 1H), 6.91 (d, J=0.8 Hz, 1H),
6.98 (dd, J=8.0, 2.4 Hz, 1H), 7.00 (d, J=1.2 Hz, 1H), 7.36 (dd,
J=8.0, 2.8 Hz, 1H), 7.53 (d, J=16.0 Hz, 1H), 7.60 (d, J=16.0 Hz,
1H), 7.68 (d, J=1.2 Hz, 1H), 8.42 (s, 1H).
Example 305
Synthesis of
2-(4-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E-
)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00248##
[1380] (1) Synthesis of
5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methyli-
dene]-pentanoic acid hydrazide
[1381]
5-Chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-m-
ethylidene]pentanoic acid (CAS No. 870843-27-9, 10 g) was dissolved
in dichloromethane (130 mL). BOPCl (4.53 g), IPEA (12.3 g) and
tert-butyl carbazate (2.82 g) were added and the reaction solution
was stirred at room temperature for three hours. Water and ethyl
acetate were added to the reaction solution, and the organic layer
was separated. The organic layer was washed with a 1 N sodium
hydroxide solution and 1 N hydrochloric acid in this order. The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. A solution of 4 N hydrochloric acid in
ethyl acetate (100 mL) was added to the residue, and the reaction
solution was stirred at room temperature for two hours. The
reaction solution was concentrated under reduced pressure to obtain
3.87 g of a crude product of the title compound. The property value
of the compound is as follows.
[1382] ESI-MS; m/z 349 [M.sup.++H].
(2) Synthesis of
2-(4-bromophenyl)-N-{3-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-
-(E)-methylidene]-2-oxopiperidin-1-yl}acetamide
[1383] EDC (109 mg), HOBT (76.9 mg) and IPEA (408 .mu.L) were added
to a mixture of 4-bromophenylacetic acid (102 mg),
5-chloro-2-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E)-methyli-
dene]-pentanoic acid hydrazide (200 mg) and DMF (4 mL), and the
reaction solution was stirred at room temperature for 14 hours. The
reaction solution was heated to 80.degree. C. and stirred for two
hours. The reaction solution was brought to room temperature. A
saturated sodium bicarbonate solution was added, followed by
separatory extraction with ethyl acetate. The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(carrier: Chromatorex NH; elution solvent: heptane:ethyl
acetate=1:1->ethyl acetate->ethyl acetate:methanol=8:1) to
obtain the title compound (111 mg). The property value of the
compound is as follows.
[1384] ESI-MS; m/z 508 [M.sup.++H].
(3) Synthesis of
2-(4-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E-
)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1385] Phosphorus oxychloride (2.4 mL) was added to
2-(4-bromophenyl)-N-{3-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-
-(E)-methylidene]-2-oxopiperidin-1-yl}acetamide (111 mg), and the
reaction solution was stirred at 100.degree. C. for one hour. The
reaction solution was concentrated under reduced pressure. The
residue was diluted with acetic acid (1 mL) and then ammonium
acetate (336 mg) was added. The reaction solution was stirred at
140.degree. C. for one hour and 30 minutes. Ethyl acetate and a
sodium bicarbonate solution were added to the reaction solution,
and the organic layer was separated. The organic layer was dried
over magnesium sulfate and then concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(carrier: Chromatorex NH; elution solvent: heptane:ethyl
acetate=2:1->ethyl acetate) to obtain the title compound (50
mg). The property values of the compound are as follows.
[1386] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.11-2.16 (m, 2H),
2.30 (s, 3H), 2.92-2.95 (m, 2H), 3.85 (s, 3H), 4.04 (s, 2H), 4.22
(t, J=4 Hz, 2H), 6.93 (s, 1H), 7.03-7.06 (m, 2H), 7.24-7.26 (m,
3H), 7.41-7.44 (m, 2H), 7.66 (s, 1H), 7.72 (s, 1H).
Example 306
Synthesis of
2-(3-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E-
)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00249##
[1388] The title compound (38 mg) was obtained using
3-bromophenylacetic acid (102 mg) as a starting material according
to the method in Example 305.
[1389] The property values of the title compound are as
follows.
[1390] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.11-2.17 (m, 2H),
2.30 (s, 3H), 2.92-2.96 (m, 2H), 3.85 (s, 3H), 4.06 (s, 2H), 4.24
(t, J=5.6 Hz, 2H), 6.93 (s, 1H), 7.03-7.07 (m, 2H), 7.16-7.36 (m,
4H), 7.51 (s, 2H), 7.67 (s, 1H), 7.72 (s, 1H).
Example 307
Synthesis of
2-(2-bromobenzyl)-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]-(E-
)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00250##
[1392] The title compound (43 mg) was obtained using
2-bromophenylacetic acid (102 mg) as a starting material according
to the method in Example 305.
[1393] The property values of the title compound are as
follows.
[1394] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.11-2.17 (m, 2H),
2.30 (s, 3H), 2.93-2.96 (m, 2H), 3.85 (s, 3H), 4.22-4.25 (m, 4H),
6.93 (s, 1H), 7.04-7.13 (m, 3H), 7.25-7.34 (m, 3H), 7.56-7.59 (m,
1H), 7.68 (s, 1H), 7.70 (s, 1H).
Examples 308 and 309
Synthesis of
2-[(S)-1-(4-fluorophenyl)ethyl]-8-[1-[3-methoxy-4-(4-methyl-1H-imidazol-1-
-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyri-
dine and
2-[(R)-1-(4-fluorophenyl)ethyl]-8-[1-[3-methoxy-4-(4-methyl-1H-im-
idazol-1-yl)phenyl]-(E)-methylidene]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
##STR00251##
[1396] A racemate of the title compound (64 mg) was obtained using
4-fluoro-.alpha.-methyl-phenylacetic acid (109 mg) as a starting
material according to the method in Example 305. The resulting
racemate (64 mg) was separated by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
hexane:ethanol=8:2, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 26 minutes and
positive optical rotation (15 mg) and the title optically active
compound with a retention time of 31 minutes and negative optical
rotation (16 mg).
[1397] The property values of the title optically active compound
with a retention time of 26 minutes are as follows.
[1398] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.70 (d, J=7.2 Hz,
3H), 2.10-2.16 (m, 2H), 2.23 (m, 3H), 2.90-2.94 (m, 2H), 3.85 (s,
3H), 4.22-4.30 (m, 3H), 6.93-7.06 (m, 5H), 7.24 (s, 1H), 7.35-7.38
(m, 2H), 7.66 (s, 1H), 7.71 (s, 1H).
[1399] The property values of the title optically active compound
with a retention time of 31 minutes are as follows.
[1400] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.70 (d, J=7.2 Hz,
3H), 2.10-2.16 (m, 2H), 2.23 (m, 3H), 2.90-2.94 (m, 2H), 3.85 (s,
3H), 4.22-4.30 (m, 3H), 6.93-7.06 (m, 5H), 7.24 (s, 1H), 7.35-7.38
(m, 2H), 7.66 (s, 1H), 7.71 (s, 1H).
Examples 310 and 311
Synthesis of (+) and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-t-
rifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol
o[1,5-a]pyridine
##STR00252##
[1402] 457 mg of the racemic title compound was obtained from
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (467 mg) and
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic acid
(500 mg) by the same method as in Examples 194 and 195. The racemic
title compound (457 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=1:1) to obtain the title optically
active compound with positive optical rotation and a retention time
of 12 minutes (209 mg) and the title optically active compound with
negative optical rotation and a retention time of 18 minutes (206
mg).
[1403] The property values of the title optically active compound
with a retention time of 12 minutes are as follows.
[1404] ESI-MS; m/z 480 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.89-2.00 (m, 1H), 2.08-2.35 (m, 2H), 2.29 (d, J=0.8
Hz, 3H), 2.40-2.52 (m, 1H), 3.84 (s, 3H), 4.27-4.40 (m, 2H), 4.70
(dd, J=6.4, 8.8 Hz, 1H), 6.89-6.92 (m, 1H), 7.01-7.08 (m, 2H),
7.11-7.16 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz,
1H), 7.45-7.52 (m, 2H), 7.69 (d, J=1.2 Hz, 1H), 7.73 (d, J=8.0 Hz,
1H).
[1405] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[1406] ESI-MS; m/z 480 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.89-2.00 (m, 1H), 2.08-2.35 (m, 2H), 2.29 (d, J=0.8
Hz, 3H), 2.40-2.52 (m, 1H), 3.84 (s, 3H), 4.27-4.40 (m, 2H), 4.70
(dd, J=6.4, 8.8 Hz, 1H), 6.89-6.92 (m, 1H), 7.01-7.08 (m, 2H),
7.11-7.16 (m, 2H), 7.21 (d, J=8.0 Hz, 1H), 7.40 (dd, J=7.6, 7.6 Hz,
1H), 7.45-7.52 (m, 2H), 7.69 (d, J=1.2 Hz, 1H), 7.73 (d, J=8.0 Hz,
1H).
Examples 312 and 313
Synthesis of (+) and
(-)-2-{(E)-2-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]viny-
l}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]py-
ridine
##STR00253##
[1408] 292 mg of the racemic title compound was obtained from
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (514 mg) and
(E)-3-[2-fluoro-5-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylic
acid (500 mg) by the same method as in Examples 194 and 195. The
racemic title compound (18 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=1:1) to obtain the title optically
active compound with positive optical rotation and a retention time
of 17 minutes (6 mg) and the title optically active compound with
negative optical rotation and a retention time of 32 minutes (6
mg).
[1409] The property value of the title optically active compound
with a retention time of 17 minutes is as follows.
[1410] ESI-MS; m/z 498 [M.sup.++H].
[1411] The property values of the title optically active compound
with a retention time of 32 minutes are as follows.
[1412] ESI-MS; m/z 498 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.89-2.02 (m, 1H), 2.10-2.34 (m, 2H), 2.29 (s, 3H),
2.40-2.52 (m, 1H), 3.82 (s, 3H), 4.28-4.41 (m, 2H), 4.69 (dd,
J=6.0, 8.0 Hz, 1H), 6.91 (s, 1H), 6.97-7.06 (m, 2H), 7.09-7.20 (m,
2H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.49 (dd, J=7.6, 7.6 Hz, 1H),
7.58 (d, J=16.4 Hz, 1H), 7.69-7.78 (m, 2H).
Examples 314 and 315
Synthesis of (+) and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-t-
rifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-o-
l
##STR00254##
[1414] 123 mg of the racemic title compound was obtained by the
same method as in Examples 53 and 54 from the optically active
compound synthesized by the method in Examples 310 and 311 with
positive optical rotation and a retention time of 12 minutes,
2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-8-(2-trifl-
uoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
(183 mg). The racemic title compound (123 mg) was separated by
CHIRALPAK.TM. IA manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 13 minutes (47 mg) and the title optically
active compound with negative optical rotation and a retention time
of 21 minutes (48 mg).
[1415] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1416] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.13 (m, 1H), 2.29 (d, J=0.8 Hz, 3H), 2.25-2.58
(m, 3H), 3.80 (s, 3H), 4.12-4.24 (m, 1H), 4.30-4.40 (m, 1H), 4.74
(brs, 1H), 6.85-6.90 (m, 1H), 6.95-7.07 (m, 3H), 7.15 (d, J=8.0 Hz,
1H), 7.40 (d, J=16.4 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 7.58
(dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.0 Hz,
1H), 7.79 (brs, 1H).
[1417] The property values of the title optically active compound
with a retention time of 21 minutes are as follows.
[1418] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.02-2.13 (m, 1H), 2.29 (d, J=0.8 Hz, 3H), 2.25-2.58
(m, 3H), 3.80 (s, 3H), 4.12-4.24 (m, 1H), 4.30-4.40 (m, 1H), 4.74
(brs, 1H), 6.85-6.90 (m, 1H), 6.95-7.07 (m, 3H), 7.15 (d, J=8.0 Hz,
1H), 7.40 (d, J=16.4 Hz, 1H), 7.46 (dd, J=7.6, 7.6 Hz, 1H), 7.58
(dd, J=7.6, 7.6 Hz, 1H), 7.66 (d, J=1.2 Hz, 1H), 7.74 (d, J=8.0 Hz,
1H), 7.79 (brs, 1H).
Examples 316 and 317
Synthesis of (+) and
(-)-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-7-(2-t-
rifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00255##
[1420] 254 mg of the title compound as a racemate was obtained from
ethyl
(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate
dihydrochloride (1.20 g) and
4-chloro-2-(2-trifluoromethylphenyl)butyric acid hydrazide
hydrochloride (1.25 g) by the same method as in Examples 140 and
141. The racemic title compound (254 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=4:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 28 minutes (55 mg) and the title optically
active compound with negative optical rotation and a retention time
of 48 minutes (40 mg).
[1421] The property value of the title optically active compound
with a retention time of 28 minutes is as follows.
[1422] ESI-MS; m/z 466 [M.sup.++H].
[1423] The property value of the title optically active compound
with a retention time of 48 minutes is as follows.
[1424] ESI-MS; m/z 466 [M.sup.++H].
Examples 318 and 319
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00256##
[1425] Synthesis of 1-amino-3-o-tolylpiperidin-2-one
[1426] 339 mg of the title compound was obtained using
o-tolylacetic acid (1 g) as a starting material according to the
method in Examples 20 and 21. The property values of the compound
are as follows.
[1427] ESI-MS; m/z 205 [M.sup.++H].
[1428] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.70-2.20 (m, 4H),
3.33 (s, 3H), 3.40-3.98 (m, 3H), 4.63 (brs, 2H), 6.66-7.38 (m,
4H).
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(o-tolyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
[1429] 175.7 mg of a racemate of the title compound was obtained
using 1-amino-3-O-- tolylpiperidin-2-one (339 mg) as a starting
material according to the method in Examples 168 and 169. The
resulting racemate (100 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: ethanol) to obtain a (+)-isomer of the title
optically active compound with a retention time of 12 minutes (42.6
mg; 99% ee) and a (-)-isomer of the title optically active compound
with a retention time of 25 minutes (44.7 mg; 99% ee).
[1430] The property values of the title optically active compound
with a retention time of 12 minutes are as follows.
[1431] ESI-MS; m/z 427 [M.sup.++H].
[1432] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.76-2.52 (m, 10H),
4.04 (s, 3H), 4.21-4.40 (m, 2H), 4.55 (t, J=6.0 Hz, 1H), 6.72 (d,
J=7.6 Hz, 1H), 6.88-7.01 (m, 2H), 7.06-7.32 (m, 3H), 7.40-7.51 (m,
2H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
[1433] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[1434] ESI-MS; m/z 427 [M.sup.++H].
[1435] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.76-2.52 (m, 10H),
4.04 (s, 3H), 4.21-4.40 (m, 2H), 4.55 (t, J=6.0 Hz, 1H), 6.72 (d,
J=7.6 Hz, 1H), 6.88-7.01 (m, 2H), 7.06-7.32 (m, 3H), 7.40-7.51 (m,
2H), 7.66 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
Examples 320 and 321
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridi-
ne
##STR00257##
[1436] Synthesis of
1-amino-3-(3-trifluoromethylphenyl)piperidin-2-one
[1437] 282.7 mg of the title compound was obtained using methyl
3-(trifluoromethyl)phenylacetate (1 g) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1438] ESI-MS; m/z 259 [M.sup.++H].
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(3-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine
[1439] 60.7 mg of a racemate of the title compound was obtained
using 1-amino-3-(3-trifluoromethylphenyl)piperidin-2-one (282.7 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (60.7 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain a
(+)-isomer of the title optically active compound with a retention
time of 16 minutes (20 mg; >99% ee) and a (-)-isomer of the
title optically active compound with a retention time of 52 minutes
(19.1 mg; >99% ee).
[1440] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1441] ESI-MS; m/z 481 [M.sup.++H].
[1442] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.48 (m, 7H),
4.05 (s, 3H), 4.26-4.45 (m, 3H), 6.91-6.99 (m, 2H), 7.32 (d, J=8.0
Hz, 1H), 7.41-7.52 (m, 4H), 7.56 (d, J=8.0 Hz, 1H), 7.65 (d, J=15.6
Hz, 1H), 7.78 (brs, 1H).
[1443] The property values of the title optically active compound
with a retention time of 52 minutes are as follows.
[1444] ESI-MS; m/z 481 [M.sup.++H].
[1445] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.98-2.48 (m, 7H),
4.05 (s, 3H), 4.26-4.45 (m, 3H), 6.91-6.99 (m, 2H), 7.32 (d, J=8.0
Hz, 1H), 7.41-7.52 (m, 4H), 7.56 (d, J=8.0 Hz, 1H), 7.65 (d, J=15.6
Hz, 1H), 7.78 (brs, 1H).
Examples 322 and 323
Synthesis of
[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanol
and
[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl-
]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methan-
ol
##STR00258##
[1446] Synthesis of 5-chloro-2-(2-hydroxymethylphenyl)pentanoic
acid hydrazide
[1447] 1.29 g of the title compound was obtained using
3-isochromanone (25 g) as a starting material according to the
method in Examples 1 and 2. The property value of the compound is
as follows.
