U.S. patent application number 10/811989 was filed with the patent office on 2004-09-16 for sulfonamide compounds and pharmaceutical use thereof.
This patent application is currently assigned to Fujisawa Pharmaceutical Co., Ltd.. Invention is credited to Abe, Yoshito, Hamashima, Hitoshi, Hiramura, Takahiro, Imoto, Takafumi, Kayakiri, Hiroshi, Mizutani, Tsuyoshi, Nishikawa, Masahiro, Oku, Teruo, Onomura, Osamu, Sawada, Hitoshi, Yamasaki, Noritsugu.
Application Number | 20040180947 10/811989 |
Document ID | / |
Family ID | 26453401 |
Filed Date | 2004-09-16 |
United States Patent
Application |
20040180947 |
Kind Code |
A1 |
Kayakiri, Hiroshi ; et
al. |
September 16, 2004 |
Sulfonamide compounds and pharmaceutical use thereof
Abstract
A sulfonamide compound of the formula (I):
R.sup.1--SO.sub.2NHCO-A-X--R.sup.2 (I) wherein R.sup.1 is alkyl,
alkenyl, alkynyl and the like; A is an optionally substituted
heteropolycylic group except benzimidazolyl, indolyl,
4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl; X is
alkylene, oxa, oxa(lower)alkylene and the like; and R.sup.2is
optionally substituted aryl, substituted biphenylyl and the like, a
salt thereof and a pharmaceutical composition comprising the same.
The sulfonamide compound is effective for the diseases treatable
based on their blood sugar level-depressing activity, cGMP-PDE
(especially PDE-V)-inhibiting activity, smooth muscle relaxing
activity, bronchodilating activity, vasodilating activity, smooth
muscle cell suppressing activity, and antiallergic activity.
Inventors: |
Kayakiri, Hiroshi;
(Suita-shi, JP) ; Abe, Yoshito; (Tsukuba-shi,
JP) ; Hamashima, Hitoshi; (Kyoto-shi, JP) ;
Sawada, Hitoshi; (Tsukuba-shi, JP) ; Mizutani,
Tsuyoshi; (Tsukuba-shi, JP) ; Oku, Teruo;
(Takatsuki-shi, JP) ; Yamasaki, Noritsugu;
(Himeji-shi, JP) ; Onomura, Osamu; (Nagasaki-shi,
JP) ; Nishikawa, Masahiro; (Arai-shi, JP) ;
Hiramura, Takahiro; (Arai-shi, JP) ; Imoto,
Takafumi; (Arai-shi, JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Fujisawa Pharmaceutical Co.,
Ltd.
Osaka-shi
JP
|
Family ID: |
26453401 |
Appl. No.: |
10/811989 |
Filed: |
March 30, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10811989 |
Mar 30, 2004 |
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10047093 |
Jan 17, 2002 |
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10047093 |
Jan 17, 2002 |
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09446110 |
Feb 14, 2000 |
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6348474 |
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09446110 |
Feb 14, 2000 |
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PCT/JP98/02877 |
Jun 24, 1998 |
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Current U.S.
Class: |
514/444 ;
514/447; 549/59; 549/69 |
Current CPC
Class: |
C07D 333/54 20130101;
C07D 487/04 20130101; C07D 405/12 20130101; C07D 471/04 20130101;
C07D 249/18 20130101; C07D 241/52 20130101; C07D 495/04 20130101;
C07D 307/79 20130101; C07D 239/96 20130101; C07D 409/12 20130101;
C07D 231/56 20130101; C07D 215/48 20130101; C07D 333/62
20130101 |
Class at
Publication: |
514/444 ;
514/447; 549/059; 549/069 |
International
Class: |
A61K 031/381; C07D
49/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 27, 1997 |
JP |
208295/1997 |
Apr 24, 1998 |
JP |
114718/1998 |
Claims
What is claimed is:
1. A sulfonamide compound of the formula (I):
R.sup.1--SO.sub.2NHCO-A-X--R (I) wherein R.sup.1 is an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cyclo(lower)alkyl,
an optionally substituted aryl or an optionally substituted
heterocyclic group; A is an optionally substituted heteropolycyclic
group except benzimidazolyl, indolyl, 4,7-dihydrobenzimidazolyl and
2,3-dihydrobenzoxazinyl; X is an allylene, an oxa, an
oxa(lower)alkylene, a lower alkylene-oxa, a carbonyl, a lower
alkenylene, an optionally substituted imino, an optionally
N-substituted imino(lower)alkylene, an optionally N-substituted
lower alkyleneimino, a thioxa(lower)-alkylene or a lower
alkylenethioxa; and R.sup.2 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl; provided that when a is 3H-imidazo[4,5-b]pyridyl
substituted by lower alkyl, R.sup.2 is an optionally substituted
aryl, an optionally substituted heterocyclic group or a biphenylyl
substituted by a group other than tetrazolyl, and when A is
quinolyl substituted by lower alkyl, R.sup.2is an optionally
substituted aryl, an optionally substituted heterocyclic group, or
a biphenylyl substituted by at least one group selected from the
group consisting of alkyl, cyclo(lower)alkyl, alkenyl, allynyl,
lower alknoyl, lower alkoxy, phenyl, heterocyle(lower)alkyl other
than substituted tetrazlylmethyl, halogen, amino, substituted
amino, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio,
cyano, carbamoyl, monolower)alkylcarbamoyl,
di(lower)alkylcarbamoyl, nitro, halo(lower)alkyl, aryl(lower)alkyl,
aryl(lower)alkenyl, aryl(lower)alkoxy, lower alkoxy substituted by
substituted amino, cyclo(lower)alkyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycle-oxy(lower)alk- yl, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group, or a salt
thereof:
2. The sulfonamide compound of claim 1, wherein, R.sup.1 is an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cyclo(lower)alkyl, an optionally substituted aryl or an optionally
substituted heterocyclic group, wherein, when these groups are
substituted, the substituent is at least one member selected from
the group consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl,
lower alkanoyl, lower alkoxy, aryl, heterocycle(lower)alkyl,
halogen, amino, substituted amino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carboxy, protected carboxy,
carbamoyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl,
nitro, halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycleoxy(lower)alkyl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group; A is a heteropolycyclic group having at least
one hetero atom of oxygen atom, sulfur atom, selenium atom and
nitrogen atom, exclusive of benzimidazolyl, indolyl,
4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl, said
heterocyclic group being optionally substituted by at least one
member selected from the group consisting of alkyl, oxo, thioxo,
halogen, lower alkoxy, lower alkylthio, cyclo(lower)alkyl,
optionally substituted amino, aryl, heterocyclic group, lower
alkylsulfonyl and lower alkylsulfinyl; and R.sup.2 is an optionally
substituted aryl, an optionally substituted heterocyclic group or a
substituted biphenylyl, wherein, when these groups are substituted,
the substituent is at least one member selected from the group
consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl, lower
alkanoyl, lower alkoxy, aryl, heterocycle(lower)alkyl, halogen,
amino, substituted amino, lower alkylsulfonyl, lower alkylsulfinyl,
lower alkylthio, cyano, carboxy, protected carboxy, carbamoyl,
mono(lower)alkylcarbamoyl, di(lower) alkylcarbamoyl, nitro,
halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycleoxy(lower)alkyl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group; provided that when A is
3H-imidazo[4,5-b]pyridyl substituted by lower alkyl, R.sup.2 is
optionally substituted aryl, optionally substituted heterocyclic
group or biphenylyl substituted by a substituent other than
tetrazolyl, and when A is quinolyl substituted by lower alkyl,
R.sup.2 is optionally substituted aryl, optionally substituted
heterocyclic group or substituted biphenylyl, when the
above-mentioned aryl and heterocyclic group are substituted, the
substituent is at least one member selected from the group
consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl, lower
alkanoyl, lower alkoxy, phenyl, heterocycle(lower)alkyl, halogen,
amino, substituted amino, lower alkylsulfonyl, lower alkylsulfinyl,
lower alkylthio, cyano, carboxy, protected carboxy, carbamoyl,
mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl, nitro,
halo(lower)alkyl, arylpower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxypower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono-
or dipower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycle-oxy(lower)alkyl, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group, and the substituent
for the above-mentioned biphenylyl is at least one member selected
from the group consisting of alkyl, cyclo(lower)alkyl, alkenyl,
alkynyl, lower alkanoyl, lower alkoxy, phenyl,
heterocycle(lower)alkyl other than substituted tetrazlylmethyl,
halogen, amino, substituted amino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carbamoyl,
-mono(lower)alkylcarbam- oyl, di(lower)alkylcarbamoyl, nitro,
halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alkyl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group, or a salt thereof.
3. The sulfonamide compound of claim 2, wherein, R.sup.1 is an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cyclo(lower)alkyl, an optionally substituted phenyl or an
optionally substituted heterocyclic group, wherein, when these
groups are substituted, the substituent is at least one member
selected from the group consisting of alkyl, cyclo(lower)alkyl,
alkenyl, alkynyl, lower alkanoyl, lower alkoxy, phenyl,
heterocyclepower)alkyl, halogen, amino, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)a- lkylamino,
arylsulfonylamino, arylcarbonylamino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carboxy, protected carboxy,
carbamoyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl,
nitro, halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
arylpower)alkoxy, lower alkanoylamino(lower)alkoxy,
mono(lower)alkylamino(lower)alkoxy,
di(lower)alkylamino(lower)alkoxy,
N-power)alkyl-N-acylamino(lower)alkoxy, lower
alkylsulfonylaminopower)alkoxy, aryl(lower)alkylamino(lower)alkoxy,
N-heterocycle-N-(lower)alkylamino(lower)alkoxy,
arylsulfonylamino(lower)a- lkoxy, arylcarbonylamino(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxypower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alkyl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group; and A is a heterodicyclic group of the
following (A) to (I) exclusive of benzimidazolyl, indolyl,
4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl, wherein said
heterocyclic group is optionally substituted by at least one member
selected from the group consisting of alkyl, oxo, thioxo, halogen,
lower alkoxy, lower alkylthio, cyclo(lower)alkyl, amino, lower
alkanoylamino, mono(lower)alkylamino, di(lower)alkylamino,
N-power)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)alkylamino,
arylsulfonylamino, arylcarbonylamino, aryl, heterocyclic group,
lower alkylsulfonyl and lower alkylsulfinyl, provided that when A
is 3H-imidazo[4,5-b]pyridyl substituted by lower alkyl, R.sup.2 is
an optionally substituted aryl, optionally substituted heterocyclic
group or biphenylyl substituted by a group other than tetrazolyl,
and when A is quinolyl substituted by lower alkyl, R.sup.2 is an
optionally substituted phenyl, optionally substituted naphthyl,
optionally substituted heterocyclic group or substituted
biphenylyl, the substituent for the above-mentioned phenyl,
naphthyl and heterocyclic group being at least one member selected
from the group consisting of alkyl, cyclo(lower)alkyl, alkenyl,
alkynyl, lower alknoyl, lower alkoxy, phenyl,
heterocycle(lower)alkyl, halogen, amino, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)a- lkylamino,
arylsulfonylamino, arylcarbonylamino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carboxy, protected carboxy,
carbamoyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl,
nitro, halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkanoylamino(lower)alkoxy,
mono(lower)alkylamino(lower)alkoxy,
di(lower)alkylamino(lower)alkoxy,
N-(lower)alkyl-N-acylamino(lower)alkoxy, lower
alkylsulfonylamino(lower)a- lkoxy,
aryl(lower)alkylamino(lower)alkoxy,
N-heterocycle-N-(lower)alkylami- no(lower)alkoxy,
arylsulfonylamino(lower)alkoxy, arylcarbonylamino(lower)a- lkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alk- yl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, alkyl substituted by optionally substituted
divalent heterocyclic group and optionally substituted heterocyclic
group, the substituent for the above-mentioned biphenylyl being at
least one member selected from the group consisting of alkyl,
cyclo(lower)alkyl, alkenyl, alkynyl, lower alkanoyl, lower alkoxy,
phenyl, heterocycle(lower)alkyl other than substituted
tetrazolylmethyl, halogen, amino, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)alkylamino,
arylsulfonylamino, arylcarbonylamino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carbamoyl,
mono(lower)alkylcarbamo- yl, di(lower)alkylcarbamoyl, nitro,
halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkanoylamino(lower)alkoxy,
mono(lower)alkylamino(lower)alkoxy,
di(lower)alkylamino(lower)alkoxy,
N-(lower)alkyl-N-acylamino(lower)alkoxy, lower
alkylsulfonylamino(lower)a- lkoxy,
aryl(lower)alkylamino(lower)alkoxy,
N-heterocycle-N-(lower)alkylami- no(lower)alkoxy,
arylsulfonylamino(lower)alkoxy, arylcarbonylamino(lower)a- lkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alk- yl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group, and the above-mentioned heterocyclic group
means the following (A) to (T): (A) saturated or unsaturated 7- to
12-membered heterobicyclic group having 1 to 4 nitrogen atoms (B)
saturated or unsaturated 7- to 12-membered heterobicyclic group
having 1 to 3 oxygen atoms (C) saturated or unsaturated 7-to
12-membered heterobicyclic group having 1 to 3 sulfur atoms (D)
saturated or unsaturated 7- to 12-membered heterobicyclic group
having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms (E) saturated
or unsaturated 7- to 12-membered heterobicyclic group having 1 to 3
nitrogen atoms and 1 or 2 sulfur atoms (F) saturated or unsaturated
7- to 12-membered heterobicyclic group having 1 or 2 oxygen atoms
and 1 or 2 sulfur atoms (G) saturated or unsaturated 7- to
12-membered heterobicyclic group having 1 nitrogen atom, 1 oxygen
atom and 1 sulfur atom (H) saturated or unsaturated 7- to
12-membered heterobicyclic group having 1 or 2 selenium atoms (I)
saturated or unsaturated 7- to 12-membered heterobicyclic group
having 1 or 2 selenium atoms and 1 to 3 nitrogen atoms (J)
unsaturated 3- to 8-membered heteromonocyclic group having 1 to 4
nitrogen atoms (K) saturated 3- to 8-membered heteromonocyclic
group having 1 to 4 nitrogen atoms (L) unsaturated 3- to 8-membered
heteromonocyclic group having 1 or 2 oxygen atoms and 1 to 3
nitrogen atoms (M) saturated 3- to 8-membered heteromonocyclic
group having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms (N)
unsaturated 3- to 8-membered heteromonocyclic group having 1 or 2
sulfur atoms and 1 to 3 nitrogen atoms (O) saturated 3- to
8-membered heteromonocyclic group having 1 or 2 sulfur atoms and 1
to 3 nitrogen atoms (P) unsaturated 3- to 8-membered
heteromonocyclic group having 1 or 2 sulfur atoms (Q) unsaturated
3- to 8-membered heteromonocyclic group having 1 or 2 oxygen atoms
(R) unsaturated 3- to 8-membered heteromonocyclic group having 1
oxygen atom (S) spiroheterocyclic group having 1 or 2 oxygen atoms
(T) unsaturated 3- to 8-membered heteromonocyclic group having 1
oxygen atom and 1 or 2 sulfur atoms, or a salt thereof.
4. The sulfonamide compound of claim 3, wherein A is a heterocyclic
group selected from the group consisting of
2,3-dihydrobenzimidazolyl, pyrazolopyrimidinyl,
tetrahydropyrazolopyrimidinyl, imidazopyrazolyl,
dihydroimidazopyrazolyl, imidazopyridyl, pyrrolopyridyl,
pyrazolopyridyl, benzopyrazolyl, dihydrobenzimidazolyl,
benzotriazolyl, indolizinyl, isoindolyl, indazolyl, indolinyl,
isoindolinyl, purinyl, quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthalidinyl, quinoxalinyl, dihydroquinoxalinyl,
tetrahydroquinoxalinyl, quinazolinyl, dihydroquinazolinyl,
tetrahydroquinazolinyl, cinnolinyl, pteridinyl,
pyrazinopyridazinyl, imidazotriazinyl, imidazopyrazinyl,
imidazopyrimidinyl, imidazopyridazinyl, 1H-1-(or 2)pyrinedinyl,
benzofuranyl, isobenzofuranyl, furopyridyl, chromenyl, chromanyl,
isochromanyl, benzoxepinyl, cyclopentapyranyl, furopyranyl,
benzothiophenyl, dihydrodithianaphthalenyl, dithianaphthalenyl,
dioxoloimidazolyl, benzoxazinyl, pyridoxazinyl, pyrazolooxazolyl,
furopyridyl, thienoimidazolyl, thienopyridyl, dithiadiazaindanyl,
thienofuranyl, oxathiolopyrrolyl, benzoselenophenyl, selenopyridyl,
benzoselenol, selenopyridyl and cyclopentadienopyridyl, and said
heterocyclic groups are optionally substituted by at least one
member selected from the group consisting of lower alkyl and oxo,
or a salt thereof.
5. The sulfonamide compound of claim 4, wherein, R.sup.1 is an
alkyl, an alkenyl, a phenyl(lower)alkenyl, a quinolyl, a phenyl
optionally substituted by a substituent selected from the group
consisting of nitro, alkyl and alkenyl or a thienyl optionally
substituted by halogen; A is a heterocyclic group selected from the
group consisting of 2,3-dihydrobenzimidazolyl, imidazopyrazolyl,
imidazopyridyl, pyrrolopyridyl, pyrazolopyridyl, benzotriazolyl,
indolizinyl, indazolyl, quinolyl, dihydroquinoxalinyl,
tetrahydroquinoxalinyl, dihydroquinazolinyl,
tetrahydroquinazolinyl, benzofuranyl, benzothiophenyl and
thienoimidazolyl, said heterocyclic group being optionally
substituted by alkyl or oxo; X is a lower alkylene, an
oxa(lower)alkylene or an oxa; and R.sup.2 is a phenyl optionally
substituted by a substituent selected from the group consisting of
alkyl, alkenyl, alkynyl, lower alkanoyl, lower alkoxy, phenyl,
imidazolyl(lower)alkyl, piperidinyl(lower)alkyl, halogen, amino,
lower alkanoylamino, mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-(lower)alkanoylamino,
N-(lower)alkyl-N-benzoylamino, lower alkylsulfonylamino,
phenyl(lower)alkylamino, phenylsulfonylamino, benzoylamino, lower
alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, cyano,
carboxy, lower alkoxycarbonyl, cyclo(lower)alkyloxycarbonyl,
mono(lower)alkylcarbamoyl, nitro, halo(lower)alkyl,
phenyl(lower)alkyl, phenyl(lower)alkenyl, phenyl(lower)alkoxy,
(N-pyridyl-N-(lower)alkylamino- )(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)al- kyl,
phenoxy(lower)alkyl, lower alkylsulfonyloxy(lower)alkyl,
hydroxy(lower)alkyl, di(lower)alkylamino(lower)alkyl,
phenyl(lower)alkoxy(lower)alkyl, phenylthio(lower)alkyl,
thienyl(lower)alkoxy, pyridyloxy(lower)alkyl,
phenyl(lower)alkylthio, phenylureido, lower alkoxy(lower)alkoxy,
phenyl(lower)alkynyl, dioxothiazolidylidene(lower)alkyl and thienyl
optionally substituted by halogen; naphthyl optionally substituted
by halogen; a 4-phenylphenyl substituted by halogen; a thienyl
optionally substituted by halogen; a benzothienyl optionally
substituted by halogen; a quinolyl optionally substituted by
halogen; or a benzooxolanyl optionally substituted by halogen, or a
salt thereof.
6. The sulfonamide compound of claim 5, wherein, R.sup.1 is an
alkyl, an alkenyl, a phenyl(lower)alkenyl, a phenyl optionally
substituted by a substituent selected from the group consisting of
alkyl and alkenyl or a thienyl optionally substituted by halogen; A
is a heterocyclic group selected from the group consisting of
3H-imidazo[4,5-b]pyridyl, pyrazolol 1,5-a]pyridyl, indolizinyl,
1H-indazolyl, benzo[b]furanyl and benzo[b]thiophenyl, said
heterocyclic group being optionally substituted by one or two
alkyl; X is an alkylene; and R.sup.2 is a phenyl optionally
substituted by a substituent selected from the group consisting of
alkyl, alkenyl, alkynyl, lower alkoxy, phenyl, halogen,
di(lower)alkylamino, lower alkylthio, lower alkoxycarbonyl, nitro,
halo(lower)alkyl, phenyl(lower)alkyl, phenyl(lower)alkenyl,
phenyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkoxy,
phenoxy(lower)alkyl, phenyl(lower)alkoxy(lower)alkyl,
phenyl(lower)alkynyl and thienyl optionally substituted by halogen;
a naphthyl optionally substituted by halogen; or a 4-phenylphenyl
substituted by halogen, or a salt thereof.
7. The sulfonamide compound of claim 6, wherein, A is a
3H-imidazo[4,5-b]pyridyl, a 1H-indazolyl or a benzo[b]furanyl,
these heterocyclic groups being optinoally substituted by alkyl;
and R.sup.2 is a phenyl substituted by halogen, said phenyl being
optionally substituted by a substituent selected from the group
consisting of alkyl, alkenyl, alkynyl, lower alkoxy, phenyl,
halogen, di(lower)alkylamino, lower alkylthio, lower
alkoxycarbonyl, nitro, halo(lower)alkyl, phenyl(lower)alkyl,
phenyl(lower)alkenyl, phenyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy, phenoxy(lower)alkyl,
phenyl(lower)alkoxy(lower)alkyl, phenyl(lower)alkynyl and thienyl
optionally substituted by halogen, or a naphthyl substituted by
halogen, or a salt thereof.
8. The sulfonamide compound of claim 7, wherein A is
3H-imidazo[4,5-b]pyridyl substituted by 1 or 2 lower alkyl, or a
salt thereof.
9. The sulfonamide compound of claim 7, wherein A is 1H-indazolyl
substituted by one lower alkyl, or a salt thereof.
10. The sulfonamide compound of claim 7, wherein A is
benzo[b]furanyl substituted by one lower alkyl, or a salt
thereof.
11. A method for producing a compound of the formula (I)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.2 (I) wherein R.sup.1 is an
optionally substituted alkyl, an optionally substituted alkenyl, an
optionally substituted alkynyl, an optionally substituted
cyclo(lower)alkyl, an optionally substituted aryl or an optionally
substituted heterocyclic group; A is an optionally substituted
heteropolycyclic group except benzimidazolyl, indolyl,
4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl; X is an
alkylene, an oxa, an oxa(lower)alkylene, a lower alkylene-oxa, a
carbonyl, a lower alkenylene, an optionally substituted imino, an
optionally N-substituted imino(lower)alkylene, an N-substituted
lower alkyleneimino, a thioxa(lower)alkylene or a lower
alkylenethioxa; and R.sup.2 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl; provided that when A is 3H-imidazo[4,5-b]pyridyl
substituted by lower alkyl, R.sup.2 is an optionally substituted
aryl, an optionally substituted heterocyclic group or a biphenylyl
substituted by a group other than tetrazolyl, and when A is
quinolyl substituted by lower alkyl, R.sup.2is an optionally
substituted aryl, an optionally substituted heterocyclic group, or
a biphenylyl substituted by at least one group selected from the
group consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl,
lower alkanoyl, lower alkoxy, phenyl, heterocycle(lower)alkyl other
than substituted tetrarolylmethyl, halogen, amino, substituted
amino, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio,
cyano, carbamoyl, mono(lower)alkylcarbamoyl,
di(lower)alkylcarbamoyl, nitro, halo(lower)alkyl, aryl(lower)alkyl,
aryl(lower)alkenyl, aryl(lower)alkoxy, lower alkoxy substituted by
substituted amino, cyclo(lower)alkyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycle-oxy(lower)alk- yl, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group, or a salt thereof,
comprising the step of (1) reacting a compound of the formula (II)
R.sup.1--SO.sub.2NH.sub.2 (II) wherein each symbol is as defined
above, or a salt thereof, and a compound of the formula (III)
HOOC-A-X--R.sup.2 (III) wherein each symbol is as defined above, or
a reactive derivative thereof at carboxy or a salt thereof, to give
a compound of the formula (I) R.sup.1--SO.sub.2NHCO-A-X--R.sup.2
(I) wherein each symbol is as defined above, or a salt thereof; or
(2) reducing a compound of the formula (I-1)
R.sup.1--SO.sub.2NHCO-A-X--R.sup- .201 (I-1) wherein R.sup.201 is
an optionally substituted aryl, an optionally substituted
heterocyclic group or a substituted biphenylyl, all of which having
at least alkynyl, aryl(lower)alkenyl, terminal nitro or terminal
formyl and other symbols are as defined above, or a salt thereof,
to give a compound of the formula (I-2) R.sup.1--SO.sub.2NHCO-A--
X--R.sup.202 (I-2) wherein R.sup.202 is an optionally substituted
aryl, an optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least alkyl, aryl(lower)alkyl,
terminal amino or hydroxymethyl, and other symbols are as defined
above, or a salt thereof; or (3) oxidizing a compound of the
formula (I-3) R.sup.1--SO.sub.2NHCO-A-- X--R.sup.203 (I-3) wherein
R.sup.203 is an optionally substituted aryl, an optionally
substituted heterocyclic group or a substituted biphenylyl, all of
which having at least terminal formyl, and other symbols are as
defined above, or a salt thereof, to give a comopund of the formula
(I-4) R.sup.1--SO.sub.2NHCO-A-X--R.sup.204 (I-4) wherein R.sup.204
is an optionally substituted aryl, an optionally substituted
heterocyclic group or a substituted biphenylyl, all of which having
at least carboxy, and other symbols are as defined above, or a salt
thereof; or (4) acylating a compound of the formula (I-5)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.205 (I-5) wherein R.sup.205 is an
optionally substituted aryl, an optionally substituted heterocyclic
group or a substituted biphenylyl, all of which having at least
hydroxy(lower)alkyl, and other symbols are as defined above, or a
salt thereof, to give a compound of the formula (I-6)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.206 (I-6) wherein R.sup.206 is an
optionally substituted aryl, an optionally substituted heterocyclic
group or a substituted biphenylyl, all of which having at least
acyloxy(lower)alkyl, and other symbols are as defined above, or a
salt thereof; or (5) introducing an aryloxy group into a comopund
of the formula (I-6) R.sup.1--SO.sub.2NHCO-A-X--R.sup.206 (I-6)
wherein each symbol is as defined above, or a salt thereof, to give
a compound of the formula (I-7) R.sup.1--SO.sub.2NHCO-A-X--R207
wherein R.sup.207 is an optionally substituted aryl, an optionally
substituted heterocyclic group or a substituted biphenylyl, all of
which having at least aryloxy(lower)alkyl, and other symbols are as
defined above, or a salt thereof; or (6) introducing a
carboxy-protecting group into a compound of the formula (I-4)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.204 (I-4) wherein each symbol is
as defined above, or a reactive derivative thereof, to give a
compound of the formula (I-8) R.sup.1--SO.sub.2NHCO-A-X--R.sup.208
(I-8) wherein R.sup.208 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least protected carboxy, and
other symbols are as defined above, or a salt thereof; or (7)
amidating a compound of the formula (I-4)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.204 (I-4) wherein each symbol is
as defined above, or a reactive derivative thereof, to give a
compound of the formula (I-9) R.sup.1--SO.sub.2NHCO-A-X--R.sup.209
(I-9) wherein R.sup.209 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least optionally substituted
amide, and other symbols are as defined above, or a salt thereof;
or (8) adding a nitrogen-containing heterocyclic group to a
compound of the formula (I-10) R.sup.1--SO.sub.2NHCO-A-X--R.sup.210
(I-10) wherein R.sup.210 is an optionally substituted aryl having
at least a halogen atom, and other symbols are as defined above, or
a salt thereof, to give a compound of the formula (I-11)
R.sup.1--SO.sub.2NHCO-A-X--R.sup.211 (I-11) wherein R.sup.211 is an
aryl substituted by at least heterocyclic group having nitrogen,
and other symbols are as defined above, or a salt thereof.
12. A pharmaceutical composition comprising the sulfonamide
compound of claim 1 or a pharmaceutically acceptable salt
thereof.
13. A method for treating a disease treatable based on a blood
sugar level-depressing activity or a disease treatable based on a
cGMP-PDE inhibiting activity, smooth muscle relaxing activity,
bronchodilating activity, vasodilating activity, smooth muscle cell
suppressing activity or antiallergic activity, by the use of the
sulfonamide compound of claim 1 or a pharmaceutically acceptable
salt thereof.
14. A use of the sulfonamide compound of claim 1 or a
pharmaceutically acceptable salt thereof for the production of a
therapeutic agent for a disease treatable based on a blood sugar
level-depressing activity, or a disease treatable based on a
cGMP-PDE inhibiting activity, smooth muscle relaxing activity,
bronchodilating activity, vasodilating activity, smooth muscle cell
suppressing activity or antiallergic activity.
Description
TECHNICAL FIELD OF THE INVENTION
[0001] The present invention relates to novel sulfonamide
compounds. More particularly, the present invention relates to
novel sulfonamide compounds and salts thereof having hypoglycemic
activity or PDE-V inhibitory activity. Moreover, the present
invention relates to a method for producing the above-mentioned
sulfonamide compound and salts thereof. The present invention also
relates to pharmaceutical compositions comprising the
above-mentioned sulfonamide compound or a salt thereof as an active
ingredient.
BACKGROUND OF THE INVENTION
[0002] The present invention aims at providing novel sulfonamide
compounds, pharmaceutically acceptable salts thereof and
pharmaceutical preparations comprising the above-mentioned
sulfonamide compound or a pharmaceutically acceptable salt thereof
as an active ingredient, which can be used for the prophylaxis and
treatment of impaired glucose tolerance disorder, diabetes (e.g.,
type II diabetes), diabetic complications (e.g., diabetic gangrene,
diabetic arthropathy, diabetic bone resorption, diabetic
glomerulosclerosis, diabetic nephropathy, diabetic dermatopathy,
diabetic neuropathy, diabetic cataract, diabetic retinopathy and
the like), insulin resistant syndrome (e.g., insulin receptor
disorders, Rabson-Mendenhall syndrome, leprechaunism,
Kobberling-Dunnigan syndrome, Seip syndrome, Lawrence syndrome,
Cushing syndrome, acromegaly and the like), polycystic ovary
syndrome, hyperlipidemia, atherosclerosis, cardiovascular disorders
(e.g., stenocardia, cardiac failure and the like), hypoglycemia
(e.g., those characterized by abnormal saccharometabolism such as
feeding disorders), hypertension, pulmonary hypertension,
congestive heart failure, glomerulopathy (e.g., diabetic
glomerulosclerosis), tubulointerstitial disorders (e.g., kidney
diseases induced by FK506, cyclosporine and the like), renal
failure, angiostenosis (e.g., after percutaneous arterioplasty),
distal angiopathy, cerebral apoplexy, chronic reversible
obstructions (e.g., bronchitis, asthma inclusive of chronic asthma
and allergic asthma), autoimmune diseases, allergic rhinitis,
urticaria, glaucoma, diseases characterized by enteromotility
(e.g., hypesensitive enteropathy), impotence (e.g., organic
impotence, psychic impotence and the like), nephritis, cancer
cachexia or restenosis after PTCA, pancreatitis, cachexia (e.g.,
progressive weight loss due to lipolysis, myolysis, anemia, edema,
anorexia and the like in chronic diseases such as cancer,
tuberculosis, endocrine diseases and AIDS), and the like.
SUMMARY OF THE INVENTION
[0003] The novel sulfonamide compound of the present invention has
the following formula (I):
R.sup.1--SO.sub.2NHCO-A-X--R.sup.2 (I)
[0004] wherein
[0005] R.sup.1 is an optionally substituted alkyl, an optionally
substituted alkenyl, an optionally substituted alkynyl, an
optionally substituted cyclo(lower)alkyl, an optionally substituted
aryl or an optionally substituted heterocyclic group;
[0006] A is an optionally substituted heteropolycyclic group except
benzimidazolyl, indolyl, 4,7-dihydrobenzimidazolyl and
2,3-dihydrobenzoxazinyl;
[0007] X is an alkylene, an oxa, an oxa(lower)alkylene, a lower
alkylene, a carbonyl, a lower alkenylene, an optionally substituted
imino, an optionally N-substituted imino(lower)alkylene, an
optionally N-substituted lower alkyleneimino, a
thioxa(lower)alkylene or a lower alkylenethioxa; and
[0008] R.sup.2 is an optionally substituted age, an optionally
substituted heterocyclic group or a substituted biphenylyl;
[0009] provided that when A is 3H-imidazo[4,5b]pyridyl substituted
by lower alkyl, R.sup.2 is an optionally substituted aryl, an
optionally substituted heterocyclic group, or a biphenylyl
substituted by a group other than tetrazolyl, and when A is
quinolyl substituted by lower alkyl, R.sup.2 is an optionally
substituted aryl, an optionally substituted heterocyclic group, or
a biphenylyl substituted by at least one group selected from the
group consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl
lower alkanoyl, lower alkoxy, phenyl, heterocycle(lower)alkyl other
than substituted thiazolylmethyl, halogen, amino, substituted
amino, lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio,
cyano, carbamoyl, mono(lower)alkylcarbamoyl,
di(lower)alkylcarbamoyl, nitro, halo(lower)alkyl, aryl(lower)alkyl,
aryl(lower)alkenyl, aryl(lower)alkoxy, lower alkoxy substituted by
substituted amino, cyclo(lower)alkyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycle-oxy(lower)alk- yl, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group, (hereinafter also
referred to as objective compound (I)).
[0010] Preferred salts of the objective compound (I) are
conventional salts that are non-toxic and acceptable for use as
pharmaceuticals. Examples thereof include salts of alkali metal
such as sodium and potassium, salts of alkaline earth metal such as
calcium and magnesium, salts with inorganic base such as ammonium
salt, salts with organic amine such as triethylamine, pyridine,
picoline, ethanolamine and triethanolamine, salts with inorganic
acid such as hydrochloric acid, hydrobromic acid, sulfuric acid and
phosphoric acid, salts with organic carboxylic acid such as formic
acid, acetic acid, trifluoroacetic acid, maleic acid and tartaric
acid, addition salts with sulfonic acid such as methanesulfonic
acid, benzenesulfonic acid and p-toluenesulfonic acid, addition
salts with basic amino acid such as arginine, and addition salts
with acidic amino acid such as aspartic add and glutamic acid.
[0011] The objective compound (I) and a salt thereof can be
produced by the method shown by the following reaction formula.
1
[0012] wherein each symbol in the formula is as defined above.
[0013] The objective compound (I) and a salt thereof can be also
produced by the methods shown by the following reaction formulas.
2
[0014] wherein R.sup.201 is an optionally substituted aryl an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least alkynyl,
aryl(lower)alkenyl, terminal nitro or terminal formyl, R.sup.202 is
an optionally substituted aryl, an optionally substituted
heterocyclic group or a substituted biphenylyl, all of which having
at least alkyl, aryl(lower)alkyl, terminal amino or hydroxymethyl,
and other symbols are as defined above. 3
[0015] wherein R.sup.203 is an optionally substituted aryl an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least terminal formyl, R.sup.204
is an optionally substituted aryl, an optionally substituted
heterocyclic group or a substituted biphenylyl, all of which having
at least carboxy, and other symbols are as defined above. 4
[0016] wherein R.sup.205 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least hydroxy(lower)alkyl,
R.sup.206 is an optionally substituted aryl, an optionally
substituted heterocyclic group or a substituted biphenylyl, all of
which having at least acyl(lower)alkyl, and other symbols are as
defined above. 5
[0017] wherein R.sup.207 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl all of which having at least aryloxy(lower)alkyl, and
other symbols are as defined above. 6
[0018] wherein R.sup.208 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least protected carboxy, and
other symbols are as defined above. 7
[0019] wherein R.sup.209 is an optionally substituted aryl, an
optionally substituted heterocyclic group or a substituted
biphenylyl, all of which having at least optionally substituted
amide, and other symbols are as defined above. 8
[0020] wherein R.sup.210 is an optionally substituted aryl having
at least a halogen atom, 9
[0021] is a heterocyclic group having nitrogen, R.sup.211 is an
aryl substituted by at least heterocyclic group having nitrogen,
and other symbols are as defined above.
[0022] Various definitions included in the entire specification are
explained in detail in the following.
[0023] "Lower" means 1 to 6 carbon atoms, unless otherwise
specified.
[0024] "Higher" means 7 to 20 carbon atoms, unless otherwise
specified.
[0025] "Alkyl" and "alkyl moiety" are preferably linear or branched
lower alkyl and higher alkyl, respectively. Specific examples
include methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,
t-butyl, sec-butyl, n-pentyl, i-pentyl, sec-pentyl, t-pentyl,
methylbutyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl,
2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1-ethylbutyl,
2-ethylbutyl, 3-ethylbutyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl,
3,3-dimethylbutyl, 1-ethyl-1-methylpropyl, n-heptyl, 1-methylhexyl,
2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5methylhexyl,
1-ethylpentyl, 2-ethylpentyl, 3-ethylpentyl, 4-ethylpentyl,
1,1-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl,
4,4-dimethylpentyl, 1-propylbutyl, n-octyl, 1-methylheptyl,
2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl,
4-ethylhexyl, 5ethylhexyl, 5-ethylhexyl 1,1-dimethylhexyl,
2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl,
5,5-dimethylhexyl, 1-propylpentyl, 1-propylpentyl and the like.
[0026] Of these, particularly preferred is alkyl having 2 to 8
carbon atoms.
[0027] "Alkenyl" and "lower alkenyl moiety" are preferably
exemplified by linear or branched lower alkenyl and higher alkenyl,
such as ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl,
3-butenyl, 1,3-butadienyl, 1-pentenyl, 2-pentenyl, 3-pentenyl,
4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl
and the like.
[0028] Of these, particularly preferred is alkenyl having 2 to 8
carbon atoms.
[0029] "Alkynyl" is preferably a linear or branched lower alkynyl
or higher alkynyl, such as ethynyl, 1-propynyl, 2-propynyl,
1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl,
3-pentynyl, 4-pentynyl, 2-methyl-3-butynyl, 1,1-dimethyl-2-butynyl,
1-hexynyl, 5-hexynyl, and the like.
[0030] Of these, particularly preferred is alkynyl having 2 to 8
carbon atoms.
[0031] "Cyclo(lower)alkyl" is cycloalkyl having 3 to 10, preferably
3 to 7, carbon atoms. Examples thereof include cyclopropyl,
cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, with
preference given to cyclopropyl, cyclobutyl and cyclohexyl.
[0032] Examples of preferable aryl include aryl having 6 to 10
carbon atoms, such as phenyl, naphthyl and pentalenyl.
[0033] Of these, particularly preferred are phenyl and
naphthyl.
[0034] "Heterocyclic group" is a saturated or unsaturated,
heteromonocyclic or heteropolycyclic group having at least one
hetero atom, such as oxygen atom, sulfur atom, nitrogen atom and
selenium atom. Particularly, heteropolycyclic group (specifically
heterobicyclic group) and unsaturated 3- to 8-membered
heteromonocyclic group having 1 or 2 sulfur atom(s) are
preferable.
[0035] Preferred heterocyclic group includes the following.
[0036] Heteromonocyclic group includes the following.
[0037] Unsaturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group having 1 to 4 nitrogen atoms,
such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,
dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g.,
4H-1,2,4-triazolyl, 1H-1,2,3-triazolyl and 2H-1,2,3-triazolyl),
tetrazolyl (e.g., 1H-tetrazolyl and 2H-tetrazolyl) and the
like.
[0038] Saturated 3 to 8-membered (more preferably 5- or 6-membered)
heteromonocyclic group having 1 to 4 nitrogen atoms, such as
pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and the
like.
[0039] Unsaturated 3 to 8-membered (more preferably 5- or
6-membered) heteromonocyclic group having 1 or 2 oxygen atoms and 1
to 3 nitrogen atoms, such as oxazolyl, isooxazolyl, oxadiazolyl
(e.g., 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl and 1,2,5-oxadiazolyl)
and the like.
[0040] Saturated 3 to 8-membered (more preferably 5- or 6-membered)
heteromonocyclic having 1 or 2 oxygen atoms and 1 to 3 nitrogen
atoms, such as morpholinyl, sydnonyl and the like.
[0041] Unsaturated 3 to 8-membered (more preferably 5- or
6-membered) heteromonocyclic group having 1 or 2 sulfur atoms and 1
to 3 nitrogen atoms, such as thiazolyl, isothiazolyl, thiadiazolyl
(e.g., 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl
and 1,2,5-thiadiazolyl), dihydrothiazinyl and the like.
[0042] Saturated 3 to 8-membered (more preferably 5- or 6-membered)
heteromonocyclic group having 1 or 2 sulfur atoms and 1 to 3
nitrogen atoms, such as thiazolidinyl and the like.
[0043] Unsaturated 3 to 8-membered (more preferably 5- or
6-membered) heteromonocyclic group having 1 or 2 sulfur atoms, such
as thienyl, dihydrodithinyl, dihydrodithionyl and the like.
[0044] Unsaturated 3 to 8-membered (more preferably 5- or
6-membered) heteromonocyclic group having 1 or 2 oxygen atoms, such
as tetrahydrofuryl, tetrahydropyranyl and the like.
[0045] Unsaturated 3 to 8-membered (more preferably 5- or
6-membered) heteromonocyclic group having one oxygen atom, such as
furyl and the like.
[0046] Spiroheterocyclic group having 1 or 2 oxygen atoms, such as
dioxaspiroundecanyl (e.g., 1,5-dioxaspiro[5,5]undecanyl) and the
like.
[0047] Unsaturated 3 to 8-membered (more preferably 5 or
6-membered) heteromonocyclic group having one oxygen atom and 1 or
2 sulfur atoms, such as dihydroxathinyl.
[0048] Examples of heteropolycyclic group include the
following.
[0049] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 to 4 nitrogen atoms, exclusive of benzimidazolyl and
indolyl.
[0050] Specific examples thereof include 2,3-dihydrobenzmidazolyl,
pyrazolopyrimidinyl (e.g., pyrazolo[1,5-a]pyrimidinyl),
tetrahydropyrazolopyrimidinyl (e.g.,
4,5,6,7-tetrahydropyrazolo[1,5-a]pyr- imidinyl), imidazopyrazolyl
(e.g., 4H-imidazo[1,2-b]pyrazolyl), dihydroimidazopyrazolyl (e.g.,
2,3-dihydroimidazo[1,2-b]pyrazolyl), imidazopyridyl (e.g.,
imidazo[1,5-a] (or [1,2-a] or [3,4-a])pyridyl, 1H (or
3H)-imidazo[4,5-b] (or [4,5-c])pyridyl), pyrrolopyridyl (e.g.,
1H-pyrrolo[3,2-b]pyridyl), pyrazolopyridyl (e.g., pyrazolo[1,5-a]
(or [2,3-a]pyridyl, 1H (or 2H)-pyrazolo[4,3-b]pyridyl),
benzopyrazolyl (e.g., 1H (or 2H)-benzo[c]pyrazolyl),
dihydrobenzimidazolyl, benzotriazolyl (e.g.,
benzo[d][1H-1,2,3]triazolyl), indolizinyl, isoindolyl (e.g.,
1H-isoindolyl), indazolyl (e.g, 1H (or 2H or 3H)-indazolyl),
indolinyl, isoindolinyl, purinyl, quinolizinyl (e.g.,
4H-quinolizinyl), isoquinolyl, quinolyl, phthalazinyl,
naphthalidinyl (e.g., 1,8-naphthalidinyl), quinoxalinyl,
dihydroquinoxalinyl (e.g, 1,2-dihydroquinoxalinyl),
tetrahydroquinoxalinyl (e.g., 1,2,3,4-tetrahydroquinoxalinyl),
quinazolinyl, dihydroquinazolinyl (e.g., 1,4 (or
3,4)-dihydroquinazolinyl- ), tetrahydroquinazolinyl (e.g.,
1,2,3,4-tetrahydroquinazolinyl), cinnolinyl, pteridinyl,
pyrazinopyridazinyl (e.g., pyrazino[2,3-d]pyridazinyl),
imidazotriazinyl (e.g., imidazo[1,2-b][1,2,4] triazinyl,
imidazopyrazinyl (e.g., 1H-imidazo[4,5-b]pyrazinyl),
imidazopyrmidine (e.g., 3H-purine and imidazo[1,5-a] (or
[3,4-a])pyrimidine), imidazopyridazinyl (e.g., imidazo[2,3-b] (or
[3,4-b])pyridazinyl), 1H-1-(or 2)pyrinedinyl and the like.
[0051] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 to 3 oxygen atoms.
[0052] Specific examples thereof include benzofuranyl (e.g.,
benzo[b] (or [c])furanyl), isobenzofuranyl, furopyridyl, chromenyl
(e.g., 2H-chromenyl), chromanyl, isochromanyl, benzoxepinyl (e.g.,
3-benzoxepinyl), cyclopentapyranyl (e.g., cyclopenta[b]pyranyl),
furopyranyl (e.g., 2H-furo[3,2-b]pyranyl), and the like.
[0053] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 to 3 sulfur atoms.
[0054] Specific examples thereof include benzothiophenyl (e.g,
benzo[b]thiophenyl), dihydrodithianaphthalenyl (e.g,
4H-1,3-dithianaphthalenyl), dithianaphthalenyl (e.g.,
1,4-dithianaphthalenyl) and the like.
[0055] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycylic (more preferably heterodicyclic)
group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms.
[0056] Specific examples thereof include diaxoloimidazolyl (e.g.,
4H-1,3-dioxolo[4,5-d]imidazolyl, benzoxazinyl (e.g.,
4H-3,1-benzoxazinyl), pyridooxazinyl (e.g.,
5H-pyrido[2,3-d]oxazinyl), pyrazoloxazolyl (e.g.,
1H-pyrazolo[4,3-d]oxazolyl), furopyridyl, and the like.
[0057] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms.
[0058] Specific examples thereof include thienoimidazolyl (e.g.,
thieno[2,3-d]imidazolyl), thienopyridyl, dithiadiazaindanyl (e.g,
2,3-dithia-1,5-diazindanyl) and the like.
[0059] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 to 3 oxygen atoms and 1 or 2 sulfur atoms.
[0060] Specific examples thereof include thienofuranyl (e.g.,
thieno[2,3-b]furanyl), and the like.
[0061] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom.
[0062] Specific examples thereof include oxathiolopyrrolyl (e.g.,
4H[1,3]-oxathiolo[5,4-b]pyrrolyl, and the like.
[0063] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 or 2 selenium atoms.
[0064] Specific examples thereof include benzoselenophenyl (e.g.,
benzo[b] (or [c])selenophenyl), and the like.
[0065] Saturated or unsaturated 7 to 12-membered (more preferably 8
to 10-membered) heteropolycyclic (more preferably heterodicyclic)
group having 1 or 2 selenium atoms and 1 to 3 nitrogen atoms.
[0066] Specific examples thereof include selenopyridyl (e.g.,
seleno[3,2-b]pyridyl), and the like.
[0067] Examples of preferable lower alkylene include methylene,
ethylene, propylene, butylene, pentylene, hexylene and the like,
with preference given to alkylene having up to 4 carbon atoms.
[0068] Examples of preferable lower alkenylene include ethenylene,
1-propenylene, 2-propenylene, 1-butenylene, 2-butenylene,
3-butenylene, 1-pentenylene, 2-pentenylene, 3-pentenylene,
4-pentenylene, 1-hexenylene, 2-hexenylene, 3-hexenylene,
4-hexenylene, 5-hexenylene and the like, with preference given to
alkenylene having up to 4 carbon atoms.
[0069] The lower alkylene moiety of oxa(lower)alkylene, lower
alkyleneoxa, imino(lower)alkylene, lower alkyleneimino,
thioxa(lower)alkylene and lower alkylenethioxa is the same as that
of the above-mentioned alkylene.
[0070] Lower alkanoyl is a linear or branched alkylcarbonyl having
up to 6 carbon atoms. Examples thereof include acetyl, propionyl,
n-butyryl, isobutyryl, valeryl, isovaleryl, sec-butylcarbonyl,
t-butylcarbonyl n-pentylcarbonyl i-pentylcarbonyl,
sec-pentylcarbonyl, t-pentylcarbonyl, 2-methylbutylcarbonyl and the
like.
[0071] More preferred is alkanoyl having up to 4 carbon atoms.
[0072] Lower alkoxy is a linear or branched alkyloxy having up to 6
carbon atoms. Examples thereof include methoxy, ethoxy,
n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy,
t-butyloxy, n-pentyloxy, i-pentyloxy, sec-pentyloxy, t-pentyloxy,
2-methylbutoxy, n-hexyloxy, i-hexyloxy, t-hexyloxy, sec-hexyloxy,
2-methylpentyloxy, 3-methylpentyloxy, 1-ethylbutyloxy,
2-ethylbutyloxy, 1,1-diethylbutyloxy, 2,2-dimethylbutyloxy,
3,3-dimethylbutyloxy, 1-ethyl-1-methylpropyloxy, and the like.
[0073] More preferred is alkoxy having up to 4 carbon atoms, such
as methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy,
i-butyloxy, sec-butyloxy, t-butyloxy, and the like.
[0074] Heterocycle(lower)alkyl means lower alkyl substituted by the
above-mentioned heterocyclic group.
[0075] Halogen is exemplified by fluorine atom, chlorine atom,
bromine atom and iodine atom.
[0076] The substituted amino of "substituted amino" and "optionally
substituted amino" is, for example, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)a- lkylamino,
arylsulfonylamino, arylcarbonylamino and the like. Examples of
N-(lower)alkyl-N-acylamino include
N-(lower)alkyl-N-(arylcarbonyl)amino and the like.
[0077] "Lower alkanoylamino is amino substituted by the
above-mentioned lower alkanoyl.
[0078] "Mono or di(lower)alkylamino" is amino substituted by linear
or branched alkyl having up to 6 carbon atoms. Examples thereof
include methylamino, ethylamino, n-propylamino, i-propylamino,
n-butylamino, i-butylamino, sec-butylamino, t-butylamino,
n-pentylamino, i-pentylamino, sec-pentylamino, t-pentylamino,
2-methylbutylamino, n-hexylamino, 1-methylpentylamino,
2-methylpentylamino, 3-methylpentylamino, 4-methylpentylamino,
1-ethylbutylamino, 2-ethylbutylamino, 3-ethylbutylamino,
1,1-dimethylbutylamino, 2,2-dimethylbutylamino,
3,3-dimethylbutylamino, 1-ethyl-1-methylpropylamino and the
like.
[0079] Preferred is alkylamino having up to 4 carbon atoms, such as
methylamino, ethylamino, n-propylamino, i-propylamino,
n-butylamino, i-butylamino, sec-butylamino, t-butylamino and the
like.
[0080] Preferable "acyl" in "N-(lower)alkyl-N-acylamino" is
exemplified by carbamoyl, aliphatic acyl, aromatic acyl, and acyl
having a heterocycle, such as heterocyclic acyl.
[0081] Examples of the above-mentioned acyl include carbamoyl;
lower or higher (having not less than 7, preferably 7 to 25, carbon
atoms) alkanoyl, such as formyl, acetyl, propanoyl, butanoyl,
2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl,
heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl,
tridecancyl, tetradecanoyl, pentadecanoyl, hexadecanoyl,
heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl and the like;
lower or higher alkoxycarbonyl, such as methoxycarbonyl,
ethoxycarbonyl, t-butoxycarbonyl, t-pentyloxycarbonyl,
heptyloxycarbonyl and the like; lower or higher alkanesulfonyl,
such as methanesulfonyl, ethanesulfonyl and the like; aliphatic
acyl such as lower or higher alkoxysulfonyl (e.g., methoxysulfonyl
and ethoxysulfonyl); aroyl such as benzoyl, toluoyl, naphthoyl and
the like; phenyl(lower)alkanoyl, such as phenylacetyl
phenylpropanoyl, phenylbutanoyl, phenylisobutyryl phenylpentanoyl,
phenylhexanoyl and the like and aryl(lower)alkanoyl (e.g.,
naphthyl(lower)alkanoyl such as naphthylacetyl, naphthylpropanoyl
and naphthylbutanoyl); phenyl(lower)alkenoyl such as
phenylpropenoyl phenylbutenoyl, phenylmethacryloyl,
phenylpentenoyl, phenylhexenoyl and the like and
aryl(lower)alkenoyl such as naphthyl(lower)alkenoyl (e.g., naphthyl
propenoyl, naphthyl butenoyl and naphthyl pentenoyl);
aryl(lower)alkoxycarbonyl such as phenyl(lower)alkoxycarbonyl
(e.g., benzyloxycarbonyl); aryloxycarbonyl such as phenoxycarbonyl,
naphthyloxycarbonyl and the like; aryloxy(lower)alkanoyl such as
phenoxyacetyl phenoxypropionyl and the like; arylcarbanoyl such as
phenylcarbamoyl and the like; arylthiocarbamoyl such as
phenylthiocarbamoyl and the like; arylglyoxyloyl such as
phenylglyoxyloyl, naphthylglyoxyoyl and the like; aromatic acyl
such as arenesulfonyl (e.g., benzenesulfonyl and
p-toluenesulfonyl); heterocyclecarbonyl; heterocycle(lower)alkanoyl
such as thienylacetyl, thienylpropanoyl, thienylbutanoyl,
thienylpentanoyl, thienylhexanoyl, thiazolylacetyl,
tetrazolylacetyl and the like; heterocycle(lower)alkenoy- l such as
heterocycle propenoyl, heterocyclebutenoyl, hetercyclepentenoyl,
heterocyclehexenoyl and the like; heterocycleglyoxyloyl such as
thiazolyglyoxyloyl, thienylglyoxyloyl and the like.
[0082] The preferable heterocycle moiety of the above-mentioned
"heterocycle carbonyl", "heterocycle(lower)alkanoyl",
"heterocycle(lower)alkenoyl" and "heterocycleglyoxyloyl" is a
saturated or unsaturated heteromonocyclic or heteropolycyclic group
having at least one hetero atom such as oxygen atom, sulfur atom,
nitrogen atom and the like, with preference given to the
heterocyclic groups mentioned above.
[0083] The aforementioned acyl moiety may have 1 to 10 same or
different suitable substituent(s), such as halogen (e.g., fluorine,
chlorine, bromine and iodine), hydroxy, nitro, lower alkyl (e.g.,
methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl
and hexyl), amino, protected amino, heterocycle(lower)alkylamino
having the above-mentioned heterocycle moiety and lower alkyl
moiety, lower alkoxy (e.g, methoxy, ethoxy, propoxy, butyloxy,
t-butyloxy, pentyloxy and hexyloxy), carboxy, protected carboxy,
N,N-di(lower)alkylamino(lower)alkyl (e.g., N,N-dimethylaminomethyl,
N,N-diethylaminomethyl, N,N-dipropylaminomethyl,
N,N-dimethylaminoethyl N,N-diethylaminoethyl,
N,N-dipropylaminoethyl, N,N-dimethylaminopropyl,
N,N-diethylaminopropyl, N,N-dipropylaminopropyl,
N,N-dibutylaminomethyl, N,N-dipentylaminomethyl and
N,N-dihexylaminomethyl), hydroxyimino(lower)alkyl (e.g.,
hydroxyiminomethyl, hydroiminoethyl, hydroxyiminopropyl,
hydroiminobutyl, hydroxyiminopentyl and hydroxyiminohexyl),
arylimino(lower)alkyl such as phenylimino(lower)alkyl (e.g.,
phenyliminomethyl, phenyliminoethyl, phenyliminopropyl,
phenyliminobutyl, phenyliminopentyl and phenyliminohexyl), acyl
such as lower alkanoyl (e.g., formyl, acetyl, propanoyl, butanoyl,
pentanoyl and hexanoyl), hydroxy(lower)alkylheterocy-
cle(lower)alkyl having the above-mentioned lower alkyl moiety and
heterocyclic moiety, mono- (or di- or tri-)halo(lower)alkyl,
arylamino (e.g., phenylamino) and the like.
[0084] "Lower alkylsulfonyl" and "lower alkylsulfinyl" are sulfonyl
and sulfinyl respectively substituted by the above-mentioned lower
alkyl.
[0085] "Lower alkylthio" is a linear or branched alkylthio having
up to 6 carbon atoms. Examples thereof include methylthio,
ethylthio, n-propylthio, i-propylthio, n-butylthio, i-butylthio,
sec-butylthio, t-butylthio, n-pentylthio, i-pentylthio,
sec-pentylthio, t-pentylthio, 2-methylbutylthio, n-hexylthio,
i-hexylthio, t-hexylthio, sec-hexylthio, 2-methylpentylthio,
3-methylpentylthio, 1-ethylbutylthio, 2-ethylbutylthio,
1,1-dimethylbutylthio, 2,2-dimethylbutylthio,
3,3-dimethylbutylthio, 1-ethyl-1-methylpropylthio and the like.
[0086] More preferred is alkylthio having up to 4 carbon atoms,
such as methylthio, ethylthio, n-propylthio, i-propylthio,
n-butylthio, i-butylthio, sec-butylthio, t-butylthio and the
like.
[0087] "Mono- or di(lower)alkylcarbamoyl" is carbamoyl mono- or
di-substituted by the above-mentioned lower alkyl.
[0088] "Halo(lower)alkyl" is a linear or branched alkyl having up
to 6 carbon atoms, which is substituted by fluorine atom, chlorine
atom, bromine atom or iodine atom, and is preferably exemplified by
a linear or branched alkyl having up to 6 carbon atoms, which is
substituted by fluorine atom, chlorine atom or bromine atom.
Examples thereof include fluoromethyl, difluoromethyl,
trifluoromethyl chloromethyl dichloromethyl, trichloromethyl,
bromomethyl, dibromomethyl, tribromomethyl, 1-fluoroethyl,
1-chloroethyl, 1-bromoethyl, 2-fluoroethyl, 2-chloroethyl,
2-bromoethyl, 1,2-difluoroethyl, 1,2-dichloroethyl,
1,2-dibromoethyl, 2,2,2-trifluoroethyl, heptafluoroethyl,
1-fluoropropyl, 1-chloropropyl, 1-bromopropyl, 2-fluoropropyl,
2-chloropropyl, 2-bromopropyl, 3-fluoropropyl, 3-chloropropyl,
3-bromopropyl, 1,2-difluoropropyl, 1,2-dichloropropyl,
1,2-dibromopropyl, 2,3-difluoropropyl, 2,3-dichloropropyl,
2,3-dibromopropyl, 3,3,3-trifluoropropyl,
2,2,3,3,3-pentafluoropropyl, 2-fluorobutyl, 2-chlorobutyl,
2-bromobutyl, 4-fluorobutyl, 4-chlorobutyl, 4-bromobutyl,
4,4,4-trifluorobutyl, 2,2,3,3,4,4,4-heptafluorobutyl,
perfluorobutyl, 2-fluoropentyl, 2-chloropentyl, 2-bromopentyl,
5-fluoropentyl, 5-chloropentyl, 5-bromopentyl, perfluoropentyl,
2-fluorohexyl, 2-chlorohexyl, 2-bromohexyl, 6-fluorohexyl,
6-chlorohexyl, 6-bromohexyl, perfluorohexyl, 2-fluoroheptyl,
2-chloroheptyl, 2-bromoheptyl, 7-fluoroheptyl, 7-fluoroheptyl,
7-cloroheptyl, 7-bromoheptyl, perfluoroheptyl and the like.
[0089] Examples of preferable aryl(lower)alkyl include
C.sub.6-C.sub.10aryl(C.sub.1-C.sub.6)alkyl such as benzyl,
phenylethyl, phenylpropyl, phenylbutyl, phenylpentyl, phenylhexyl,
naphthylmethyl, naphthylethyl, naphthylpropyl, naphthylbutyl,
naphthylpentyl, naphthylhexyl and the like.