[1448] ESI-MS; m/z 257 [M.sup.++H].
Synthesis of
[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]methanol
and
[2-((+)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl-
]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl)phenyl]metha-
nol
[1449] 4.4 mg of a racemate of the title compound was obtained
using 5-chloro-2-(2-hydroxymethylphenyl)pentanoic acid hydrazide
(388 mg) as a starting material according to the method in Examples
1 and 2. The resulting racemate (4.4 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain a (+)-isomer of
the title optically active compound with a retention time of 11
minutes (0.91 mg; >99% ee) and a (-)-isomer of the title
optically active compound with a retention time of 17 minutes (0.89
mg; >99% ee).
[1450] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[1451] ESI-MS; m/z 443 [M.sup.++H].
[1452] .sup.1H-NMR (acetone-d.sub.6) .delta. (ppm): 1.80-2.50 (m,
7H), 4.07 (s, 3H), 4.27-4.38 (m, 2H), 4.52-4.88 (m, 3H), 7.02-7.10
(m, 1H), 7.14-7.38 (m, 5H), 7.46-7.59 (m, 2H), 7.77 (d, J=7.6 Hz,
1H), 7.87 (brs, 1H).
[1453] The property values of the title optically active compound
with a retention time of 17 minutes are as follows.
[1454] ESI-MS; m/z 443 [M.sup.++H].
[1455] .sup.1H-NMR (acetone-d.sub.6) .delta. (ppm): 1.80-2.50 (m,
7H), 4.07 (s, 3H), 4.27-4.38 (m, 2H), 4.52-4.88 (m, 3H), 7.02-7.10
(m, 1H), 7.14-7.38 (m, 5H), 7.46-7.59 (m, 2H), 7.77 (d, J=7.6 Hz,
1H), 7.87 (brs, 1H).
Examples 324 and 325
Synthesis of (+) and
(-)-8-(2-fluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol--
1-yl)-pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e
##STR00259##
[1457]
{2-{2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]v-
inyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-yl}phenyl}methano-
l (350 mg) was dissolved in dichloromethane (40 mL). This was added
dropwise to a solution of DAST (1.04 mL) in dichloromethane (6 mL)
cooled to -78.degree. C., and the reaction solution was stirred for
one hour. Saturated sodium bicarbonate water was added to the
reaction solution, followed by extraction with dichloromethane. The
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure. The resulting residue was purified by
silica gel chromatography (carrier: NH silica, elution solvent:
ethyl acetate:methanol=9:1) to obtain a racemate of the title
compound (70 mg). The resulting racemate was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to
obtain the title optically active compound with a retention time of
7 minutes and positive optical rotation (20 mg) and the title
optically active compound with a retention time of 9 minutes and
negative optical rotation (20 mg), where the retention time is an
analysis result in CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (Lot. IB00CD-FD026, mobile phase: ethanol, flow
rate: 0.5 mL/min).
[1458] The property values of the title optically active compound
with a retention time of 7 minutes under the analysis conditions
are as follows.
[1459] ESI-MS; m/z 455 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.16 (m, 2H), 2.23-2.30 (m, 4H), 2.42 (m, 1H),
4.04 (s, 3H), 4.33 (m, 2H), 4.58 (m, 1H), 5.48 (dd, J=10.8, 108.8
Hz, 1H), 5.60 (m, 1H) 6.92-6.95 (m, 3H), 7.30-7.47 (m, 5H), 7.65
(d, J=15.6 Hz, 1H), 7.79 (m, 1H).
[1460] The property values of the title optically active compound
with a retention time of 9 minutes under the analysis conditions
are as follows.
[1461] ESI-MS; m/z 455 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.16 (m, 2H), 2.23-2.30 (m, 4H), 2.42 (m, 1H),
4.04 (s, 3H), 4.33 (m, 2H), 4.58 (m, 1H), 5.48 (dd, J=10.8, 108.8
Hz, 1H), 5.60 (m, 1H) 6.92-6.95 (m, 3H), 7.30-7.47 (m, 5H), 7.65
(d, J=15.6 Hz, 1H), 7.79 (m, 1H).
Examples 326 and 327
Synthesis of (+) and
(-)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00260##
[1462] Synthesis of 1-amino-3-(2-fluorophenyl)piperidin-2-one
[1463] 1.12 g of the title compound was obtained using
2-fluorophenylacetic acid (3.0 g) as a starting material according
to the method in Examples 20 and 21. The property value of the
compound is as follows.
[1464] ESI-MS; m/z 209 [M.sup.++H].
Synthesis of (+) and
(-)-8-(2-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1465] A racemate of the title compound (21 mg) was obtained using
1-amino-3-(2-fluorophenyl)piperidin-2-one (300 mg) as a starting
material according to the method in Examples 168 and 169. The
resulting racemate (219 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 11.4 minutes and
positive optical rotation (90 mg) and the title optically active
compound with a retention time of 19 minutes and negative optical
rotation (90 mg).
[1466] The property values of the title optically active compound
with a retention time of 11.4 minutes are as follows.
[1467] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.27 (m, 2H),
2.29 (s, 3H), 2.34-2.42 (m, 1H), 4.05 (s, 3H), 4.28-4.34 (m, 2H),
4.61 (dd, J=7.0, 7.0 Hz, 1H), 6.93 (d, J=9.4 Hz, 1H), 6.92-6.98 (m,
1H), 7.06-7.12 (m, 2H), 7.46 (d, J=15.6 Hz, 1H), 7.47 (d, J=9.4 Hz,
1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
[1468] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1469] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.27 (m, 2H),
2.29 (s, 3H), 2.34-2.42 (m, 1H), 4.05 (s, 3H), 4.28-4.34 (m, 2H),
4.61 (dd, J=7.0, 7.0 Hz, 1H), 6.93 (d, J=9.4 Hz, 1H), 6.92-6.98 (m,
1H), 7.06-7.12 (m, 2H), 7.46 (d, J=15.6 Hz, 1H), 7.47 (d, J=9.4 Hz,
1H), 7.65 (d, J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
Examples 328 and 329
Synthesis of
(+)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
##STR00261##
[1470] Synthesis of
1-amino-3-(5-fluoro-2-trifluoromethylphenyl)piperidin-2-one
[1471] 890 mg of the title compound was obtained using
5-fluoro-2-trifluoromethylphenylacetic acid (1 g) as a starting
material according to the method in Examples 194 and 195. The
property value of the compound is as follows.
[1472] ESI-MS; m/z 277 [M.sup.++H].
Synthesis of
(+)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
[1473] A racemate of the title compound (132 mg) was obtained using
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid trifluoroacetate (353 mg) and
1-amino-3-(5-fluoro-2-trifluoromethylphenyl)piperidin-2-one (200
mg) as starting materials according to the method in Examples 168
and 169. The resulting racemate (132 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase; hexane:ethanol=7:3, flow rate: 11
mL/min) to obtain the title optically active compound with a
retention time of 18 minutes and positive optical rotation (46 mg),
and the title optically active compound with a retention time of 31
minutes and negative optical rotation (45 mg).
[1474] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[1475] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.87-2.00 (m, 1H),
2.10-2.33 (m, 2H), 2.28 (s, 3H), 2.42-2.52 (m, 1H), 4.03 (s, 3H),
4.27-4.42 (m, 2H), 4.68 (dd, J=8.4, 6.4 Hz, 1H), 6.73 (dd, J=9.2,
2.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 7.08
(ddd, J=8.8, 8.0, 2.4 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.46 (d,
J=7.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 7.73 (dd, J=8.8, 5.6 Hz,
1H), 7.76 (d, J=1.2 Hz, 1H).
[1476] The property values of the title optically active compound
with a retention time of 31 minutes are as follows.
[1477] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.87-2.00 (m, 1H),
2.10-2.33 (m, 2H), 2.28 (s, 3H), 2.42-2.52 (m, 1H), 4.03 (s, 3H),
4.27-4.42 (m, 2H), 4.68 (dd, J=8.4, 6.4 Hz, 1H), 6.73 (dd, J=9.2,
2.4 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.95 (d, J=1.2 Hz, 1H), 7.08
(ddd, J=8.8, 8.0, 2.4 Hz, 1H), 7.43 (d, J=15.6 Hz, 1H), 7.46 (d,
J=7.6 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 7.73 (dd, J=8.8, 5.6 Hz,
1H), 7.76 (d, J=1.2 Hz, 1H).
Examples 330 and 331
Synthesis of
(+)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
##STR00262##
[1478] Synthesis of
1-amino-3-(6-fluoro-2-trifluoromethylphenyl)piperidin-2-one
[1479] 381 mg of the title compound was obtained using
6-fluoro-2-trifluoromethylphenylacetic acid (1 g) as a starting
material according to the method in Examples 20 and 21. The
property value of the compound is as follows.
[1480] ESI-MS; m/z 277 [M.sup.++H].
Synthesis of
(+)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine and
(-)-8-(6-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyridine
[1481] A racemate of the title compound (181 mg) was obtained using
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid (340 mg) and
1-amino-3-(6-fluoro-2-trifluoromethylphenyl)piperidin-2-one (200
mg) as starting materials according to the method in Examples 168
and 169. The resulting racemate (181 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=7:3, flow rate: 12
mL/min) to obtain the title optically active compound with a
retention time of 18 minutes and positive optical rotation (76 mg)
and the title optically active compound with a retention time of 34
minutes and negative optical rotation (75 mg).
[1482] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[1483] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.07-2.41 (m, 7H),
4.01 (s, 3H), 4.19-4.26 (m, 1H), 4.39-4.43 (m, 1H), 4.52-4.56 (m,
1H), 6.91 (d, J=6.9 Hz, 1H), 6.94 (s, 1H), 7.22 (t, J=8.8 Hz, 1H),
7.37-7.45 (m, 3H), 7.55 (d, J=7.6 Hz, 1H), 7.60 (d, J=15.6 Hz, 1H)
7.75 (s, 1H).
[1484] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[1485] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.07-2.41 (m, 7H),
4.01 (s, 3H), 4.19-4.26 (m, 1H), 4.39-4.43 (m, 1H), 4.52-4.56 (m,
1H), 6.91 (d, J=6.9 Hz, 1H), 6.94 (s, 1H), 7.22 (t, J=8.8 Hz, 1H),
7.37-7.45 (m, 3H), 7.55 (d, J=7.6 Hz, 1H), 7.60 (d, J=15.6 Hz, 1H)
7.75 (s, 1H).
Examples 332 and 333
Synthesis of (+) and
(-)-8-(3-fluoro-2-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine
##STR00263##
[1487] A racemate of the title compound (21 mg) was obtained using
1-amino-3-(3-fluoro-2-methylphenyl)piperidin-2-one (197 mg) as a
starting material according to the method in Examples 168 and 169.
The resulting racemate (21 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 12.5 minutes and
positive optical rotation (8 mg) and the title optically active
compound with a retention time of 27 minutes and negative optical
rotation (8 mg).
[1488] The property values of the title optically active compound
with a retention time of 12.5 minutes are as follows.
[1489] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.27 (m, 3H),
2.28-2.38 (m, 1H), 2.29 (s, 3H), 2.30 (s, 3H) 4.04 (s, 3H),
4.24-4.38 (m, 2H), 4.53-4.60 (m, 1H), 6.53 (d, J=7.7 Hz, 1H),
6.91-6.98 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 7.05-7.12 (m, 1H) 7.46
(d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.65 (d, J=15.7 Hz,
1H), 7.77 (d, J=1.1 Hz, 1H).
[1490] The property values of the title optically active compound
with a retention time of 27 minutes are as follows.
[1491] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.27 (m, 3H),
2.28-2.38 (m, 1H), 2.29 (s, 3H), 2.30 (s, 3H) 4.04 (s, 3H),
4.24-4.38 (m, 2H), 4.53-4.60 (m, 1H), 6.53 (d, J=7.7 Hz, 1H),
6.91-6.98 (m, 2H), 6.93 (d, J=7.7 Hz, 1H), 7.05-7.12 (m, 1H) 7.46
(d, J=15.7 Hz, 1H), 7.47 (d, J=7.7 Hz, 1H), 7.65 (d, J=15.7 Hz,
1H), 7.77 (d, J=1.1 Hz, 1H).
Examples 334 and 335
Synthesis of (+) and
(-)-8-(4-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine
##STR00264##
[1492] Synthesis of 2-(4-fluoro-3-methylphenyl)acetamide
[1493] 4-Fluoro-3-methylphenylacetonitrile (1.1 g) was dissolved in
toluene (35 ml), and trimethylsiloxypotassium (3.7 g) was added.
After stirring at 110.degree. C. for 2.5 hours, saturated sodium
bicarbonate water was added, followed by separation with ethyl
acetate. The organic layer was washed with brine, dried over
magnesium sulfate and concentrated under reduced pressure to obtain
863 mg of the title compound. The property values of the compound
are as follows.
[1494] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.27 (s, 3H), 3.52
(s, 2H), 5.24-5.60 (m, 1H), 6.92-7.15 (m, 3H).
Synthesis of ethyl 2-(4-fluoro-3-methylphenyl)acetate
[1495] 2-(4-Fluoro-3-methylphenyl)acetamide (863 mg) was dissolved
in saturated hydrochloric acid/ethanol (20 ml), and the reaction
solution was stirred at 85.degree. C. for 10 hours. The reaction
solution was concentrated under reduced pressure and then diluted
with ethyl acetate, followed by separation with water. The organic
layer was washed with saturated aqueous sodium bicarbonate and
brine and then dried over magnesium sulfate. 919 mg of the title
compound was obtained by concentration under reduced pressure. The
property values of the compound are as follows.
[1496] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.25 (t, J=8.4 Hz,
3H), 2.05 (s, 3H), 2.26 (s, 3H) 3.54 (s, 2H), 4.15 (q, J=8.4 Hz,
1H), 6.92-6.97 (m, 1H), 7.03-7.10 (m, 2H).
Synthesis of 1-amino-3-(4-fluoro-3-methylphenyl)piperidin-2-one
[1497] 396 mg of the title compound was obtained using ethyl
2-(4-fluoro-3-methylphenyl)acetate (919 mg) as a starting material
according to the method in Examples 20 and 21. The property value
of the compound is as follows.
[1498] ESI-MS; m/z 223 [M.sup.++H].
Synthesis of (+) and
(-)-8-(4-fluoro-3-methylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidaz-
ol-1-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine
[1499] A racemate of the title compound (44.5 mg) was obtained
using 1-amino-3-(4-fluoro-3-methylphenyl)piperidin-2-one (135 mg)
as a starting material according to the method in Examples 168 and
169. The resulting racemate (44.5 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to
obtain the title optically active compound with a retention time of
12.5 minutes and positive optical rotation (20 mg) and the title
optically active compound with a retention time of 19 minutes and
negative optical rotation (20 mg).
[1500] The property values of the title optically active compound
with a retention time of 12.5 minutes are as follows.
[1501] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-1.98 (m, 1H),
1.98-2.14 (m, 1H), 2.25 (s, 3H), 2.26-2.40 (m, 2H), 2.29 (s, 3H),
4.05 (s, 3H), 4.21-4.36 (m, 3H), 6.88-7.00 (m, 5H), 7.46 (d, J=7.7
Hz, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H),
7.75-7.78 (m, 1H).
[1502] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1503] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-1.98 (m, 1H),
1.98-2.14 (m, 1H), 2.25 (s, 3H), 2.26-2.40 (m, 2H), 2.29 (s, 3H),
4.05 (s, 3H), 4.21-4.36 (m, 3H), 6.88-7.00 (m, 5H), 7.46 (d, J=7.7
Hz, 1H), 7.47 (d, J=15.7 Hz, 1H), 7.65 (d, J=15.7 Hz, 1H),
7.75-7.78 (m, 1H).
Examples 336 and 337
Synthesis of (+) and
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
##STR00265##
[1505] A racemate of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylic
acid ditrifluoroacetate (800 mg) and
1-amino-3-(3,5-difluorophenyl)piperidin-2-one (445 mg) according to
the method in Examples 168 and 169. The resulting racemate was
separated by CHIRALCEL.TM. OD-H manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: ethanol) to
obtain the title optically active compound with a retention time of
6.1 minutes and positive optical rotation (35.6 mg, >99% ee) and
the title optically active compound with a retention time of 8.1
minutes and negative optical rotation (40.6 mg, >99% ee).
[1506] The property values of the title compound with positive
optical rotation are as follows.
[1507] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.25 (m, 3H), 2.30 (s, 3H), 2.35-2.40 (m, 1H),
4.06 (s, 3H), 4.28-4.35 (m, 3H), 6.67-6.77 (m, 3H), 6.95 (d, J=8.0
Hz, 1H), 6.97 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.47 (d, J=16.0 Hz,
1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (s, 1H).
[1508] The property values of the title compound with negative
optical rotation are as follows.
[1509] ESI-MS; m/z 449 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.25 (m, 3H), 2.30 (s, 3H), 2.35-2.40 (m, 1H),
4.06 (s, 3H), 4.28-4.35 (m, 3H), 6.67-6.77 (m, 3H), 6.95 (d, J=8.0
Hz, 1H), 6.97 (s, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.47 (d, J=16.0 Hz,
1H), 7.65 (d, J=16.0 Hz, 1H), 7.78 (s, 1H).
Examples 338 and 339
Synthesis of (R) and
(S)-2-{(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2,3,4-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyridin-
e
##STR00266##
[1510] Synthesis of
1-amino-3-(2,3,4-trifluorophenyl)piperidin-2-one
[1511] The title compound (220 mg) was obtained from
2,3,4-trifluorophenylacetic acid (1.48 g) by the same method as in
Examples 1 and 2. The property values of the compound are as
follows.
[1512] ESI-MS; m/z 245 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.90-2.04 (m, 3H), 2.11-2.17 (m, 1H), 3.56-3.70 (m,
2H), 3.81-3.86 (m, 1H), 4.58 (brs, 2H), 6.82-6.96 (m, 2H).
Synthesis of (R) and
(S)-2-{(E)-3-[6-methoxy-5-(4-methylimidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-
,3,4-trifluorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazole[1,5-a]pyridine
[1513] The racemic title compound (100 mg) was obtained from
1-amino-3-(2,3,4-trifluorophenyl)piperidin-2-one (220 mg) by the
same method as in Examples 168 and 169. The resulting racemic title
compound (100 mg) was separated by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=7:3) to obtain the title optically active compound
with positive optical rotation and a retention time of 53 minutes
(19.5 mg) and the title optically active compound with negative
optical rotation and a retention time of 90 minutes (13.5 mg). The
property values of the compound are as follows.
[1514] The title optically active compound with a retention time of
53 minutes
[1515] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.08 (m, 1H), 2.09-2.25 (m, 2H), 2.29 (s, 3H),
2.35-2.43 (m, 1H), 4.05 (s, 3H), 4.25-4.35 (m, 2H), 4.53-4.57 (m,
1H), 6.68-6.74 (m, 1H), 6.90-6.96 (m, 3H), 7.44 (d, J=16.0 Hz, 1H),
7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0 Hz, 1H), 7.78 (d, J=1.2 Hz,
1H).
[1516] The title optically active compound with a retention time of
90 minutes
[1517] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.99-2.08 (m, 1H), 2.09-2.25 (m, 2H), 2.29 (s, 3H),
2.35-2.43 (m, 1H), 4.05 (s, 3H), 4.25-4.35 (m, 2H), 4.53-4.57 (m,
1H), 6.68-6.74 (m, 1H), 6.90-6.96 (m, 3H), 7.44 (d, J=16.0 Hz, 1H),
7.47 (d, J=8.0 Hz, 1H), 7.64 (d, J=16.0 Hz, 1H), 7.78 (d, J=1.2 Hz,
1H).
Examples 340 and 341
Synthesis of (+) and
(-)-8-benzo[1,3]dioxol-4-yl-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-
-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00267##
[1518] Synthesis of
1-amino-3-benzo[1,3]dioxol-4-yl-piperidin-2-one
[1519] 1.19 g of the title compound was obtained using
benzo[1,3]dioxol-4-carbaldehyde (5.0 g) as a starting material
according to the method in Examples 293 and 294. The property value
of the compound is as follows.
[1520] ESI-MS; m/z 235 [M.sup.++H].
Synthesis of (+) and
(-)-8-benzo[1,3]dioxol-4-yl-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-
-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1521] A racemate of the title compound (810 mg) was obtained using
1-amino-3-benzo[1,3]dioxol-4-yl-piperidin-2-one (1.19 g) as a
starting material according to the method in Examples 168 and 169.
The resulting racemate (100 mg) was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm,
mobile phase: ethanol, flow rate: 10 mL/min) to obtain the title
optically active compound with a retention time of 14.6 minutes and
positive optical rotation (40 mg) and the title optically active
compound with a retention time of 21 minutes and negative optical
rotation (40 mg).
[1522] The property values of the title optically active compound
with a retention time of 14.6 minutes are as follows.
[1523] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.28 (m, 3H),
2.28-2.38 (m, 1H), 2.29 (s, 3H), 4.05 (s, 3H), 4.24-4.32 (m, 2H),
4.44 (dd, J=6.6, 5.6 Hz, 1H), 5.92 (s, 2H), 6.50 (dd, J=7.0, 1.6
Hz, 1H), 6.74-6.82 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.95-6.97 (m,
1H), 7.46 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.65 (d,
J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
[1524] The property values of the title optically active compound
with a retention time of 21 minutes are as follows.
[1525] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.04-2.28 (m, 3H),
2.28-2.38 (m, 1H), 2.29 (s, 3H), 4.05 (s, 3H), 4.24-4.32 (m, 2H),
4.44 (dd, J=6.6, 5.6 Hz, 1H), 5.92 (s, 2H), 6.50 (dd, J=7.0, 1.6
Hz, 1H), 6.74-6.82 (m, 2H), 6.93 (d, J=7.8 Hz, 1H), 6.95-6.97 (m,
1H), 7.46 (d, J=7.8 Hz, 1H), 7.48 (d, J=15.6 Hz, 1H), 7.65 (d,
J=15.6 Hz, 1H), 7.77 (d, J=1.2 Hz, 1H).
Examples 342 and 343
Synthesis of (+) and
(-)-8-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-{(E)-2-[6-methoxy-5-(4-methy-
l-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00268##
[1526] Synthesis of
5-chloro-2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)valeric acid
hydrazide
[1527] 580 mg of the title compound was obtained using
2,2-difluoro-benzo[1,3]dioxol-4-carbaldehyde (1.8 g) as a starting
material according to the method in Examples 293 and 294. The
property value of the compound is as follows.
[1528] ESI-MS; m/z 307 [M.sup.++H].
Synthesis of (+) and
(-)-8-(2,2-difluoro-benzo[1,3]dioxol-4-yl)-2-{(E)-2-[6-methoxy-5-(4-methy-
l-1H-imidazol-1-yl)-pyridin-2-yl]-vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
[1529] A racemate of the title compound (280 mg) was obtained using
5-chloro-2-(2,2-difluoro-benzo[1,3]dioxol-4-yl)valeric acid
hydrazide (555 mg) and ethyl
(E)-3-[6-methoxy-5-(4-methylimidazol-1-yl)-pyridin-2-yl]acrylimidate
(482 mg) as starting materials according to the method in Examples
1 and 2. The resulting racemate (280 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 10 mL/min) to
obtain the title optically active compound with a retention time of
13 minutes and positive optical rotation (110 mg) and the title
optically active compound with a retention time of 18 minutes and
negative optical rotation (120 mg).
[1530] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1531] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.07-2.28 (m, 3H),
2.30 (s, 3H), 2.38-2.47 (m, 1H), 4.05 (s, 3H), 4.29-4.34 (m, 2H),
4.54 (dd, J=6.6, 5.8 Hz, 1H), 6.74 (dd, J=7.8, 1.4 Hz, 1H), 6.94
(d, J=7.6 Hz, 1H), 6.95-6.97 (m, 1H), 6.98-7.06 (m, 2H), 7.46 (d,
J=15.7 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.67 (d, J=15.7 Hz, 1H),
7.78 (d, J=1.2 Hz, 1H).
[1532] The property values of the title optically active compound
with a retention time of 21 minutes are as follows.
[1533] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.07-2.28 (m, 3H),
2.30 (s, 3H), 2.38-2.47 (m, 1H), 4.05 (s, 3H), 4.29-4.34 (m, 2H),
4.54 (dd, J=6.6, 5.8 Hz, 1H), 6.74 (dd, J=7.8, 1.4 Hz, 1H), 6.94
(d, J=7.6 Hz, 1H), 6.95-6.97 (m, 1H), 6.98-7.06 (m, 2H), 7.46 (d,
J=15.7 Hz, 1H), 7.47 (d, J=7.6 Hz, 1H), 7.67 (d, J=15.7 Hz, 1H),
7.78 (d, J=1.2 Hz, 1H).
Example 344
Synthesis of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[(S)-8-(2-trifluoromethylphenyl)-5-
,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol
##STR00269##
[1535] Reaction was carried out using
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (2.0 g) as a
starting material, and the resulting crude product was purified by
silica gel column chromatography (amino silica, 40 .mu.m, 53 g,
ethyl acetate:heptane=0:1 to 1:0) to obtain
8-(2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-
-yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
(739 mg) and a racemate of the title compound (88 mg) according to
the method in Examples 194 and 195. The property values of the
compound are as follows.
[1536] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.00 (m, 1H),
2.10-2.23 (m, 1H), 2.23-2.30 (m, 1H), 2.28 (s, 3H), 2.40-2.51 (m,
1H) 4.30-4.42 (m, 2H), 4.68 (dd, J=8.8, 5.6 Hz, 1H), 6.34 (d, J=7.8
Hz, 1H), 7.00 (d, J=7.4 Hz, 1H), 7.13-7.23 (m, 3H), 7.37-7.42 (m,
2H), 7.46-7.52 (m, 1H), 7.73 (d, J=7.4 Hz, 1H), 8.14 (d, J=1.2 Hz,
1H).
Examples 345 and 346
Synthesis of (+) and
(-)-2-{(E)-2-[6-chloro-5-(4-methyl-1H-imidazol-1-yl]vinyl}-8-(2-trifluoro-
methylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00270##
[1538] A solution of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7-
,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol
(500 mg) in phosphorus oxychloride (10 ml) was heated and stirred
at 100.degree. C. overnight. The reaction solution was concentrated
under reduced pressure. Ethyl acetate and a saturated sodium
bicarbonate solution were added and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain a racemate of the title
compound (176 mg). The resulting racemate was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=7:3) to obtain the
title optically active compound with positive optical rotation (46
mg, >99% ee) and the title optically active compound with
negative optical rotation (47 mg, >99% ee).
[1539] The property values of the title optically active compound
with positive optical rotation are as follows.
[1540] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.00 (m, 1H),
2.07-2.22 (m, 1H), 2.22-2.32 (m, 1H), 2.31 (s, 3H), 2.42-2.50 (m,
1H), 4.29-4.41 (m, 2H), 4.69 (dd, J=8.8, 6.0 Hz, 1H), 6.88 (d,
J=1.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.40
(t, J=7.6 Hz, 1H), 7.45-7.51 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.61
(d, J=1.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.73 (d, J=7.6 Hz,
1H).
[1541] The property values of the title optically active compound
with negative optical rotation are as follows.
[1542] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.00 (m, 1H),
2.07-2.22 (m, 1H), 2.22-2.32 (m, 1H), 2.31 (s, 3H), 2.42-2.50 (m,
1H), 4.29-4.41 (m, 2H), 4.69 (dd, J=8.8, 6.0 Hz, 1H), 6.88 (d,
J=1.6 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.30 (d, J=7.6 Hz, 1H), 7.40
(t, J=7.6 Hz, 1H), 7.45-7.51 (m, 2H), 7.56 (d, J=8.0 Hz, 1H), 7.61
(d, J=1.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.73 (d, J=7.6 Hz,
1H).
Examples 347 and 348
Synthesis of (+) and
(-)-2-{(E)-2-[6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-
-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e
##STR00271##
[1543] Synthesis of
N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]-3-p-tolylsulfanylprop-
ionamide
[1544] EDC (9.01 g), HOBT (6.34 g) and IPEA (21.8 ml) were added to
a solution of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one
(8.08 g) and 3-[(4-methylphenyl)thio]propionic acid (7.37 g) in DMF
(80 ml) under cooling in an ice water bath. The reaction solution
was stirred at room temperature for four hours. Ethyl acetate and a
sodium bicarbonate solution were added to the reaction solution,
and the organic layer was separated. The resulting organic layer
was washed with brine and then dried over anhydrous sodium sulfate.
The drying agent was separated by filtration, and then the organic
layer was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography to obtain the title
compound (13.51 g). The property values of the compound are as
follows.
[1545] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.12 (m, 3H),
2.20-2.28 (m, 1H), 2.32 (s, 3H), 2.44-2.58 (m, 2H), 3.12-3.24 (m,
2H), 3.58-3.64 (m, 1H), 3.84-3.92 (m, 1H), 4.08-4.14 (m, 1H), 7.11
(d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 7.34 (dd, J=8.0, 7.6 Hz,
1H), 7.42 (d, J=7.6 Hz, 1H), 7.53 (dd, J=8.0, 7.6 Hz, 1H), 7.64 (d,
J=8.0 Hz, 1H), 7.79 (brs, 1H).
Synthesis of
2-(2-p-tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-
[1,2,4]triazolo[1,5-a]pyridine
[1546] A solution of
N-[2-oxo-3-(2-trifluoromethylphenyl)piperidin-1-yl]-3-p-tolylsulfanylprop-
ionamide in phosphorus oxychloride (80 ml) was heated and stirred
at 120.degree. C. for one hour. The reaction solution was
concentrated under reduced pressure, followed by addition of acetic
acid (100 ml) and sodium acetate (23.8 g) heated and dried under
reduced pressure. The reaction solution was heated and stirred at
150.degree. C. for 1.5 hours. After leaving to cool, the reaction
solution was concentrated under reduced pressure. Ethyl acetate and
a saturated sodium bicarbonate solution were added and the organic
layer was separated. The resulting organic layer was washed with
brine and then dried over anhydrous sodium sulfate. The drying
agent was separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by NH
silica gel column chromatography to obtain the title compound (8.8
g). The property values of the compound are as follows.
[1547] ESI-MS; m/z 419 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.80-1.92 (m, 1H), 2.04-2.15 (m, 1H), 2.15-2.27 (m,
1H), 2.30 (s, 3H), 2.36-2.45 (m, 1H), 2.95-3.00 (m, 2H), 3.18-3.23
(m, 2H), 4.18-4.30 (m, 2H), 7.56 (dd, J=8.6, 6.2 Hz, 1H), 6.93 (d,
J=7.6 Hz, 1H), 7.07 (d, J=8.0 Hz, 2H), 7.27 (d, J=8.0 Hz, 2H), 7.35
(dd, J=8.0, 7.6 Hz, 1H), 7.45 (dd, J=8.0, 7.6 Hz, 1H), 7.68 (d,
J=8.0 Hz, 1H).
Synthesis of
2-[2-(toluene-4-sulfinyl)ethyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-tetra-
hydro[1,2,4]triazolo[1,5-a]pyridine
[1548]
2-(2-p-Tolylsulfanylethyl)-8-(2-trifluoromethylphenyl)-5,6,7,8-tetr-
ahydro[1,2,4]triazolo[1,5-a]pyridine (8.8 g) was dissolved in a
mixed solvent of methanol-water (2:1 v/v) (300 ml). Sodium
periodide (6.78 g) was added under cooling with an ice water bath,
and the reaction solution was stirred at room temperature
overnight. Ethyl acetate and water were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with brine and then dried over anhydrous
sodium sulfate. The drying agent was separated by filtration and
the organic layer was concentrated under reduced pressure to obtain
the title compound (8.87 g). The property values of the compound
are as follows.
[1549] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.80-1.93 (m, 1H),
2.02-2.15 (m, 1H), 2.16-2.28 (m, 1H), 2.36-2.45 (m, 1H), 2.39 (s,
3H), 2.83-2.98 (m, 1H), 3.05-3.30 (m, 3H), 4.17-4.30 (m, 2H),
4.54-4.60 (m, 1H), 6.93 (d, J=7.6 Hz, 1H), 7.26-7.32 (m, 2H), 7.36
(dd, J=8.0, 7.6 Hz, 1H), 7.43-7.52 (m, 3H), 7.69 (d, J=7.6 Hz,
1H).
Synthesis of
8-(2-trifluoromethylphenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-
-a]pyridine
[1550]
2-[2-(Toluene-4-sulfinyl)ethyl]-8-(2-trifluoromethylphenyl)-5,6,7,8-
-tetrahydro[1,2,4]triazolo[1,5-a]pyridine (8.87 g) was dissolved in
toluene (300 ml), and the reaction solution was heated under reflux
for three days. After leaving to cool, the reaction solution was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain the title compound (4.27
g). The property values of the compound are as follows.
[1551] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.87-1.97 (m, 1H),
2.08-2.16 (m, 1H), 2.18-2.28 (m, 1H), 2.38-2.48 (m, 1H), 4.22-4.34
(m, 2H), 4.66 (dd, J=8.2, 1.8 Hz, 1H), 5.43 (dd, J=11.2, 1.4 Hz,
1H), 6.13 (dd, J=17.6, 1.4 Hz, 1H), 6.65 (dd, J=17.6, 11.2 Hz, 1H),
6.97 (d, J=8.0 Hz, 1H), 7.37 (dd, J=8.0, 7.2 Hz, 1H), 7.46 (dd,
J=7.6, 7.2 Hz, 1H), 7.70 (d, J=7.6 Hz, 1H).
Synthesis of 2,6-difluoro-3-nitropyridine
[1552] Tetramethylammonium nitride (4.5 g) was suspended in
dichloromethane (10 ml), and a solution of trifluoromethanesulfonic
anhydride (5.56 ml) in dichloromethane (5 ml) was added dropwise at
room temperature. After stirring at room temperature for 1.5 hours,
a solution of 2,6-difluoropyridine (2 ml) in dichloromethane (5 ml)
was added at room temperature, and the reaction solution was heated
under reflux overnight. After leaving to cool, the reaction
solution was poured into an ice-cooled saturated sodium bicarbonate
solution. Dichloromethane was added and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration and the organic layer was concentrated
under reduced pressure to obtain the title compound (3.84 g). The
property values of the compound are as follows.