[0090] "Aryl(lower)alkenyl" and "aryl(lower)alkoxy" are
respectively the above-mentioned lower alkenyl and lower alkoxy
substituted by the above-mentioned aryl.
[0091] "Protected carboxy" is preferably esterified carboxy.
[0092] Examples of preferable ester moiety of the esterified
carboxy include lower alkyl esters such as methyl ester, ethyl
ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester,
t-butyl ester, pentyl ester and hexyl ester. These groups may have
at least one appropriate substituent, which is exemplified by
(lower)alkanoyloxy-(lowe- r)alkyl ester such as acetoxymethyl
ester, propionylymethyl ester, butyryloxymethyl ester,
valeryloxymethyl ester, pivaloyloxymethyl ester, hexanoyloxymethyl
ester, 1 (or 2)-acetoxyethyl ester, 1 (or 2 or 3)-acetoxypropyl
ester, 1 (or 2 or 3 or 4)-acetoxybutyl ester, 1 (or
2)-propionyloxyethyl ester, 1 (or 2 or 3)-propionyloxypropyl ester,
1 (or 2)-butyryloxyethyl ester, 1 (or 2)-isobutyryloxyethyl ester,
1 (or 2)-pivaloyloxyethyl ester, 1 (or 2)-hexanoyloxyethyl ester,
isobutyryloxy-methyl ester, 2-ethylbutyryloxymethyl ester,
3,3-dimethylbutyryloxymethyl ester, 1 (or 2)-pentanoyloxyethyl
ester), and the like, lower alkanesulfonyl(lower)alkyl ester (e.g.,
2-mesylethyl ester), mono- (or di- or tri)halo(lower)alkyl ester
(e.g., 2-iodoethyl ester and 2,2,2-trichloroethyl ester), lower
alkoxycarbonyloxy(lower)alky- l ester (e.g.,
methoxycarbonyloxymethyl ester, ethoxycarbonyloxyethyl ester,
2-methoxy-carbonyloxyethyl ester, 1-ethoxycarbonyloxyethyl ester
and 1-isopropoxycarbonyl-oxyethyl ester),
phthalidylidene(lower)alkyl ester and
(5-(lower)alkyl-2-oxo-1,3-dioxol-4-yl(lower)alkyl ester (e.g.,
(5-methyl-2-oxo-1,3-dioxol-4-yl)methyl ester,
(5-ethyl-2-oxo-1,3-dioxol-4- -yl)methyl ester and
(5-propyl-2-oxo-1,3-dioxol-4-yl)ethyl ester);
[0093] lower alkenyl ester (e.g, vinyl ester and allyl ester);
[0094] lower alkynyl ester (e.g, ethynyl ester and propynyl
ester);
[0095] aryl(lower)alkyl ester optionally having at least one
suitable substituent, such as mono- (or di- or
tri-)phenyl(lower)alkyl ester optionally having at least one
suitable substituent, which is exemplified by benzyl ester,
4-methoxybenzyl ester, 4-nitrobenzyl ester, phenylethyl ester,
trityl ester, benzhydryl ester, bis(methoxyphenyl)methyl ester,
3,4-dimethoxybenzyl ester and 4-hydroxy-3,5-di-t-butylbenzyl
ester;
[0096] aryl ester optionally having at least one suitable
substituent, such as phenyl ester, 4-chlorophenyl ester, tolyl
ester, t-butylphenyl ester, xylyl ester, mesityl ester and cumenyl
ester;
[0097] cyclo(lower)alkyl ester (e.g., cyclohexyl ester); phthalidyl
ester, and the like.
[0098] The heterocyclic group having nitrogen, which is represented
by 10
[0099] is exemplified by the above-mentioned heterocyclic group
having nitrogen.
[0100] The preferable objective compound (I) is a compound of the
formula (I) having the following groups and pharmaceutically
acceptable salts thereof. R.sup.1 is an optionally substituted
alkyl, an optionally substituted alkenyl, an optionally substituted
alkynyl, an optionally substituted cyclo(lower)alkyl, an optionally
substituted aryl or an optionally substituted heterocyclic group,
where, when the above groups are substituted, the substituent is at
least one member selected from the group consisting of alkyl,
cyclo(lower)alkyl alkenyl, alkynyl, lower alkanoyl, lower alkoxy,
aryl, heterocycle(lower)alkyl, halogen, amino, substituted amino,
lower alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, cyano,
carboxy, protected carboxy, carbamoyl, mono(lower)alkylcarbamoyl,
di(lower)alkylcarbamoyl, nitro, halo(lower)alkyl, aryl(lower)alkyl,
aryl(lower)alkenyl, aryl(lower)alkoxy, lower alkoxy substituted by
substituted amino, cyclo(lower)alkyl(lower)alkoxy,
cyclo(lower)alkyl-(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycleoxy(lower)alky- l, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group. A is a
heteropolycyclic group having at least one hetero atom, such as
oxygen atom, sulfur atom, selenium atom and nitrogen atom,
exclusive of benzimidazolyl, indolyl, 4,7-dihydrobenzmidazolyl and
2,3-dihydrobenzoxazinyl, said heterocyclic group being optionally
substituted by at least one member selected from the group
consisting of alkyl, oxo, thioxo, halogen, lower alkoxy, lower
alkylthio, cyclo(lower)alkyl, optionally substituted amino, aryl,
heterocyclic group, lower alkylsulfonyl and lower alkylsulfinyl
R.sup.2 is optionally substituted aryl optionally substituted
heterocyclic group or substituted biphenylyl, wherein, when these
groups are substituted, the substituent is at least one member
selected from the group consisting of alkyl cyclo(lower)alkyl,
alkenyl alkynyl lower alkanoyl, lower alkoxy, aryl,
heterocycle(lower)alkyl, halogen, amino, substituted amino, lower
alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, cyano,
carboxy, protected carboxy, carbamoyl, mono(lower)alkylcarbamoyl,
di(lower)alkylcarbamoyl, nitro, halo(lower)alkyl, aryl(lower)alkyl,
aryl(lower)alkenyl, aryl(lower)alkoxy, lower alkoxy substituted by
substituted amino, cyclo(lower)alkyl-(lower)alkoxy,
cyclo(lower)alkyl(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy-(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycleoxy(lower)alkyl, aryl(lower)alkylthio, arylureido, lower
alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl substituted by
optionally substituted divalent heterocyclic group and optionally
substituted heterocyclic group,
[0101] provided that when A is 3H-imidazo[4,5b]pyridyl substituted
by lower alkyl, R.sup.2 is optionally substituted aryl, optionally
substituted heterocyclic group or biphenylyl substituted by a
substituent other than tetrazolyl, and when A is quinolyl
substituted by lower alkyl, R.sup.2 is optionally substituted aryl,
optionally substituted heterocyclic group or substituted
biphenylyl.
[0102] When the above-mentioned aryl and heterocyclic group are
substituted, the substituent is at least one member selected from
the group consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl,
lower alkanoyl lower alkoxy, phenyl, heterocycle(lower)alkyl,
halogen, amino, substituted amino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carboxy, protected carboxy,
carbamoyl, mono(lower(alkylcarbamoyl, di(lower)alkylcarbamoyl,
nitro, halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)-alkylamino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alk- yl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group.
[0103] The substituent for the above-mentioned biphenylyl is at
least one member selected from the group consisting of alkyl,
cyclo(lower)alkyl, alkenyl, alkynyl, lower alkanoyl, lower alkoxy,
phenyl, heterocycle(lower)alkyl other than substituted
tetrazolylmethyl, halogen, amino, substituted amino, lower
alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, cyano,
carbamoyl, mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl,
nitro, halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkoxy substituted by substituted amino,
cyclo(lower)alkyl-(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy-(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alkyl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group.
[0104] Of the above-mentioned compounds, a compound of the formula
(I) having the following and pharmaceutically acceptable salts
thereof are particularly preferable. R.sup.1 is an optionally
substituted alkyl, an optionally substituted alkenyl, an optionally
substituted alkynyl, an optionally substituted cyclo(lower)alkyl,
an optionally substituted phenyl or an optionally substituted
heterocyclic group, wherein, when these groups are substituted, the
substituent is at least one member selected from the group
consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl, lower
alkanoyl, lower alkoxy, phenyl, heterocycle(lower)alkyl, halogen,
amino, lower alkanoylamino, mono(lower)alkylamino,
di(lower)alkylamino, N-(lower)alkyl-N-acylamino, lower
alkylsulfonylamino, aryl(lower)alkylamino,
N-heterocycle-N-(lower)alkylam- ino, arylsulfonylamino,
arylcarbonylamino, lower alkylsulfonyl, lower alkylsulfinyl, lower
alkylthio, cyano, carboxy, protected carboxy, carbamoyl
mono(lower)alkylcarbamoyl, di(lower)alkylcarbamoyl, nitro,
halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkanoylamino(lower)alkoxy,
mono(lower)alkylamino-(lower)alkoxy,
di(lower)alkylamino(lower)alkoxy,
N-(lower)alkyl-N-acylamino(lower)-alkoxy, lower
alkylsulfonylamino(lower)- alkoxy,
aryl(lower)alkylamino(lower)alkoxy, N-heterocycle-N-(lower)alkylam-
ino(lower)alkoxy, arylsulfonylamino(lower)alkoxy,
arylcarbonylamino(lower)- alkoxy, cyclo(lower)alkyl(lower)alkoxy,
cyclo(lower)alkyl-di(lower)alkyl, aryloxy(lower)alkyl,
acyloxy(lower)alkyl, hydroxy(lower)alkyl, mono- or
di(lower)alkylamino(lower)alkyl, aryl(lower)alkoxy(lower)alkyl,
arylthio(lower)alkyl, heterocycle(lower)alkoxy,
heterocycle-oxy(lower)alk- yl, aryl(lower)alkylthio, arylureido,
lower alkoxy(lower)alkoxy, aryl(lower)alkynyl, lower alkyl
substituted by optionally substituted divalent heterocyclic group
and optionally substituted heterocyclic group. A is a heterocyclic
group of the following (A) to (I) exclusive of benzimidazolyl,
indolyl, 4,7-dihydrobenzimidazolyl and 2,3-dihydrobenzoxazinyl,
wherein said heterocyclic group may be substituted by at least one
member selected from the group consisting of alkyl, oxo, thioxo,
halogen, lower alkoxy, lower alkylthio, cyclo(lower)alkyl, amino,
lower alkanoylamino, mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)alkylam- ino,
arylsulfonylamino, arylcarbonylamino, aryl, heterocyclic group,
lower alkylsulfonyl and lower alkylsulfinyl,
[0105] provided that when A is 3H-imidazo[4,5-b]pyridyl substituted
by lower alkyl, R.sup.2 is an optionally substituted aryl,
optionally substituted heterocyclic group or biphenylyl substituted
by a group other than tetrazolyl, and when A is quinolyl
substituted by lower alkyl, R.sup.2 is an optionally substituted
phenyl, optionally substituted naphthyl, optionally substituted
heterocyclic group or substituted biphenylyl.
[0106] The substituent for the above-mentioned phenyl, naphthyl and
heterocyclic group is at least one member selected from the group
consisting of alkyl, cyclo(lower)alkyl, alkenyl, alkynyl, lower
alkanoyl, lower alkoxy, phenyl, heterocycle(lower)alkyl, halogen,
amino, lower alkanoylamino, mono(lower)-alkylamino,
di(lower)alkylamino, N-(lower)alkyl-N-acylamino, lower
alkylsulfonyl-amino, aryl(lower)alkylamino,
N-heterocycle-N-(lower)alkylamino, arylsulfonylamino,
arylcarbonylamino, lower alkylsulfonyl, lower alkylsulfinyl, lower
alkylthio, cyano, carboxy, protected carboxy, carbamoyl,
mono(lower)alkylcarbamoyl, di(lower)alkyl-carbamoyl, nitro,
halo(lower)alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)-alkoxy, lower alkanoylamino(lower)alkoxy,
mono(lower)alkylamino(lower)alkyl,
di(lower)alkylamino(lower)alkoxy,
N-(lower)alkyl-N-acylamino(lower)alkoxy, lower
alkylsulfonylamino(lower)a- lkoxy,
aryl(lower)alkylamino(lower)alkoxy,
N-heterocycle-N-(lower)alkylami- no(lower)alkoxy,
arylsulfonylamino(lower)alkoxy, arylcarbonyl-amino(lower)- alkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)alkyl
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkyl-amino(lower)alkyl,
aryl(lower)alkoxy(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alk- yl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group.
[0107] The substituent for the above-mentioned biphenylyl is at
least one member selected from the group consisting of alkyl,
cyclo(lower)alkyl, alkenyl, alkynyl, lower alkanoyl, lower alkoxy,
phenyl, heterocycle(lower)alkyl other than substituted
tetrazolylmethyl, halogen, amino, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-acylamino, lower alkylsulfonylamino,
aryl(lower)alkylamino, N-heterocycle-N-(lower)alkylamino,
arylsulfonylamino, arylcarbonylamino, lower alkylsulfonyl, lower
alkylsulfinyl, lower alkylthio, cyano, carbamoyl,
mono(lower)alkylcarbamo- yl, di(lower)alkylcarbamoyl, nitro,
halo(lower)-alkyl, aryl(lower)alkyl, aryl(lower)alkenyl,
aryl(lower)alkoxy, lower alkanoylamino-(lower)alkoxy,
mono(lower)alkylamino(lower)alkoxy,
di(lower)alkylamino(lower)alkoxy,
N-(lower)alkyl-N-acylamino(lower)alkoxy, lower
alkylsulfonylamino(lower)a- lkoxy,
aryl(lower)alkylamino(lower)alkoxy,
N-heterocycle-N-(lower)alkylami- no(lower)alkoxy,
arylsulfonylamino(lower)alkoxy, arylcarbonylamino(lower)a- lkoxy,
cyclo(lower)alkyl-(lower) alkoxy, cyclo(lower)alkyl(lower)alkyl,
aryloxy(lower)alkyl, acyloxy(lower)alkyl, hydroxy(lower)alkyl,
mono- or di(lower)alkylamino(lower)alkyl,
aryl(lower)alkoxy-(lower)alkyl, arylthio(lower)alkyl,
heterocycle(lower)alkoxy, heterocycle-oxy(lower)alk- yl,
aryl(lower)alkylthio, arylureido, lower alkoxy(lower)alkoxy,
aryl(lower)alkynyl, lower alkyl substituted by optionally
substituted divalent heterocyclic group and optionally substituted
heterocyclic group.
[0108] The above-mentioned heterocyclic group means the following
(A) to (T):
[0109] (A) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 to 4 nitrogen atoms
[0110] (B) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 to 3 oxygen atoms
[0111] (C) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 to 3 sulfur atoms
[0112] (D) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 to 3 nitrogen atoms and 1 or 2 oxygen atoms
[0113] (E) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 to 3 nitrogen atoms and 1 or 2 sulfur atoms
[0114] (F) saturated or unsaturated 7 to 12-member-ed
heterobicyclic group having 1 or 2 oxygen atoms and 1 or 2 sulfur
atoms
[0115] (G) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 nitrogen atom, 1 oxygen atom and 1 sulfur atom
[0116] (H) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 or 2 selenium atoms
[0117] (I) saturated or unsaturated 7 to 12-membered heterobicyclic
group having 1 or 2 selenium atoms and 1 to 3 nitrogen atoms
[0118] (J) unsaturated 3 to 8-membered heteromonocyclic group
having 1 to 4 nitrogen atoms
[0119] (K) saturated 3 to 8-membered heteromonocyclic group having
1 to 4 nitrogen atoms
[0120] (L) unsaturated 3 to 8-membered heteromonocyclic group
having 1 or 2 oxygen atoms and 1 to 3 nitrogen atoms
[0121] (M) saturated 3 to 8-membered heteromonocyclic group having
1 or 2 oxygen atoms and 1 to 3 nitrogen atoms
[0122] (N) unsaturated 3 to 8-membered heteromonocyclic group
having 1 or 2 sulfur atoms and 1 to 3 nitrogen atoms
[0123] (O) saturated 3 to 8-membered heteromonocyclic group having
1 or 2 sulfur atoms and 1 to 3 nitrogen atoms
[0124] (P) unsaturated 3 to 8-membered heteromonocyclic group
having 1 or 2 sulfur atoms
[0125] (Q) unsaturated 3- to 8-membered heteromonocyclic group
having 1 or 2 oxygen atoms
[0126] (R) unsaturated 3 to 8-membered heteromonocyclic group
having 1 oxygen atom
[0127] (S) spiroheterocyclic group having 1 or 2 oxygen atoms
[0128] (T) unsaturated 3 to 8-membered heteromonocyclic group
having 1 oxygen atom and 1 or 2 sulfur atoms
[0129] Of the above-mentioned compounds, a compound of the formula
(I) wherein A is a heterocyclic group selected from the group
consisting of 2,3-dihydrobenzmidazolyl, pyrazolopyrimidinyl,
tetrahydropyrzolopyrimidin- yl, imidazopyrazolyl,
dihydro-imidazopyrazolyl, imidazopyridyl pyrrolopyridyl,
pyrazolopyridyl, benzopyrazolyl, dihydrobenzimidazolyl,
benzotriazolyl, indolizinyl isoindolyl, indazolyl, indolinyl,
isoindolinyl, purinyl, quinolizinyl, isoquinolyl, quinolyl,
phthalazinyl, naphthalidinyl, quinoxalinyl, dihydroquinoxalinyl,
tetrahydroquinoxalinyl, quinazolinyl, dihydroquinazolinyl,
tetrahydroquinazolinyl, cinnolinyl, pteridinyl,
pyrazinopyridazinyl, imidazotriazinyl, imidazopyrazinyl,
imidazopyrimidinyl, imidazopyridazinyl, 1H-1-(or 2)pyridazinyl,
benzofuranyl isobenzofuranyl, furopyridyl, chromenyl, chromanyl,
isochromanyl, benzoxepinyl, cyclopentapyranyl, furopyranyl,
benzothiophenyl, dihydrodithianaphthaleny- l, dithianaphthalenyl,
diaxoloimidazolyl, benzoxazinyl, pyridoxazinyl, pyrazolooxazolyl,
furopyridyl, thienoimidazolyl, thienopyridyl, dithiadiazaindanyl,
thienofuranyl, oxathiolopyrrolyl, benzoselenophenyl, selenopyridyl,
benzoselenol, selenopyridyl and cyclopentadienopyridyl. These
heterocyclic groups are preferably optionally substituted by lower
alkyl and/or oxo.
[0130] Of the above-mentioned compounds, preferably exemplified is
a compound of the formula (I) wherein R.sup.1 is an alkyl, an
alkenyl, a phenyl(lower)alkenyl, a quinolyl, a phenyl optionally
substituted by a substituent selected from the group consisting of
nitro, alkyl and alkenyl or a thienyl optionally substituted by
halogen; A is a heterocyclic group selected from the group
consisting of 2,3-dihydrobenzmidazolyl, imidazopyrazolyl,
imidazopyridyl, pyrrolopyridyl, pyrazolopyridyl, benzotriazolyl,
indolizinyl, indazolyl, quinolyl, dihydroquinoxalinyl,
tetrahydroquinxalinyl, dihydroquinazolinyl, tetrahydroquinazolinyl,
benzofuranyl, benzothiophenyl and thienoimidazolyl, said
heterocyclic group being optionally substituted by alkyl or oxo; X
is a lower alkylene, an oxa(lower)alkylene or an oxa; and R.sup.2
is a phenyl optionally substituted by a substituent selected from
the group consisting of alkyl, alkenyl, alkynyl lower alkanoyl,
lower alkoxy, phenyl, imidazolyl(lower)alkyl,
piperidinyl-(lower)alkyl, halogen, amino, lower alkanoylamino,
mono(lower)alkylamino, di(lower)alkylamino,
N-(lower)alkyl-N-(lower)alkanoylamino,
N-(lower)alkyl-N-benzoylamino, lower alkylsulfonylamino,
phenyl(lower)alkylamino, phenyl-sulfonylamino, benzoylamino, lower
alkylsulfonyl, lower alkylsulfinyl, lower alkylthio, cyano,
carboxy, lower alkoxycarbonyl, cyclo(lower)alkyloxycarbonyl,
mono(lower)-alkylcarbamoyl, nitro, halo(lower)alkyl,
phenyl(lower)alkyl, phenyl(lower)alkenyl, phenyl(lower)alkoxy,
(N-pyridyl-N-(lower)alkylamino- )(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy, cyclo(lower)alkyl(lower)al- kyl,
phenoxy(lower)alkyl, lower alkylsulfonyloxy(lower)alkyl,
hydroxy(lower)alkyl, di(lower)alkylamino-(lower)alkyl,
phenyl(lower)alkoxy(lower)alkyl, phenylthio(lower)alkyl,
thienyl(lower)-alkoxy, pyridyloxy(lower)alkyl,
phenyl(lower)alkylthio, phenylureido, lower alkoxy(lower)alkoxy,
phenyl(lower)alkynyl, dioxothiazolidylidene(lower)alkyl and thienyl
optionally substituted by halogen; a naphthyl optionally
substituted by halogen; a 4-phenylphenyl substituted by halogen; a
thienyl optionally substituted by halogen; a benzothienyl
optionally substituted by halogen; a quinolyl optionally
substituted by halogen; or a benzooxolanyl optionally substituted
by halogen.
[0131] Of the above-mentioned compounds, preferred is a compound of
the formula (I) wherein R.sup.1 is an alkyl, an alkenyl, a
phenyl(lower)alkenyl, a phenyl optionally substituted by a
substituent selected from the group consisting of alkyl and alkenyl
or a thienyl optionally substituted by halogen; A is a heterocyclic
group selected from the group consisting of
3H-imidazo[4,5-b]pyridyl, pyrazolo[1,5-a]pyridyl, indolizinyl,
1H-indazolyl, benzo[b]furanyl and benzo[b]thiophenyl, said
heterocyclic group being optionally substituted by one or two
alkyl; X is an alkylene; and R.sup.2 is a phenyl optionally
substituted by a substituent selected from the group consisting of
alkyl, lower alkoxy, phenyl, halogen, di(lower)alkylamino, lower
alkylthio, lower alkoxycarbonyl, nitro, halo(lower)alkyl,
phenyl(lower)alkyl, phenyl(lower)alkenyl, phenyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy- , phenoxy(lower)alkyl,
phenyl(lower)alkoxy(lower)alkyl and thienyl optionally substituted
by halogen; a naphthyl optionally substituted by halogen; or a
4-phenylphenyl substituted by halogen.
[0132] Of the above-mentioned compounds, preferred is a sulfonamide
compound (I) wherein A is a 3H-imidazo[4,5-b]pyridyl, a
1H-indazolyl or a benzo[b]furanyl, these heterocyclic groups being
optionally substituted by alkyl; and R.sup.2 is a phenyl
substituted by halogen, said phenyl being optionally substituted by
a substituent selected from the group consisting of alkyl, alkenyl,
alkynyl, lower alkoxy, phenyl, halogen, di(lower)alkylamino, lower
alkylthio, lower alkoxycarbonyl, nitro, halo(lower)alkyl,
phenyl(lower)alkyl, phenyl(lower)alkenyl, phenyl(lower)alkoxy,
cyclo(lower)alkyl(lower)alkoxy, phenoxy(lower)alkoxy(lower)alkyl,
phenyl(lower)alkynyl and thienyl optionally substituted by halogen,
or a naphthyl substituted by halogen, or a salt thereof. Above all,
a sulfonamide compound (I) wherein A is 3H-imidazo[4,5-b]pyridyl
substituted by one or two lower alkyl, 1H-indazolyl substituted by
one lower alkyl or benzo[b]furanyl substituted by one lower alkyl
is preferable.
[0133] Particularly preferable groups are as follows.
[0134] R.sup.1: phenyl, 2-nitrophenyl, o- or p-tolyl, n-pentenyl,
n-butyl, n-pentyl n-hexyl, thienyl, 8-quinolyl,
(E)-2-phenylethenyl, 4-pentenyl, 4-vinylphenyl
5-chlorothiophen-2-yl, 5-bromothiophen-2-yl, 4-ethylphenyl,
[0135] X: methylene, --OCH.sub.2--, oxa
[0136] R.sup.2: 2,4-dichlorophenyl, 2-chlorophenyl,
4-bromo-2-chlorophenyl, 2,4-dichloro-5-fluorophenyl,
3,4-dichlorophenyl, 2,3-dichlorophenyl, 2,5-dichlorophenyl,
2-bromo-4-chlorophenyl, 4-chloro-2-methoxyphenyl,
4-chloro-2-methylphenyl, 4-phenyl-phenyl, 2-chloro-4-phenylphenyl,
1-bromo-2-naphthyl, 3-chlorobenzo[b]thiophen-2-y- l,
2-chloro-4-(thiophen-2-yl)phenyl,
2-chloro-4-(5-chlorothiophen-2-yl)phe- nyl, 2-chloro-4-ethylphenyl,
2-chloro-4-vinylphenyl, 2-chloro-4-methylphenyl,
2-chloro-4-(n-pentyl)phenyl, 2-chloro-4-(i-butyl)phenyl,
2-chloro-4-(cyclohexylmethyl)phenyl,
(E)-2-chloro-4-(2-phenylethenyl)phenyl, 4-benzyloxy-2-chlorophenyl,
2-chloro-4-methoxyphenyl, 2-chloro-4-isopropoxyphenyl,
2-chloro-4-(n-butoxy)phenyl,
2-chloro-4-((cyclohexylmethyl)oxy)phenyl,
2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)-amino)ethyl)oxy)phenyl,
2-chloro-4-(methylthio)phenyl, 2-chloro-4-(methylsulfinyl)-phenyl,
2-chloro-4-(methanesulfonyl)phenyl, 4-(benzylamino)-2-chlorophenyl,
4-(n-butylamino)-2-chlorophenyl,
2-chloro-4-(N,N-dimethylamino)phenyl 4-acetylamino-2-chlorophenyl,
2-chloro-4-(methanesulfonylamino)phenyl 2-chloro-4-nitrophenyl,
2-chloro-4-formylphenyl 2-chloro-4-[(2,4-dioxol-1-
,3-thiazolidin-5-ylidene)methyl]-phenyl, 2-chloro-4-fluorophenyl,
2,4,6-trichlorophenyl, 2,3,4-trichlorophenyl,
2-chloro-4-iodophenyl, 2,5-dichlorothiophen-3-yl,
2-chloro-4,5-(methylenedioxy)-phenyl, 2-chloroquinolin-3-yl,
2-chloro-4-(trifluoromethyl)phenyl, 2-chloro-4-cyanophenyl,
2-chloro-4-(2-phenylethyl)phenyl, 2-chloro-aminophenyl,
2-chloro-4-(hydroxymethyl)phenyl, 4-carboxy-2-chlorophenyl,
2-chloro-4-((methane-sulfonyloxy)methyl)phenyl,
2-chloro-4-((phenyloxy)methyl)phenyl,
2-chloro-4-(ethoxycarbonyl)phenyl,
2-chloro-4-(methylcarbamoyl)phenyl,
2-chloro-4-(dimethyl-aminomethyl)phen- yl,
2-chloro-4-((imidazol-1-yl)methyl)phenyl,
2-chloro-4-((piperidin-1-yl)- methyl)phenyl,
2-chloro-4-(phenylthiomethyl)phenyl,
4-(benzyloxy)-methyl)-2-chlorophenyl,
4-(benzimidazol-2-yl)-2-chloropheny- l,
4-(1-methylbenz-imidazol-2-yl)-2-chlorophenyl,
1-ethylbenzimidazol-2-yl- , 2-chloro-4-(n-pentanethio)-phenyl,
4-(benzylthio)-2-chlorophenyl,
2-chloro-4-((3-pyridyloxy)methyl)phenyl,
2-chloro-4-ethylthiophenyl, 4-(N-butyrylamino)-2-chlorophenyl,
4-(N-benzoylamino)-2-chlorophenyl
4-(N-benzoyl-N-methylamino)-2-chlorophenyl,
4-(N-butyryl-N-methyl-amino)-- 2-chlorophenyl,
2-chloro-4-(N-(n-pentyl)amino)phenyl,
2-chloro-4-(N-methyl-N-n-pentyl)amino)phenyl,
4-(N-benzenesulfonylamino)-- 2-chlorophenyl,
2-chloro-4-(isopropoxylcarbonyl)phenyl,
2-chloro-4-(cyclohexyloxycarbonyl)phenyl,
2-chloro-4-(3-phenylureido)phen- yl, 2-chloro-4-propoxyphenyl,
2-chloro-4-(n-pentoxy)phenyl, 2-chloro-4-ethoxyphenyl,
2-chloro-4-(2-methoxyethoxy)phenyl,
2-chloro-4-[(thiophen-2-yl)methyloxy]phenyl,
2-chloro-4-[(thiophen-3-yl)m- ethyloxy]phenyl,
2-chloro-4-phenylethynylphenyl, 2-chloro-4-(cyclopentylme-
thyloxy)phenyl, 2-chloro-4-(1-hexynyl)phenyl,
2-chloro-4-hexylphenyl, 2-chloro-4-piperidinophenyl,
2-chloro-4-morpholinophenyl, 2-chloro-4-(hexamethyleneimino)phenyl,
2-chloro-4-pyrrolidino-phenyl,
2-chloro-4-(4-methylpiperazin-1-yl)phenyl A:
4H-imidazo[1,2-b]pyrazolyl, 3H-thieno[2,3-d]imidazolyl,
1H-thieno[2,3-d]imidazolyl, imidazo[1,2-a]pyridyl,
1H-pyrrolo[3,2-b]pyridyl, 2,3-dihydrobenzo-[d]imid- azolyl,
1H-indazolyl, indolizinyl, benzotriazolyl, 1H-imidazo[4,5-b]pyridy-
l, 3H-imidazo[4,5-b]pyridyl, pyrazolo[1,5-a]pyridyl,
benzo[b]furanyl, benzo[b]thiophenyl, 3,4-dihydroquinazolinyl,
1,2-dihydroquinoxalinyl, 1,2,3,4-tetrahydroquinoxalinyl, quinolyl,
1,2,3,4-tetrahydroquinazolinyl, 1,4-dihydroquinazolinyl,
2H-indazolyl Substituent of A: methyl, ethyl n-propyl,oxo
[0137] Preferred objective compounds (I) are as follows.