[1553] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 7.03-7.07 (m, 1H),
8.66-8.73 (m, 1H).
Synthesis of 2,6-difluoro-3-aminopyridine
[1554] 2,6-Difluoro-3-nitropyridine (3.84 g) was dissolved in
ethanol (42 ml). A solution of iron powder (4.03 g) and ammonium
chloride (2.57 g) in water (14 ml) was added, and the reaction
solution was heated and stirred at 80.degree. C. for one hour.
After leaving to cool, the reaction solution was filtered through
celite. Ethyl acetate and water were added and the organic layer
was separated. The resulting organic layer was washed with brine
and then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain the title compound (2.06
g). The property values of the compound are as follows.
[1555] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 3.66 (brs, 2H), 6.65
(dd, J=8.2, 3.0 Hz, 1H), 7.22 (ddd, 10.4, 8.2, 6.8 Hz, 1H).
Synthesis of N-(2,6-difluoropyridin-3-yl)formamide
[1556] Acetic anhydride (6 ml) was added to formic acid (6 ml),
followed by stirring at room temperature for 20 minutes. Then, a
solution of 2,6-difluoro-3-aminopyridine (2.06 g) in tert-butyl
methyl ether (7 ml) was added so that the reaction solution was
maintained at room temperature. The reaction solution was further
stirred at room temperature for four hours. Ethyl acetate and a
saturated sodium bicarbonate solution were added to the reaction
solution, and the organic layer was separated. The resulting
organic layer was washed with brine and then dried over anhydrous
sodium sulfate. The drying agent was separated by filtration, and
then the organic layer was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography to obtain
the title compound (2.42 g). The property values of the compound
are as follows.
[1557] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 6.86 (dd, J=8.8, 2.8
Hz, 1H), 7.42 (brs, 1H), 8.49 (s, 1H), 8.83-8.90 (m, 1H).
Synthesis of
N-(2,6-difluoropyridin-3-yl)-N-(2-oxopropyl)formamide
[1558] Chloroacetone (1.83 ml), cesium carbonate (7.99 g) and
potassium iodide (254 mg) were added to a solution of
N-(2,6-difluoropyridin-3-yl)formamide (2.42 g) in
N,N-dimethylformamide (50 ml), and the reaction solution was
stirred at room temperature for two hours. Ethyl acetate and water
were added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain the title compound (2.52
g). The property values of the compound are as follows.
[1559] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.21 (s, 3H), 4.54
(s, 2H), 6.93 (dd, J=8.0, 3.2 Hz, 1H), 7.99 (ddd, J=9.6, 8.4, 7.2
Hz, 1H), 8.28 (s, 1H).
Synthesis of 2,6-difluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine
[1560] Trifluoroacetic acid (1.08 ml) and ammonium acetate (1.08 g)
were added to a solution of
N-(2,6-difluoropyridin-3-yl)-N-(2-oxopropyl)formamide (2.52 g) in
toluene (40 ml), and the reaction solution was heated under reflux
in a nitrogen atmosphere for four hours. After leaving to cool,
ethyl acetate and a saturated sodium bicarbonate solution were
added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain the title compound (2.19
g). The property values of the compound are as follows.
[1561] ESI-MS; m/z 196 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.31 (s, 3H), 6.95-7.00 (m, 2H), 7.71-7.72 (m, 1H),
7.90 (ddd, J=9.2, 8.6, 6.8 Hz, 1H).
Synthesis of
2-amino-6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine
[1562] 28% aqueous ammonia (5 ml) was added to
2,6-difluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine (750 mg), and
the reaction solution was heated and stirred at 125.degree. C. for
one hour using a microwave synthesizer. Ethyl acetate and water
were added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration and then the organic layer was concentrated
under reduced pressure. The residue was purified by NH silica gel
column chromatography to obtain the title compound (92 mg),
6-amino-2-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine (252 mg) and
2,6-diamino-5-(4-methyl-1H-imidazol-1-yl)pyridine (53 mg).
[1563] The property values of the title compound are as
follows.
[1564] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.28 (s, 3H), 4.67
(brs, 2H), 6.40 (dd, J=8.2, 1.2 Hz, 1H), 6.84 (d, J=1.0 Hz, 1H),
7.49 (dd, J=9.6, 8.2 Hz, 1H), 7.57 (d, J=1.0 Hz, 1H).
[1565] The property values of
6-amino-2-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine are as
follows.
[1566] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 4.63
(brs, 2H), 6.352 (dd, J=8.2, 3.0 Hz, 1H), 6.79 (d, J=0.8 Hz, 1H),
7.44 (dd, J=8.2, 7.2 Hz, 1H), 7.49 (d, J=0.8 Hz, 1H).
[1567] The property values of
2,6-diamino-5-(4-methyl-1H-imidazol-1-yl)pyridine are as
follows.
[1568] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.28 (s, 3H), 4.25
(brs, 2H), 4.37 (brs, 2H), 5.91 (d, J=8.2 Hz, 1H), 6.73 (d, J=1.4
Hz, 1H), 7.13 (d, J=8.2 Hz, 1H), 7.43 (d, J=1.4 Hz, 1H).
Synthesis of
6-bromo-2-fluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine
[1569] Copper sulfate pentahydrate (438 mg) and sodium bromide (289
mg) were dissolved in water (8 ml), and a solution sodium sulfite
(176 mg) in water (6 ml) was added dropwise at room temperature.
After stirring at room temperature for 15 minutes, the supernatant
was removed and the resulting precipitate was washed with water. A
24% hydrobromic acid solution (5 ml) was added thereto to obtain a
copper bromide solution. In another reaction vessel,
2-amino-6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridine was
dissolved in a 24% hydrobromic acid solution (5 ml), and a solution
of sodium nitrite (105 mg) in water (6 ml) was added dropwise under
ice-cooling. The resulting diazonium salt solution was added to the
copper bromide solution prepared above, and the reaction solution
was further stirred under ice-cooling for one hour. The reaction
solution was neutralized with a 5 N sodium hydroxide solution.
Aqueous ammonia and tert-butyl methyl ether were added and the
organic layer was separated. The resulting organic layer was washed
with brine and then dried over anhydrous sodium sulfate. The drying
agent was separated by filtration, and then the organic layer was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography to obtain the title compound (115
mg). The property values of the compound are as follows.
[1570] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.30 (s, 3H), 6.99
(s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.66 (dd, J=8.8, 8.0 Hz, 1H), 7.76
(s, 1H).
Synthesis of (+) and
(-)-2-{(E)-2-[6-fluoro-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-
-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridin-
e
[1571] 6-Bromo-2-fluoro-3-(4-methyl-1H-imidazol-1-yl)pyridine (156
mg) and
8-(2-trifluoromethylphenyl)-2-vinyl-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-
-a]pyridine (179 mg) were dissolved in toluene (5 ml).
Tris(dibenzylideneacetone)dipalladium (167 mg),
tri-o-tolylphosphine (111 mg) and triethylamine (340 ul) were added
and the reaction solution was heated and stirred in a nitrogen
atmosphere at 120.degree. C. for 1.3 hours. After leaving to cool,
ethyl acetate and water were added. The reaction solution was
filtered through celite and the organic layer was separated. The
resulting organic layer was washed with brine and then dried over
anhydrous sodium sulfate. The drying agent was separated by
filtration, and then the organic layer was concentrated under
reduced pressure. The residue was purified by NH silica gel column
chromatography to obtain a racemate of the title compound (65 mg).
The resulting racemate was separated by CHIRALPAK.TM. IB
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: hexane:ethanol=6:4) to obtain the title optically
active compound with positive optical rotation (20 mg, >99% ee)
and the title optically active compound with negative optical
rotation (20 mg, >99% ee).
[1572] The property values of the title optically active compound
with positive optical rotation are as follows.
[1573] ESI-MS; m/z 469 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.90-2.00 (m, 1H), 2.10-2.21 (m, 1H), 2.21-2.35 (m,
1H), 2.30 (s, 3H), 2.40-2.51 (m, 1H), 4.28-4.40 (m, 2H), 4.70 (dd,
J=7.6, 5.6 Hz, 1H), 6.97-7.03 (m, 2H), 7.22-7.28 (m, 1H), 7.37-7.52
(m, 3H), 7.57-7.77 (m, 4H).
[1574] The property values of the title optically active compound
with negative optical rotation are as follows.
[1575] ESI-MS; m/z 469 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.90-2.00 (m, 1H), 2.10-2.21 (m, 1H), 2.21-2.35 (m,
1H), 2.30 (s, 3H), 2.40-2.51 (m, 1H), 4.28-4.40 (m, 2H), 4.70 (dd,
J=7.6, 5.6 Hz, 1H), 6.97-7.03 (m, 2H), 7.22-7.28 (m, 1H), 7.37-7.52
(m, 3H), 7.57-7.77 (m, 4H).
Examples 349 and 350
Synthesis of (+) and
(-)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-pyridin-2-yl]vinyl}-8-(2-trif-
luoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00272##
[1576] Synthesis of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7-
,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-yl
trifluoromethanesulfonate
[1577] Pyridine (200 .mu.L) was added to a solution of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7-
,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol
synthesized in Example 344 (200 mg) in dichloromethane (2 mL), and
trifluoromethanesulfonic anhydride (78.3 .mu.L) was added dropwise
under ice-cooling. The reaction solution was stirred at room
temperature for one hour. Water was added to the reaction solution
under ice-cooling, followed by separatory extraction with ethyl
acetate. The resulting organic layer was dried over magnesium
sulfate and concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (carrier:
Chromatorex NH; elution solvent: heptane:ethyl
acetate=2:1->ethyl acetate) to obtain the title compound (64
mg).
[1578] The property value of the compound is as follows.
[1579] ESI-MS; m/z 599 [M.sup.++H].
Synthesis of (+) and
(-)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-trifl-
uoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1580] Triethylsilane (40.9 .mu.L) and a
1,1'-bis(diphenylphosphino)ferrocene palladium (II)
dichloride-dichloromethane complex (4.37 mg) were added to a
solution of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7-
,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-yl
trifluoromethanesulfonate (64 mg) in DMF (2 mL). The reaction
solution was stirred at 70.degree. C. for five hours. The reaction
solution was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (carrier:
Chromatorex NH; elution solvent: heptane:ethyl
acetate=4:1->ethyl acetate) to obtain a racemate of the title
compound (25 mg). The resulting racemate (25 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: ethanol, flow rate: 11 mL/min) to
obtain the title optically active compound with a retention time of
21 minutes and positive optical rotation (10 mg) and the title
optically active compound with a retention time of 30 minutes and
negative optical rotation (10 mg).
[1581] The property values of the title optically active compound
with a retention time of 21 minutes are as follows.
[1582] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.28-4.39 (m, 2H), 4.70 (dd, J=7.6, 6.4 Hz, 1H), 7.00-7.02 (m, 2H),
7.37-7.61 (m, 6H), 7.72 (d, J=7.6 Hz, 1H), 7.76 (s, 1H), 8.67 (d,
J=2.8 Hz, 1H).
[1583] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[1584] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.28-4.39 (m, 2H), 4.70 (dd, J=7.6, 6.4 Hz, 1H), 7.00-7.02 (m, 2H),
7.37-7.61 (m, 6H), 7.72 (d, J=7.6 Hz, 1H), 7.76 (s, 1H), 8.67 (d,
J=2.8 Hz, 1H).
Examples 351 and 352
Synthesis of (+) and
(-)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-6-(2,2,2-trifluoroethoxy)pyri-
din-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]tria-
zolo[1,5-a]pyridine
##STR00273##
[1586] Cesium carbonate (83.7 mg) and 2,2,2-trifluoroethyl
trifluoromethanesulfonate (35.7 .mu.L) were added to a mixture of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[842-trifluoromethylphenyl)-5,6,7,-
8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol
synthesized in Example 344 (100 mg) and DMF (1.2 mL), and the
reaction solution was stirred at room temperature for four hours.
Water and ethyl acetate were added to the reaction solution, and
the organic layer was separated. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (carrier:
Chromatorex NH; elution solvent: heptane:ethyl
acetate=4:1->ethyl acetate) to obtain a racemate of the title
compound (110 mg). The resulting racemate (110 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=5:5, flow rate: 11
mL/min) to obtain the title optically active compound with a
retention time of 13 minutes and positive optical rotation (51 mg)
and the title optically active compound with a retention time of 18
minutes and negative optical rotation (53 mg).
[1587] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1588] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.30-4.40 (m, 2H), 4.70 (dd, J=8.4, 6.0 Hz, 2H), 4.84-4.93 (m, 2H),
6.96-7.04 (m, 3H), 7.37-7.58 (m, 5H), 7.25 (d, J=7.6 Hz, 1H), 7.78
(d, J=1.2 Hz, 1H).
[1589] The property values of the title optically active compound
with a retention time of 18 minutes are as follows.
[1590] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.30-4.40 (m, 2H), 4.70 (dd, J=8.4, 6.0 Hz, 2H), 4.84-4.93 (m, 2H),
6.96-7.04 (m, 3H), 7.37-7.58 (m, 5H), 7.25 (d, J=7.6 Hz, 1H), 7.78
(d, J=1.2 Hz, 1H).
Examples 353 and 354
Synthesis of (+) and
(-)-2-{(E)-2-[5-(4-methyl-1H-imidazol-1-yl)-6-(2,2-difluoroethoxy)pyridin-
-2-yl]vinyl}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00274##
[1592] Cesium carbonate (83.7 mg) and 2-bromo-1,1-difluoroethane
(34.1 mg) were added to a mixture of
3-(4-methyl-1H-imidazol-1-yl)-6-{(E)-2-[8-(2-trifluoromethylphenyl)-5,6,7-
,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-2-yl]vinyl}pyridin-2-ol
synthesized in Example 344 (100 mg) and DMF (1.2 mL), and the
reaction solution was stirred at room temperature for 48 hours.
Water and ethyl acetate were added to the reaction solution, and
the organic layer was separated. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (carrier:
Chromatorex NH; elution solvent: heptane:ethyl
acetate=4:1->ethyl acetate) to obtain a racemate of the title
compound (80 mg). The resulting racemate (80 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=4:6, flow rate: 11
mL/min) to obtain the title optically active compound with a
retention time of 14 minutes and positive optical rotation (33 mg)
and the title optically active compound with a retention time of 25
minutes and negative optical rotation (35 mg).
[1593] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[1594] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.31-4.40 (m, 2H), 4.62-4.72 (m, 3H), 5.99-6.92 (m, 1H), 6.96 (s,
1H), 6.96-7.02 (m, 3H) 7.26-7.57 (m, 5H), 7.25 (d, J=7.2 Hz, 1H),
7.77 (d, J=1.2 Hz, 1H).
[1595] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[1596] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.49 (m, 7H),
4.31-4.40 (m, 2H), 4.62-4.72 (m, 3H), 5.99-6.92 (m, 1H), 6.96 (s,
1H), 6.96-7.02 (m, 3H) 7.26-7.57 (m, 5H), 7.25 (d, J=7.2 Hz, 1H),
7.77 (d, J=1.2 Hz, 1H).
Examples 355 and 356
Synthesis of (+) and
(-)-2-{(E)-2-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]vinyl}-8-(2-trif-
luorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00275##
[1597] Synthesis of tert-butyl
(E)-3-{5-[(2,2-dimethoxyethyl)formylamino]-6-methoxypyridin-2-yl}acrylate
[1598] tert-Butyl
(E)-3-(5-formylamino-6-methoxypyridin-2-yl)acrylate synthesized
according to the method in Examples 168 and 169 (4 g) was dissolved
in DMF (60 mL). Cesium carbonate (9.38 g) was added and the
reaction solution was heated to 60.degree. C. Bromoacetaldehyde
dimethylacetal (2.08 mL) was added to the reaction solution. The
reaction solution was stirred for two hours, heated to 110.degree.
C. and stirred for 10 hours. The reaction solution was left to
cool. Ice water was added under ice-cooling, followed by extraction
with ethyl acetate. The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (carrier: Chromatorex Si;
elution solvent: heptane:ethyl acetate=7:1->heptane:ethyl
acetate=1:2) to obtain the title compound (3.99 g). The property
values of the compound are as follows.
[1599] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.54 (s, 9H), 3.30
(s, 6H), 3.83 (d, J=5.2 Hz, 2H), 4.01 (s, 3H), 4.53 (t, J=5.2 Hz,
1H), 6.84 (d, J=15.6 Hz, 1H), 7.00 (d, J=8.0 Hz, 1H), 7.46 (d,
J=15.2 Hz, 1H), 7.46 (d, J=7.2 Hz, 1H), 8.17 (s, 1H).