[0138]
3-(3,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo-
[b]thiophene
[0139]
3-(2,3-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo-
[b]thiophene
[0140]
3-(2,5-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo-
[b]thiophene
[0141]
3-(2,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)pyraz-
olo[1,5-a]pyridine
[0142]
3-(2,4-dichlorobenzyl)-2-methyl-5-(bezenesulfonylcarbamoyl)pyrazolo-
[1,5-a]pyridine
[0143]
1-(2,4-dichlorobenzyl)-2-methyl-7-(n-pentanesulfonylcarbamoyl)indol-
izine
[0144]
7-n-butanesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylindolizi-
ne
[0145]
1-(2,4-dichlorobenzyl)-2-methyl-7-(benzenesulfonylcarbamoyl)indoliz-
ine
[0146]
2-methyl-7-(n-pentanesulfonylcarbamoyl)-1-(4-phenylbenzyl)indolizin-
e
[0147]
6-(n-pentanesulfonylcarbamoyl)-4-(4-phenylbenzyl)quinoline
[0148]
3-(2,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-3H-i-
midazo[4,5-b]pyridine
[0149]
5-(n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methyl-3H-im-
idazo[4,5-b]pyridine
[0150]
5-benzenesulfonylcarbomoyl-3-(2,4-dichlorobenzyl)-2-methyl-3H-imida-
zo[4,5-b]pyridine
[0151]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-
-3H-imidazo[4,5-b]pyridine
[0152]
3-(1-bromo-2-naphthyl)methyl-2-methyl-5-(n-pentanesulfonylcarbamoyl-
)-3H-imidazo[4,5-b]pyridine
[0153]
2-methyl-5-(n-pentanesulfonylcarbamoyl)-3-(4-phenylbenzyl)-3H-imida-
zo[4,5-b]pyridine
[0154]
3-(4-bromo-2-chlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)--
3H-imidazo[4,5-b]pyridine
[0155]
3-(4-bromo-2-chlorobenzyl)-5-(n-butanesulfonylcarbamoyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine
[0156]
5-benzenesulfonylcarbamoyl)-3-(4-bromo-2-chlorobenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine
[0157]
3-(2-bromo-4-chlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)--
3H-imidazo[4,5-b]pyridine
[0158]
5-(benzenesulfonylcarbamoyl)-3-(2-bromo-4-chlorobenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine
[0159]
3-(2-bromo-4-chlorobenzyl)-5-(n-butanesulfonylcarbamoyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine
[0160]
3-(2,4-dichlorobenzyl)-2-methyl-6-(n-pentanesulfonylcarbamoyl)indol-
izine
[0161]
3-(2,4-dichlorobenzyl)-2-methyl-6-(n-butanesulfonylcarbamoyl)indoli-
zine
[0162]
3-(2,4-dichlorobenzyl)-2-methyl-6-(bezenesulfonylcarbamoyl)indolizi-
ne
[0163]
3-(2,4-dichlorobenzyl)-2-ethyl-7-methyl-5-(n-pentanesulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0164]
2-ethyl-7-methyl-5-(n-pentanesulfonylcarbamoyl)-3-(4-phenylbenzyl)--
3H-imidazo[4,5-b]pyridine
[0165]
3-(2,4-dichlorobenzyl)-2-methyl-5-(bezenesulfonylcarbamoyl)benzo[b]-
thiophene
[0166]
3-(2,4-dichlorobenzyl)-2-methyl-5-(n-butanesulfonylcarbamoyl)benzo[-
b]thiophene
[0167]
3-(4-phenylbenzyl-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]th-
iophene
[0168]
3-(2-chlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]t-
hiophene
[0169]
3-(4-bromo-2-chlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)--
benzo[b]thiophene
[0170]
3-(2,4-dichloro-5-fluorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbam-
oyl)-benzo[b]thiophene
[0171]
3-((3-chlorobenzo[b]thiophen-2-yl)methyl)-2-methyl-5-(n-pentanesulf-
onyl-carbamoyl)benzo[b]thiophene
[0172]
3-(1-bromonaphthalen-2-yl)methyl-2-methyl-5-(n-pentanesulfonyl-carb-
amoyl)benzo[b]thiophene
[0173]
1-(2,4-dichlorobenzyl)-2-methyl-5-n-pentanesulfonylcarbamoyl-1H-thi-
eno[2,3-d]imidazole
[0174]
3-(2,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-3H-t-
hieno[2,3-d]imidazole
[0175]
1-(2,4-dichlorobenzyl)-2-methyl-(n-pentanesulfonylcarbamoyl)-1H-imi-
dazo[4,5-b]pyridine
[0176]
3-(2,4-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)pyrro-
lo[3,2-b]pyridine
[0177]
3-(2,4-dichlorobenzyl)-2-methyl-5-(benzenesulfonylcarbamoyl)pyrrolo-
[3,2-b]pyridine
[0178]
3-(4-chloro-2-methoxybenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl-
)-3H-imidazo[4,5-b]pyridine
[0179]
3-(4-chloro-2-methylbenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-
-3H-imidazo[4,5-b]pyridine
[0180]
5-benzenesulfonylcarbamoyl-3-(4-chloro-2-methylbenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine
[0181]
5-benzenesulfonylcarbamoyl-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine
[0182]
5-(n-butanesulfonylcarbamoyl)-3-(2-chloro-4-phenylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine
[0183]
3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoylbenz-
o[b]furan
[0184]
5-(benzenesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methylbenzo[b-
]furan
[0185]
2-(2,4-dichorobenzyl)-3,5-dimethyl-7-(1-n-pentanesulfonylcarbamoyl)-
benzo[b]furan
[0186]
7-(benzenesulfonylcarbamoyl)-2-(2,4-dichorobenzyl)-3,5-dimethylbenz-
o[b]furan
[0187]
2-methyl-5-(1-n-pentanesulfonylcarbamoyl)-3-(4-phenylbenzyl)benzo[b-
]furan
[0188]
5-(1-benzenesulfonylcarbamoyl)-2-methyl-3-(4-phenylbenzyl)benzo[b]f-
uran
[0189]
5-(1-n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methylbenz-
o[b]furan
[0190]
3-(2,4-dichlorobenzyl)-5-(1-n-hexanesulfonylcarbamoyl)-2-methylbenz-
o[b]furan
[0191]
3-(2,4-dichlorobenzyl)-2-methyl-5-(2-thiophenesulfonylcarbamoyl)ben-
zo[b]furan
[0192]
3-(2,4-dichlorobenzyl)-2-ethyl-5-(1-n-pentanesulfonylcarbamoyl)benz-
o[b]furan
[0193]
5-(benzenesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]-
furan
[0194]
3-(2,4-dichlorobenzyl)-2-ethyl-5-(8-quinolinesulfonylcarbaomyl)benz-
o[b]furan
[0195]
3-(2,4-dichlorobenzyl)-2-yl-5-((2-methylbenzene)sulfonylcarbamoyl)--
benzo[b]furan
[0196]
3-(2,4-dichlorobenzyl)-5-(1-n-pentanesulfonylcarbamoyl)-2-propylben-
zo[b]furan
[0197]
5-(benzenesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-propylbenzo[b-
]furan
[0198]
3-(2,4-dichlorobenzyl)-5-ethyl-(2-nitrobenzenesulfonylcarbamoyl-2-p-
ropylbenzo[b]furan
[0199]
3-(2,4-dichlorobenzyl)-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]fura-
n
[0200]
3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl-ben-
zo[b]thiophene
[0201]
2-(2,4-dichlorobenzyl)-3-ethyl-7-(1-n-pentanesulfonylcarbamoyl)benz-
o[b]thiophene
[0202]
7-(benzenesulfonylcarbamoyl)-2-(2,4-dichlorobenzyl)-3-ethylbenzo[b]-
thiophene
[0203]
6-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-methyl-2-b-
enzimidazolone
[0204]
1-(2,4-dichlorobenzyl)-3-methyl-6-(1-pentanesulfonylcarbamoyl)-1H-i-
ndazole
[0205]
6-(benzenesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-methyl-1H-ind-
azole
[0206]
(E)-1-(2,4dichlorobenzyl)-3-methyl-6-((2-phenylethenyl)-sulfonylcar-
bamoyl)-1H-indazole
[0207]
6-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)benzotriazole
[0208]
6-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-methyl-1H--
indazole
[0209]
7-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-ethyl-4(3H-
)-quinazolinone
[0210]
7-(1-n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-1-methyl-4(3-
H)-quinazolinone
[0211]
7-(1-n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-4(3H)-quinaz-
olinone
[0212]
7-(1-n-butanesulfonylcarbamoyl)-2-(2,4-dichlorobenzyl)-3-methyl-4(3-
H)-quinazolinone
[0213]
6-(1-n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-3,4-dihydro--
2-methylquinazoline.hydrochloride
[0214]
1-(2,4-dichlorobenzyl)-2-methyl-7-(1-n-pentanesulfonylcarbamoyl)-4(-
1H)-quinazolinone
[0215]
7-(benzenesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-2-methyl-4(1H)--
quinazolinone
[0216]
1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methyl-7-(1-n-pentanesulfonyl--
carbamoyl)quinazoline.hydrochloride
[0217]
7-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-methyl-2(1-
H)-quinoxalinone
[0218]
7-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-4-methyl-2,3-
-(1H,4H)-quinoxalinedione
[0219]
4-(2,4-dichlorobenzyl)-5-ethyl-3-(1-n-pentanesulfonylcarbamoyl)imid-
azo[1,2-b]pyrazole
[0220]
3-(2,4-dichlorobenzyl)-2-methyl-6-(1-n-pentanesulfonylcarbamoyl)imi-
dazo[1,2-a]pyridine
[0221]
6-(n-pentanesulfonylcarbamoyl)-4-(4-phenylphenyloxy)quinoline
[0222]
6-(n-pentanesulfonylcarbamoyl)-4-(4-phenylbenzyloxy)quinoline
[0223]
3-(2,4-dichlorobenzyl)-2-ethyl-5-(((E)-pentene-1-sulfonyl)carbamoyl-
)benzo[b]furan
[0224]
1-(2,4-dichlorobenzyl)-3-ethyl-6-(1-n-pentanesulfonylcarbamoyl)-1H--
indazole
[0225]
6-(benzenesulfonylcarbamoyl)-1-(2,4-dichlorobenzyl)-3-ethyl-1H-inda-
zole
[0226]
6-(benzenesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methylimidazo-
[1,2-a]pyridine
[0227]
3-(2,3-dichlorobenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-3H-i-
midazo[4,5-b]pyridine
[0228]
3-((3-chlorobenzo[b]thiophen-2-yl)methyl)-2-methyl-5-n-pentanesulfo-
nyl-carbamoyl-3H-imidazo[4,5-b]pyridine
[0229]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)-
-benzo[b]thiophene
[0230]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(((E)-1-pentene-1-sulfonyl)c-
arbamoyl)-3H-imidazo[4,5-b]pyridine
[0231]
1-(2-chloro-4-phenylbenzyl)-3-methyl-6-(1-pentanesulfonylcarbamoyl)-
-1H-indazole-6-(benzenesulfonylcarbamoyl)-1-(2-chloro-4-phenylbenzyl)-3-me-
thyl-1H-indazole
[0232]
(E)-1-(2-chloro-4-phenylbenzyl)-3-methyl-6-((2-phenylethenyl)sulfon-
ylcarbamoyl)-1H-indazole
[0233]
1-(2-chloro-4-phenylbenzyl)-3-methyl-6-(((E)-1-pentene-1-sulfonyl)c-
arbamoyl)-1H-indazole
[0234]
1-(2-chloro-4-phenylbenzyl)-3-methyl-6-((4-vinylbenzene)sulfonylcar-
bamoyl-1H-indazole
[0235]
1-(2-chloro-4-phenylbenzyl)-3-methyl-6-((4-methylbenzene)sulfonylca-
rbamoyl)-1H-indazole
[0236]
1-(4-bromo-2-chlorobenzyl)-3-methyl-6-(1-pentanesulfonylcarbamoyl)--
1H-indazole
[0237]
6-(bezenesulfonylcarbamoyl)-1-(4-bromo-2-chlorobenzyl)-3-methyl-1H--
indazole
[0238]
(E)-1-(4-bromo-2-chlorobenzyl)-3-methyl-6-((2-phenylethenyl)sulfony-
lcarbamoyl)-1H-indazole
[0239]
3-(2,4-dichlorobenzyl)-2-methyl-5-(((E)-1-pentene-1-sulfonyl)carbam-
oyl)-benzo[b]furan
[0240]
(E)-3-(2,4-dichlorobenzyl)-2-methyl-5-((2-phenylethenyl)sulfonylcar-
bamoyl)-benzo[b]furan
[0241]
3-(2,4-dichorobenzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl-
)-benzo[b]furan
[0242]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-
-benzo[b]furan
[0243]
5-bezenesulfonylcarbamoyl)-3-(2-chloro-4-phenylbenzyl)-2-methylbenz-
o[b]furan
[0244]
(E)-3-(2-chloro-4-phenylbenzyl)-2-methyl-5-((2-phenylethenyl)sulfon-
yl-carbamoyl)benzo[b]furan
[0245]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(4-vinylbenzenesulfonylcarba-
moyl)-benzo[b]furan
[0246]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-(((E)-1-pentene-1-sulfonyl)c-
arbamoyl)-benzo[b]furan
[0247]
3-(4-bromo-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)--
benzo[b]furan
[0248]
5-(benzenesulfonylcarbamoyl)-3-(4-bromo-2-chlorobenzyl)-2-methylben-
zo[b]furan
[0249]
(E)-3-(4-bromo-2-chlorobenzyl)-2-methyl-5-((2-phenylethenyl)sulfony-
lcarbamoyl)-benzo[b]furan
[0250]
3-(2,4-dichlorobenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0251]
3-(2,4-dichlorobenzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcarbamoy-
l]-3H-imidazo[4,5-b]pyridine
[0252]
(E)-3-(2,4-dichlorobenzyl)-2-methyl-5-[(2-phenylethenyl)sulfonylcar-
bamoyl]-3H-imidazo[4,5-b]pyridine
[0253]
5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-3-(2,4-dichlorobenzyl--
2-methyl-3H-imidazo[4,5-b]pyridine
[0254]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)--
2-methyl-3H-imidazo[4,5-b]pyridine
[0255]
(E)-3-(4-bromo-2-chlorobenzyl)-2-methyl-5-[(2-phenylethenyl)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0256]
3-(4-bromo-2-chlorobenzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcarb-
amoyl]-3H-imidazo[4,5-b]pyridine
[0257]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcar-
bamoyl]-3H-imidazo[4,5-b]pyridine
[0258] (E)
-3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(2-phenylethenyl)sulfo-
nylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0259]
3-(2-chloro-4-phenylbenzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarba-
moyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0260]
3-(2-chloro-4-phenylbenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylca-
rbamoyl]-3H-imidazo[4,5-b]pyridine
[0261]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0262]
3-(2-chloro-4-phenylbenzyl)-5-[(4-ethylbenzene)sulfonylcarbamoyl]-2-
-methyl-3H-imidazo[4,5-b]pyridine
[0263]
5-(benzenesulfonylcarbamoyl)-3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-
-methyl-3H-imidazo[4,5-b]pyridine
[0264]
5-(benzenesulfonylcarbamoyl)-3-[2-chloro-4-(5-chlorothiophen-2-yl)b-
enzyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0265]
3-(2-chloro-4-ethylbenzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)--
3H-imidazo[4,5-b]pyridine
[0266]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-ethylbenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine
[0267]
3-(2-chloro-4-ethylbenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcar-
bamoyl]-3H-imidazo[4,5-b]pyridine
[0268]
(E)-3-(2-chloro-4-ethylbenzyl-2-methyl-5-[(2-phenylethenyl)sulfonyl-
carbamoyl]-3H-imidazo[4,5-b]pyridine
[0269]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine
[0270]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-methylbenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine
[0271]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(n-pentyl)benzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine
[0272]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-isobutylbenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine
[0273]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(cyclohexylmethyl)benzyl-
)-2-methyl-3H-imidazo[4,5-b]pyridine
[0274]
(E)-5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethenyl)ben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0275]
5-bezenesulfonylcarbamoyl)-3-(4-benzyloxy-2-chlorobenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine
[0276]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-methoxybenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine
[0277]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-isopropybenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine
[0278]
5-benezenesulfonylcarbamoyl)-3-(4-(n-butoxy)-2-chlorobenzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine
[0279]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((cyclohexylmethyl)oxy)b-
enzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0280]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((2-(N-methyl-N-(2-pyrid-
inyl)amino)-ethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0281]
5-(benezenesulfonylcarbamoyl)-3-(2-chloro-4-(methylthio)benzyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine
[0282]
5-benezenesulfonylcarbamoyl)-3-(2-chloro-4-(methylsulfinyl)benzyl)--
2-methyl-3H-imidazo[4,5-b]pyridine
[0283]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(methanesulfonyl)benzyl)-
-2-methyl-3H-imidazo[4,5-b]pyridine
[0284]
5-benezenesulfonylcarbamoyl)-3-(4-(benzylamino)-2-chlorobenzyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine
[0285]
5-(benzenesulfonylcarbamoyl)-3-(4-(n-butylamino)-2-chlorobenzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine
[0286]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(N,N-dimethylamino)benzy-
l)-2-methyl-3H-imidazo[4,5-b]pyridine
[0287]
3-(4-(acetamide)-2-chlorobenzyl)-5-(benzenesulfonylcarbamoyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine
[0288]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(methanesulfonylamino)be-
nzyl)-2-methyl-3H-imidazo[4,5-b]pyridine p1
5-(benzenesulfonylcarbamoyl)-3-
-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0289]
5-benezenesulfonylcarbamoyl)-3-(2-chloro-4-formylbenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine
[0290]
5-(benzenesulfonylcarbamoyl)-3-[2-chloro-4-[(2,4-dioxol-1,3-thiazol-
idin-5-ylidene)methyl]benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0291]
5-(benezenesulfonylcarbamoyl)-3-(2-chloro-4-fluorobenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine
[0292]
5-(benezenesulfonylcarbamoyl)-2-methyl-3-(2,4,6-trichlorobenzyl)-3H-
-imidazo[4,5-b]pyridine
[0293]
5-(benzenesulfonylcarbamoyl)-2-methyl-3-(2,3,4-trichlorobenzyl-3H-i-
midazo[4,5-b]pyridine
[0294]
5-(benzenesulfonylcarbamoyl)-3-(2,4-dichloro-5-fluorobenzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine
[0295]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-iodobenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine
[0296]
5-(benzenesulfonylcarbamoyl)-3-((2,5-dichlorothiophen-3-yl)methyl)--
2-methyl-3H-imidazo[4,5-b]pyridine
[0297]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4,5-(methylenedioxy)benzyl-
)-2-methyl-3H-imidazo[4,5-b]pyridine
[0298]
5-(benzenesulfonylcarbamoyl)-3-((2-chloroquinolin-3-yl)methyl)-2-me-
thyl-3H-imidazo[4,5-b]pyridine
[0299]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(trifluoromethyl)benzyl)-
-2-methyl-3H-imidazo[4,5-b]pyridine
[0300]
3-[2-chloro-4-(trifluoromethyl)benzyl]-2-methyl-5-(1-pentanesulfony-
lcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0301]
3-[2-chloro-4-(trifluoromethyl)benzyl]-2-methyl-5-[(4-methylbenzene-
)sulfonyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0302]
5-(benzenesulfonylcarbamoyl)-3-(1-bromonaphthalen-2-ylmethyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine
[0303]
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-5-(pentanesulfonylcar-
bamoyl)-3H-imidazo[4,5-b]pyridine
[0304]
5-(benzenesulfonylcarbamoyl)-3-(1-bromonaphthalen-2-ylmethyl)-2,7di-
methyl-3H-imidazo[4,5-b]pyridine
[0305]
(E)-3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-5-((2-phenylethen-
yl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0306]
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-5-((4-methylbenzene)s-
ulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0307]
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-5-((4-vinylbenzene)su-
lfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0308]
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-5-((5-chlorothiophen--
2-yl)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0309]
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0310]
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0311]
(E)-3-(4-bromo-2-chlorobenzyl)-2,7-diethyl-5-[(2-phenylethenyl)sulf-
onyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0312]
3-(4-bromo-2-chlorobenzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarbam-
oyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0313]
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-vinylbenzene)sulfonyl-
carbamoyl]-3H-imidazo[4,5-b]pyridine
[0314]
3-(4-bromo-2-chlorobenzyl)-5-[(5-bromothiophen-2-yl)sulfonylcarbamo-
yl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0315]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-nitrobenzyl)-2,7-dimethy-
l-3H-[4,5-b]pyridine
[0316]
3-(2-chloro-4-nitrobenzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfony-
lcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0317]
(E)-3-(2-chloro-4-nitrobenzyl)-2,7-dimethyl-5-((2-phenylethenyl)sul-
fonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0318]
3-(2-chloro-4-nitrobenzyl)-2,7-dimethyl-5-((4-vinylbenzene)sulfonyl-
carbamoyl)-3H-imidazo[4,5-b]pyridine
[0319]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-cyanobenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine
[0320]
(E)-3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-5-((2-phenyleth-
enyl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0321]
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-5-((4-vinylbenzene)-
sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0322]
3-(2-chloro-4-(trifluoromethyl)benzyl)-5-((5-chlorothiophen-2-yl)su-
lfonyl-carbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0323]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2-chloro-4-(trifluor-
omethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0324]
5-(benezenesulfonylcarbamoyl)-3-(2-chloro-4-phenylbenzyl)-2-methylb-
enzo-[b]thiophene
[0325]
1-(2-chloro-4-phenylbenzyl)-6-((5-chlorothiophen-2-yl)sulfonylcarba-
moyl)-3-methyl-1H-indazole
[0326]
6-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-1-(2-chloro-4-phenylben-
zyl)-3-methyl-1H-indazole
[0327]
3-(1-bromonaphthalen-2-ylmethyl)-5-((5-bromothiophen-2-yl)sulfonylc-
arbamoyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0328]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine
[0329]
3-(4-amino2-chlorobenzyl)-5-(benzenesulfonylcarbamoyl)-2-methyl-3H--
imidazo[4,5-b]pyridine
[0330]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(hydroxymethyl)benzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine
[0331]
5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chlorobenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine
[0332]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)met-
hyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0333]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)benzy-
l)-2-methyl-3H-imidazo[4,5-b]pyridine
[0334]
5-bezenesulfonylcarbamoyl)-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine
[0335]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(methylcarbamoyl)benzyl)-
-2-methyl-3H-imidazo[4,5-b]pyridine
[0336]
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-5-((4-methylben-
zene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0337]
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-5-((4-vinylbenz-
ene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0338]
3-(2-chloro-4-(E)-(2-phenylethenylbenzyl)-2-methyl-5-(E)-((2-phenyl-
ethenyl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0339]
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-5-((5-chlorothiophen-2-y-
l)sulfonyl-carbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridin
[0340]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(E)-(2-chloro-4-(2-ph-
enylethenyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0341]
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-5-(1-pentanesul-
fonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0342]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-((4-methylbenzene)s-
ulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0343]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-((4-vinylbenzene)su-
lfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0344]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-(E)-((2-phenylethen-
yl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0345]
3-(2-chloro-4-(2-phenylethyl)benzyl)-5-((5-chlorothiophen-2-yl)sulf-
onylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0346]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2-chloro-4-(2-phenyl-
ethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0347]
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-5-(1-pentanesulfonylc-
arbamoyl)-3H-imidazo[4,5-b]pyridine
[0348]
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfony-
lcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0349]
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-5-((4-vinylbenzene)sulfonyl-
carbamoyl)-3H-imidazo[4,5-b]pyridine
[0350]
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-5-(E)-((2-phenylethenyl)sul-
fonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0351]
3-(4-benzyloxy-2-chlorobenzyl)-5-((5-chlorothiophen-2-yl)sulfonylca-
rbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0352]
3-(4-benzyloxy-2-chlorobenzyl)-5-((5-bromothiophen-2-yl)sulfonylcar-
bamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0353]
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-5-(1-pentanesulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0354]
3-(2-chloro-4-((cyclohexylmethyloxy)benzyl)-2-methyl-5-((4-methylbe-
nzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0355]
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-((4-vinylbenz-
ene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0356]
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-5)-(E)-((2-ph-
enylethenyl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0357]
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-5-((5-chlorothiophen-2-
-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0358]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2-chloro-4-((cyclohe-
xylmethyl)-oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0359]
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-5-(1-pentanes-
ulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0360]
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-5-[(4-methylbenzene)-sul-
fonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0361]
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-5-[(4-vinylbenzene)sulfo-
nylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0362]
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-5-(E)-[(2-phenylethenyl)-
-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0363]
3-(2-chloro-(methylthio)benzyl)-5-[(5-chlorothiophen-2-yl)sulfonylc-
arbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0364]
3-[2-chloro-4-(methylthio)benzyl-5-[(5-bromothiophen-2-yl)sulfonylc-
arbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0365]
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-5-(1-pentanesulfonylcarb-
amoyl)-3H-imidazo[4,5-b]pyridine
[0366]
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-5-((4-methylbenzene)-
-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0367]
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-5-((4-vinylbenzene)--
sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0368]
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-5-(E)-((2-phenylethe-
nyl)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0369]
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-5-((5-chlorothiophen-2-yl)sul-
fonyl-carbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0370]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl-3-(2-chloro-4-(ethoxycar-
bonyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0371]
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-5-(1-pentanesulfonyl-
carbamoyl)-3H-imidazo[4,5-b]pyridine
[0372]
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-5-[(4-methylbenze-
ne)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0373]
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-5-[(4-vinylbenzen-
e)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0374]
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-5-[(E)-(2-phenyle-
thenyl)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0375]
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-5-[(5-chlorothiophen-2-yl)-
sulfonyl-carbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0376]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-((phenylo-
xy)methyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0377]
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-5-(1-pentanesulfo-
nyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0378]
3-[2-chloro-4-(dimethylaminomethyl)benzyl]-2-methyl-5-[(4-methylben-
zene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0379]
3-[2-chloro-4-((imidazol-1-yl)methyl)benzyl]-2-methyl-5[(4-methylbe-
nzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0380]
3-[2-chloro-4-((piperidin-1-yl)methyl)benzyl]-2-methyl-5-[(4-methyl-
benzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0381]
3-[2-chloro-4-(phenylthiomethyl)benzyl]-2-methyl-5-[(4-methylbenzen-
e)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0382]
3-(4-(benzyloxy)methyl)-2-chlorobenzyl)-2-methyl-5-[(4-methylbenzen-
e)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0383]
3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-5-[(4-methylbenze-
ne)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0384]
2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3-[4-(1-methylbenzi-
midazol-2-yl)-2-chlorobenzyl]-3H-imidazo[4,5-b]pyridine
[0385]
3-[(1-ethylbenzimidazol-2-yl)methyl]-2-methyl-5-[(4-methylbenzene)--
sulfonylcarbamoyl]-3H-in-imidazo[4,5-b]pyridine
[0386]
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-5-(1-pentanesulfonylc-
arbamoyl)-3H-imidazo[4,5-b]pyridine
[0387]
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-5-[(4-methylbenzene)--
sulfonylcarbamoyl]-3H-imidazol4,5-b]pyridine
[0388]
3-(2-chloro-4-(thiophen-2-yl)benzyl)-5-[(5-chlorothiophen-2-yl)sulf-
onylcarbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0389]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-(thiophen-2-
-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0390]
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-5-[(E)-(2-phenylethen-
e)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0391]
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-5-[(4-vinylbenzene)su-
lfonyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0392]
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-5-(1-pentanes-
ulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0393]
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-5-[(4-methylb-
enzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0394]
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-5-[(5-chlorothiophen-2-
-yl)sulfonylcarbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
[0395]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-(5-chloro-
thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0396]
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-5-[(E)-(2-phe-
nylethene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0397]
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-5-[(4-vinylbe-
nzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0398]
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbam-
oyl)-3H-imidazo[4,5-b]pyridine
[0399]
3-(2-chloro-4-phenylbenzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarba-
moyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0400]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylben-
zyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0401]
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-5-[(4-vinylbenzene)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0402]
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-5-(1-pentanesulfo-
nylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0403]
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-5-[(4-methylbenze-
ne)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0404]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(thiophen-
-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0405]
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-5-[(E)-(2-phenyle-
thenyl)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0406]
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-5-[(4-vinylbenzen-
e)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0407]
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-5-(1-pent-
anesulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0408]
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-5-[(4-met-
hylbenzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0409]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-[2-chloro-4-(5-chloro-
thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine
[0410]
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-5-[(E)-(2-
-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0411]
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-5-[(4-vin-
ylbenzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0412]
3-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-5-[(4-methylbenzene)--
sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0413]
3-[4-(benzylthio)-2-chloro]benzyl-2-methyl-5-[(4-methylbenzene)sulf-
onyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0414]
3-(2-chloro-4-((3-pyridyloxy)methyl)benzyl)-2-methyl-5-[(4-methylbe-
nzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0415]
3-(2-chloro-4-ethylthiobenzyl)-2-methyl-5-[(4-methylbenzene)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0416]
3-(4-(N-butyrylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)-
-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0417]
3-(4-(N-benzoylamino)-2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)-
-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0418]
3-(4-N-benzoyl-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methyl-
benzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0419]
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-phenylbenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine sodium salt
[0420]
5-[(4-vinylbenzene)sulfonylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine sodium salt
[0421]
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3-(2-chloro-4-phenylben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine sodium salt
[0422]
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine sodium salt
[0423]
3-(4-(N-butyryl-N-methylamino)-2-chlorobenzyl)-2-methyl-5-((4-methy-
lbenzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0424]
3-(2-chloro-4-N-(n-pentyl)amino)benzyl)-2-methyl-5((4-methylbenzene-
)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0425]
3-(2-chloro-4-(N-methyl-N-(n-pentyl)amino)benzyl)-2-methyl-5-((4-me-
thylbenzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0426]
3-(4-(N-benzenesulfonylamino)-2-chlorobenzyl)-2-methyl-5-((4-methyl-
benzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0427]
3-(2-chloro-4-(isopropoxylcarbonyl)benzyl)-2-methyl-5-((4-methylben-
zene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0428]
3-(2-chloro-4-(cyclohexyloxycarbonyl)benzyl)-2-methyl-5-((4-methylb-
enzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0429]
3-(2-chloro-4-(3-phenylureido)benzyl)-2-methyl-5-((4-methylbenzene)-
sulfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0430]
3-[2-chloro-4-propoxybenzyl]-2-methyl-5-[(4-methylbenzene)sulfonylc-
arbamoyl]-3H-imidazo[4,5-b]pyridine
[0431]
3-[2-chloro-4-(n-pentoxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfo-
nyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0432]
3-(2-chloro-4-ethoxy)benzyl-2-methyl-5-[(4-methylbenzene)sulfonylca-
rbamoyl]-3H-imidazo[4,5-b]pyridine
[0433]
3-[2-chloro-4-(2-methoxyethoxy)benzyl]-2-methyl-5-[(4-methylbenzene-
)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0434]
3-2-chloro-4-(thiophen-2-yl)methyloxy]benzyl]-2-methyl-5-[(4-methyl-
benzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0435]
3-[2-chloro-4-[(thiophene-3-yl)methyloxy]benzyl]-2-methyl-5-[(4-met-
hylbenzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0436]
3-(2-chloro-4-phenylethynyl)benzyl-2,7-dimethyl-5-[(4-methylbenzene-
)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0437]
3-[2-chloro-4-(cyclopentylmethyloxy)benzyl]-2-methyl-5-[(4-methylbe-
nzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0438]
3-(2-chloro-4-phenylethynyl)benzyl-2,7-dimethyl-5-(1-pentanesulfony-
lcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0439]
3-(2-chloro-4-(1-hexynyl)benzyl-2-methyl-5-(N-(4-methylphenylsulfon-
yl)carbamoyl-3H-imidazo[4,5-b]pyridine
[0440]
3-(2-chloro-4-(cyclohexylmethyloxy)-2,7-dimethyl-5-((1-pentanesulfo-
nyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0441]
3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2,7-dimethyl-5-[(4-methy-
lbenzene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0442]
3-(2-chloro-4-ethylbenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0443]
3-(2-chloro-4-ethylbenzyl)-2,7-dimethyl-5-[4-methylbenzene)sulfonyl-
carbamoyl]-3H-imidazo[4,5-b]pyridine
[0444]
3-(2-chloro)-4-(trifluoromethyl)benzyl)-2,7-dimethyl-5-(1-pentanesu-
lfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0445]
3-(2-chloro-4-(trifluoromethyl)benzyl)-2,7-dimethyl-5-[(4-methylben-
zene)-sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0446]
3-(2-chloro-4-ethoxybenzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbam-
oyl]-3H-3H-imidazo[4,5-b]pyridine
[0447]
3-(2-chloro-4-ethoxybenzyl-2,7-dimethyl-5-[(4-methylbenzene)sulfony-
lcarbamoyl]-3H-imidazo[4,5-b]pyridine
[0448]
3-(2,4-dichorobenzyl)-2-methyl-5-(p-toluenesulfonylcarbamoyl)benzo[-
b]furan
[0449]
5-((5-bromothiophen-2-yl)sulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)--
2-methylbenzo[b]furan
[0450]
5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-
-2-methylbenzo[b]furan
[0451]
3-(2-chloro-4-phenylbenzyl-4-2-methyl-5-((4-pentene)sulfonylcarbamo-
yl)-3H-imidazo[4,5-b]pyridine
[0452]
2-(2-chloro-4-phenylbenzyl)-3-methyl-6(p-toluenesulfonylcarbamoyl)--
2H-indazole
[0453]
3-(2-chloro-4-hexylbenzyl)-2-methyl-5-(N-(4-methylphenylsulfonyl)ca-
rbamoyl-3H-imidazo[4,5-b]pyridine
[0454]
3-(2-chloro-4-piperidinobenzyl)-2,7-dimethyl-5-((4-methylbenzene)su-
lfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0455]
3-(2-chloro-4-morpholinobenzyl)-2,7-dimethyl-5-((4-methylbenzene)su-
lfonyl-carbamoyl)-3H-imidazo[4,5-b]pyridine
[0456]
3-(2-chloro-4-(hexamethyleneimino)benzyl)-2,7-dimethyl-5-((4-methyl-
benzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0457]
3-(2-chloro-4-(1-pyrrolidinyl)benzyl)-2,7-dimethyl-5-((4-methylbenz-
ene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0458]
3-(2-chloro-4-(4-methylpiperazin-1-yl)benzyl)-2,7-dimethyl-5-((4-me-
thylbenzene)-sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
[0459]
3-(2-chloro-4-methylthiobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)su-
lfonyl-carbamoyl]-3H-imidazo[4,5-b]pyridine
[0460]
3-(2-chloro-4-methylthiobenzyl)-2,7-dimethyl-5-(1-pentanesulfonylca-
rbamoyl)-3H-imidazo[4,5-b]pyridine
[0461] The methods for producing the objective compound (A are
described in detail in the following.
[0462] Production Method 1:
[0463] The objective compound (I) and a salt thereof can be
produced by reacting compound (II) or a salt thereof with compound
(III) or a reactive derivative thereof at its carboxy group or a
salt thereof.
[0464] The compound (II), compound (III) and reactive derivative at
carbonyl group thereof are exemplified by those shown with regard
to compound (I).
[0465] Preferable reactive derivative at carbon of compound (III)
is acid halide, acid anhydride such as intramolecular add
anhydride, intermolecular acid anhydride and mixed acid anhydride,
active amide, active ester and the lie. Preferable examples thereof
include add chloride, add azide, mixed acid anhydride with acid
such as substituted phosphoric acid (e.g., dialkylphosphinic add,
phenylphosphonic acid, diphenylphosphino add, diphenylphosphino
acid and halogenated phosphoric acid), dialkylphosphinic acid,
sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acid
(e.g., methanesulfonic add), aliphatic carboxylic add (e.g., acetic
acid, propionic acid, butyric acid, isobutyric acid, pivalic add,
pentanoic acid, isopentanoic acid, 2-ethylbutyric acid and
trichloroacetic acid), aromatic carboxylic add (e.g., benzoic
acid), and the like; symmetric add anhydride; active amide with
imidazole, 4-substituted imidazole, dimethylpyrzole, triazole or
tetrazole; active ester (e.g, cyanomethyl ester, methoxymethyl
ester, dimethylaminomethyl [(CH.sub.3).sub.2N.sup.+.dbd.CH--]
ester, vinyl ester, propargyl ester, p-nitrophenyl ester,
2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenol
ester, mesylphenyl ester, phenylazophenyl ester, phenylthio ester,
p-nitrophenylthio ester, p-cresylthio ester, carboxymethylthio
ester, pyranyl ester, pyridyl ester, piperidyl ester and
8-quinolylthio ester); esters with N-hydroxy compound (e.g.,
N,N-dimethylhydroxylamine, 1-hydroxy-2-1H-pyridine,
N-hydroxysuccinimide and 1-hydroxy-1H-benzotriazole); and the like.
These reactive derivatives can be appropriately selected according
to the kind of compound (III) to be used.
[0466] The reaction generally proceeds in a conventional solvent
such as water, alcohol (e.g, methanol and ethanol), acetone,
dioxane, acetonitrile, chloroform, methylene chloride, ethylene
chloride, tetrahydrofuran, ethyl acetate, N,N-dimethylformamide and
pyridine, or in a solvent which does not adversely affect the
reaction. These conventional solvents may be used alone or in
combination.
[0467] When compound (III) is used in the form of a free acid or a
salt thereof in this reaction, the reaction is preferably carried
out in a conventional condensing agent such as
N,N'-dicyclohexylcarbodiimide,
N-cyclohexyl-N'-morpholinoethyl-carbodiimide,
N-cyclohexyl-N'-(4-diethyla- minocyclohexyl)-carbodiimide,
N,N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,
N-ethyl-N'-(3-dimethylamino-propyl)carbodii- mide,
N,N'-carbonylbis(2-methylimidazole),
pentamethyleneketen-N-cyclohexy- lamine,
diphenylene-N-cyclohexylene, ethoxyacetylene, 1-alkoxy-
1-chloroethylene, trialkyl phosphite, ethyl polyphosphorate,
isopropyl polyphosphorate, phosphorous oxychloride (phosphoryl
chloride), phosphorous trichloride, diphenylphosphoryl azide,
diphenyl chlorophosphate, diphenylphosphino add chloride,
thionylchloride, oxalyl chloride, lower allyl haloformate (e.g.,
methyl chloroformate and isopropyl chloroformate),
triphenylphosphine, 2-ethyl-7-hydroxybenmwisoxl- zolium salt,
intramolecular salt of 2-ethyl-5-(m-sulfopheny)isoxazoliumhyd-
ride, 1-(p-cloroberensulfonyloxy)-6-chloro-1H-benzothiazole, and
solved Vilsmeier reagent(prepared from N,N-dimethylformamide with
thionyl chloride, phosgene, trichloromethyl chloroformate, or
phosphoryl chloride, and so on.), and the like.
[0468] The reaction can be carried out in the presence of an
inorganic or organic base such as alkali metal bicarbonate,
tripower)alkylamine, pyridine, 4dimethyl-aminopyridine,
N-(lower)alkylmorpholine, N,N-dimethalyanlline (e.g.,
N,N-dimethylaniline), N,N di(lower)alkylbenzylamine, and the
like.
[0469] The reaction temperature is not particularly limited, and
the reaction is generally carried out from under cooling to
heating.
[0470] Production Method 2:
[0471] The objective compound (I-2) and a salt thereof can be
prepared by reducing compound (I-1) or a salt thereof.
[0472] The method for producing objective compound (I-2) by
reduction includes chemical reduction and catalytic reduction.
[0473] The preferable reducing agent used in the chemical reduction
is, for example, metal such as tin, zinc and iron, or a combination
of a metal compound, such as chromium chloride and chromium
acetate, and an organic acid or inorganic acid such as formic acid,
acetic add, propionic acid, trifluoroacetic acid, p-toluenesulfonic
acid, hydrochloric acid and hydrobromic acid.
[0474] The preferable reducing agent used in the catalytic
reduction is, for example, platinum cast such as platinum plate,
platinum sponge, platinum black platinum colloid, platinum oxide
and platinum wire, palladium catalyst such as palladium sponge,
palladium bla, palladium oxide, palladium-carbon, palladium
colloid, palladium-barium sulfate and palladium-barium carbonate,
nickel catalyst such as reduced nickel and Raney-nickel, cobalt
catalyst such as reduced cobalt and Raney cobalt, iron catalyst
such as reduced iron and Raney iron, copper catalyst such as
reduced copper, Raney copper and Ullmann copper, and the like.
[0475] The reduction is generally carried out in a conventional
solvent that does not adversely influence the reaction, such as
water, methanol, ethanol, propanol and N,N-dimethylformamide, or a
mixed solvent thereof. When the above-mentioned acid to be used for
the chemical reduction is liquid, it can be used as a solvent
[0476] The preferable solvent to be used for the catalog reduction
includes, besides the above-mentioned solvents, other conventional
solvents such as diethyl ether, dioxane and tetrahydrofuran and
mixtures thereof.
[0477] The reaction temperature of the reduction is not
particularly limited, and the reaction is generally carried out
from under cooling to heating.
[0478] Production Method 3:
[0479] The objective compound (I-4) and a salt thereof can be
produced by oxidizing compound (I-3) or a salt thereof.
[0480] When objective compound (I-4) is produced by oxidation, an
oxidizing agent such as sodium chlorate, chromic anhydride and
potassium permanganate, and a solvent such as water and acetone are
used. The reaction temperature is not particularly limited, and the
reaction is generally carried out from under cooling to
heating.
[0481] Production Method 4:
[0482] The objective compound (I-6) and a salt thereof can be
produced by acylation of compound (I-5) or a salt thereof.
[0483] When objective compound (I-6) is to be obtained by
acylation, compound (I-5) having terminal hydroxy is reacted with
an acylating agent Examples of the acylating agent include lower
alkanesulfonyl halide (e.g., methanesulfonyl chloride) and lower
alkanesulfonic anhydride (e.g., methanesulfonic anhydride). The
solvent may be dichloromethane, tetrahydrofuran and the like, and
the reaction proceeds from under from ice-cooling to heating.
[0484] Production Method 5:
[0485] The objective compound (I-7) and a salt thereof can be
produced by introducing an aryloxy group into compound (I-6) or a
salt thereof. For the introduction of the aryloxy group, compound
(I-6) having terminal acyloxy(lower)alkyl is reacted with
hydroxyaryl compound (e.g., phenol) in the presence of a base such
as sodium hydride. As the solvent, N,N-dimethylformamide,
tetrahydrofuran and the like can be used, and the reaction proceeds
from under ice cooling to heating.
[0486] Production Method 6:
[0487] The objective compound (I-8) and a salt thereof can be
produced by introducing a carboxy-protecting group into compound
(I-4) or a reactive derivative thereof.
[0488] The carboxy-protecting group can be introduced by, for
example, reacting compound (I-4) having terminal carboxyl or a
reactive derivative thereof with an alkyl alcohol such as ethanol.
As the solvent, N,N-dimethylformamide, dichloromethane and the like
can be used, and the reaction proceeds from under ice-cooling to
heating.
[0489] The preferable reactive derivative at carboxy includes acid
halide, add anhydride, active amide, active ester and the like.
Preferable examples thereof are add chloride, acid azide, mixed
acid anhydride with acid such as substituted phosphoric add (e.g.,
dialkyl phosphoric add, phenylphosphonic acid, diphenyl-phosphonic
acid, diphenylphosphino acid and halogenated phosphoric acid),
dialkylphosphinic acid, sulfurous acid, thiosunfuric acid, sulfuric
add, sulfonic add (e.g., methanesulfonic acid), aliphatic
carboxylic acid (e.g, acetic add, propionic add, butyric add,
isobutyric acid, pivalic acid, pentanoic add, isopentanoic acid,
2-ethylbutyric add and trichloroacetic acid), aromatic carboxylic
add (e.g., benzoic acid), and the like; symmetric acid anhydride;
active amide with imidazole, 4-substituted imidazole,
dimethylpyrzole, triazole or tetrazole; active ester (e.g.,
cyanomethyl ester, methoxymethyl ester, dimethylaminomethyl
[(CH.sub.3).sub.2N.sup.+50 CH--] ester, vinyl ester, propargyl
ester, p-nitrophenyl ester, 2,4-initrophenyl ester, trichlorophenyl
ester, pentachlorophenol ester, mesylphenyl ester, phenylazophenyl
ester, phenylthio ester, p-nitrophenylthio ester, p-cresylthio
ester, carboxymethylthio ester, Mrnyl ester, pyridyl ester,
piperidyl ester and 8-quinolyl ester, esters with N-hydroxy
compound (e.g, N,N-diethylhydroxylamine, 1-hydroxy-2-1H-pyridine,
N-hydroxysuccinmide, N-hydroxyphthaljmide and
1-hydroxy-1H-benzotrizole), and the like. These reactive
derivatives can be selected according to the kind of compound to be
used.
[0490] Production Method 7:
[0491] The objective compound (I-9) and a salt thereof can be
produced by introducing a carboxy-protecting group into compound
(I-4) or a salt thereof.
[0492] When compound (I-4) is reacted with alkylamine such as
methylamine and ethylamine, this compound is amidated. The solvent
to be used is, for example, tetrahydrofuran, dichloromethane, N,N
dimethylformamide and the like, and the reaction proceeds from
under ice-cooling to heating.
[0493] Production Method 8:
[0494] The objective compound (I-11) and a salt thereof can be
produced by adding a heterocyclic group containing nitrogen to
compound (I-10) or a salt thereof.
[0495] This reaction is preferably carried out in the presence of a
base such as sodium tert-butylate and the above-mentioned inorganic
or organic base. The reaction is preferably carried out in the
presence of a catalyst such as
tris(dibenzylideneacetone)-dipalladium(0), (R)-(+)-BINAP
[2,2'-bis(diphenyl-phosphino)-1,1'-binaphthyl] and the like.
[0496] While the reaction temperature is not particularly limited,
the reaction is carried out from room temperature to heating, and
the reaction can be also carried out in the presence of a solvent
such as toluene, which does not adversely affect the reaction.
[0497] The above-mentioned compounds can be purified as necessary
according to a conventional method for purifying an organic
compound, such as recrystallization, column chromatography,
thin-layer chromatography, high performance liquid chromatography
and the like. The compound can be identified by NMR spectrometric
analysis, mass spectrometric analysis, IR spectrometric analysis,
elemental analysis, melting point measurement and the like.
[0498] The compound of the present invention may have one or more
chiral centers and includes enantiomers and diastereomers. Some
compounds having alkenyl may be present as a cis or trans isomer.
The present invention encompasses such my and respective
isomers.
[0499] The inventive compound and a salt thereof may be in the form
of a solvate, which is also encompassed in the present invention.
The solvate is preferably exemplified by hydrate and
ethanolate.
[0500] The pharmaceutical data of compound (I) are shown in the
following to demonstrate the utility of the objective compound
(I).
EXPERIMENTAL EXAMPLE 1
[0501] (Blood Sugar Level Depressing Activity in dd/db Mice)
[0502] Test Compound
[0503] Compound A
[0504]
3-(2,4-Dichlorobenzyl)-2-methyl-5-(1-n-pentanesulfonylcarbamoyl)-be-
nzo[b]furan (compound of Example 30-1)
[0505] Test Animal
[0506] Female C57BL/KsJ-dbm db+/db+, C57BL/KsJ-dbm +m/+m (Jackson
Laboratory) mice (5 weeks old) were purchase and subjected to the
test after 2-3 weeks of acclimating period.
[0507] Drug Administration
[0508] The test drug was mixed with a powder diet (Cr2, clea Japan,
Inc.) in a mortar. In the case of administration in 100 mg/kg, the
mixing proportion of the test drug to the diet was 0.1%, in the
case of 30 mg/kg, the proportion was 0.03% and in the case of 10
mg/kg, the proportion was 0.01%. The diet was changed twice aweek
The amount of the diet given and the amount left were recorded and
the diet intake was calculated by determining the difference.
[0509] Test Schedule
[0510] The female db/db mice were grouped according to body weight,
blood sugar level and triglyceride concentration in blood. Then,
the drug-mixed diet was given for 14 days, during which period the
mice were 8 to 10 weeks of age. At day 7 and day 14 in the morning,
blood was taken from supraorbital plexus venosus using a
heparinized glass capillary tube (Chase Heparinized capillary
tube), and centrifuged to give plasma fractions. The blood sugar
value, triglyceride concentration in plasma and insulin
concentration in plasma were measured at day 0 and day 14, and
blood sugar value and tride concentration in blood were measured at
day 7. Body weight was measured at day 0, day 7 and day 14. After
final blood sampling, the mice were slaughtered with
CO.sub.2gas.
[0511] Measurement Method
[0512] Blood sugar value was measured using 10-15 .mu.l of plasma
and in accord with glucose oxidase method (glucose CII-test Waco,
Waco Pure Chemicals Co., Ltd.). The triglyceride concentration in
plasma was measured using 10-15 .mu.l of plasma and in accord with
GPO-chlorophenol method (triglyceride G-test Waco) or GPO-DAOS
method (triglyceride E-test Waco). The measurement was done
promptly after blood sampling. The insulin concentration in plasma
was measured using 20 .mu.l of plasma (preservable at -20.degree.
C.) and in accord with an antibody method (Phadesef Insulin RIA
kit, Kabi Pharmacia).
[0513] Result
[0514] Using the difference between db/db mice control group and
+/+ mice in blood sugar value and triglyceride concentration in
plasma as 100%, the proportion (%) of decrease in the blood sugar
value and triglyceride concentration in plasma of the group
administered with the test drug was determined. The results are
shown in Table 1.
1 TABLE 1 Test compound Dose (mg/kg) Blood sugar decrease (%)
Compound A 10 71
[0515] The compound (I) of the present invention can be used for
therapeutic purposes in the form of a pharmaceutical preparation.
This pharmaceutical preparation contains any one of the compounds.
(I) as an active ingredient in admire with a pharmaceutically
acceptable organic or inorganic excipient which is a solid,
semi-solid or liquid and which is suitable for oral, parenteral or
external (local) administration. Examples of the dosage form
include capsules, tablets, sugar coating tablets, granules,
suppositories, liquid, lotion, suspension, emulsion, ointment, gel
and the like. When desired, these preparations may contain adjuvant
auxiliary, auxiliary substance, stabilizer, moistening agent,
emulsifier, buffering agent, and other conventional additives.
[0516] While the dose of the compound (I) varies depending on the
age and symptom of patients, compound (I) is administered for the
therapy of the above-mentioned diseases in an average single dose
amount of about 0.1 mg, 1 mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg
or 1000 mg In general, its daily dose is about 0.1 mg/patient to
about 1000 mg/patient
EXAMPLES
[0517] The present invention is described in more detail by way of
Preparation Examples and Examples.
Preparation Example 1-1
Methyl
3-(3,4-dichlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0518] In the same manner as in Preparation Example 16-2 to be
described later, the objective compound was obtained from methyl
2-methylbenzo[b]thiophene-5-carboxylate and 3,4-dichlorobenzoyl
chloride.
[0519] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 3.89(3H, s),
7.52-7.68(2H, m), 7.79-8.04(3H, m), 8.23(1H, s) Mass(ESI): m/e
377(M-H).sup.-
Preparation Example 1-2
Methyl 3-(3,4-Dichlorobenzyl)-2-methylbenzo[b
thiophene-5-carboxylate
[0520] To a solution of methyl
3-(3,4-dichlorobenzoyl)-2-methylbenzo[b]thi- ophene-5-carboxylate
(259 mg) in tetrahydrofuran (2.6 ml)-methanol (0.26 ml) was added
sodium borohydride (36 mg) under ice-cooling, and the mixture was
stirred for 10 min. Trifluoroacetic acid (15 ml) was placed in a
different reaction vessel, and sodium borohydride (255 mg) was
portionwise added with stirring under ice-cooling. Thereto was
added the above-mentioned reaction mixture, and the mixture was
stirred for 3 hr at room temperature. The reaction mixture was
concentrated, diluted with water under ice-cooling and neutralized
with a 15% aqueous sodium hydroide solution. The resulting product
was extended with ethyl acetate. The obtained organic layer was
washed with brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give the objective compound (224 mg) as a
white powder.
[0521] .sup.1H-NMR(CDCl.sub.3): 2.51(3H, s), 3.91(3H, s), 4.14(2H,
s), 6.97(1H, dd, J=8 and 2 Hz), 7.20(1H, d, J=2 Hz), 7.31(1H, d,
J=8 Hz), 7.82(1H, d, J=8 Hz), 7.93(1H, dd, J=8 and 2 Hz), 8.18(1H,
d, J=2 Hz) Mass(ESI): m/e 363(M-H).sup.-
Preparation Example 1-3
3-(3,4-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0522] In the same manner as in Preparation Example 4-7 to be
described later, the objective compound was obtained from methyl
3-(3,4-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate.
[0523] .sup.1H-NMR(DMSO-d.sub.6): 2.56(3H, s), 4.24(2H, s),
7.10(1H, d, J=8 Hz), 7.43 (1H, s), 7.51(1H, d, J=8 Hz), 7.82(1H, d,
J=8 Hz), 7.95(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass(ESI): m/e
349(M-H).sup.-
Preparation Example 2-1
Methyl
3-(2,3-dichlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0524] In the same manner as in Preparation Example 1-1, the
objective compound was obtained using 2,3-dichlorobenzoyl
chloride.
[0525] .sup.1H-NMR(CDCl.sub.3): 2.40(3H, s), 3.90(3H, s),
7.31-7.41(2H, m), 7.58-7.69(1H, m), 7.81(1H, d, J=8 Hz), 8.01(1H,
d, J=8 Hz), 8.59(1H, s) Mass(ESI): m/e 377(M-H).sup.-
Preparation Example 2-2
Methyl
3-(2,3-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0526] In the same manner as in Preparation Example 1-2, the
objective compound was obtained from the obtained methyl ester.
[0527] .sup.1H-NMR(CDCl.sub.3): 2.45(3H, s), 3.89(3H, s), 4.27(2H,
s), 6.57(1H, d, J=8 Hz), 6.97(1H, t, J=8 Hz), 7.31(1H, d, J=8 Hz),
7.82(1H, d, J=8 Hz, 7.94(1H, d, J=8 Hz), 8.11(1H, s) Mass(ESI): m/e
363(M-H).sup.-
Preparation Example 2-3
3-(2,3-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0528] In the same manner as in Preparation Example 1-3, the
objective compound was obtained from the obtained methyl ester.
[0529] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 4.32(2H, s),
6.71(1H, d, J=8 Hz), 7.19 (1H, t, J=8 Hz), 7.51(1H, d, J=8 Hz),
7.83(1H, d, J=8 Hz), 8.01(1H, s), 8.02(1H, d, J=8 Hz) Mass(ESI: m/e
349(M-H).sup.-
Preparation Example 3-1
Methyl
3-(2,5-dichlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0530] In the same manner as in Preparation Example 1-1, the
objective compound was obtained using 2,5-dichlorobenzoyl
chloride.
[0531] .sup.1H-NMR(CDCl.sub.3): 2.42(3H, s), 3.90(3H, s),
7.35-7.51(3H, m), 7.81(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz),
8.06(1H, s) Mass(ESI): m/e 377(M-H).sup.-
Preparation Example 3-2
Methyl
3-(2,5-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0532] In the same manner as in Preparation Example 1-2, the
objective compound was obtained from the obtained methyl ester.
[0533] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 3.90(3H, s), 4.21(2H,
s), 6.64(1H, s), 7.11(1H, d, J=8 Hz), 7.34(1H, d, J=8Hz), 7.83(1H,
d, J=8 Hz), 7.95(1H, d, J=8 Hz), 8.13(1H, s) Mass(ESI): m/e
363(M-H).sup.-
Preparation Example 3-3
3-(2,5-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0534] In the same manner as in Preparation Example 1-3, the
objective compound was obtained from the obtained methyl ester.
[0535] .sup.1H-NMR (DMSO-d.sub.6): 2.52(3H, s), 4.28(2H, s),
6.75(1H, d, J=2 Hz), 7.33 (1H, dd, J=8 and 2 Hz), 7.55(1H, d, J=8
Hz), 7.84(1H, d, J=8 Hz), 7.89-8.11(2H, m) Mass(ESI): m/e
349(M-H).sup.-
Preparation Example 4-1
Ethyl N-aminoisonicotinate 2,4-dinitrophenyl salt
[0536] Ethyl isonicotinate (10.0 g) was dissolved in
tetrahydrofuran (100 ml), and O-(2,4-dinitrophenyl)hydroxylamine
(11.9 g) was added at room temperature, which was followed by
refluxing under heating for 2 hr. The solvent was evaporated under
reduced pressure, and the obtained residue was washed with diethyl
ether and ethyl acetate to give the objective compound (10.5 g) as
an amber-colored powder.
[0537] .sup.1H-NMR(DMSO-d.sub.6): 1.36(3H, t, J=6 Hz), 4.40(2H, q,
J=6 Hz), 6.32(1H, d, J=9 Hz), 7.78(1H, dd, J=9,2 Hz), 8.34(1H, d,
J=8 Hz), 8.59(1H, d, J=2 Hz), 8.84(1H, d, J=8 Hz)
Preparation Example 4-2
Diethyl 2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylate
[0538] Ethyl N-aminoisonicotinate 2,4-dinitrophenyl salt (10.2 g)
was suspended in ethanol (147 ml), and potassium carbonate (3.77 g)
was added, which was followed by stirring at room temperature for
30 min. To the mixture was added ethyl acetoacetate (3.69 ml), and
the mixture was stirred at 60.degree. C. for 5 hr with heating. The
insoluble matter was filtered off and the filtrate was concentrated
to dryness under reduced pressure. The residue was purified by
silica gel column chromatography (eluent:hexane/ethyl acetate=7/1)
to give the objective compound (2.70 g) as an amber-colored
solid.
[0539] .sup.1H-NMR(CDCl.sub.3): 1.42(3H, t, J=6 Hz), 1.46(3H, t,
J=6 Hz), 2.70(3H, s), 4.36-4.50(4H, m), 7.46(1H, d, J=8 Hz),
7.78(1H, dd, J=9, 2 Hz), 8.43(1H, d, J==8 Hz), 8.78(1H, s)
Preparation Example 4-3
2-Methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylic acid
[0540] A mixture of diethyl
2-methylpyrazolo[1,5-a]pyridine-3,5-carboxylat- e (100 mg), a 50%
aqueous sodium hydrdide solution (160 mg), water (0.5 ml) and
ethanol (1.0 ml) was refluxed under heating for 30 min. Then, the
reaction mixture was adjusted to pH 4 under ice-cooling and stirred
at the same temperature for 30 min. The precipitate was collected
by filtration and washed with water to give the objective compound
(50 mg) as a pale-brown powder.
[0541] .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s), 7.43(1H, d, J=8 Hz),
8.46(1H, s), 8.56 (1H, d, J=8 Hz)
Preparation Example 4-4
2-Methylpyrazolo[1,5-a]pyridine-5-carboxylic acid
[0542] A mixture of
2-methylpyrazolo[1,5-a]pyridine-3,5-dicarboxylic acid (1.39 g) and
polyphosphoric acid (13.9 g) was stirred at 150.degree. C. with
heating for 2 hr, and ice (14 g) was added under ice-cooling, which
was followed by shaking to give a homogeneous solution. The
reaction re was adjusted to pH 4 at the same temperature and
diluted with dichloromethane/methanol (4:1) and water. The
precipitate was collected by filtration to give the objective
compound (610 mg) as a pale-brown powder. The organic layer of the
mother liquor was taken, and the aqueous layer was extracted with
dichloromethane/methanol (4:1). Both organic layers were combined,
dried over magnesium sulfate and concentrated to dryness under
reduced pressure. The residue was washed with ether to give second
crystals (200 mg) as a pale-brown powder.