Synthesis of tert-butyl
(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate
[1600] tert-Butyl
(E)-3-{5-[(2,2-dimethoxyethyl)formylamino]-6-methoxypyridin-2-yl}acrylate
(3.7 g) was dissolved in acetic acid (36 mL). Ammonium acetate (7
g) was added and the reaction solution was stirred at 135.degree.
C. for two hours. The reaction solution was concentrated under
reduced pressure. A saturated sodium bicarbonate solution and ethyl
acetate were added and the organic layer was separated. The organic
layer was dried over magnesium sulfate and concentrated under
reduced pressure. The residue was purified by silica gel
chromatography (carrier: Chromatorex NH; elution solvent:
heptane:ethyl acetate=9:1->heptane:ethyl acetate=1:2) to obtain
the title compound (490 mg).
[1601] The property value of the compound is as follows.
[1602] ESI-MS; m/z 302 [M.sup.++H].
Synthesis of
(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylic acid
[1603] A solution of trifluoroacetic acid (3 mL) in dichloromethane
(1.5 mL) was added to tert-butyl
(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylate (490 mg)
under ice-cooling, and the reaction solution was stirred at room
temperature for one hour. The reaction solution was concentrated
under reduced pressure, diluted with chloroform and then
concentrated under reduced pressure. Diethyl ether was added to the
residue, and the precipitated solid was collected by filtration.
The solid was washed with diethyl ether to obtain the title
compound as a solid (345 mg). The property values of the compound
are as follows.
[1604] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 4.00 (s, 3H), 6.88
(d, J=15.6 Hz, 1H), 7.52-7.70 (m, 4H), 7.90 (s, 1H), 8.10 (d, J=8.0
Hz, 1H), 9.18 (s, 1H).
Synthesis of
(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]-N-[2-oxo-3-(2-trifluor-
omethylphenyl)piperidin-1-yl]acrylamide
[1605] IPEA (742 .mu.L), EDC (206 mg) and HOBT (146 mg) were added
to a mixture of 1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one
(185 mg), (E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]acrylic
acid (340 mg) and DMF (5 mL), and the reaction solution was stirred
at room temperature for 14 hours. A saturated sodium bicarbonate
solution was added to the reaction solution, followed by extraction
with ethyl acetate. The organic layer was dried over magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel chromatography (carrier: Chromatorex NH;
elution solvent: ethyl acetate->ethyl acetate:methanol=9:1) to
obtain the title compound (453 mg). The property value of the
compound is as follows.
[1606] ESI-MS; m/z 486 [M.sup.++H].
Synthesis of (+) and
(-)-2-{(E)-2-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]vinyl}-8-(2-trif-
luorophenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1607] Phosphorus oxychloride (9 mL) was added to
(E)-3-[5-(1H-imidazol-1-yl)-6-methoxypyridin-2-yl]-N-[2-oxo-3-(2-trifluor-
omethylphenyl)piperidin-1-yl]acrylamide (340 mg), and the reaction
solution was stirred at 100.degree. C. for 35 minutes. The reaction
solution was concentrated under reduced pressure. The resulting
residue was diluted with acetic acid (5 mL). Then, ammonium acetate
(1.43 g) was added and the reaction solution was stirred at
140.degree. C. for one hour and 15 minutes. The reaction solution
was concentrated under reduced pressure. Ethyl acetate and a
saturated sodium bicarbonate solution were added to the residue,
and the organic layer was separated. The organic layer was dried
over magnesium sulfate and concentrated under reduced pressure. The
residue was purified by silica gel chromatography (carrier:
Chromatorex NH; elution solvent: heptane:ethyl
acetate=2:1->ethyl acetate) to obtain a racemate of the title
compound (200 mg). The racemate (200 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase: hexane:ethanol=5:5, flow rate: 11
mL/min) to obtain the title optically active compound with a
retention time of 16 minutes and positive optical rotation (70 mg)
and the title optically active compound with a retention time of 34
minutes and negative optical rotation (75 mg).
[1608] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1609] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.50 (m, 4H),
4.03 (s, 3H), 4.29-4.40 (m, 2H), 4.69 (dd, J=6.4, 6.0 Hz, 1H), 6.94
(d, J=7.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.17 (brm, 1H),
7.23-7.24 (m, 1H), 7.37-7.50 (m, 4H), 7.65 (d, J=15.6 Hz, 1H), 7.72
(d, J=8.0 Hz, 1H), 7.85 (m, 1H).
[1610] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[1611] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.50 (m, 4H),
4.03 (s, 3H), 4.29-4.40 (m, 2H), 4.69 (dd, J=6.4, 6.0 Hz, 1H), 6.94
(d, J=7.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.17 (brm, 1H),
7.23-7.24 (m, 1H), 7.37-7.50 (m, 4H), 7.65 (d, J=15.6 Hz, 1H), 7.72
(d, J=8.0 Hz, 1H), 7.85 (m, 1H).
Examples 357 and 358
Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]propenyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00276##
[1612] Synthesis of
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-butenoic
acid ditrifluoroacetate
[1613] Sodium hydride (401 mg; containing 60 wt % of mineral oil)
was added to a solution of tert-butyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylate
(1.58 g) and trimethylsulfonium iodide (2.21 g) in DMSO (15 mL) at
0.degree. C. Then, the reaction solution was stirred at room
temperature for one hour. Ice water and ethyl acetate were added to
the reaction solution, and the organic layer was separated. The
resulting organic layer was washed with brine and then dried over
anhydrous magnesium sulfate. The organic layer was concentrated
under reduced pressure. The residue was purified by NH-silica gel
column chromatography (elution solvent: heptane-ethyl acetate
system) to obtain a crude product. Trifluoroacetic acid (6 mL) was
added to a solution of the crude product in methylene chloride (3
mL) at room temperature, and the reaction solution was stirred at
room temperature for two hours. The reaction solvent was removed
under reduced pressure, followed by azeotropic distillation with
chloroform. Then, the resulting solid was filtered, washed with
diethyl ether and dried to obtain 1.05 g of the title compound. The
property value of the compound is as follows.
[1614] ESI-MS; m/z 274 [M.sup.++H].
Synthesis of (+) and
(-)-8-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]propenyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
[1615] A racemate of the title compound (125 mg) was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-2-butenoic
acid ditrifluoroacetate (300 mg) and
1-amino-3-(4-fluorophenyl)piperidin-2-one (163 mg) according to the
method in Examples 168 and 169. The resulting racemate was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase: hexane-ethanol
system) to obtain the title optically active compound with a
retention time of 18.7 minutes and positive optical rotation (41.7
mg, >99% ee) and the title optically active compound with a
retention time of 27.9 minutes and negative optical rotation (41.8
mg, >99% ee).
[1616] The property values of the title compound with positive
optical rotation are as follows.
[1617] ESI-MS; m/z 464 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.18 (m, 2H), 2.18-2.28 (m, 1H), 2.30 (s, 3H),
2.30-2.40 (m, 1H), 2.63 (s, 3H), 4.05 (s, 3H), 4.30-4.36 (m, 3H),
6.97 (s, 1H), 7.00-7.05 (m, 2H), 7.10-7.14 (m, 2H), 7.22 (d, J=8.0
Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.79 (d,
J=1.2 Hz, 1H).
[1618] The property values of the title compound with negative
optical rotation are as follows.
[1619] ESI-MS; m/z 464 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.00-2.18 (m, 2H), 2.18-2.28 (m, 1H), 2.30 (s, 3H),
2.30-2.40 (m, 1H), 2.63 (s, 3H), 4.05 (s, 3H), 4.30-4.36 (m, 3H),
6.97 (s, 1H), 7.00-7.05 (m, 2H), 7.10-7.14 (m, 2H), 7.22 (d, J=8.0
Hz, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.57 (d, J=1.2 Hz, 1H), 7.79 (d,
J=1.2 Hz, 1H).
Examples 359, 360, 361 and 362
Synthesis of (5R,8R), (5S,8S), (5R,8S) and
(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
##STR00277##
[1620] Synthesis of 2-(2-trifluoromethylphenyl)pentanedioic acid
5-tert-butyl ester 1-methyl ester
[1621] Methyl 2-trifluoromethylphenylacetate (5 g) was dissolved in
THF (75 mL). Potassium tert-butoxide (2.71 g) was added under
ice-cooling, and the reaction solution was stirred for 30 minutes.
tert-Butyl 3-bromopropionate (3.83 mL) was added to the reaction
solution. The reaction solution was gradually heated until room
temperature and stirred for four hours. A 1 N hydrochloric acid
aqueous solution was added to the reaction solution, followed by
extraction with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(carrier: Chromatorex Si; elution solvent: heptane:ethyl
acetate=19:1->heptane:ethyl acetate=1:1) to obtain the title
compound (6 g). The property values of the compound are as
follows.
[1622] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.42 (s, 9H),
2.02-2.43 (m, 4H), 3.66 (s, 3H), 4.06 (dd, J=7.2, 7.2 Hz, 1H),
7.35-7.41 (m, 1H), 7.50-7.67 (m, 3H).
Synthesis of methyl 5-oxo-2-(2-trifluoromethylphenyl)hexanoate
[1623] 2-(2-Trifluoromethylphenyl)pentanedioic acid 5-tert-butyl
ester 1-methyl ester (3 g) was dissolved in dichloromethane (30
mL). Trifluoroacetic acid (12 mL) was added and the reaction
solution was stirred at room temperature for one hour. The reaction
solution was concentrated under reduced pressure, and the resulting
residue was dissolved in toluene (60 mL). Thionyl chloride (1.89
mL) was added and the reaction solution was stirred at 80.degree.
C. for three hours. The reaction solution was concentrated under
reduced pressure and diluted with THF (50 mL). Then,
tributylphosphine (2.37 mL) was added at -20.degree. C. and the
reaction solution was stirred for 20 minutes. A 0.97 M solution of
methylmagnesium bromide in THF (9.78 mL) was added dropwise to the
reaction solution, and the reaction solution was stirred for 15
minutes. Then, a 1 N hydrochloric acid aqueous solution was added,
followed by extraction with ethyl acetate. The organic layer was
dried over magnesium sulfate and concentrated under reduced
pressure. The residue was purified by silica gel chromatography
(carrier: Chromatorex Si; elution solvent: heptane:ethyl
acetate=19:1->heptane:ethyl acetate=1:1) to obtain the title
compound (728 mg). The property values of the compound are as
follows.
[1624] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.01-2.51 (m, 7H),
3.65 (s, 3H), 3.98-4.02 (m, 1H), 7.35-7.38 (m, 1H), 7.51-7.57 (m,
2H), 7.56 (d, J=8.0 Hz, 1H).
Synthesis of
1-amino-6-methyl-3-2-trifluoromethylphenyl)piperidin-2-one
[1625] Methyl 5-oxo-2-(2-trifluoromethylphenyl)hexanoate (728 mg)
was dissolved in methanol (15.2 mL). Sodium borohydride (47.8 mg)
was added under ice-cooling, and the reaction solution was stirred
at the same temperature for 30 minutes. A 1 N hydrochloric acid
aqueous solution was added to the reaction solution, followed by
extraction with ethyl acetate. The resulting organic layer was
dried over magnesium sulfate and then concentrated under reduced
pressure. The resulting residue was dissolved in chloroform (15
mL). Thionyl chloride (576 .mu.L) was added and the reaction
solution was stirred at 50.degree. C. for three hours. The reaction
solution was concentrated under reduced pressure. The resulting
residue was purified by silica gel chromatography (carrier:
Chromatorex Si; elution solvent: heptane:ethyl
acetate=19:1->heptane:ethyl acetate=1:1) to obtain methyl
5-chloro-2-(2-trifluoromethylphenyl)hexanoate (380 mg) as a
diastereomer mixture. The mixture (320 mg) was dissolved in ethanol
(7.8 mL). Hydrazine monohydrate (1.5 mL) was added and the reaction
solution was stirred at 100.degree. C. for 14 hours. The reaction
solution was concentrated under reduced pressure. A saturated
sodium bicarbonate solution was added to the residue, followed by
extraction with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(carrier: Chromatorex Si; elution solvent: heptane:ethyl
acetate=19:1->heptane:ethyl acetate=1:1) to obtain the title
compound (380 mg).
[1626] The property values of the compound are as follows.
[1627] ESI-MS; m/z 273 [M.sup.++H].
Synthesis of (5R,8R), (5S,8S), (5R,8S) and
(5S,8R)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vin-
yl}-5-methyl-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazol-
o[1,5-a]pyridine
[1628] A racemate of the title compound (140 mg) was obtained using
1-amino-6-methyl-3-(2-trifluoromethylphenyl)piperidin-2-one (210
mg) as a starting material according to the method in Examples 168
and 169. The resulting racemate (140 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm, mobile phase; hexane:ethanol=8:2, flow rate: 10
mL/min) to obtain the title optically active compound with a
retention time of 30 minutes and positive optical rotation (18 mg),
the title optically active compound with a retention time of 33
minutes and positive optical rotation (10 mg), the title optically
active compound with a retention time of 43 minutes and negative
optical rotation (15 mg) and the title optically active compound
with a retention time of 71 minutes and negative optical rotation
(14 mg).
[1629] The property values of the title optically active compound
with a retention time of 30 minutes are as follows.
[1630] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.70-2.34 (m, 10H),
4.03 (s, 3H), 4.49-4.55 (m, 1H), 4.73 (dd, J=6.8, 6.8 Hz, 1H),
6.91-6.94 (m, 3H), 7.37-7.50 (m, 4H), 7.66 (d, J=15.6 Hz, 1H), 7.73
(d, J=7.6 Hz, 1H), 7.76 (s, 1H).
[1631] The property values of the title optically active compound
with a retention time of 33 minutes are as follows.
[1632] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.63-1.93 (m, 5H),
2.29-2.48 (m, 5H), 4.03 (s, 3H), 4.42-4.50 (m, 1H), 4.63-4.67 (m,
1H), 6.91-6.95 (m, 2H), 7.03-7.06 (d, J=7.6 Hz, 1H), 7.36-7.50 (m,
4H), 7.64 (d, J=15.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.76 (s,
1H).
[1633] The property values of the title optically active compound
with a retention time of 43 minutes are as follows.
[1634] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.63-1.93 (m, 5H),
2.29-2.48 (m, 5H), 4.03 (s, 3H), 4.42-4.50 (m, 1H), 4.63-4.67 (m,
1H), 6.91-6.95 (m, 2H), 7.03-7.06 (d, J=7.6 Hz, 1H), 7.36-7.50 (m,
4H), 7.64 (d, J=15.6 Hz, 1H), 7.72 (d, J=7.6 Hz, 1H), 7.76 (s,
1H).
[1635] The property values of the title optically active compound
with a retention time of 71 minutes are as follows.
[1636] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.70-2.34 (m, 10H),
4.03 (s, 3H), 4.49-4.55 (m, 1H), 4.73 (dd, J=6.8, 6.8 Hz, 1H),
6.91-6.94 (m, 3H), 7.37-7.50 (m, 4H), 7.66 (d, J=15.6 Hz, 1H), 7.73
(d, J=7.6 Hz, 1H), 7.76 (s, 1H)
Example 363
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-
-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-8-
-ol
##STR00278##
[1638]
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl-
}-8-(2-Trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyr-
idine (50 mg) was dissolved in DMF (3 mL). Sodium hydride
(containing 40% of mineral oil, 8.3 mg) was added and the reaction
solution was stirred at room temperature for 10 minutes. The
reaction solution was internally replaced with oxygen. The reaction
solution was bubbled with oxygen and stirred for two hours. A
sodium thiosulfate solution was added to the reaction solution, and
the reaction solution was stirred at room temperature for 30
minutes. Ethyl acetate was added to the reaction solution and the
organic layer was separated. The organic layer was dried over
magnesium sulfate and concentrated under reduced pressure. The
resulting residue was purified by silica gel chromatography
(carrier: Chromatorex Si; elution solvent: heptane:ethyl
acetate=1:1->ethyl acetate->ethyl acetate:methanol=9:1) to
obtain the title compound (10 mg). The property values of the
compound are as follows.
[1639] ESI-MS; m/z 497 [M.sup.++H].
[1640] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.05-2.62 (m, 7H),
3.97 (s, 3H), 4.16-4.41 (m, 2H), 6.74 (d, J=7.6 Hz, 1H), 6.91 (s,
1H), 7.29-7.60 (m, 5H), 7.72-7.75 (m, 2H), 7.86 (s, 1H).
Examples 364 and 365
Synthesis of (+) and
(-)-8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine
##STR00279##
[1642] A racemate of the title compound was obtained from
8-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine
(133 mg) according to the method in Examples 53 and 54. The
resulting racemate was separated by CHIRALPAK.TM. IC manufactured
by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile
phase: ethanol) to obtain the title optically active compound with
a retention time of 6.1 minutes and positive optical rotation (28.7
mg, >99% ee) and the title optically active compound with a
retention time of 7.0 minutes and negative optical rotation (25.5
mg, >99% ee).
[1643] The property values of the title compound with positive
optical rotation are as follows.