[0543] .sup.1H-NMR(DMSO-d.sub.6): 2.42(3H, s), 6.67(1H, s),
7.18(1H, d, J=8 Hz), 8.21 (1H, s), 8.62(1H, d, J=8 Hz)
Preparation Example 4-5
Ethyl 2-methylpyrazolo[1,5-a]pyridine-5-carboxylate
[0544] 2-Methylpyrazolo[1,5-a]pyridine-5-carboxylic acid (723 mg)
was dissolved in 10% sulfuric acid/ethanol (20 ml) and the mixture
was refluxed under heating for 2.5 hr. The reaction mixture was
neutralized under ice-cooling, extracted with ethyl acetate and
dried over magnesium sulfate. The residue was concentrated to
dryness under reduced pressure. The residue was purified by silica
gel column chromatology (hexane/ethyl acetate=4:1) to give the
objective compound (707 mg) as a pale-brown powder.
[0545] .sup.1H-NMR(CDCl.sub.3): 1.41(3H, t, J=7 Hz), 2.52(3H, s),
4.40(2H, q, J=7 Hz), 6.49(1H, s), 7.25(1H, d, J=8 Hz), 8.19(1H, s),
8.40(1H, d, J=8 Hz)
Preparation Example 4-6
Ethyl
3-(2,4-dichlorobenzyl)-2-methylpyrazolo[1,5-a]pyridine-5-carboxylate
[0546] To a solution of trifluoroacetic acid (558 mg) and
triethylsilane (1.14 g) in dry dichloromethane (2.0 ml) were added
ethyl 2-methylpyrazolo[1,5-a]pyridine-5-carboxylate (200 ng) and
2,4-dichlorobenzaldehyde (189 mg), and the mixture was stirred at
room temperature for 3 days. To the reaction mixture was added
2,4-dichlorobenzaldehyde (189 mg) and the mixture was stirred at
room temperature for one day. This step was repeated three times.
The reaction mixture was diluted with dichloromethane and washed
with a saturated aqueous sodium hydrogencarbonate solution. The
aqueous layer was extracted with dichloromethane. The organic
layers were combined, dried over magnesium sulfate, and
concentrated to dryness under reduced pressure. The residue was
purified by silica gel column chromatography (hexane/ethyl
acetate=9:1) and washed with isopropyl ether to give the objective
compound (233 mg) as a white powder.
[0547] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=7 Hz, 2.38(3H, s),
4.12(2H, s), 4.38(2H, q, J=7 Hz), 6.84(1H, d, J=8 Hz), 7.10(1H, d,
J=8 Hz), 7.27(1H, d, J=8 Hz), 7.42(1H, s), 8.00(1H, s), 8.40(1H, d,
J=8 Hz)
Preparation Example 4-7
3-(2,4-Dichlorobenzyl)-2-methylpyrazolo[1,5-a]pyridine-5-carboxylic
acid
[0548] A mixture of ethyl
3-(2,4-dichlorobenzyl)-2-methylpyrazolo[1,5-a]py-
ridine-5-carboxylate (230 mg), a 1N aqueous sodium hydroxide
solution (2.0 ml) and ethanol (2.3 ml) was refluxed under heating
for 25 min. The reaction mixture was adjusted to pH 4 under
ice-cooling with 1N hydrochloric acid. The precipitate was
collected by filtration and washed with water to give the objective
compound (208 mg) as a white powder.
[0549] .sup.1H-NMR(DMSO-d.sub.6): 2.30(3H, s), 4.19(2H, s),
7.10(1H, d, J=8 Hz), 7.16(1H, d, J=8 Hz), 7.34(1H, d, J=8 Hz),
7.62(1H, s), 8.06(1H, s), 8.62(1H, d, J=8 Hz)
Preparation Example 5-1
1-(2,4-Dichlorophenyl)-1-trimethylsilyoxyethene
[0550] Diisopropylamine (16.2 g) was dissolved in tetrahydrofuran
(133 ml), and 1.6N n-butyl lithium (100 ml) was dropwise added
thereto under icecooling The reaction mixture was stirred at the
same temperature for 10 min, and a solution of
2,4-diichloroacetophenone (25.2 g) in tetrahydrofuran (133 ml) was
dropwise added under cooling in a dry ice-acetone bath.
Hexamethylphosphoramide (26.7 ml) was added little by little. The
mixture was stirred at the same tempera for 5 min and
chlorotrimethylsilane (20.3 ml) was dropwise added, which was
followed by stirring at room temperature for 30 min. The reaction
mixture was partitioned between ice-cooled n-hexane and ice-cooled
water. The organic layer was washed twice with ice-cooling water
and then once with saturated brine, dried over sodium sulfate and
concentrated under reduced pressure to dryness to give a crude
product (37.5 g) of the objective compound as a pale-yellow
oil.
Preparation Example 5-2
1-(2,4-Dichlorophenyl)-3-hydroxy-3-methylbutanone
[0551] To a solution of titanium tetrachloride (17.8 ml) in
dichloromethane (160 ml) was dropwise added acetone (10 ml) under
cooling in a dry ice-acetone bath, and one minutes later, a
solution of the crude product (37.5 g) of
1-(2,4-dichlorophenyl)-1-trimethylsilyloxyethene in dichloromethane
(160 ml) was added. The mixture was stirred under cooling in a dry
ice-acetone bath overnight and at room temperature for 3 hr. The
reaction mitre was washed with water, and the aqueous layer was
extracted once with dichloromethane. The organic layers were
combined, washed with a saturated aqueous sodium hydrogencarbonate
solution and saturated brine, dried over magnesium sulfate and
concentrated under reduced pressure to dryness to give a brown oil
residue. The obtained residue was purified by silica gel column
chromatography.(eluent: hexane/ethyl acetate=9/1-4/1) to give the
objective compound (16.2 g) as a pale yellow oil.
[0552] .sup.1H-NMR(CDCl.sub.3): 1.34(6H, s), 3.13(2H, s), 7.33(1H,
d, J=8 Hz), 7.44(1H, d, J=8 Hz), 7.47(1H, s)
Preparation Example 5-3
1-(2,4-Dichlorophenyl)-3-methyl-3-tifuoroacetoxybutanone
[0553] To a solution of
1-(2,4-dichlorophenyl)-3-hydroxy-3-methylbutanone (16.16 g) and
triethylamine (27.4 ml) in dichloromethane (160 ml) was added
trifluoroacetic anhydride (13.9 ml) under ice-cooling. The mixture
was stirred at the same temperature for 10 min, and at room
temperature for 1 hr. The reaction mixture was washed with water
and a saturated aqueous sodium hydrogencarbonate solution, dried
over sodium sulfate, and concentrated under reduced pressure to
dryness to give a crude product of the objective compound (19.9 g)
as a brown oil.
Preparation Example 5-4
1-(2,4-Dichlorophenyl)-3-methyl-2-butanone
[0554] To a solution of the crude product (19.9 g) of
1-(2,4-dichlorophenyl)-3-methyl-3-tifuoroacetoxybutanone in toluene
(100 ml) was added 1,8-diazabicyclo[5,4,0]-undec-7-ene (4.0 ml),
and the m was stirred at room temperature for 30 min. The reaction
mixture was washed successively with ice-water, 1N hydrochloric
acid, saturated brine, a saturated aqueous sodium hydrogencarbonate
solution and saturated bane, dried over magnesium sulfate, and
concentrated under reduced pressure to dryness. The residue was
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate=49/1) to give the objective compound (12.5 g) as a
pale-brown oil.
[0555] .sup.1H-NMR(CDCl.sub.3): 2.00(3H, s), 2.24(3H, s), 6.43(1H,
s), 7.29(1H, d, J=8 Hz), 7.39-7.46(2H)
Preparation Example 5-5
(E) 4-Bromo-1-(2,4-dichlorophenyl)-3-methyl-2-butanone
[0556] To a solution of 1-(2,4-dichlorophenyl)-3-methyl-2-butanone
(9.30 g) in carbon tetrachloride (93 ml) were added
N-bromosuccinimide (7.95 g) and benzyl peroxide (983 mg), and the
mixture was refluxed under heating for 1 hr. The reaction mixture
was ice-cooled and the precipitate was filtered off. The filtrate
and washing solution were combined and washed three times with a
saturated aqueous sodium hydrogencarbonate solution and then once
with saturated brine. The organic layer was dried over magnesium
sulfate, concentrated under reduced pressure to dryness to give a
crude product (14.6 g) of the objective compound as a black
oil.
Preparation Example 5-6
(E)
1-(2,4-Dichlorophenyl)-4-(4-ethoxycarbonylpyridyl)-3-methyl-2-butanone
[0557] The crude product of (E)
4-bromo-1-(2,4-dichlorophenyl)-3-methyi-2-- butanone (14.6 g) was
dissolved in acetone (140 ml), and ethyl isonicotinate (12.1 ml)
was added. The mixture was refluxed under heating for 6 hr. The
reaction mixtu was concentrated under reduced pressre to dryness to
give a crude product (22.0 g) of the objective conpound as a brown
solid.
Preparation Example 5-7
Ethyl 1-(2,4-dichlorobenzoyl)-2-methylindoline-7-carboxylate
[0558] The crude product of (E)
1-(2,4-dichlorophenyl)-4-(4-ethoxycarbonyl-
pyridyl)-3-methyl-2-butanone (22.0 g) was dissolved in ethanol (146
ml), and potassium carbonate (5.61 g) was added. The mixture was
refluxed under heating for 12 hr. The reaction mixture was
partitioned between ethyl acetate and saturated brine, and the
organic layer was dried over magnesium sulfate and concentrated
under reduced pressure to dryness to give an amber-clored solid.
The residue was pulveid in ether to give the objective compound
(3.54 g) as a yellow powder.
[0559] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=6 Hz), 2.16(3H, s),
4.35(2H, q, J=6 Hz), 7.22(1H, s), 7.30-7.42(3H), 7.52(1H, s),
7.97(1H, d, J=8 Hz), 8.36(1H, s)
Preparation Example 5-8
Ethyl 1-(2,4-dichlorobenzyl-2-methylindolizine-7-carboxylate
[0560] Ethyl
1-(2,4-dichlorobenzoyl-2-methylindolizine-7-carboxylate (3.17 g)
was dissolved in tetrahydrofuran (32 ml), and a 10M borane dimethyl
sulfide complex (9.5 ml) was dropwise added under ice-cooling. The
mixture was stirred at room temperature for 3.5 hr, neutrlized and
pardtioned between ethyl acetate and water. The organic layer was
washed thre times with water and then with saturated brine, dried
over magnesium sulfate and concentrated under reduced pressure to
dryness. The residue was purified by silica gel column
chromatography (eluent hexane/ethyl acetate=19/1) to give the
objective compound (1.81 g) as a pale-yellow oil.
[0561] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=6 Hz), 2.13(3H, s),
4.16(2H, s), 4.33(2H, q, J=6 Hz), 6.71(1H, d, J=8 Hz), 6.99(1H, d,
J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.29(1H, s), 7.40(1H, s),
7.80(1H, d, J=8 Hz), 7.98(1H, s).
Preparation Example 5-9
1-(2,4-Dichlorobenzyl)-2-methylindolizine-7-carboxylic acid
[0562] In the same manner as in Preparation Example 4-7, the
objective compound (1.63 g) was obtained from ethyl
1-(2,4-dichlorobenzyl)-2-methyl- indolizine-7-carboxylate (1.81 g)
as a yellow powder.
[0563] .sup.1H-NMR(DMSO-d.sub.6): 2.10(3H, s), 4.17(2H, s),
6.84-6.91(2H), 7.28(1H, d, J=8 Hz), 7.60(2H, s), 7.93(1H, s),
8.19(1H, d, J=8 Hz)
Preparation Example 6-1
(E)-4-Methyl-2-(4-phenylphenyl)ethenylpyidine
[0564] A mixture of phenyl benzaldehyde (6.45 g), 2,4-lutidine
(7.59 g) and acetic anhydride (10 ml) was heated at a bath
temperature of 150.degree. C. for 12 hr, and refuxed under heating
for 12 hr. The reaction mixture was concentrated under reduced
pressure to dryness. The residue was purified by sflica gel column
chromatography (eluent hexane/ethyl acetate=9/1-5/1) to give the
objective compound (4.35 g) as a yellow solid.
[0565] .sup.1H-NMR(CDCl.sub.3): 2.38(3H, s), 6.98(1H, d, J=5 Hz),
7.12-7.28(2H), 7.34(1H, t, J=8 Hz), 7.44(2H, t, J=8 Hz),
7.56-7.71(7H), 8.47(1H, d, J=5 Hz)
Preparation Example 6-2
(E)-2-(4-Phenylphenyl)ethenylpyridine-4-carboxic acid
[0566] A mixture of (E)-4-methyl-2-(4-phenylphenyl)ethenylpyridine
(4.24 g), selenium dioxide (2.08 g) and pyridine (43 ml) was
refluxed under heating for 24 hr. The reaction mixture was
concentrated under reduced pressure to dryness. The residue was
extracted with chloroform/methanol/aqueous ammonium (65:25:4). The
extract was concentrated under reduced pressure to dryness. The
residue was pulverized in ethyl acetate to give the objective
compound (3.81 g) as a brown powder.
[0567] .sup.1H-NMR(DMSO-d.sub.6): 7.32-7.53(4H), 7.63(1H, d, J=5
Hz), 7.70-7.84(8H), 7.96(1H, s), 8.66(1H, d, J=5 Hz)
Preparation Example 6-3
Ethyl (E)-2-(4-phenylphenyl)ethenylpyridine-4-carboxylate
[0568] (E)-2-(4-Phenylphenyl)ethenylpyrdine-4-boxylic acid (3.60 g)
and a mixture of concentrated sulfuric acid/ethanol (9:1) were
refluxed under heating for 2 hr, and neutralized under ice-cooling.
The reaction mixture was partitioned between dichloromethane and
water, and the aqueous layer was extracted once with
dichloromethane. The organic layers were combined, dried over
magnesium sulfate and concentrated to dryness under reduced
pressure. The residue was purified by silica gel column
chromatography (eluent hexane/ethyl acetate=9/14/1) to give the
objective compound (3.14 g) as a white solid.
[0569] .sup.1H-NMR(CDCl.sub.3): 1.43(3H, t, J=6 Hz), 4.45(2H, q,
J=6 Hz), 7.22-7.50(4H), 7.60-7.79(8H), 7.97(1H, s), 8.74(1H, d, J=5
Hz)
Preparation Example 6-4
Ethyl 2-(4-phenylphenyl)ethylpyridine-4-carboxylate
[0570] A mixture of ethyl
(E)-2-(4-phenylphenyl)ethenylpyridine-4-carboxyl- ate (1.84 g), 10%
palladium/active carbon (184 mg), dicxane (18 ml) and ethanol (9.0
ml) was steed at 40.degree. C. for 5 hr under a hydrogen atmosphere
at 5 atm. To this reaction mixture were added dioxane (9.0 ml) and
ethanol (9.0 ml), and the mixture was stirred at 50.degree. C. for
3 hr under a hydrogen atmosphere at 5 atm. To the mixture was added
10% palladium/active carbon (184 mg), and the mixure was stirred
for 3 hr under the same conditions. The reaction mixture was
filtered through Celite and washed with chloroform/methanol (4:1).
The filtrate and the washing were combined and concentrated to
dryness under reduced pressure to give a crude product of the
objective compound (1.97 g) as a pale-yellow solid.
[0571] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=6 Hz), 3.12(2H, m),
3.22(2H, m), 4.40(2H, q, J=6 Hz), 7.22-7.36(3H), 7.43(2H, t, J=8
Hz), 7.52(2H, d, J=8 Hz), 7.58(2H, d, J=8Hz), 7.67-7.72(2H),
8.72(1H, d, J=5 Hz)
Preparation Example 6-5
Ethyl 2-methyl-1-(4-phenylbenezyl)indolizine-7-carboxylate
[0572] The crude product of ethyl
2-(4-phenylphenyl)ethylpyrine-4-carboxyl- ate (1.62 g) and
bromoacetone (803 mg) were dissolved in acetone (32 ml). The
mixture was refluxed under heating for 24 hr and concentrated to
dryness under reduced pressure. The residue was dissolved in
ethanol (16 ml). Sodium hydrogen-mrbonate was added, and the
mixture was refluxed under heating for 12 hr. The reaction mixture
was diluted with ethyl acetate and washed with water. The organic
layer was dried over magnesium sulfate and concentrated to dryness
under reduced pressure. The residue was purified by silica gel
column cromatogaphy (eluent hexane/ethyl acetate=19/1) to give the
objective compound (383 mg) as a yellow-green solid. The unreacted
starting compound, ethyl 2-(4-phenylphenyl)-ethylpyr-
idine-4-carboxylate, (1.04 g) was recovered.
[0573] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=6 Hz), 2.21(3H, s),
4.19(2H, s), 4.35(2H, q, J=6 Hz), 6.98(1H, d, J=8 Hz),
7.18-7.36(4H), 7.40(2H, t, J=8 Hz), 7.48(2H, d, J=8 Hz), 7.56(2H,
d, J=8 Hz), 7.78(1H, d, J=8 Hz), 8.12(1H, s)
Preparation Example 6-6
2-Methyl-1-(4-phenylbenzyl) indolizine-7-carboxylic acid
[0574] In the same manner as in Preparation Example 47, the
objective compound (612 mg) was obtained as a yellow powder from
ethyl 2-methyl-1-(4-phenylbenzyl)-1-indolizine-7-carboxylate (710
mg).
[0575] .sup.1H-NMR(DMSO-d.sub.6): 2.20(3H, s), 4.16(2H, s),
6.86(1H, d, J=8 Hz), 7.22(2H, d, J=8 Hz), 7.33(1H, t, J=8 Hz),
7.43(2H, t, J=8 Hz), 7.52-7.64(5), 8.06(1H, s), 8.17(1H, d, J=8
Hz)
Preparation Example 7-1
6-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)quinoline
[0576] A mixture of quinoline-6-carboxylic acid (4.00 g) and
thionyl chloride (10.1 ml) was stirred for 3 hr at room temperature
and concentrated to dryness under reduced pressure. To the residue
were added dichloromethae (60 ml) and triethylanine (16 ml), and
then 2-amino-2-methylpropanol (4.12 g) with stifing in an ice bath.
The reaction mture was stirred for 3 hr at room temperature. Water
was added to separate the organic layer. The aqueous layer was
extracted twice with dichloromethane. The organic layers were
combined, dried over anhydrous magnesium sulfate and concentrated
to dryness under reduced pressure to give a pale-brown solid (5.55
g). To thiswas added thionyl chloride (16.8 ml) while stirnng under
cooling with ice water under a nitrogen atmosphere, and the mixture
was stirred for 3 hr at room temperature. The reaction mixtre was
concentrated to dryness under reduced pressure. Water and 1N
aqueous sodium hydroide solution were added to basicify and the
mixture was extracted three times with ethyl acetate. The etact was
dried over anhydrous magnesium sulfate and concentrated to dryness
under reduced pressure. The residue was purified by silica gel
column chromoatography (eluent ethyl acetate) to give the objective
compound (3.26 g) as a light-brown solid.
[0577] .sup.1H-NMR(CDCl.sub.3):1.43(6H, s), 4.20(2H, s), 7.45(1H,
dd, J=4 Hz, 8 Hz), 8.11(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz), 8.26
(1H, d, J=8 Hz), 8.43(1H, s), 8.97 (1H, m)
Preparation Example 7-2
1-Ethoxycarbonyl-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-dimethoxyphosph-
oryl-1,2-dihydroquioline
[0578] A mixture of
6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)quinoline (543 mg) and ethyl
chloroformate (0.275 ml) was stirred for 3 hr at room temperature.
Trimethyl phosphonate (0.340 ml) was added under ice watercooling
and the mixtxe was stirred for 15 hr at room temperature. The
reaction mixture was concentrated to dryness under reduced
pressure. The residue was purified by silica gel column
chromatogrphy (eluent: ethyl acetate, ethyl acetate/methanol=20/1)
to give the objective compound (974 mg) as a pale-yellow oil.
[0579] .sup.1H-NMR(CDCl.sub.3): 1.33(3H, t, J=7 Hz), 1.39(6H, s),
3.52(3H, d, J=10 Hz), 3.64(3H, d, J=10 Hz), 4.12(2H, s),
4.26-4.38(2H, br), 5.61-5.75(1H, br), 6.06-6.14(1H, m), 6.62(1H,
m), 7.68(1H, s), 7.78(1H, dd, J=4 Hz, 8 Hz)
Preparation Example 7-3
1-Ethoxycarbonyl-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-dimethoxyphosph-
oryl-4-(4-phenylbenzyl)-1,2-dihydroquinoline
[0580]
1-Ethoxycarbonyl-6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-2-dimethox-
y-phosphoryl-1,2-dihydroquinoline (934 mg) was dissolved in THF (10
ml), and a 1.6 M n-butyllithiumhexane solution (1.8 ml) was added
under cooling with dry ice-acetone. The mixture was stirred for 1
hr at the same temperature. 4-(Iodomethyl)biphenyl (740 mg, 2.52
mmol) was added under cooling with dry ice-acetone, and the mixture
was stirred at -20.degree. C. for 1 hr and at 0.degree. C. for 1
hr. Then, water was added, and the mixture was stirred for 0.5 hr
at room temperature and extracted thrce times with ethyl acetate.
The extract was dried over anhydrous magnesium sulfate and
concentrated to dryness under reduced pressure. The residue was
purified by silica gel column chromatography (eluent: ethyl
acetate, ethyl acetate/methanol=20/1) to give the objective
compound (738 mg) as a yellow powder.
[0581] .sup.1H-NMR(CDCl.sub.3): 1.32(3H, t, J=7 Hz), 1.38(6H, s),
3.49(3H, d, J=10 Hz), 3.61(3H, d, J=10 Hz), 3.99(2H, br), 4.10(2H,
m), 4.30(2H, m), 5.5-5.74(2H, br), 7.29-7.60(10H, m), 7.84(1H, m),
7.91(1H, s) MS (m/z) 575.
Preparation Example 7-4
6-(4,5-Dihydro-4,4-dimethyloxazol-2-yl)-4-(4-phenylbenzyl)quinoline
[0582] A mixture of
1-ethoxycarbonyl-6-(4,5-dydro-4,4-dimethyloxazol-2-yl)-
-2-dimethyhosphoryl-4-(4-phenyibenzyl)-1,2-dihydroquinoline (738
mg), ethanol (20 ml) and 1N aqueous sodium hydrtwdde solution (4
ml) was refluxed under heating for 2 hr. The reaction mixture was
concentrated to dryness under reduced pressure. Water was added and
the mixe was extracted twice with ethyl acetate. The organic layers
were combined, washed once with saturated brine, dned over
anhydrous magnesium sulfate and concentrated to dryness under
reduced pressue. The residue was purified by silica gel column
chromatography (eluent: ethyl acetate) to give the objective
compound (140 mg) as awhite solid.
[0583] .sup.1H-NMR(CDCl.sub.3): 1.42(6H, s), 4.18(2H, s), 4.54(2H,
s), 7.18(1H, br, 7.27-7.46(5H, m), 7.52-7.60(4H, m), 8.16(1H, d,
J=8 Hz), 8.29(1H, d, J=8 Hz), 8.73(1H, br), 8.83(1H, d, J=7 Hz)
Preparation Example 7-5
4-(4-Phenylbenzyl)quinoline-6-carboxylic acid
[0584] A mixture of
6-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-4-(4-phenylben-
zyl)-quinoline (132 mg), ethanol (1 ml) and 3N hydrochloric acid (3
ml) was refluxed under heating for 2 hr. Then 6N hydrochloric acid
(3 ml) was added and the mau was refluxed for 4 hr. The mixture was
basified with aqueous sodium hydridde solution, and washed once
with chloroform. The aqueous layer was adjusted to pH 4 with 1N
hydhloric acid. The resulting precipitate was collected by
filtration and washed with water to give the objective compound (87
mg) as a white powder.
[0585] .sup.1H-NMR(DMSO-d.sub.6): 4.61(2H, s), 7.30-7.50(6H, m),
7.57-7.68(4H, m), 8.12(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz),
8.83(1H, s), 8.94 (1H, d, J=4 Hz)
Preparation Example 8-1
2,3-Diamino-6-chloropyridine
[0586] In the same manner as in the following Preparation Example
9-2, the objective compound (8.3 g) was obtained from
2-amino-6-chloro-3-nitropyri- dine (10.2 g) as a red-brown
solid.
[0587] .sup.1H-NMR(DMSO-d.sub.6): 4.77(2H, br s), 5.79(2H, br s),
6.34(1H, d, J=8 Hz), 6.69(1H, d, J=8 Hz) MASS(ESI): m/z
142(M-1)
Preparation Example 8-2
5-Chloro-2-methyl-1H-imidazo[4,5-b]pyridine
[0588] In the same manner as in the following Preparation Example
93, the objective compound (6.64 g) was obtained from
2,3-diamino-6-chloropyrdine (8.1 g) as light brown crystals.
[0589] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 7.22(1H, d, J=8 Hz),
7.91(1H, d, J=8 Hz) MASS(ESI): m/z 166(M-1) mp 254-255.degree.
C.
Preparation Example 8-3
5-Bromo-2-methyl-1H-imidazo[4,5-b]pyridine
[0590] In the same manner as in the following Preparation Example
9-1, the objective compound (7.54 g) was obtained from
5-chloro-2-methyl-1H-imidaz- o[4,5-b]pyridine (6.54 g) as
pale-purple crystals.
[0591] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 7.32(1H, d, J=8 Hz),
7.83(1H, d, J=8 Hz) MASS(ESI): m/z 210(M-1) mp 239-241.degree.
C.
Preparation Example 8-4
2-Methylimidazo[4,5-b]pyridine-5-carbonitrile
[0592] To a solution of 5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine
(1.92 g) in N,N-dimethylformamide (48 ml) was added Copper (I)
cyanide (2.04 g), and the mixture was stirred for 9 hr at
150.degree. C. After evaporation of the solvent under reduced
pressure, water (45 ml) and ethylenediamine (2.7 g) were added to
the residue, and the mixture was heated at 70.degree. C. for 15
min. The solution was concentrated under reduced pressure and the
residue was purified by a short silica gel column to give the
objective compound (927 mg) as a brown powder. Purification by
silica gel column chromatography (dichloromethane/methano- l=10/1)
gave a purer compound.
[0593] .sup.1H-NMR(DMSO-d.sub.6): 2.58(3H, s), 7.76(1H, d, J=8 Hz),
8.05(1H, d, J=8 Hz) Mass(ESI): m/e 157(M-H).sup.-
Preparation Example 9-1
2-Amino-6-bromo-3-nitropyridine
[0594] A 30% solution of hydrogen bromide in acetic acid (10 mnl)
was added to 2-amino-6-chloro-3-nitropyridine (1.0 g) at room
temperature and the mixture was heated at 100.degree. C. After 24
hr, a 30% solution of hydrogen bromide in acetic acid (5 ml) was
added. After 48 hr, the reaction mixture was cooled and
concentrated. The residue was neutralized with 28% aqueous ammonia
and extracted three times with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, filtered and concentrated.
The residue was crystallized from isopropyl ether to give the
objective compound (1.14 g) as yellow crystals.
[0595] .sup.1H-NMR(DMSO-d.sub.6): 6.90(1H, d, J=8 Hz), 8.25(1H, d,
J=8 Hz) MASS(ESI): m/z217(M-1)
Preparation Example 9-2
2,3-Diamio-bromopyridine
[0596] To a suspension of 2-amino-6-bromo-3-nitropyridine (21.8 g)
in ethanol (220 ml) in water (22 ml) was added iron powder (39.0 g)
at room temperature. Concentrated hydrochloric acid (0.8 ml) was
added and the mixiue was slowly heated with stirring to start the
reaction. The mixture was refluxed under heating for 2 hr and the
insoluble matter was filtered off while it was hot. The solvent was
evaporated under reduced pressure and water (200 ml) and active
carbon were added to the remaining solid, which was followed by
heating. The insoluble matter was filtered off while it was hot
Water was evaporated under reduced pressure from the filtrate to
give the objective compound (9.00 g) as a geeen-bruwn powder.
Ethanol (100 ml)-water (100 ml) was added to the solid from the
above operation and the mixture was heated for dissolution, and the
insoluble matter was filtered off. The solvent was evaporated under
reduced pressure and the residue was purified by silica gel column
chromatography (hexane/ethyl acetate=1/3) to give the objective
compound (8.25 g) as a black powder.
[0597] .sup.1H-NMR(DMSO-d.sub.6): 4.78(2H, br s), 5.80(2H, br s),
6.47(1H, d, J=8 Hz), 6.61(1H, d, J=8 Hz) Mass(ESI): m/e188, 190
(M+H).sup.+
Preparation Example 9-3
5-Bromo-2-methyl-1H-imidazo[4,5-b]pyridine
[0598] 2,3-Diaminobromopyridine (8.16 g) and triethyl orthoacetate
(12.0 ml) were mixed in acetic acid (41 ml), and the mixture was
refluxed under heating for 29 hr. The rnixtue was allowed to cool
and the solvent was evaporated to give a aude product (10 g). This
was dissolved in a sufficient amount of dichloromethane. Anhydrous
potassium carbonate and active carbon were added and the mixtxe was
stirred at room templure. The insoluble matter was filtered off and
the solvent was evaporated to give the objective compound (7.59 g)
as a pale-yellow powder.