[1644] ESI-MS; m/z 465 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.12 (m, 1H), 2.14-2.21 (m, 1H), 2.29 (s, 3H),
2.30-2.50 (m, 2H), 4.00 (s, 3H), 4.23-4.37 (m, 2H), 6.75 (m, 1H),
6.79 (d, J=8.0 Hz, 1H), 6.90-6.94 (m, 3H), 7.38 (d, J=15.6 Hz, 1H),
7.41 (d, J=8.0 Hz, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.80 (s, 1H).
[1645] The property values of the title compound with negative
optical rotation are as follows.
[1646] ESI-MS; m/z 465 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.01-2.12 (m, 1H), 2.14-2.21 (m, 1H), 2.29 (s, 3H),
2.30-2.50 (m, 2H), 4.00 (s, 3H), 4.23-4.37 (m, 2H), 6.75 (m, 1H),
6.79 (d, J=8.0 Hz, 1H), 6.90-6.94 (m, 3H), 7.38 (d, J=15.6 Hz, 1H),
7.41 (d, J=8.0 Hz, 1H), 7.62 (d, J=15.6 Hz, 1H), 7.80 (s, 1H).
Example 366
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-(2-
-trifluoromethylphenyl)-5,6-dihydro[1,2,4]triazolo[1,5-a]pyridine
##STR00280##
[1648]
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl-
}-8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyr-
idin-8-ol (56 mg) was dissolved in dichloromethane (2 ml).
Diethylaminosulfur trifluoride (45 ul) was added under ice-cooling,
and the reaction solution was stirred at room temperature for three
hours. Thereafter, diethylaminosulfur trifluoride (45 ul) was added
again at room temperature, and the reaction solution was further
stirred at room temperature overnight. Ethyl acetate and water were
added to the reaction solution, and the organic layer was
separated. The resulting organic layer was washed with brine and
then dried over anhydrous sodium sulfate. The drying agent was
separated by filtration and then the organic layer was concentrated
under reduced pressure. The residue was separated by CHIRALPAK.TM.
IB manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25
cm; mobile phase: hexane:ethanol=1:1) to obtain the title compound
(20 mg). The property values of the compound are as follows.
[1649] ESI-MS; m/z 479 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.29 (s, 3H), 2.93 (td, J=8.2, 4.4 Hz, 2H), 4.03 (s,
3H), 4.44 (t, J=8.2 Hz, 2H), 6.27 (t, J=4.4 Hz, 1H), 6.91-6.96 (m,
2H), 7.39-7.55 (m, 4H), 7.60-7.66 (m, 2H), 7.74-7.78 (m, 2H).
Examples 367 and 368
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6-dihydro-8H-[1,2,4]triazolo[5,1-c][1,4]oxaz-
ine
##STR00281##
[1651] A racemate of the title compound (190 mg) was obtained using
2-(trifluoromethyl)benzaldehyde (3 g) as a starting material
according to the method in Examples 257 and 258. The resulting
racemate (190 mg) was separated by CHIRALPAK.TM. IB manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm, mobile phase:
hexane:ethanol=1:1, flow rate: 11 mL/min) to obtain the title
optically active compound with a retention time of 27 minutes and
positive optical rotation (38 mg) and the title optically active
compound with a retention time of 41 minutes and negative optical
rotation (37 mg).
[1652] The property values of the title optically active compound
with a retention time of 27 minutes are as follows.
[1653] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 4.04
(s, 3H), 4.17-4.53 (m, 4H), 6.26 (s, 1H), 6.93-6.95 (m, 2H), 7.30
(d, J=7.6 Hz, 1H), 7.43-7.58 (m, 4H), 7.64 (d, J=15.6 Hz, 1H),
7.77-7.80 (m, 2H).
[1654] The property values of the title optically active compound
with a retention time of 41 minutes are as follows.
[1655] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 2.29 (s, 3H), 4.04
(s, 3H), 4.17-4.53 (m, 4H), 6.26 (s, 1H), 6.93-6.95 (m, 2H), 7.30
(d, J=7.6 Hz, 1H), 7.43-7.58 (m, 4H), 7.64 (d, J=15.6 Hz, 1H),
7.77-7.80 (m, 2H).
Example 369
Synthesis of
4-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyrid-
in-2-yl]vinyl}-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidine
##STR00282##
[1657] 146 mg of the racemic title compound was obtained from
(E)-N-[3-(4-fluorophenyl)-2-oxo-tetrahydropyrimidin-1-yl]-3-[6-methoxy-5--
(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide (240 mg) by the
same method as in Example 232. The property values of the compound
are as follows.
[1658] ESI-MS; m/z 432 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.33-2.42 (m, 2H), 3.83 (t,
J=5.6 Hz, 2H), 4.05 (s, 3H), 4.24 (t, J=6.0 Hz, 2H), 6.93-6.98 (m,
2H), 7.07-7.14 (m, 2H), 7.38 (d, J=15.6 Hz, 1H), 7.45-7.56 (m, 4H),
7.77 (d, J=1.2 Hz, 1H).
Example 370
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-4-(2-
-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]pyrimidin-
e
##STR00283##
[1660] 320 mg of the title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[2-oxo-3-(2-
-trifluoromethylphenyl)-tetrahydropyrimidin-1-yl]acrylamide (474
mg) by the same method as in Example 232. The property values of
the compound are as follows.
[1661] ESI-MS; m/z 482 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.25-2.55 (m, 2H), 2.29 (d, J=0.8 Hz, 3H), 3.57-3.73
(m, 2H), 4.01 (s, 3H), 4.20-4.34 (m, 2H), 6.88 (d, J=8.0 Hz, 1H),
6.93-6.96 (m, 1H), 7.26-7.32 (m, 1H), 7.43 (d, J=8.0 Hz, 1H),
7.46-7.54 (m, 3H), 7.64-7.70 (m, 1H), 7.74 (d, J=1.2 Hz, 1H),
7.77-7.82 (m, 1H).
Examples 371 and 372
Synthesis of (R) and
(S)-4-(2,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-5-methyl-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,5-a]p-
yrimidine
##STR00284##
[1663] 374 mg of the racemic title compound was obtained from
(E)-N-[3-(2,4-difluorophenyl)-4-methyl-2-oxo-tetrahydropyrimidin-1-yl]-3--
[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylamide
(500 mg) by the same method as in Example 232. The racemic title
compound (250 mg) was separated by CHIRALPAK.TM. IC manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
ethyl acetate:methanol=2:3) to obtain the title optically active
compound with a retention time of 16 minutes (110 mg) and the title
optically active compound with a retention time of 19 minutes (110
mg).
[1664] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1665] ESI-MS; m/z 464 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.4 Hz, 3H), 2.11-2.20 (m, 1H), 2.29 (s,
3H), 2.38-2.48 (m, 1H), 3.93-4.02 (m, 1H), 4.03 (s, 3H), 4.26 (t,
J=6.4 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.92-7.00 (m, 3H), 7.29 (d,
J=15.6 Hz, 1H), 7.39-7.47 (m, 2H), 7.49 (d, J=15.6 Hz, 1H), 7.76
(brs, 1H).
[1666] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1667] ESI-MS; m/z 464 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.23 (d, J=6.4 Hz, 3H), 2.11-2.20 (m, 1H), 2.29 (s,
3H), 2.38-2.48 (m, 1H), 3.93-4.02 (m, 1H), 4.03 (s, 3H), 4.26 (t,
J=6.4 Hz, 2H), 6.90 (d, J=8.0 Hz, 1H), 6.92-7.00 (m, 3H), 7.29 (d,
J=15.6 Hz, 1H), 7.39-7.47 (m, 2H), 7.49 (d, J=15.6 Hz, 1H), 7.76
(brs, 1H).
Examples 373 and 374
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
5-methyl-4-(2-trifluoromethylphenyl)-4,5,6,7-tetrahydro-[1,2,4]triazolo[1,-
5-a]pyrimidine
##STR00285##
[1669] 374 mg of the racemic title compound was obtained from
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-N-[4-methyl-2-
-oxo-3-(2-trifluoromethylphenyl)-tetrahydropyrimidin-1-yl]acrylamide
(494 mg) by the same method as in Example 232. The racemic title
compound (220 mg) was separated by CHIRALPAK.TM. IC manufactured by
Daicel Chemical Industries, Ltd. (2 cm.times.25 cm; mobile phase:
ethyl acetate:methanol=1:1) and solidified with ethyl acetate and
heptane to obtain the title optically active compound with positive
optical rotation and a retention time of 2 minutes (97 mg) and the
title optically active compound with negative optical rotation and
a retention time of 5 minutes (92 mg).
[1670] The property values of the title optically active compound
with a retention time of 2 minutes are as follows.
[1671] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.25-1.34 (m, 3H), 2.04-2.15 (m, 1H), 2.28 (s, 3H),
2.46-2.60 (m, 1H), 3.91-4.03 (m, 1H), 4.01 (s, 3H), 4.20-4.36 (m,
2H), 6.88 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H), 7.23-7.30 (m, 1H),
7.42 (d, J=7.6 Hz, 1H), 7.44-7.56 (m, 3H), 7.65-7.71 (m, 1H),
7.73-7.76 (m, 1H), 7.79-7.84 (m, 1H).
[1672] The property values of the title optically active compound
with a retention time of 5 minutes are as follows.
[1673] ESI-MS; m/z 496 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.25-1.34 (m, 3H), 2.04-2.15 (m, 1H), 2.28 (s, 3H),
2.46-2.60 (m, 1H), 3.91-4.03 (m, 1H), 4.01 (s, 3H), 4.20-4.36 (m,
2H), 6.88 (d, J=7.6 Hz, 1H), 6.94 (brs, 1H), 7.23-7.30 (m, 1H),
7.42 (d, J=7.6 Hz, 1H), 7.44-7.56 (m, 3H), 7.65-7.71 (m, 1H),
7.73-7.76 (m, 1H), 7.79-7.84 (m, 1H).
Examples 375 and 376
Synthesis of (R) and
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00286##
[1675] 60 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (250 mg) and 4-chloro-2-phenylbutyric acid
hydrazide hydrochloride (191 mg) by the same method as in Examples
253 and 254. The racemic title compound (60 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with a retention time of 13 minutes
(13 mg) and the title optically active compound with a retention
time of 23 minutes (15 mg).
[1676] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1677] ESI-MS; m/z 399 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.66-2.78 (m, 1H), 3.20-3.32
(m, 1H), 4.07 (s, 3H), 4.17-4.27 (m, 1H), 4.30-4.40 (m, 1H), 4.46
(dd, J=6.4, 8.4 Hz, 1H), 6.93-6.98 (m, 2H), 7.23-7.44 (m, 5H), 7.48
(d, J=8.0 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
[1678] The property values of the title optically active compound
with a retention time of 23 minutes are as follows.
[1679] ESI-MS; m/z 399 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.66-2.78 (m, 1H), 3.20-3.32
(m, 1H), 4.07 (s, 3H), 4.17-4.27 (m, 1H), 4.30-4.40 (m, 1H), 4.46
(dd, J=6.4, 8.4 Hz, 1H), 6.93-6.98 (m, 2H), 7.23-7.44 (m, 5H), 7.48
(d, J=8.0 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
Examples 377 and 378
Synthesis of (+) and
(-)-7-(4-fluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)p-
yridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00287##
[1681] 264 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
(800 mg) and 4-chloro-2-(4-fluorophenyl)butyric acid hydrazide
hydrochloride (807 mg) by the same method as in Examples 253 and
254. The racemic title compound (264 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 11 minutes (87 mg) and the title optically
active compound with negative optical rotation and a retention time
of 22 minutes (88 mg).
[1682] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[1683] ESI-MS; m/z 417 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.62-2.73 (m, 1H), 3.20-3.31
(m, 1H), 4.07 (s, 3H), 4.18-4.26 (m, 1H), 4.31-4.38 (m, 1H), 4.46
(dd, J=6.8, 8.4 Hz, 1H), 6.94-6.98 (m, 2H), 7.03-7.10 (m, 2H),
7.22-7.28 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H),
7.66 (d, J=15.6 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H).
[1684] The property values of the title optically active compound
with a retention time of 22 minutes are as follows.
[1685] ESI-MS; m/z 417 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.62-2.73 (m, 1H), 3.20-3.31
(m, 1H), 4.07 (s, 3H), 4.18-4.26 (m, 1H), 4.31-4.38 (m, 1H), 4.46
(dd, J=6.8, 8.4 Hz, 1H), 6.94-6.98 (m, 2H), 7.03-7.10 (m, 2H),
7.22-7.28 (m, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H),
7.66 (d, J=15.6 Hz, 1H), 7.78 (d, J=0.8 Hz, 1H).
Examples 379 and 380
Synthesis of (R) and
(S)-7-(3,4-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00288##
[1687] 71 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (500 mg) and 4-chloro-2-(3,4-difluorophenyl)butyric
acid hydrazide hydrochloride (500 mg) by the same method as in
Examples 253 and 254. The racemic title compound (71 mg) was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with a retention time of 11 minutes (20 mg) and the title optically
active compound with a retention time of 24 minutes (19 mg).
[1688] The property values of the title optically active compound
with a retention time of 11 minutes are as follows.
[1689] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.62-2.74 (m, 1H), 3.21-3.32 (m, 1H),
4.07 (s, 3H), 4.18-4.27 (m, 1H), 4.31-4.40 (m, 1H), 4.41-4.48 (m,
1H), 6.94-7.00 (m, 2H), 7.01-7.07 (m, 1H), 7.10-7.21 (m, 2H), 7.49
(d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
[1690] The property values of the title optically active compound
with a retention time of 24 minutes are as follows.
[1691] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.62-2.74 (m, 1H), 3.21-3.32 (m, 1H),
4.07 (s, 3H), 4.18-4.27 (m, 1H), 4.31-4.40 (m, 1H), 4.41-4.48 (m,
1H), 6.94-7.00 (m, 2H), 7.01-7.07 (m, 1H), 7.10-7.21 (m, 2H), 7.49
(d, J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz,
1H), 7.78 (d, J=1.2 Hz, 1H).
Examples 381 and 382
Synthesis of (+) and
(-)-7-(2,3-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00289##
[1693] 266 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
(1.0 g) and 4-chloro-2-(2,3-difluorophenyl)butyric acid hydrazide
hydrochloride (1.05 g) by the same method as in Examples 253 and
254. The racemic title compound (266 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 13 minutes (60 mg) and the title optically
active compound with negative optical rotation and a retention time
of 27 minutes (83 mg).
[1694] The property values of the title optically active compound
with a retention time of 13 minutes are as follows.
[1695] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.63-2.74 (m, 1H), 3.28-3.40 (m, 1H),
4.07 (s, 3H), 4.22-4.31 (m, 1H), 4.33-4.41 (m, 1H), 4.71 (dd,
J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 3H), 7.04-7.18 (m, 2H), 7.49 (d,
J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H),
7.78 (d, J=1.2 Hz, 1H).
[1696] The property values of the title optically active compound
with a retention time of 27 minutes are as follows.
[1697] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.63-2.74 (m, 1H), 3.28-3.40 (m, 1H),
4.07 (s, 3H), 4.22-4.31 (m, 1H), 4.33-4.41 (m, 1H), 4.71 (dd,
J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 3H), 7.04-7.18 (m, 2H), 7.49 (d,
J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H),
7.78 (d, J=1.2 Hz, 1H).
Examples 383 and 384
Synthesis of (+) and
(-)-7-(3,5-difluorophenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1--
yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00290##
[1699] 371 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (2.2 g) and 4-chloro-2-(3,5-difluorophenyl)butyric
acid hydrazide hydrochloride (1.7 g) by the same method as in
Examples 253 and 254. The racemic title compound (371 mg) was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=1:1) to obtain the title optically active compound
with positive optical rotation and a retention time of 14 minutes
(125 mg) and the title optically active compound with negative
optical rotation and a retention time of 35 minutes (134 mg).
[1700] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[1701] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.65-2.75 (m, 1H), 3.23-3.33
(m, 1H), 4.08 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40 (m, 1H),
4.42-4.49 (m, 1H), 6.73-6.80 (m, 1H), 6.81-6.89 (m, 2H), 6.95-7.01
(m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.66 (d,
J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).
[1702] The property values of the title optically active compound
with a retention time of 35 minutes are as follows.
[1703] ESI-MS; m/z 435 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.65-2.75 (m, 1H), 3.23-3.33
(m, 1H), 4.08 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40 (m, 1H),
4.42-4.49 (m, 1H), 6.73-6.80 (m, 1H), 6.81-6.89 (m, 2H), 6.95-7.01
(m, 2H), 7.49 (d, J=7.6 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.66 (d,
J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz, 1H).
Examples 385 and 386
Synthesis of (R) and
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-(2,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00291##
[1705] 120 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (500 mg) and
4-chloro-2-(2,4,5-trifluorophenyl)butyric acid hydrazide
hydrochloride (500 mg) by the same method as in Examples 253 and
254. The racemic title compound (120 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with a retention time of 9 minutes
(30 mg) and the title optically active compound with a retention
time of 22 minutes (28 mg).
[1706] The property values of the title optically active compound
with a retention time of 9 minutes are as follows.
[1707] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.58-2.70 (m, 1H), 3.27-3.38
(m, 1H), 4.08 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.39 (m, 1H),
4.59-4.66 (m, 1H), 6.94-7.04 (m, 3H), 7.09-7.17 (m, 1H), 7.49 (d,
J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H),
7.79 (d, J=1.2 Hz, 1H).
[1708] The property values of the title optically active compound
with a retention time of 22 minutes are as follows.
[1709] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=0.8 Hz, 3H), 2.58-2.70 (m, 1H), 3.27-3.38
(m, 1H), 4.08 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.39 (m, 1H),
4.59-4.66 (m, 1H), 6.94-7.04 (m, 3H), 7.09-7.17 (m, 1H), 7.49 (d,
J=7.6 Hz, 1H), 7.52 (d, J=15.6 Hz, 1H), 7.67 (d, J=15.6 Hz, 1H),
7.79 (d, J=1.2 Hz, 1H).
Examples 387 and 388
Synthesis of (+) and
(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-(2,3,4-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00292##
[1711] 226 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
(730 mg) and 4-chloro-2-(2,3,4-trifluorophenyl)butyric acid
hydrazide hydrochloride (794 mg) by the same method as in Examples
253 and 254. The racemic title compound (226 mg) was separated by
CHIRALPAK.TM. IB manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=1:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 14 minutes (52 mg) and the title optically
active compound with negative optical rotation and a retention time
of 25 minutes (78 mg).
[1712] The property values of the title optically active compound
with a retention time of 14 minutes are as follows.
[1713] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.60-2.71 (m, 1H), 3.28-3.39 (m, 1H),
4.07 (s, 3H), 4.22-4.30 (m, 1H), 4.32-4.40 (m, 1H), 4.66 (dd,
J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 4H), 7.49 (d, J=7.6 Hz, 1H), 7.51
(d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz,
1H).
[1714] The property values of the title optically active compound
with a retention time of 25 minutes are as follows.
[1715] ESI-MS; m/z 453 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.60-2.71 (m, 1H), 3.28-3.39 (m, 1H),
4.07 (s, 3H), 4.22-4.30 (m, 1H), 4.32-4.40 (m, 1H), 4.66 (dd,
J=6.8, 8.8 Hz, 1H), 6.94-7.02 (m, 4H), 7.49 (d, J=7.6 Hz, 1H), 7.51
(d, J=15.6 Hz, 1H), 7.66 (d, J=15.6 Hz, 1H), 7.79 (d, J=1.2 Hz,
1H).
Examples 389 and 390
Synthesis of (R) and
(S)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}--
7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00293##
[1717] 55 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
dihydrochloride (250 mg) and
4-chloro-2-(2-trifluoromethylphenyl)butyric acid hydrazide
hydrochloride (212 mg) synthesized from
(2-trifluoromethylphenyl)acetic acid by the same method as in
Examples 253 and 254. The racemic title compound (55 mg) was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=4:1) to obtain the title optically active compound
with a retention time of 16 minutes (12 mg) and the title optically
active compound with a retention time of 28 minutes (11 mg).
[1718] The property values of the title optically active compound
with a retention time of 16 minutes are as follows.
[1719] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.54-2.65 (m, 1H), 3.27-3.38 (m, 1H),
4.07 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.40 (m, 1H), 4.87 (dd,
J=8.0, 8.0 Hz, 1H), 6.93-6.99 (m, 2H), 7.09 (d, J=7.6 Hz, 1H),
7.39-7.45 (m, 1H), 7.46-7.57 (m, 3H), 7.65-7.75 (m, 2H), 7.79 (s,
1H).
[1720] The property values of the title optically active compound
with a retention time of 28 minutes are as follows.
[1721] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.54-2.65 (m, 1H), 3.27-3.38 (m, 1H),
4.07 (s, 3H), 4.20-4.30 (m, 1H), 4.31-4.40 (m, 1H), 4.87 (dd,
J=8.0, 8.0 Hz, 1H), 6.93-6.99 (m, 2H), 7.09 (d, J=7.6 Hz, 1H),
7.39-7.45 (m, 1H), 7.46-7.57 (m, 3H), 7.65-7.75 (m, 2H), 7.79 (s,
1H).
Examples 391 and 392
Synthesis of (R) and
(S)-7-(5-fluoro-2-trifluoromethylphenyl)-2-{(E)-2-[6-methoxy-5-(4-methyl--
1H-imidazol-1-yl)pyridin-2-yl]vinyl}-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]t-
riazole
##STR00294##
[1723] 151 mg of the racemic title compound was obtained from ethyl
(E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate
(550 mg) and 4-chloro-2-(5-fluoro-2-trifluoromethylphenyl)butyric
acid hydrazide hydrochloride (680 mg) by the same method as in
Examples 253 and 254. The racemic title compound (151 mg) was
separated by CHIRALPAK.TM. IB manufactured by Daicel Chemical
Industries, Ltd. (2 cm.times.25 cm; mobile phase:
hexane:ethanol=4:1) to obtain the title optically active compound
with a retention time of 18 minutes (46 mg) and the title optically
active compound with a retention time of 34 minutes (34 mg).
[1724] The property value of the title optically active compound
with a retention time of 18 minutes is as follows.
[1725] ESI-MS; m/z 485 [M.sup.++H].
[1726] The property values of the title optically active compound
with a retention time of 34 minutes are as follows.
[1727] ESI-MS; m/z 485 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.54-2.65 (m, 1H), 3.28-3.40 (m, 1H),
4.08 (s, 3H), 4.20-4.30 (m, 1H), 4.32-4.41 (m, 1H), 4.87 (t, J=7.6
Hz, 1H), 6.78-6.84 (m, 1H), 6.94-7.01 (m, 2H), 7.07-7.14 (m, 1H),
7.47-7.56 (m, 2H), 7.68 (d, J=15.6 Hz, 1H), 7.74 (dd, J=5.6, 8.8
Hz, 1H), 7.79 (brs, 1H).
Example 393
Synthesis of
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-ph-
enyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazol-7-ol
##STR00295##
[1729] 50 mg of the title compound was obtained by the same method
as in Examples 53 and 54 from the optically active compound
synthesized by the method in Examples 375 and 376 with a retention
time of 13 minutes,
2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-ph-
enyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole (112 mg). The
property value of the compound is as follows.
[1730] ESI-MS; m/z 415 [M.sup.++H].
Examples 394 and 395
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
8-(2-trifluoromethylphenyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyrid-
ine
##STR00296##
[1732] 230 mg of the racemic title compound was obtained from
1-amino-3-(2-trifluoromethylphenyl)piperidin-2-one (343 mg) and
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylic
acid (500 mg) by the same method as in Examples 194 and 195. The
racemic title compound (220 mg) was separated by CHIRALPAK.TM. IC
manufactured by Daicel Chemical Industries, Ltd. (2 cm.times.25 cm;
mobile phase: methanol) to obtain the title optically active
compound with positive optical rotation and a retention time of 16
minutes (92 mg) and the title optically active compound with
negative optical rotation and a retention time of 19 minutes (79
mg).
[1733] The property value of the title optically active compound
with a retention time of 16 minutes is as follows.
[1734] ESI-MS; m/z 481 [M.sup.++H].
[1735] The property values of the title optically active compound
with a retention time of 19 minutes are as follows.
[1736] ESI-MS; m/z 481 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 1.90-2.01 (m, 1H), 2.10-2.35 (m, 2H), 2.29 (s, 3H),
2.43-2.52 (m, 1H), 3.95 (s, 3H), 4.27-4.41 (m, 2H), 4.69 (dd,
J=6.0, 8.4 Hz, 1H), 7.02 (d, J=8.0 Hz, 1H), 7.08 (d, J=16.4 Hz,
1H), 7.40 (dd, J=7.6, 7.6 Hz, 1H), 7.44-7.53 (m, 4H), 7.73 (d,
J=8.0 Hz, 1H), 8.13 (d, J=1.6 Hz, 1H), 8.34 (s, 1H).
Examples 396 and 397
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
7-phenyl-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00297##
[1738] 167 mg of the racemic title compound was obtained from ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate
dihydrochloride (1.0 g) and 4-chloro-2-phenylbutyric acid hydrazide
hydrochloride (965 mg) by the same method as in Examples 255 and
256. The racemic title compound (167 mg) was separated by
CHIRALPAK.TM. AD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: ethanol) to obtain the title
optically active compound with positive optical rotation and a
retention time of 28 minutes (50 mg) and the title optically active
compound with negative optical rotation and a retention time of 42
minutes (47 mg).
[1739] The property values of the title optically active compound
with a retention time of 28 minutes are as follows.
[1740] ESI-MS; m/z 399 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.67-2.78 (m, 1H), 3.21-3.32 (m, 1H),
3.99 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40 (m, 1H), 4.46 (dd,
J=6.8, 8.8 Hz, 1H), 7.12 (d, J=16.0 Hz, 1H), 7.22-7.34 (m, 3H),
7.34-7.41 (m, 2H), 7.47-7.56 (m, 2H), 7.58 (d, J=16.0 Hz, 1H), 8.16
(d, J=1.6 Hz, 1H), 8.36 (s, 1H).
[1741] The property values of the title optically active compound
with a retention time of 42 minutes are as follows.
[1742] ESI-MS; m/z 399 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (s, 3H), 2.67-2.78 (m, 1H), 3.21-3.32 (m, 1H),
3.99 (s, 3H), 4.18-4.27 (m, 1H), 4.32-4.40 (m, 1H), 4.46 (dd,
J=6.8, 8.8 Hz, 1H), 7.12 (d, J=16.0 Hz, 1H), 7.22-7.34 (m, 3H),
7.34-7.41 (m, 2H), 7.47-7.56 (m, 2H), 7.58 (d, J=16.0 Hz, 1H), 8.16
(d, J=1.6 Hz, 1H), 8.36 (s, 1H).
Examples 398 and 399
Synthesis of (+) and
(-)-2-{(E)-2-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]vinyl}--
7-(2-trifluoromethylphenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole
##STR00298##
[1744] 230 mg of the racemic title compound was obtained from ethyl
(E)-3-[5-methoxy-6-(4-methyl-1H-imidazol-1-yl)pyridin-3-yl]acrylimidate
dihydrochloride (1.0 g) and
4-chloro-2-(2-trifluoromethylphenyl)butyric acid hydrazide
hydrochloride (1.17 g) by the same method as in Examples 255 and
256. The racemic title compound (230 mg) was separated by
CHIRALCEL.TM. OD-H manufactured by Daicel Chemical Industries, Ltd.
(2 cm.times.25 cm; mobile phase: hexane:ethanol=4:1) to obtain the
title optically active compound with positive optical rotation and
a retention time of 29 minutes (41 mg) and the title optically
active compound with negative optical rotation and a retention time
of 33 minutes (43 mg).
[1745] The property values of the title optically active compound
with a retention time of 29 minutes are as follows.
[1746] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.54-2.65 (m, 1H), 3.28-3.38
(m, 1H), 3.99 (s, 3H), 4.20-4.29 (m, 1H), 4.32-4.40 (m, 1H), 4.87
(t, J=7.8 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.13 (d, J=16.4 Hz, 1H),
7.42 (dd, J=7.6, 7.6 Hz, 1H), 7.47-7.55 (m, 3H), 7.57 (d, J=16.4
Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.36 (d,
J=1.2 Hz, 1H).
[1747] The property values of the title optically active compound
with a retention time of 33 minutes are as follows.
[1748] ESI-MS; m/z 467 [M.sup.++H]. .sup.1H-NMR (CDCl.sub.3)
.delta. (ppm): 2.30 (d, J=1.2 Hz, 3H), 2.54-2.65 (m, 1H), 3.28-3.38
(m, 1H), 3.99 (s, 3H), 4.20-4.29 (m, 1H), 4.32-4.40 (m, 1H), 4.87
(t, J=7.8 Hz, 1H), 7.09 (d, J=8.0 Hz, 1H), 7.13 (d, J=16.4 Hz, 1H),
7.42 (dd, J=7.6, 7.6 Hz, 1H), 7.47-7.55 (m, 3H), 7.57 (d, J=16.4
Hz, 1H), 7.73 (d, J=8.0 Hz, 1H), 8.17 (d, J=1.6 Hz, 1H), 8.36 (d,
J=1.2 Hz, 1H).
Reference Example 5
[1749] Another Example of method for preparation of the compound of
the Example 195.
Synthesis of 5-Chloro-2-(2-trifluoromethylphenyl)pentanenitrile
##STR00299##
[1751] (2-Trifluoromethylphenyl)acetonitrile (12.47 g, 67.3 mmol)
was dissolved in THF (87.3 mL) at room temperature under nitrogen
atmosphere. The reaction solution was cooled to -10.degree. C.
Then, potassium tert-butoxide (7.93 g, 70.7 mmol) was added to the
reaction solution and the reaction mixture was stirred at
-10.degree. C. for 10 minutes. 1-Bromo-3-chloropropane (6.99 mL,
70.7 mmol) was added dropwise to the reaction mixture over 14
minutes, and the reaction mixture was stirred at 0.degree. C. for 2
hours. The reaction was quenched with 10% NH.sub.4Cl aq. (8.6 mL).
After the mixture was stirred, the aqueous layer was separated. The
organic layer was concentrated under the reduced pressure to obtain
the title compound (23.24 g). The yield was calculated as over 99%
by HPLC external standard method.
[1752] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 2.18-1.88
(m, 4H), 3.58 (m, 2H), 4.18 (m, 1H), 7.47 (t, 1H, J=7.6 Hz), 7.65
(t, 1H, J=7.6 Hz), 7.71 (m, 2H).
Synthesis of Ethyl
5-chloro-2-(2-trifluoromethylphenyl)pentanimidoate
hydrochloride
##STR00300##
[1754] 5-Chloro-2-(2-trifluoromethylphenyl)pentanenitrile (2.0 g,
7.64 mmol) was dissolved in ethanol (5.36 mL, 91.72 mmol) at room
temperature under nitrogen atmosphere. Then, the solution was
cooled to 0.degree. C. Acetyl chloride (4.34 mL, 61.14 mmol) was
added dropwise to the solution, and the reaction mixture was
stirred at room temperature for 67 hours. The reaction mixture was
cooled to 10.degree. C. Traces of seed crystal of the title
compound which was obtained by the method similar to this step and
tert-butylmethylether (hereinafter referred to as "MTBE") (40 mL)
were added to the reaction mixture and the reaction mixture was
stirred. The solid was collected by filtration, washed with MTBE to
obtain the title compound (2.14 g, 81.6% yield).
[1755] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 1.38 (t,
3H, J=7.2 Hz), 1.78-1.65 (m, 1H), 1.95-1.83 (m, 1H), 2.43-2.32 (m,
1H), 2.65-2.50 (m, 1H), 3.62-3.55 (m, 2H), 4.47 (t, 1H, J=8 Hz),
4.65 (q, 2H, J=7.2 Hz), 7.47 (t, 1H, J=8.0 Hz), 7.66 (t, 1H, J=8.0
Hz), 7.71 (d, 1H, J=8.0 Hz), 7.85 (d, 1H, J=8.0 Hz), 12.05 (brs,
1H), 12.58 (brs, 1H).
Synthesis of tert-Butyl
2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-eno-
yl}hydrazinecarboxylate
##STR00301##
[1757] DMF (52 mL) was added to the
6-Bromo-2-methoxy-3-(4-methyl-1H-imidazol-1-yl)pyridine (13.0 g,
48.5 mmol) and the tert-Butyl 2-acryloylhydrazinecarboxylate (9.9
g, 53.3 mmol) at room temperature under nitrogen atmosphere, And
the mixture was stirred at 50.degree. C. for 10 minutes.
Tri(o-tolyl)phosphine (885 mg, 2.90 mmol), Palladium (II) acetate
(327 mg, 1.45 mmol) and N,N-diisopropylethylamine (12.7 mL, 72.7
mmol) were added to the mixture, and the reaction mixture was
stirred at 100.degree. C. for 4 hours. The reaction mixture was
cooled to room temperature and filtrated through Celite. The
residue was washed twice with DMF (6 mL). Water (104 mL) was added
dropwise to the filtrate at room temperature over 10 minutes. The
mixture was stirred at room temperature for 15 hours. After the
mixture was filtrated, the residue was washed with water/DMF=2:1(30
mL) and MTBE (30 mL). The obtained solid was suspended in MTBE (50
mL) at room temperature for 2 hours, filtrated and dried under the
reduced pressure to obtain the title compound (15.8 g, 87%
yield).
[1758] .sup.1H-NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 1.50 (s,
9H), 2.28 (d, J=1.2 Hz, 3H), 4.03 (s, 3H), 6.83 (brs, 1H),
6.97-7.02 (m, 3H), 7.51 (d, J=8.0 Hz, 1H), 7.59 (d, J=15.2 Hz, 1H),
7.82 (s, 1H), 8.01 (br s, 1H).