[0599] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 7.31(1H, d, J=8 Hz),
7.82(1H, d, J=8 Hz) Mass(ESI): m/e 212, 214 (M+H).sup.+
Preparation Example 10-1
3-(2,4-Dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitride
and
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitr-
ile
[0600] In the same manner as in the following Preparation Example
14-2, two isomers,
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carbonitrile (138 mg) and
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b-
]pyridine-5-carbonitrile (67 mg) were respectively obtained as
pale-brown a crystals from
2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile (200 mg).
3-(2,4-Dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile
[0601] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 5.55(2H, s), 6.64(1H,
d, J=8 Hz), 7.14(1H, dd, J=8, 2 Hz), 7.48(1H, br s), 7.65(1H, d,
J=8 Hz), 8.09(1H, br d, J=8 Hz) MASS(ESI): m/z317(M+1), mp
180-182.degree. C.
1-(2,4-Dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitrile
[0602] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, br s), 5.42(2H, s),
6.46(1H, d, J=8 Hz), 7.18(1H, d, J=8 Hz), 7.49-7.60(3H, m)
MASS(ESI): m/z 317(M+1)
Preparation Example 10-2
3-(2,4-Diclorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxic
acid
[0603] To a suspension of
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carbonitrile (113 mg) in ethanol (0.6 ml) was added a
30% aqueous sodium hydroxide solution (0.3 ml), and the mixture was
refluxed under heating for 12 hr. After 12 hr, a 30% aqueous sodium
hydriode solution (0.5 ml) was added and the mixture was refluxed
under heating 3 hr. The reaction mixture was cooled, adjusted to pH
1 with 6N hydrochloric acid, stirred for 1 hr and adjusted to pH 4
with a saturated aqueous sodium hydrogencarbnate solution. The
precipitated crystals were collected by filtration to give the
objective compound (144 mg) as colorless astals.
[0604] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.60(2H, s),
6.60(1H, d, J=8 Hz), 7.31(1H, br d, J=8 Hz), 7.76(1H, br s),
8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) MASS(ESI): m/z 334(M-1)
mp>260.degree. C.
Preparation Example 11-1
2-Chloro-4-phenylbenzyl alcohol
[0605] To a suspension of lithium chloride (482 mg) in anhydrous
1,4-dioxane (12 ml) were added 4-bromo-2-chlorobenzyl alcohol (1.05
g), phenyl tnbutyl tin (1.74 g) and
tetralds(triphenylphosphine)palladium(0) (110 mg) under a nitrogen
atmosphere, and the mixture was refluxed under heating. After 5 hr,
the reaction mlxture was cooled and water was added. The mixture
was extracted with ethyl acetate. The orgaiic layer was washed with
a saturated aqueous sodium hydrogencarbonate solution and saturated
brine, and dried over anhydrous magnesium sulfate. The filtrate was
concentrated, and the residue was subjected to flash silica gel
column chromatography (silica gel, 50 ml, eluent: hane-ethyl
acetate=2-1). The eluate was washed with hexane to give the
objective compound (220 mg) as colorless cystals.
[0606] .sup.1H-NMR(CDCl.sub.3): 4.72(2H, s), 7.32-7.61(8H, m) mp
69-70.degree. C.
Preparation Example 11-2
2-Chloro-phenylbenzyl alcohol
[0607] To a suspension of tetrakis(triphenylphosphine) pallaium(0)
(16 mg) in toluene (1 mnl) was added 4-bromo-2-chlorobenzyl alcohol
(100 mg) at room temperature, and the mixture was stirred. After 10
min, to the reaction mixture were added a solution of phenylboric
acid (83 mg) in ethanol (0.1 mnl) and a 2M aqueous sodium carbonate
solution (0.9 ml), and the mixtre was refluxed under heating After
1 hr, the reaction mixture was cooled, ethyl acetate was added, and
the mixture was filtered through Celite. The organic layer was
washed with saturated brine and dried over anhydrous magnesium
sulfate. The filtrate was concentrated, and the residue was
subjected to fash silica gel column chromatography (silica gel, 40
ml, eluent: hexane-ethyl acetate=3-1) to give crude crystals. The
crystals were washed with hexane to give the objective compound (76
mg) as colorless crystals.
[0608] .sup.1H-NMR(CDCl.sub.3): 4.72(2H, s), 7.32-7.61(8H, m) mp
69-70.degree. C.
Preparation Example 11-3
2-Chloro-1-methanesulfonyloxymethyl-4-phenylbenzene
[0609] In the same manner as in the following Preparation Example
14-1, the objective compound (422 mg) was obtained from
2-chloro-4-phenylbenzyl alcohol (305 mg) as a colorless oil.
[0610] .sup.1H-NMR(CDCl.sub.3): 3.05(3H, s), 5.39(2H, s),
7.34-7.60(7H, m), 7.66(1H, br s)
Preparation Example 11-4
3-(2-Chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitr-
ile and
1-(2-chloro-4-phenylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-c-
arbonitrile
[0611] In the same manner as in the following Preparation Example
14-2,
3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-inidazo[4,5-b]pyridine-5-carbonit-
rile (163 mg) and
1-(2-chloro-4-phenylbenzyl)-2-methyl-1H-imidazo[4,5-b]py-
ridine-5-carbonitrie (113 mg) were rspectively obtained as
pale-yellow crystals and pale-yellow amorphous from
2-methyl-1H-imidazo[4,5b]pyridine- -5-carbonitrile (200 mg).
3-(2-Chlophenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile:
[0612] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.64(2H, s), 6.74(1H,
d, J=8 Hz), 7.31-7.56(6H, m), 7.62-7.70(2H, m), 8.10(1H, brd, J=8
Hz) MASS(ESI): m/z 359(M+1), mp 202-205.degree. C.
1-(2-Chloro-4-phenylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitr-
ile:
[0613] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, br s), 5.52(2H, s),
6.60(1H, d, J=8 Hz), 7.31-7.60(8H, m), 7.70(1H, br d, J=1 Hz)
MASS(ESI): m/z359(M+1)
Preparation Example 11-5
3-(2-Chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[0614] In the same manner as in Preparation Example 10-2, the
objective compound (168 mg) was obtained from
3-(2-chloro-4-phenylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carbonitrile (159 mg) as colorless
crystals.
[0615] .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s), 5.65(2H, s),
6.60(1H, d, J=8 Hz), 7.33-7.55(3H, m), 7.65(2H, br d, J=8 Hz),
7.85(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz)
MASS(ESI): m/z376(M-1) mp 238-243.degree. C.
Preparation Example 12-1
3-(1-Bromonaphthalen-2-yl)methyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
onitrile and
1-(1-bromonaphthalen-2-yl)methyl-2-methyl-1H-imidazo[4,5-b]py-
ridine-5-carbonitrile
[0616] In the same manner as in the following Prearation Example
142,
3-(1-bromonaphthalen-2-yl)methyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
bonitrie (139 mg) and
1-(1-bromo-naphthalen-2-yl)methyl-2-methyl-1H-imidaz-
o[4,5-b]pyridine-5-carbonitrile (96 mg) were respectively obtained
as pale-brown crystals and pale-brown amorphous firm
2-methyl-1H-imidazo[4,5- -b]pyridine-5-carbonitrile (200 mg).
3-(1-Bromonaphthalen-2-yl)methyl-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carbonitrile:
[0617] .sup.1H-NMR(CDCl.sub.3): 2.58(3H, s), 5.85(2H, s), 6.70(1H,
d, J=8 Hz), 7.58(1H, br t, J=8 Hz), 7.62-7.71(3H, m), 7.81(1H, br
d, J=8 Hz), 8.10(1H, d, J=8 Hz), 8.39(1H, br d, J=8 Hz) MASS(ESI):
m/z377(M+1) mp 215-218.degree. C.
1-(1-Bromonaphthalen-2-yl)methyl-2-methyl-1H-imidazo[4,5-b]pyridine-5-carb-
onitrile
[0618] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 5.69(2H, s), 6.56(1H,
d, J=8 Hz), 7.49-7.74(5H, m), 7.82(1H, d, J=8 Hz), 8.37(1H, d, J=8
Hz) MASS(ESI): m/z 377(M+1)
Preparation Example 12-2
3-(1-Bromonaphthalen-2
-yl)methyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-car- boxylic
acid
[0619] In the same manner as in Preparation Example 10-2, the
objective compound (235 mg) was obtained from
3-(1-bromonaphthalen-2-yl)methyl-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carbonitile (138 mg) as
pale-yellow crystals.
[0620] .sup.1H-NMR(DMSO-d.sub.6): 2.40(3H, s), 5.80(2H, s),
6.51(1H, d, J=8 Hz), 7.61(1H, br t, J=8 Hz), 7.75(1H, br t, J=8
Hz), 7.84(1H, d, J=8 Hz), 8.30(1H, d, J=8 Hz) MASS(ESI):
m/z394(M-1) mp>250.degree. C.
Preparation Example 13-1
2-Methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-arbonitrle
and
2-methyl-1-(4-phenylbenzy)-1H-imidazo[4,5-b]pyridine-5-carbonitrie
[0621] In the same manner as in the following Preparation Example
14-2, 2-methyl-3-(4-
phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile (140 mg) and
2-methyl-1-(4-phenylbenzyl)-4-1H-imidazo[4,5-b]pyridine-carb- onile
(113 mg) were respectively obtained as pale-brown crystals and
pale-yellow amorphous from
2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonite (200 mg).
2-Methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5carbonitile
[0622] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 5.52(2H, s),
7.22-7.59(9H, m), 7.65(1H. d, J=8 Hz), 8.05(1H. d, J=8 Hz)
MASS(ESI): m/z 325(M+1) mp 225-226.degree. C.
2-Methyl-1-(4-phenylbenzyl)-1H-imidazo[4,5-b]pyridine-5-carbonitrile
[0623] .sup.1H-NMR(CDCl.sub.3):2.72(3H, br s), 5.41(2H, s),
7.10(2H. d, J=8 Hz),7.32-7.68(9H, m) MASS(ESI): m/z 325(M+1)
Preparation Example 13-2
2-Methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[0624] In the same manner as in Preparation Example 14-2, the
objective compound (133 mg) was obtained as colorless cystals from
2-methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-carbonitrile
(135 mg.
[0625] .sup.1H-NMR(DMSO-d.sub.6): 2.58(3H, s), 5.61(2H, s),
7.30(2H, d, J=8 Hz), 7.35 (1H, d, J=8 Hz), 7.40-7.49(2H, m),
7.59-7.68(4H, m), 8.00(1H. d, J=8 Hz), 8.10(1H. d, J=8 Hz)
MASS(ESI): m/z 342(M-1) mp>250.degree. C.
Preparation Example 14-1
4-Bromo-2-chloro-1-methanesulfonyloxymethylbene
[0626] To a solution of 4-bromo-2-chlorobenzyl alcohol (3.56 g) and
anhydrous triethylamine (3 ml) in anhydrous dichloromethane (36 ml)
was dropwise added methanesulfonyl chloride (1.4 ml) under
anitrogen atmosphere and ice-cooling. The reaction mixture was
stirred for 1 hr, washed with water, a saturated aqueous sodium
hydrogencarbonate solution and saturated brine, and dried over
anhydrous magnesium sulfate. The filtrate was concentrated to give
the objective compound (4.77 g) as a ight brown solid.
[0627] .sup.1H-NMR(CDCl.sub.3): 3.03(3H, s), 5.29(2H, s), 7.37(1H,
d, J=8 Hz), 7.47(1H, dd, J=8, 1 Hz), 7.60(1H, d, J=1 Hz) MASS(ESI):
m/z 298(M-1)
Preparation Example 14-2
3-(4-Bromo-2chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitril-
e and
1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carb-
onitrile
[0628] To a suspension of
2-methylimidazo[4,5-pyridine-5-carbonitrile (200 mg) in
N,N-dimethylformamide (2 ml) was added sodium hydride (70% in
mineral oil, 55 mg) under ice-cooling, and the mixu was stirred for
30 min. To this reaction mixture was added 4-bromo-2-chlorobenzyl
methanesulfonate (450 mg), and the mix was stirred for 2 hr at room
temprature. The reaction mixture was poured into water and the
product was extracted three times with ethyl acetate. The organic
layers were combined and washed successively with water and
saturated brine, dried over anhydrous magnesium sulfate and the
solvent was evaporated. The residue was subjected to silica gel
column chromatography (dichioromethane/ethyl acetate=5/1) to give
two isomers,
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitr-
ile (Rf 0.4, 233 mg) and
1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo-4,-
5b]pyridine-5-carbonitrile (Rf 0.1, 163 mg) as awhite powder and a
pale-yellow powder.
3-(4-Bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5b]pyridine-5-carbonitril-
e
[0629] .sup.1H-NMR(CDCl.sub.3): 2.58(3H, s), 5.52(2H, s), 6.55(1H,
d, J=8 Hz), 7.27(1H, dd, J=8 and 2 Hz), 7.61(1H, d, J=2 Hz),
7.64(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz) Mass(ESI): m/e 359, 361
(M-H).sup.-
1-(4-Bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carbonitri-
le
[0630] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 5.39(2H, s), 6.39(1H,
d, J=8 Hz), 7.31(1H, dd, J=8 and 2 Hz), 7.53(2H, s), 7.65(1H, d,
J=2 Hz) Mass(ESI): m/e 359, 361 (M-H).sup.-
Preparation Example 14-3
3-(4-Bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[0631] To
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5b]pyridine-5-c-
arbonitrile (226 mg) was added 6N hydrloric acid (2.5 ml) and the
mixture was mfluxed under heating for 1.5 hr. The reaction mixture
was cooled with ice and adjusted to pH 5 with a 1N aqueous sodium
hydroide solution. The precipitate was collected by ftrationr This
was dried under reduced pressure to give the objective compound
(226 mg) as a white powder.
[0632] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.58(2H, s),
6.52(1H, d, J=8 Hz), 7.43 (1H, dd, J=8 and 2 Hz), 7.85(1H, d, J=2
Hz), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) Mass(ESI): m/e 378,
380 (M-H).sup.-
Preparation Example 15-1
5-Bromo-3-(2-bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
and
5-bromo-1-(2-bromo-4chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine
[0633] In the same manner as in Preparation Example 14-2,
5-bromo-3-(2-bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(2.30 g) and
5-bromo-1-(2-bromo-4-chorobenzyl)-2-methyl-1H-imidazo[4,5-b]-
pyridine (1.32 g) were obtained as white powders from
5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (2.12 g).
5-Bromo-3-(2-brmo-4 orobenzyl)-2-methyl-3H-idazD[4,5-b]pyridine
[0634] .sup.1H-NMR(CDCl.sub.3): 2.51(3H, s), 5.49(2H, s), 6.48 (1H,
d, J=8 Hz), 7.16(1H, dd, J=8 and 2 Hz), 7.43(1H, d, J=8 Hz),
7.65(1H, d, J=2 Hz), 7.89(1H, d, J=8 Hz) Mass(ESI): m/e 414, 416,
418 (1:2:1, M+H).sup.+
5-Bromo-1-(2-bromo-4-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine
[0635] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.34(2H, s), 6.37(1H,
d, J=8 Hz), 7.19(1H, dd, J=8 and 2 Hz), 7.29(2H, s), 7.68(1H, d,
J=2 Hz) Mass(ESI): m/e 414, 416, 418 (1:2:1, M+H).sup.+
Preparation Example 15-2
3-(2-Bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitri-
le
[0636] In the same manner as in Preparation example 8-4, the
objective compound (268 mg) was obtained as a pale-yellow powder
from
5-bromo-3-(2-bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(2.07 g).
[0637] .sup.1H-NMR(CDCl.sub.3): 2.59(3H, s), 5.04(2H, s), 6.51(1H,
d, J=8 Hz), 7.17(1H, dd, J=8 and 2 Hz), 7.66(1H, d, J=8 Hz),
7.68(1H, d, J=2 Hz), 8.10(1H, d, J=8 Hz) Mass(ESI): m/e 361, 363
(M+H).sup.+
Preparation Example 15-3
3-(2-Bromol-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[0638] In the same manner as in Preparation Example 14-3, the
objective compound (214 mg) was obtained as a pale-yellow powder
from
3-(2-bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbonitr-
ile (253 mg).
[0639] .sup.1H-NMR(DMSO-d.sub.6): 2.54(3H, s), 5.56(2H, s),
6.55(1H, d, J=8 Hz), 7.34(1H, dd, J=8 and 2 Hz), 7.90(1H, d, J=2
Hz), 8.04(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz) Mass(ESI): m/e 378,
380 (M-H).sup.-
Preparation Example 16-1
Methyl 2-methylindolizine-6-carboxylate
[0640] Methyl 6-methyl-3-pyridinecrboxlate (9.83 g) and
bromoacetone (11.8 g) were mixed in acetone (98 ml) and the mixture
was rfluxed under heating for 20 hr. The solvent was evaporated
under reduced pressure and the residue was dissolved in methanol
(98 ml). Sodium hydogencarbonate (16.4 g) was added and the mixture
was refluxed under heating for 24 hr. The reaction mixture was
concentrated under reduced pressure, water was added and the
prepitate was collected by filtration. This was from hexane-ethyl
acetate to give the objective compound (5.94 g) as a pale-yellow
solid.
[0641] .sup.1H-NMR(CDCl.sub.3): 2.31(3H, s), 3.89(3H, s), 6.29(1H,
s), 7.06-7.29(3H, m), 8.63(1H, s) Mass(ESI): m/e 190(M+H).sup.+
Preparation Example 16-2
Methyl 3-(2,4-dichlorobenzoyl)-2-methylindolizine-6-carboxylate
[0642] To a suspension of anhydrous aluminium chloride (3.18 g) in
dichioromethane (19 ml) was added 2,4-dichlorobenzoyl chloride
(2.93 g) under ice-cooling, and the mixture was stirred for 10 min.
To this solution was added methyl 2-methylindolizine-6-carbolate
(1.89 g) and the mixture was stirred for 4 hr at room temperature.
The reaction mixture was slowly poured into ice water and the
resulting product was extracted with ethyl acetate. The organic
layer was washed successively with water, a saturated aqueous
sodium hydrogencarbonate solution and saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was evaporated and
the residue was purified by silica gel column chromatography
(hexane/ethyl acetate=5/1) to give the objective compound (2.39 g)
as a pale-yellow solid.
[0643] .sup.1H-NMR(CDCl.sub.3): 1.85(3H, s), 3.95(3H, s), 6.39(1H,
s), 7.25(1H, s), 7.29(1H, d, J=8 Hz), 7.37(1H, d, J=8 Hz),
7.41-7.52(2H, m), 7.76(1H, d, J=8 Hz) Mass(ESI): m/e
362(M-H).sup.-
Preparation Example 16-3
Methyl 3-(2,4-dichlorobenzyl)-2-methylindolizine-6-carboxylate
[0644] To a solution of methyl
3-(2,4-dichlorobenzoyl)-2-methylindolizin-6- -carboxylate (2.34 g)
in tetrahydrofuran (47 ml) was dropwise added a
borane-dimethylsulfide complex (10.0 M, 6.5 ml) under icecooling.
The mixtre was stirred for 4 hr at room temperature. To this
reaction mixture was carefully added dropwise 1N hydrhloric acid
(6.5 ml) under ice-cooling, and the mixture was stirred for 30 min
at room temperure. The reaction mixture was neutralized with
saturated aqueous sodium hydrogencarbonate solution, and the
resulting product was extracted three times with ethyl acetate. The
organic layers were combined, washed with saturated brine and dried
over magnesium sulfate. The solvent was evaporated and the residue
was purified by silica gel column chromatography (heane/ethyl
acetate=5/1) to give the objective compound (490.4 mg) as a
pale-yellow solid.
[0645] .sup.1H-NMR(CDCl.sub.3): 2.27(3H, s), 3.83(3H, s), 4.28(2H,
s), 6.42(1H, d, J=8 Hz), 7.01(1H, dd, J=8 and 2 Hz), 7.13(1H, d,
J=8 Hz), 7.24(1H, s), 7.30(1H, d, J=8 Hz), 7.44(1H, d, J=2 Hz),
8.29(1H, s)
Preparation Example 16-4
3-(2,4-Dichlorobenzyl)-2-methylindolizine-6-carboxylic acid
[0646] In the same manner as in Preparation Example 4-7, the
objective compound (487 mg) was obtained as ayellow powder from
methyl 3-(2,4-dichlorobenzyl)-2-methylindolizine-6-carboxylate (460
mg).
[0647] .sup.1H-NMR(DMSO-.sub.6): 2.24(3H, s), 4.38(2H, s), 6.46(1H,
s), 6.58(1H, d, J=8 Hz, 7.03(1H, d, J=8 Hz), 7.27(1H, dd, J=8 and 3
Hz), 7.40(1H, d, J=8 Hz), 7.67(1H, d, J=3 Hz), 8.33(1H, s)
Preparation Example 17-1
Ethyl
3-(2,4-dichlorobenzyl)-2-ethyl-7-methyl-3H-imidazo-4,5-b]pyridine-5--
carboxylate
[0648] In the same manner as in Preparation Example 14-2, the
objective compound (210 mg) was obtained from ethyl
2-ethyl-7-methyl-3H-imidazo[4,5- -b]pyridine-5-carboxylate (300
mg).
[0649] .sup.1H-NMR(CDCl.sub.3): 1.36(3H, t, J=7 Hz), 1.42(3H, t,
J=7 Hz), 2.73(3H, s), 2.79(2H, q, J=7 Hz), 4.45(2H, q, J=7 Hz),
5.61(2H, s), 6.55(1H, d, J=8 Hz), 7.07(1H, dd, J=8, 1 Hz), 7.45(1H,
d, J=1 Hz), 7.95(1H, s) Mass(ESI): m/e 394(M+1) mp: 143-144.degree.
C.
Preparation Example 17-2
3-(2,4-Dichlorobenzyl)-2-ethyl-7-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylic acid
[0650] In the same marner as in Preparation Example 4-7, the
objective compound (181 mg) was obtained from ethyl
3-(2,4-dichlorobenzyl)-2-ethyl--
7-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg).
[0651] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=7 Hz), 2.76(3H, s),
2.87(2H, q, J=7 Hz), 5.53(2H, s), 6.49(1H, d, J=8 Hz), 7.11(1H, br
d, J=8 Hz), 7.49(1H, br s), 8.05(1H, s) Mass(ESI): m/e 362(M-1) mp:
214-216.degree. C.
Preparation Example 18-1
Ethyl
2-ethyl-7-methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[0652] In the same manner as in Preparation Example 142, the
objective compound (294 mg) was obtained from ethyl
2-ethyl-7-methyl-3H-imidazo[4,5- -b]pyridine-5-carboxylate (292
mg).
[0653] .sup.1H-NMR(CDCl.sub.3): 1.36(3H, t, J=7 Hz), 1.45(3H, t,
J=7 Hz), 2.73(3H, s), 2.78(2H, q, J=7 Hz), 4.48(2H, q, J=7 Hz),
5.61(2H, s), 7.19-7.29(2H, m), 7.30-7.45(3H, m), 7.49-7.57(4H, m),
7.95(1H, s) Mass(ESI): m/e 400(M+1) mp: 153-154.degree. C.
Preparation Example 18-2
2-Ethyl-7-methyl-3-(4-phenylbenzyl)-3H-imidazo[4,5b]pyridine-5-carboxylic
acid
[0654] In the same manner as in Preparation Example 4-7, the
objective compound (249 mg) was obtained fidm ethyl
2-ethyl-7-methyl-3-(4-phenylben-
zyl)-3H-imidazo[4,5-b]pyridine-5-carboxylate (287 mg).
[0655] .sup.1H-NMR(DMSO-d.sub.6): 1.28(3H, t, J=7 Hz), 2.63(3H, s),
2.90(2H, q, J=7 Hz), 5.61(2H, s), 7.24(2H, d, J=8 Hz),
7.30-7.48(3H, m), 7.59-7.68(4H, m), 7.78(1H, s) Mass(ESI): m/e
370(M-1) mp 171-174.degree. C.
Preparation Example 19-1
Methyl
3-(4-bromo-2-chlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0656] In the same manner as in Preparation Example 1-1, the
objective compound (297 mg) was obtained as pale-green crystals
from methyl 2-methylbenzo[b]-thiophene-5-carboxylate (191 mg).
[0657] .sup.1H-NMR(CDCl.sub.3): 2.43(3H, s), 3.92(3H, s), 7.38(1H,
d, J=8 Hz), 7.56(1H, d, J=8 Hz), 7.65(1H, s), 7.80(1H, d, J=8 Hz),
8.00(1H, d, J=8 Hz), 8.49(1H, s)
Preparation Example 19-2
Methyl
3-(4-bromo-2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0658] In the same manner as in Preparation Example 1-2, the
objective compound (271 mg) was obtained as white crystals from
methyl
3-(4bromo-2-chlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
(280 mg).
[0659] .sup.1H-NMR(CDCl.sub.3): 2.47(3H, s), 3.90(3H, s), 4.20(2H,
s), 6.55(1H, d, J=8 Hz), 7.14(1H, dd, J=2, 8 Hz), 7.58(1H, d, J=3
Hz), 7.83(1H, d, J=8 Hz), 7.93(1H, d, J=8 Hz, 8.13(1H, s)
Preparation Example 19-3
3-(4-Bromo-2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0660] In the same manner as in Preparation Example 4-7, the
objective compound (237 mg) was obtained as white crystals from
methyl
3-(4-bromo-2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
(255 mg).
[0661] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 4.22(2H, s),
6.72(1H, d, J=8 Hz), 7.39(1H, dd, J=2, 8 Hz), 7.77(1H, s), 7.82(1H,
d, J=8 Hz), 8.01(1H, s), 8.03(1H, d, J=8 Hz)
Preparation Example 20-1
Methyl
3-(2,4-dichloro-5-fluorobenzoyl)-2-methylbenzo[b]thiophene-5-carbox-
ylate
[0662] In the same manner as in Preparation Example 16-2, the
objective compound (341 mg) was obtained as pale-green crystals
from methyl 2-methylbenzo[b]-thiophene-5-carboxylmethylate (200
mg).
[0663] .sup.1H-NMR(CDCl.sub.3): 2.47(3H, s), 3.92(3H, s), 7.32(1H,
d, J=8 Hz), 7.56(1H, d, J=4 Hz), 7.82(1H, d, J=8 Hz), 8.03(1H, d,
J=8 Hz), 8.51(1H, s)
Preparation Example 20-2
Mrthyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methylbenzo[b]thiophene-5-carboxy-
late
[0664] In the same manner as in Preparation Example 1-2, the
objective compound (307 mg) was obtained as white crystals from
methyl
3-(2,4-dichloro-5-fluorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
(318 mg).
[0665] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 3.91(3H, s), 4.19(2H,
s), 6.43(1H, d, J=8 Hz), 7.50(1H, dd, J=2, 7 Hz), 7.84(1H, d, J=8
Hz,7.96(1H, dd, J=2, 8 Hz), 8.10(1H, s)
Preparation Example 20-3
3-(2,4-Dichloro-5-fluorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0666] In the same manner as in Preparation Example 4-7, the
objective compound (241 mg) was obtained as white crystals from
methyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
(290 mg).
[0667] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 4.27(2H, s),
6.78(1H, d, J=9 Hz), 7.84(1H, d, J=8 Hz), 7.89(1H, d, J=7 Hz),
8.03(1H, d, J=7 Hz), 8.04(1H, s)
Preparation Example 21-1
Methyl
3-((3-chlorobenzo[b]thiophen-2-yl)carbonyl)-2-methylbenzo[b]thiophe-
ne-5-carboxylate
[0668] In the same manner as in Preparation Example 16-2, the
objective compound (389 mg) was obtained as pale-yellow crystals
from methyl 2-methylbenzo-[b]thiophene-5-carboxylate (200 mg).
[0669] .sup.1H-NMR(CDCl.sub.3): 2.56(3H, s), 3.87(3H, s),
7.48-7.63(2H, m), 7.82-8.05(4H, m), 8.37(1H, s)
Preparation Example 21-2
Methyl
3-((3-chlorobenzo[b]thiophen-2-yl)hydroxymethyl)-2-methylbenzo[b]th-
iophene-5-carboxylate
[0670] In the same manner as in the following Preparation Example
35-5, the objective compound (297 mg) was obtained as white
crystals from methyl
3-((3-chlorobenzo-[b]thiophen-2-yl)carbonyl)-2-methylbenzo[b]thiop-
hene-5-carboxylate (380 mg).
[0671] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 3.91(3H, s), 6.72(1H,
s), 7.32-7.43(2H, m), 7.72-7.77(3H, m), 7.90(1H, d, J=8 Hz),
8.84(1H, s)
Preparation Example 21-3
Methyl
3-((3-chlorobenzo[b]thiophen-2-yl)methyl)-2-methylbenzo[b]thiophene-
-5-carboxylate
[0672] In the same manner as in the following Preparation Example
35-6, the objective compound (266 mg) was obtained as white
crystals from methyl
3-((3-chlorobenzo-[b]thiophen-2-yl)hydroxymethyl)-2-methylbenzo[b]-
thiophene-5-carboxylate (280 mg).
[0673] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 3.92(3H, s), 2.47(2H,
s), 7.30(1H, d, J=8 Hz), 7.41(1H, t, J=8 Hz), 7.60(1H, d, J=7 Hz),
7.78-7.82(2H, m), 7.94(1H, dd, J=2, 8 Hz, 8.41(1H, s)
Preparation Example 21-4
3-((3-Chlorobenzo[b]thiophen-2-yl)methyl)-2-methylbenzo[b]thiophene-5-carb-
oxylic acid
[0674] In the same manner as in Preparation Example 47, the
objecive compound (243 mg) was obtained as white crystals from
methyl
3-((3-chlorobenzo[b]thiophen-2-yl)methyl)-2-methylbenzo[b]thiophene-5-car-
boxylate (250 mg).