Synthesis of
(2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazi-
de dihydrochloride
##STR00302##
[1760] Conc. HCl (5.85 mL) was added to the suspension of
tert-Butyl
2-{(2E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]prop-2-eno-
yl}hydrazinecarboxylate (1.17 g, 3.13 mmol) in methanol (5.85 mL)
with an ice-bath cooling. The reaction mixture was stirred at room
temperature for 30 minutes. 1-Butanol (5.85 mL) and MTBE (5.85 mL)
were added to the reaction mixture, and the mixture was stirred for
20 minutes with an ice-bath cooling. The mixture was filtrated, and
the residue was washed with 1-butanol-MTBE (2:8) (5.85 mL) and
dried under the reduced pressure to obtain the title compound (937
mg, 78.2% yield).
[1761] .sup.1H NMR (100 MHz, d.sub.6-DMSO) .delta. (ppm): 2.36 (d,
J=0.8 Hz, 3H), 3.82 (brs, 2H), 4.04 (s, 3H), 7.28 (d, J=15.2 Hz,
1H), 7.54 (d, J=8.0 Hz, 1H), 7.70 (d, J=15.2 Hz, 1H), 7.83 (d,
J=1.6 Hz, 1H), 8.15 (d, J=7.6 Hz), 9.44 (d, J=1.6 Hz, 1H), 11.56
(s, 1H).
Synthesis of
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-8-[2-
-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridin-
e
##STR00303##
[1763] Imidazole (4.75 g, 69.7 mmol) and Ethyl
5-chloro-2-(2-trifluoromethylphenyl)pentanimidoate hydrochloride
(2.00 g, 5.81 mmol) were added the solution of
(2E)-3-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylohydrazi-
de dihydrochloride in methanol (10 mL) at 0.degree. C. under
nitrogen atmosphere. The reaction mixture was stirred at 30.degree.
C. for 40 hours. The reaction mixture was adjusted to the pH6.5
with 5N HCl aq., and extracted with ethyl acetate (22 mL). The
organic layer was washed with water (4 mL), concentrated under the
reduced pressure and azeotroped with 2-propanol under the reduced
pressure to obtain the title compound (2.4 g, 86% yield). Traces of
seed crystal of the title compound which was obtained by the method
similar to this step was added to the solution of the crude title
compound in 2-propanol (10 mL), and the mixture was stirred at room
temperature for 13.5 hours. The suspension was stirred for 2 hours
with an ice-bath cooling. The solids were collected by filtration
and washed with 2-propanol and dried under the reduced pressure to
obtain the title compound (1.55 g, 56% yield).
[1764] .sup.1H-NMR (CDCl.sub.3) .delta. (ppm): 1.90-2.01 (m, 1H),
2.10-2.35 (m, 2H), 2.29 (d, J=1.2 Hz, 3H), 2.42-2.51 (m, 1H), 4.03
(s, 3H), 4.28-4.41 (m, 2H), 4.70 (dd, J=8.4, 6.0 Hz, 1H), 6.92 (d,
J=8.0 Hz, 1H), 6.95 (t, J=1.2 Hz, 1H), 7.01 (d, J=7.6 Hz, 1H), 7.39
(t, J=7.6 Hz, 1H), 7.44 (d, J=16.0 Hz, 1H), 7.45 (d, J=8.0 Hz, 1H),
7.49 (t, J=7.6 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.72 (d, J=7.6 Hz,
1H), 7.76 (d, J=1.2 Hz, 1H).
Synthesis of
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-
-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine (2S,3S)-2,3-bis(benzoyloxy)succinate (1/1)
##STR00304##
[1766]
2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl-
}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]py-
ridine (100 mg, 0.208 mmol) was dissolved in the mixture of
2-propanol (1.6 mL) and acetonitrile (2.0 mL) at 45.degree. C., and
the solution of (2S,3S)-2,3-bis(benzoyloxy)succinic acid (D-DBTA)
(89.5 mg, 0.250 mmol) in acetonitrile (1.6 mL) was added. Traces of
seed crystal of the title compound which was obtained by the method
similar to this step was added to the solution at 33.degree. C.,
and the mixture was stirred at room temperature for 18 hours. The
solids were collected by filtration, washed with
acectonitrile/2-propanol=2/1 (0.5 mL) and dried at 50.degree. C.
under the reduced pressure to obtain the title compound (62.3 mg,
35.7% yield, 90.7% de). The title compound (50.7 mg, 90.7% de) was
suspended in acectonitrile/2-propanol=1/1 (0.5 mL), and the mixture
was stirred at 80.degree. C. for 25 minutes, and then stirred at
room temperature for 15 hours. The solids were collected by
filtration and dried at 50.degree. C. under the reduced pressure to
obtain the title compound (35.9 mg, 70.8% yield, 98.1% de)
[1767] .sup.1H NMR (400 MHz, CDCl.sub.3) .delta. (ppm): 1.90-2.00
(1H, m), 2.12-2.20 (1H, m), 2.15 (3H, s), 2.27-2.32 (2H, m), 3.98
(3H, s), 4.27-4.31 (2H, m), 4.48-4.52 (1H, dd, J=5.9, 9.5 Hz), 5.84
(2H, s), 7.24-7.34 (4H, m), 7.44-7.51 (2H, m), 7.56-7.63 (5H, m),
7.69-7.80 (4H, m), 7.96-8.00 (5H, m).
Synthesis of
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-
-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine
##STR00305##
[1769]
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-
vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-
-a]pyridine (2S,3S)-2,3-bis(benzoyloxy)succinate (1/1) (20 mg,
0.024 mmol) was added to the mixed solution of ethyl acetate (0.1
mL) and 5N HCl aq. (0.1 mL), and the organic layer was separated.
Ethyl acetate (0.2 mL) and 5N sodium hydrate aq. (0.1 mL) were
added to the aqueous layer, and the organic layer was separated.
The organic layer was washed twice with water (0.1 mL), and dried
under the reduced pressure to obtain the title compound (11.5 mg,
99.9% yield).
Synthesis of
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-
-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyr-
idine (2S,3S)-tartarate (2/3)
##STR00306##
[1771]
(8S)-2-{(E)-2-[6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]-
vinyl}-8-[2-(trifluoromethyl)phenyl]-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-
-a]pyridine and D-tartaric acid (48.4 mg, 0.323 mmol) were solved
in 1-butanol (2.0 mL) at 70.degree. C. The solution was cooled to
60.degree. C., and then 1-butanol (1.0 mL) was added. The mixture
was stirred at 8.degree. C. for 11 hours. The solids were collected
by filtration, washed with 1-butanol/n-heptan=1/2 (5.0 mL) and
dried at 50.degree. C. for 3 hours to obtain the title compound
(127.1 mg, 86.6% yield).
[1772] .sup.1H-NMR (400 MHz, DMSO-d.sub.6) .delta. (ppm): 1.94-1.99
(1H, m), 2.14 (3H, d, J=1.0 Hz), 2.14-2.17 (2H, m), 2.27-2.32 (1H,
m), 3.98 (3H, s), 4.26-4.31 (2H, m), 4.29 (3H, s), 4.48-4.52 (1H,
m), 7.22-7.33 (4H, m), 7.43-7.51 (2H, m), 7.59-7.63 (1H, m),
7.56-7.79 (2H, m), 7.90 (1H, d, J=1.0 Hz).
Test Example 1
Quantification of A.beta. Peptide in Culture of Neurons from Rat
Fetus Brain
[1773] The present inventors performed the following tests in order
to exhibit utility of the compound of the general formula (I) of
the present invention.
(1) Rat Primary Neuronal Culture
[1774] Primary neuronal cultures were prepared from the cerebral
cortex of embryonic day 18 Wistar rats (Charles River Japan,
Yokohama, Japan). Specifically, the embryos were aseptically
removed from pregnant rats under ether anesthesia. The brain was
isolated from the embryo and immersed in an ice-cold L-15 medium
(Invitrogen Corp. Cat #11415-064, Carlsbad, Calif., USA, or SIGMA
L1518, for example). The cerebral cortex was collected from the
isolated brain under a stereoscopic microscope. The cerebral cortex
fragments collected were enzymatically treated in an enzyme
solution containing 0.25% trypsin (Invitrogen Corp. Cat #15050-065,
Carlsbad, Calif., USA) and 0.01% DNase (Sigma D5025, St. Louis,
Mo., USA) at 37.degree. C. for 30 minutes to disperse the cells.
Here, the enzymatic reaction was stopped by adding inactivated
horse serum to the solution. The enzymatically treated solution was
centrifuged at 1,500 rpm for five minutes to remove the
supernatant. 5 to 10 ml of a medium was added to the resulting cell
mass. Neurobasal medium (Invitrogen Corp. Cat #21103-049, Carlsbad,
Calif., USA) supplemented with 2% B27 supplement (Invitrogen Corp.
Cat #17504-044, Carlsbad, Calif., USA), 25 .mu.M 2-mercaptoethanol
(2-ME, WAKO Cat #139-06861, Osaka, Japan), 0.5 mM L-glutamine
(Invitrogen Corp. Cat #25030-081, Carlsbad, Calif., USA), and
Antibiotics-Antimycotics (Invitrogen Corp. Cat #15240-062,
Carlsbad, Calif., USA) was used as the medium
(Neurobasal/B27/2-ME). However, the above Neurobasal medium not
supplemented with 2-ME (Neurobasal/B27) was used for the assay. The
cells were redispersed by mild pipetting of the cell mass to which
the medium was added. The cell dispersion was filtered through a
40-.mu.m nylon mesh (Cell Strainer, Cat #35-2340, Becton Dickinson
Labware, Franklin Lakes, N.J., USA) to remove the remaining cell
mass, and thus a neuronal cell suspension was obtained. The
neuronal cell suspension was diluted with the medium and then
plated in a volume of 100 .mu.l/well at an initial cell density of
5.times.10.sup.5 cells/cm.sup.2 in a 96-well polystyrene culture
plate pre-coated with poly-L or D-lysine (Falcon Cat #35-3075,
Becton Dickinson Labware, Franklin Lakes, N.J., USA coated with
poly-L-lysine using the method shown below, or BIOCOAT.TM. cell
environments Poly-D-lysine cell ware 96-well plate, Cat #35-6461,
Becton Dickinson Labware, Franklin Lakes, N.J., USA). Poly-L-lysine
coating was carried out as follows. 100 .mu.g/ml of a poly-L-lysine
(SIGMA P2636, St. Louis, Mo., USA) solution was aseptically
prepared with a 0.15 M borate buffer (pH 8.5). 100 .mu.l/well of
the solution was added to the 96-well polystyrene culture plate and
incubated at room temperature for one or more hours or at 4.degree.
C. overnight or longer. The coated 96-well polystyrene culture
plate was washed with sterile water four or more times, and then
dried or rinsed with, for example, sterile PBS or medium, and used
for cell plating. The plated cells were cultured in the culture
plate at 37.degree. C. in 5% CO.sub.2-95% air for one day. Then,
the total amount of the medium was replaced with a fresh
Neurobasal.TM./B27/2-ME medium, and then the cells were cultured
for further three days.
Addition of Compounds
[1775] The drug was added to the culture plate on Day 4 of culture
as follows. The total amount of the medium was removed from the
wells, and 180 .mu.l/well of Neurobasal medium not containing 2-ME
and containing 2% B-27 (Neurobasal/B27) was added thereto. A
solution of the test compound in dimethyl sulfoxide (hereinafter
abbreviated as DMSO) was diluted with Neurobasal/B27 at 10-fold of
the final concentration. 20 .mu.l/well of the dilution was added to
and sufficiently mixed with the medium. The final DMSO
concentration was 1% or less. Only DMSO was added to the control
group.
Sampling
[1776] The cells were cultured for three days after addition of the
compound, and the total amount of the medium was collected. The
resulting medium was used as an ELISA sample. The sample was not
diluted for ELISA measurement of A.beta.x-42 and diluted to 5-fold
with a diluent supplied with an ELISA kit for ELISA measurement of
A.beta.x-40.
Evaluation of Cell Survival
[1777] Cell survival was evaluated by an MTT assay according to the
following procedure. After collecting the medium, 100 .mu.l/well of
a pre-warmed medium was added to the wells. Further, 8 .mu.l/well
of a solution of 8 mg/ml of MTT (SIGMA M2128, St. Louis, Mo., USA)
in D-PBS(-) (Dulbecco's phosphate buffered Saline, SIGMA D8537, St.
Louis, Mo., USA) was added to the wells. The 96-well polystyrene
culture plate was incubated in an incubator at 37.degree. C. in 5%
CO.sub.2-95% air for 20 minutes. 100 .mu.l/well of an MTT lysis
buffer was added thereto, and MTT formazan crystals were
sufficiently dissolved in the buffer in the incubator at 37.degree.
C. in 5% CO.sub.2-95% air. Then, the absorbance at 550 nm in each
well was measured. The MTT lysis buffer was prepared as follows.
100 g of SDS (sodium dodecyl sulfate (sodium lauryl sulfate), WAKO
191-07145, Osaka, Japan) was dissolved in a mixed solution of 250
mL of N,N-dimethylformamide (WAKO 045-02916, Osaka, Japan) with 250
mL of distilled water. 350 .mu.l each of concentrated hydrochloric
acid and concentrated acetic acid were further added to the
solution to allow the solution to have a final pH of about 4.7.
[1778] Upon measurement, wells having no cells plated and
containing only the medium and MTT solution were set as background
(bkg). The measured values were respectively applied to the
following formula including subtracting bkg values from them. Thus,
the proportion against the control group (group not treated with
the drug, CTRL) (% of CTRL) was calculated to compare and evaluate
cell survival activities.
% of CTRL=((A550_sample-A550_bkg)/(A550-CTRL-bkg)).times.100
(A550_sample: absorbance at 550 nm of sample well, A550_bkg:
absorbance at 550 nm of background well, A550STRL: absorbance at
550 nm of control group well)
A.beta. ELISA
[1779] For A.beta. ELISA, Human/Rat .beta. Amyloid (42) ELISA Kit
Wako (#290-62601) from Wako Pure Chemical Industries, Ltd. or Human
Amyloid beta (1-42) Assay Kit (#27711) from IBL Co., Ltd. was used.
A.beta. ELISA was carried out according to the protocols
recommended by the manufacturers (methods described in the attached
documents). However, the A.beta. calibration curve was created
using beta-amyloid peptide 1-42, rat (Calbiochem, #171596
[A.beta..sub.42]). The results are shown in Table 1 as percentage
to the A.beta. concentration in the medium of the control group (%
of CTRL).
(2) The measurement results are shown in Tables 9, 10, 11 and 12 as
percentage to the A.beta. concentration in the medium of the
control group (% of CTRL).
TABLE-US-00009 TABLE 9 A.beta.42 production reducing effect Test
compound IC50 (nM) Example 2 28 Example 3 48 Example 5 21 Example 7
30 Example 10 33 Example 12 135 Example 19 43 Example 20 30 Example
22 25 Example 24 12 Example 45 30 Example 55 28 Example 59 45
Example 61 31 Example 72 26 Example 80 29 Example 94 52 Example 96
63 Example 97 38 Example 99 20 Example 102 20 Example 103 32
Example 106 39 Example 108 29 Example 110 33 Example 114 51 Example
116 173 Example 133 65 Example 141 36 Example 143 41 Example 150
41
TABLE-US-00010 TABLE 10 A.beta.42 production reducing effect Test
compound IC50 (nM) Example 156 48 Example 165 115 Example 169 22
Example 171 17 Example 173 37 Example 175 38 Example 179 22 Example
183 48 Example 185 34 Example 187 38 Example 189 43 Example 193 80
Example 195 17 Example 199 23 Example 207 28 Example 209 20 Example
212 100 Example 215 74 Example 218 69 Example 229 169 Example 232
33 Example 233 42 Example 236 39 Example 243 50 Example 246 39
Example 247 45 Example 250 44 Example 252 146 Example 254 50
Example 262 74 Example 271 57
TABLE-US-00011 TABLE 11 A.beta.42 production reducing effect Test
compound IC50 (nM) Example 280 18 Example 282 29 Example 283 27
Example 286 8 Example 287 24 Example 290 16 Example 294 26
TABLE-US-00012 TABLE 12 A.beta.42 production reducing effect Test
compound IC50 (nM) Example 311 11 Example 317 25 Example 319 15
Example 321 23 Example 327 20 Example 329 17 Example 331 22 Example
333 10 Example 337 13 Example 339 21 Example 354 37 Example 361 12
Example 362 9 Example 365 21 Example 368 25 Example 371 27 Example
373 29 Example 376 28 Example 380 29 Example 384 36 Example 390 26
Example 392 22
[1780] The results from Tables 9, 10, 11 and 12 confirmed that the
compound of the present invention has an A.beta.42 production
reducing effect.
[1781] Accordingly, the compound of the general formula (I) or
pharmaceutically acceptable salt thereof according to the present
invention have an A.beta.42 production reducing effect. Thus, the
present invention can particularly provide a prophylactic or
therapeutic agent for a neurodegenerative disease caused by A.beta.
such as Alzheimer's disease or Down's syndrome.
[1782] The compound of the general formula (I) of the present
invention has an A.beta.40 and A.beta.42 production reducing
effect, and thus is particularly useful as a prophylactic or
therapeutic agent for a neurodegenerative disease caused by A.beta.
such as Alzheimer's disease or Down's syndrome.
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