[0675] .sup.1H-NMR(DMSO-d.sub.6) : 2.64(3H, s), 4.57(2H, s),
7.39(1H, t, J=8 Hz), 7.49(1H, t, J=8 Hz), 7.76(1H, d, J=7 Hz),
7.84(1H, d, J=7 Hz), 7.87(1H, d, J=7 Hz), 8.02(1H, d, J=8 Hz),
8.30(1H, s)
Preparation Example 22-1
Methyl
3-(1-bromonaphthalen-2-yl)carbonyl-2-methylbenzo[b]thiophene-5-carb-
oxylate
[0676] In the same manner as in Preparation Example 16-2, the
objective compound (358 mg) was obtained as pale-green crystals
from methyl 2-methylbenzo-[b]thiophene-5-carboxylate (200 mg).
[0677] .sup.1H-NMR(CDCl.sub.3): 2.30(3H, s), 3.83(3H, s), 7.48(1H,
d, J=8 Hz), 7.62-7.72(2H, m), 7.80(1H, d, J=8 Hz), 7.90-8.03(3H,
m), 8.38(1H, d, J=8 Hz, 8.73(1H, s)
Preparation Example 22-2
Methyl
3-(1-bromonaphthalen-2-yl)methyl-2-methylbenzo[b]thiophene-5-carbox-
ylate
[0678] In the same manner as in Preparation Example 1-2, the
objective compound (331 mg) was obtained as white crystals from
methyl
3-(1-bromonaphtho-2-yl)-2-methylbenzo[b]thiophene-5-carboxylate
(342 mg).
[0679] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 3.85(3H, s), 4.52(2H,
s), 6.84(1H, d, J=8 Hz), 7.48(1H, t, J=8 Hz), 7.55-7.63(2H, m),
7.74(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 7.93(1H, d, J=8 Hz),
8.23(1H, s), 8.39(1H, d, J=8 Hz)
Preparation Example 22-3
3-(1-bromonaphthalen-2-yl)methyl-2-methyl[b]thiophene-5-carboxylic
acid
[0680] In the same manner as in Preparation Example 47, the
objective compound (284 mg) was obtained as white crystals from
methyl
3-(1-bromonaphthalen-2-yl)methyl-2-methylbenzo[b]thiophene-5-carboxylate
(315 mg).
[0681] .sup.1H-NMR(DMSO-d.sub.6): 2.57(3H, s), 4.53(2H, s),
6.94(1H, d, J=8 Hz), 7.57(1H, t, J=7 Hz), 7.70(1H, t, J=7 Hz),
7.78(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 7.90(1H, d, J=8 Hz),
8.08(1H, s), 8.30(1H, d, J=8 Hz)
Preparation Example 23-1
4,5-Dibromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol
[0682] 4,5-Dibromo-2-methylimidazol (4.91 g) was dissolved in
N,N-dimethyl-formamide (50 ml) and 60% sodium hydride (901 mg) was
gradually added under icecooling. The mixtue was stirred for 1 hr
at room temperature, and 2-(tnmethylsilyl)ethoxymethyl chloride
(3.75 g) was gradually added dropwise under ice-cooling and the
mixture was stirred at room temperature overnight. The solvent was
evaporated under reduced pressure and ethyl acetate was added to
the residue. The residue was washed with a saturated aqueous sodium
hydrogencarbonate solution, and then with brine. The organic layer
was dried over anhydrous magnesium sulfate and evaporated under
reduced pressure to remove the solvent. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=3/1) to give
the objective compound (7.6 g) as a colorless oil.
[0683] .sup.1H-NMR(CDCl.sub.3): 0.00(9H, s), 0.92(2H, t, J=8 Hz),
2.47(3H, s), 3.55(2H, t, J=8 Hz), 5.24(2H, s)
Preparation Example 23-2
4-Bromo-2-methyl-1-(2-(trimethylsyl)ethoxymethyl)imidazol-5-carboxaldehyde
[0684]
4,5-Dibromo-2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)imidazol
(29.2 g) was dissolved in tetrhydrofurae (250 ml) and a 1.63N
n-butyl lithium/hexane solution (58.1 ml) was dropwise added over
20 min at -55.degree. C. to -60.degree. C. The mixture was stirred
at -60.degree. C. for 30 min and N,N-dimethylformamide (58 g) was
dropwise added at -55.degree. C. to -60.degree. C., and the mixture
was stirred at room temperature for 1 hr. Saturated brine was added
and the mixture was extacted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and the solvent was
evaporated under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=3/1) to give
the objective compound (18.5 g) as a pale-yellow on
[0685] .sup.1H-NMR(CDCl.sub.3): 0.00(9H, s), 0.91(2H, t, J=8 Hz),
2.52(3H, s), 3.58(2H, t, J=8 Hz), 5.70(2H, s), 9.71(1H, s)
Preparation Example 23-3
Ethyl
2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-thieno[2,3-d]imidazol-
-5-carboxylate
[0686] 2. 68 M Sodium ethylate was dissolved in ethanol (50 ml) and
a solution (25 ml) of ethyl thiuycolate in ethanol was added.
Thereto was added a solution (150 ml) of
4-bromo-2-methyl-1-(2-(trimethylsilyl)ethoxy-
methyl)imidazol-5-carboxaldehyde (3.16 g) in ethanol and the mixtre
was stirred at 80.degree. C. for 2 hr. The solvent was evaporated
under reduced pressure and water was added. The mixture was
extacted twice with ethyl acetate. The organic layer was washed
with brine and dried over anhydrous magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
obtained by silica gel column chromatography (hexane/ethyl
acetate=9/1). Hexane was added to the purified product and crystals
were collected by filtration to give the objective compound (765
mg) as pale-brown crystals.
[0687] .sup.1H-NMR(CDCl.sub.3): 0.00(9H, s), 0.94(2H, t, 8 Hz,
1.43(3H, t, 8 Hz, 2.15(3H, s), 3.56(2H, t, 8 Hz), 4.40(2H, q, 8
Hz), 5.42(2H, s), 7.64(1H, s)
Preparation Example 23-4
Ethyl 2-methylthieno[2,3-d]imidazol-5-carboxylate
[0688] Ethyl
2-methyl-1-(2-(trimethylsilyl)ethoxymethyl)-1H-thieno[2,3-d]i-
midazol-5-carboxylate (745 mg) was dissolved in ethanol (10 ml) and
6N hydrochloric acid (10 ml) was added, which was followed by relux
under heating for 1 hr. A saturated aqueous sodium
hydrogencarbonate solution was added under ice-cooling unti the
solution became weak alkaline, and the mnur was extracted with
ethyl acetate. The organic layer was washed with a saturated
aqueous sodium hydrogencarbonate solution and brine, and dried over
anhydrous sodium sulfate. The solvent was evaporated under reduced
pressure to give the objective compound (370 mg) as white
crystals.
[0689] .sup.1H-NMR(CDCl.sub.3): 1.39(3H, t, 7 Hz), 2.56(3H, s),
4.36(2H, q, 7 Hz), 7.62(1H, s)
Preparation Example 23-5
Ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-thieno[2,3d]imidazol-5-carboxylat-
e and ethyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-thieno[2,3-d]imidazol-5-car-
boxylate
[0690] In the same manner as in Preparation Example 142, ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-thieno[2,3-d]imidazol-5-carboxylate
(340 mg) and ethyl
3-(2,4-dichorobenzyl)-2-methyl-3H-theno[2,3-d]imidazol-
-5-carboxylate (168 mg) were obtained both as white crystals from
ethyl 2-methylthieno[2,3]imidazol-5-carboxylate (350 mg). The
structures of the both were determined by NOE.
Ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-thieno[2,3-d]imidazol-5-carboxyla-
te
[0691] .sup.1H-NMR(CDCl.sub.3): 1.36(3H, t, 7 Hz), 2.54(3H, s),
4.32(2H, q, 8 Hz), 5.29(2H, s), 6.62(1H, d, 8 Hz), 7.17(1H, dd, 2,
8 Hz), 7.38(1H, s), 7.47(1H, d, 2 Hz)
Ethyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-thieno[2,3-d]imidazol-5-carboxyla-
te
[0692] .sup.1H-NMR(CDCl.sub.3): 1.36(3H, t, 8 Hz), 2.60(3H, s),
4.32(2H, q, 8 Hz), 5.23(2H, s), 6.97(1H, d, 8 Hz), 7.29(1H, dd, 2,
8 Hz, 7.47(1H, d, 2 Hz, 7.80(1H, d, 2 Hz)
Preparation Example 23-6
1-(2,4-Dichlorobenzyl)-2-methyl-1H-thieno[2,3-d]imidazol-5-carboxylic
acid
[0693] In the same manner as in Preparation Example 4-7, the
objective compound (151 mg) was obtained as white crystals from
ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-thieno[2,3-d]imidazol-5-carboxylate
(170 mg) was obtained.
[0694] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 5.48(2H, s),
6.97(1H, d, 8 Hz), 7.44(1H, dd, 2, 8 Hz), 7.50(1H, s), 7.73(1H, d,
2Hz)
Preparation Example 23-7
3-(2,4-Dichloraobenzyl-2-methyl-3H-thieno[2,3-d]imidazol-5-carboxylic
acid
[0695] In the same manner as in Preparation Example 4-7, the
objective compound (112 mg) was obtained as white crystals from
ethyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-thieno[2,3-d]imidazol-5-carboxylate
(130 mg).
[0696] .sup.1H-NMR(DMSO-d.sub.6): 2.57(3H, s), 5.40(2H, s),
7.50(1H, d, 8 Hz), 7.56(1H, dd, 2, 8 Hz), 7.65(1H, s), 7.77(1H, d,
2 Hz)
Preparation Example 24-1
Ethyl 6-amino-5-nitronicotinate
[0697] In the same manner as in Preparation Example 4-5, the
objective compound (92 g) was obtained as yellow crystals from
6amino5-nitronicotinic acid (182 g).
[0698] .sup.1H-NMR(CDCl.sub.3): 1.41(3H, t, J=7 Hz), 4.40(2H, q,
J=7 Hz), 8.95(1H, d, J=2 Hz) 9.01(1H, s). MASS(ESI): m/z
210(M-1)
Preparation Example 24-2
Ethyl 5,6-diaminonicotinate
[0699] To a suspension of ethyl 6-amino-5-nitro-5-nicotinate (500
mg) and ammonium chloride (50 mg) in water (0.5 ml) and ethanol
(4.5 ml) was added reduced inon (496 mg) at 50.degree. C. and the
mitu was refluxed under heating. Three hours later, reduced iron
(200 mg) was added and the rrre was refluxed under heating for 3
hr. The reaction mixture was cooled, filtered thrugh Celite and
washed with chloroform. The filtrate was washed with water and the
organic layer was dried over anhydrous magnesium sulfate, filtrated
and concentrated. The residue was cystaly from isopropyl ether to
give the objective compound (307 mg) as red-brawn crrstal.
[0700] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=7 Hz), 3.30(2H, br
s), 4.32(2H, q, J=7 Hz), 4.70(2H, br s), 7.49(1H, d, J=1 Hz),
8.37(1H, d, J=1 Hz) MASS(ESI): m/z 182(M+1)
Preparation Example 24-3
Ethyl 6-amino-5-(1-aza-2-(2,4-dichlorophenyl)vinyl)nicotinate
[0701] A mixture of ethyl 5,6-diaminonicotinate (3.17 g),
benaldehyde (4 g) and molecular sieves 4 .ANG. (15 g) in
tetrahydrofurane (60 ml) was refluxed with heating for 2 days. The
reaction mixture was filtrated and the residue was concentrated and
crystallized from ethyl acetate to give the objective compound
(2.89 g) as yellow crystals.
[0702] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=7 Hz), 3.30(2H, br
s), 4.32(2H, q, J=7 Hz), 4.70(2H, br s), 7.49(1H, d, J=1 Hz,
8.37(1H, d, J=1 Hz) MASS(E:S: m/z 182(M+1)
Preparation Example 24-4
Ethyl 6-amino-5-(2,4-dichlorobenzylamino)nicotinate
[0703] To a suspension of ethyl
6-amino-5-(1-aza-2-(2,4-dichlorophenyl)vin- yl)nicotinate (2.88 g)
in ethanol (30 ml) was added sodium borohydride (644 mg) at room
temperature, and the mixture was stre. Three hours later, water was
added to the reaction nbh and the mixu was extracted with
dilorofomL The organic layer was washed with water, dried over
anhydrous magnesium sulfate and filtrated. The filtrate was
concentrated and the residue was crystalz from ethyl acetate to
give the objective compound (1.68 g) as yellow crystals. The mother
liquor was concentrated and crystallized from isopropyl ether to
give the objective compound (594 mg) as yellow
[0704] .sup.1H-NMR(CDCl.sub.3): 1.37(3H, t, J=7 mz), 3.49(1H, br t,
J=6 Hz),4.32(2H, q, J=7 Hz), 4.40(2H, d, J=6Hz), 4.69(2H, br s),
7.22(1H, d, J=8Hz), 7.31(1H, d, J=8 Hz), 7.39(1H, br s), 7.45(1H,
d, J=1 Hz), 8.35(1H, d, J=1 Hz) MASS(ESI): m/z340(M+1)
Preparation Example 24-5
Ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-carboxyl-
ate
[0705] A suspension of ethyl
6-aimino5-(2,4-dichlorobenzylamino)nicotinate (300 mg and acetic
acid (132 mg) in polyphosphoric acid (6 g) was heated to
100.degree. C. Two hours later, the reaction mixture was cooled and
ice (5 g) was added. The mixture was neutralized with a saturated
aqueous sodium hydrogencarbonate and extracted with
dichloromethane. The organic layer was washed with water, dried
over anhydrous sulfate and filtrated. The filtrate was concentrated
and the residue was crystallized from isopropyl ether to give the
objective compound (288 mg) as pale-brown crystals.
[0706] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=7 Hz), 2.64(3H, s),
4.41(2H, q, J=7H), 5.41(2H, s), 6.39(1H, d, J=8 Hz), 7.11(1H, dd,
J=8, 2 Hz), 7.50(1H,s), 8.12(1H, br s), 9.20(1H, d, J=2 Hz)
MASS(ESI): m/z 364(M+1)
Preparation Example 24-6
1-(2,4-Dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-carboxylic
acid
[0707] In the same manner as in Preparation Example 4-7, the
objective compound (309 mg) was obtained as pale-brown crystals
from ethyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-6-carboxylate
(337 mg).
[0708] .sup.1H-NMR(DMSO-d.sub.6): 2.57(3H, s), 5.68(2H, s),
6.68(1H, d, J=8 Hz), 7.34(1H, dd, J=8, 2 Hz), 7.74(1H, d, J=2 Hz),
8.35(1H, d, J=2 Hz), 8.91(1H, s) MASS(ESI): m/z 334(M-1)
Preparation Example 25-1
Ethyl-2-chloro-3-pyridyl carbamate
[0709] To a mixture of 3-amino-2-chloropyridine (10 g) in a 1N
aqueous sodium hydroxide solution (156 ml) and 1,4-dioxane (100 ml)
was dropwise added ethyl chorocarbonate (9 ml) at 10-20.degree. C.
under icecooling. The mixture was stirred at room temperature for
10 minutes. Two hours later, ethyl chlorocarbonate (4 ml) was
added. At 4, 5 and 6 hours later, ethyl chlorocarbonate (4 ml) and
an aqueous sodium hydrwide solution (40 ml) were added at each
time. After standing the mixtre ovenght, water was added to the
reaction mixture and the mixture was extraed with ethyl acetate.
The organic layer was washed with water and saturated brine, and
dried over anhydrous magnesium sulfate. The extract was
concentrated and the residue was subjected to flash silica gel
chromataphy (silica gel 400 ml, eluent hexane-ethyl acetate=5-1) to
give the objective compound (14.8 g as a colorless solid.
[0710] .sup.1H-NMR(CDCl.sub.3): 1.34(3H, t, J=7 Hz), 4.28(2H, q,
J=7 Hz), 7.11(1H, br s), 7.25(1H, dd, J=8, 5 Hz), 8.08(1H, d, J=5
Hz), 8.50(1H, d, J=8 Hz) MASS(ESI): m/z 199(M-1)
Preparation Example 25-2
Ethyl-2-(1-propyn-1-yl)-3-pyridyl carbamate
[0711] To a suspension of lithium chloride (7 g) in 1,4-dioxane
(135 ml) were added ethyl-2-chloro-3-pyridylcarbamate (13.5 g),
tributyl (1-propyn-1-yl)tin (22 g) and
tetzkis(triphenylphosphine)palladium(0) (1.56 g), and the mixture
was refluxed with heating, After 1.5 hr, the reaction mixtu was
cooled and water was added, which was followed by extraction with
ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium hydrogencarbonate and saturated brine,
and died over anhydrous magresium sulfate. The extact was
concentrated and the residue was subjected to flash silica gel
chromatography (silica gel 400 ml, eluent hexane-ethyl acetate=2-1)
to give the objective compound (10.9 g) as a pale-yellow solid.
[0712] .sup.1H-NMR(CDCl.sub.3): 1.36(3H, t, J=7 Hz), 2.19(3H, s),
4.25(2H, q, J=7 Hz), 7.20(1H, dd, J=8, 5 Hz), 7.33(1H, br s),
8.20(1H, d, J=5 Hz), 8.45(1H, br d, J=8 Hz) MASS(ESI): m/z 205(M+1)
mp 90-91.degree. C.
Preparation Example 25-3
2-Methylpyrrolo[3,2-b]pyridine
[0713] To a solution of ethyl-2-(1-propyn-1-yl)-3-pyridyl bamate
(10.9 g) in ethanol was added a 21% solution (50 ml) of sodium
ethylate in ethanol, and the mixture was refluxed under heating.
After 1.5 hr, the reaction mixture was cooled and water was added,
which was followed by thre times of extaction with dichloromethane.
The organic layer was dried over anhydrous magnesium sulfate, and
fitrated. The ffiltate was concentrated and the reirdue was
crystallized from ethyl acetate to give the objective compound (6.5
g) as pale-bromwn crystals.
[0714] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 6.23(1H, s), 6.97(1H,
dd, J=8, 5 Hz), 7.60(1H, d, J=8 Hz), 8.19(1H, br d, J=5 Hz
MASS(ESI): m/z 133(M+1) mp 193-195.degree. C.
Preparation Example 25-4
3-(2,4-Dichlorobenzoyl)-2-methylpyrrolo[3,2-b]pyridine
[0715] In the same manner as in Preparation Example 16-2, the
objective compound (1.23 g) was obtained as a colorless solid from
2-methylpyrrolo[2-pyridine (500 mg).
[0716] .sup.1H-NMR(DMSO-d.sub.6): 2.75(3H, s), 7.07(1H, dd, J=8, 5
Hz), 7.38(1H, d, J=8Hz), 7.48(1H, d, J=8 Hz), 7.65(1H, s), 7.74(1H,
d, J=8 Hz), 8.14(1H, d, J=5 Hz). MASS(ESI): m/z 303(M-1)
Preparation Example 25-5
3-((2,4-Dichlorophenyl)hydroxymethyl)-2-methylpyrrolo[3,2-b]pyridine
[0717] In the same manner as in Preparation Example 35-5 to be
described later, the objective compound (850 ng) was obtained as a
colorless solid from
3-(2,4-dichlorobenzoyl)-2-methylpyrrolo[3,2-b]pyridine (1.11
g).
[0718] .sup.1H-NMR(DMSO-d.sub.6): 2.28(3H, s), 5.69(1H, d, J=5 Hz),
6.30(1H, d, J=5 Hz), 6.98(1H, dd, J=8, 5 Hz), 7.41-7.48(2H, m),
7.58(1H, d, J=8 Hz), 8.05(1H, d, J=8 Hz), 8.20(1H, d, J=5 Hz)
MASS(ESI): m/z 307(M+1) mp 195-197.degree. C.
Preparation Example 25-6
3-(2,4-Dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine
[0719] In the same manner as in Preparation Example 35-6 to be
described later, the objective compound (580 mg) was obtained as a
colorless solid from
3-((2,4-dichlorophenyl)hydoymethyl)-2-methylpyrrolo[3,2-b]pyridine
(840 mg).
[0720] .sup.1H-NMR(DMSO-d.sub.6): 2.39(3H, s), 4.18(2H, s),
6.98(1H, dd, J=8, 5 Hz), 7.21-7.33(2H, m), 7.62(1H, d, J=2 Hz),
8.06(1H, br d, J=8 Hz), 8.38(1H, d, J=5 Hz) MASS(ESI): m/z 291(M+1)
mp 228-229.degree. C.
Preparation Example 25-7
Ethyl
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate
[0721] In the same manner as in Preparation Example 142, the
objective compound (405 mg) was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine (528 mg).
[0722] .sup.1H-NMR(CDCl.sub.3): 1.50(3H, t, J=7 Hz), 2.58(3H, s),
4.21(2H, s), 4.52(2H, q, J=7 Hz), 6.96(1H, d, J=8 Hz), 7.02(1H, dd,
J=8, 1 Hz), 7.19(1H, dd, J=8, 5 Hz), 7.39(1H, d, J=1 Hz), 8.32(1H,
d, J=8 Hz), 8.49(1H, d, J=5 Hz) MASS(ESI): m/z 363(M+1) mp
92-93.degree. C.
Preparation Example 25-8
Ethyl
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-1-carboxylate
N-oxide
[0723] To a solution of ethyl
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b-
]pyridine-1-carboxylate (400 mg) in chloroform (6 ml) was added
mchloroperbenzoic add (462 mg) at room temperare, and the mixtu was
stirtil overnight The reaction rxewas subjected to flash silica gel
chromatography (silica gel, 40 ml, eluted with ethyl acetate and
then with ethyl acetate-methanol=10-1), and crystaed from ether to
give the objective compound (417 mg) as colorless crystals.
[0724] .sup.1H-NMR(CDCl.sub.3): 1.50(3H, t, J=7 Hz), 2.51(3H, s),
4.53(2H, q, J=7 Hz), 4.61(2H, s), 6.96(1H, d, J=8 Hz),
7.01-7.11(2H, m), 7.39(1H, s), 8.00-8.09(2H, m) MASS(ESI): m/z
379(M+1) mp 126-127.degree. C.
Preparation Example 25-9
Ethyl
3-(2,4-dichlorobenzyl)-5-cyano-2-methylpyrrolo[3,2-b]pyridine-1-carb-
oxylate
[0725] To a suspension of ethyl
3-(2,4-dichlorobenzyl-2-methylpyrrolo[3,2--
b]pyridine-1-carboxylate N-odde (414 mg) in anhydrous triethylarine
(4 ml) was added trimethylsiylcyanide (704 mg) at room temperature
in a nitrogen atmosphere, and the mixture was refluxed with heating
overmight The reaction mixture was cooled and a saturated aqueous
sodium hydrogencarbonate solution was added. The mixture was
extracted with ethyl acetate, and washed with water and saturated
brine. The organic layer was dried over anhydrous magnesium
sulfate. After filtration, the filtrate was concentrated, and the
residue was subjected to fas silica gel chiomatography (silica gel,
80 ml, eluted with hexane-ethyl acetate=5-1) and crystal from
isopropyl ether to give the objective compound (204 mg) as
colorless crystals.
[0726] .sup.1H-NMR(CDCl.sub.3): 1.51(3H, t, J=7 Hz), 2.62(3H, s),
4.21(2H, s), 4.55(2H, q, J=7 Hz), 7.05-7.15(2H, m), 7.58(1H, d, J=8
Hz), 8.31(1H, d, J=8 Hz) MASS(ESI): m/z 388(M+1) mp 112-113.degree.
C.
Preparation Example 25-10
3-(2,4-Dichlorobenzyl)-2-methylpyrrolo[3,2-b]pyridine-5-carboxylic
acid
[0727] A solution of ethyl
3-(2,4-dichlorobenzyl)-5-cyan-2-methylpyrrolo[3-
,2-b]pyridine-1-carboxylate (180 mg) in acetic acid (1 ml) and
concentrated hydrochloric acid (1 ml) was refluxed under heating.
The mixture was allowed to react overight, and concentrated
hydrochloric acid (1 ml) was added, which was followed by reflux
under heating for 10 hr. The reaction mixture was cooled and
adjusted to pH 7 with a 30% aqueous solution of sodium hydroxide.
After stirring for 2 hr, crystals were collected by filtration to
give the object compound (135 mg) as yellow crystals.
[0728] .sup.1H-NMR(DMSO-d.sub.6): 2.37(3H, s), 4.19(2H, s),
7.05(1H, d, J=8 Hz), 7.23(1H, dd, J=8, 1 Hz), 7.60(1H, d, J=1 Hz),
7.85(2H, s) MASS(ESI): m/z 333(M-1) mp 235-236.degree. C.
Preparation Example 26-1
5-Bromo-3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
and
5-bromo-1-(4-chloro-2-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridi-
ne
[0729] In the same manner as in Preparation Example 14-2, the
objectve compounds of
5-bromo-3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine (200 mg) and
5-bromo-1-(4-chloro-2-methoxybenyl)-2-methyl-1H-i-
midazo[4,5-b]pyridine (138 mg) were respectively obtained as
pale-yellow crystals and a pale-brown oil from
5-bromo-2-methyl-1H-imidazo[4,5-b]pyri- dine (305 mg).
5-Bromo-3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0730] .sup.1H-NMR(CDCl.sub.3): 2.69(3H, s), 3.86(3H, s), 5.41(2H,
s), 6.85-6.95(3H, m), 7.45(1H, d, J=8 Hz), 7.92(1H, d, J=8 Hz)
MASS(ESI): m/z 368(M+1) mp 149-150.degree. C.
5-Bromo-1-(4chloro-2-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine
[0731] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 3.81(3H, s), 5.25(2H,
s), 6.68(1H, d, J=8 Hz), 6.84-6.91(2H, m), 726(1H, d, J=8 Hz),
7.38(1H, d, J=8 Hz) MASS(ESI) m/z 368(M+1)
Preparation Example 26-2
Methyl
3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate
[0732] To a solution of
5-bromo-3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine (200 mg) in anhydrous methanol (1.8 ml) and
an anhydrous N,N-dimethylformamide (2 ml) were added anhydrous
triethylamine (129 mg), palladium acetate (35 mg) and
1,3-bis(diphenylphosiphino)propan- e (72 mg) and the mixture was
placed in an autoclave. After replacing with carbon monoxide 4
times, the mixture was stirred at 85.degree. C. and 10 atm. After
18 hr, the reaction mixture was cooled and water was added. The
mixture was extracted with ethyl acetate. The organic layer was
washed with water (three times) and saturated brine, then dried
over anhydrous magnesium sulfate. The residue was subjected to
flash silica gel chromatography (silica gel, 40 ml, eluent:
dichloromethane-methanol=5- 0-1) and crystallized from ethanol to
give the objective compound (148 mg) as pale-yellow crystals.
[0733] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 3.86(3H, s), 4.00(3H,
s), 5.53(2H, s), 6.81-6.90(2H, m), 6.98(1H, br d, J=8 Hz), 8.10(1H,
d, J=8 Hz), 8.17(1H, d, J=8 Hz) MASS(ESI): m/z 346(M+1), mp
166-168.degree. C.
Preparation Example 26-3
3-(4-Chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ic acid
[0734] In the same manner as in Preparation Example 4-7, the
objective compound (105 mg) was obtained as colorless crystal from
methyl
3-(4-chloro-2-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (144 mg) .
[0735] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 3.90(3H, s),
5.44(2H, s), 6.62(1H, d, J=8 Hz), 6.89(1H, dd, J=8, 1 Hz), 7.15(1H,
d, J=1 Hz), 7.98(1H, d, J=8 Hz), 8.09(1H, d, J=8 Hz) MASS(ESI): m/z
330(M-1) mp 243-246.degree. C.
Preparation Example 27-1
5-Bromo-3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
and
5-bromo-1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazol4,5-b]pyridine
[0736] In the same manner as in Preparation Example 14-2, a mixture
(399 mg) of
5-bromo-3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine and
5-bromo-1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyr-
idine was obtained as a pale-brown solid from
5-bromo-2-methyl-1H-imidazo[- 4,5-b]pyridine (305 mg). The isomers
were used in the next reaction without separation.
Preparation Example 27-2
Methyl
3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate and methyl
1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazo[4,5-b-
]pyridine-5-carboxylate
[0737] In the same manner as in Preparation Example 26-2, methyl
3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imnidazo[4,5-b]pyridine-5-carboxy-
late (148 mg) was obtained as colorless crystals and methyl
1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (87 mg) as a brown powder from a mixture (390 mg) of
5-bromo-3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
and
5-bromo-1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e.
Methyl
3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[0738] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 2.56(3H, s), 4.00(3H,
s), 5.53(2H, s), 6.44(1H, d, J=8 Hz), 7.03(1H, br d, J=8 Hz),
7.22(1H, br s), 8.12(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz) MASS(ESI):
m/z 330(M+1) mp 175-176.degree. C.
Methyl
1-(4-chloro-2-methylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[0739] .sup.1H-NMR(CDCl.sub.3): 2.38(3H, s), 2.65(3H, s), 4.01(3H,
s), 5.30(2H, s), 6.48(1H, d, J=8 Hz), 7.05(1H, br d, J=8 Hz),
7.26(1H, br s), 7.48(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz) MASS(ESI):
m/z 330(M+1)
Preparation Example 27-3
3-(4-Chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[0740] In the same manner as in Preparation Example 4-7, the
objective compound (144 mg) was obtained as colorless crystals from
methyl
3-(4-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (163 mg).
[0741] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 2.45(3H, s),
2.49(3H, s), 5.51(2H, s), 6.31(1H, d, J=8 Hz), 7.10(1H, br d, J=8
Hz), 7.37(1H, br s), 8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz)
MASS(ESI): m/z 314(M-1) mp 219-212.degree. C.
Preparation Example 28-1
5-Bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
and
5-bromo-1-(2-chloro-4-phenylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine
[0742] In the same manner as in Preparation Example 14-2,
5-bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(883 mg) was obtained as colorless crystals and
5-bromo-1-(2-chloro-4-phe-
nylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine (681 mg) as
pale-yellow crystals from
5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (800 mg).
5-Bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[0743] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 5.59(2H, s), 6.64(1H,
br d, J=8 Hz), 7.30-7.47(5H, m), 7.49-7.54(2H, m), 7.66(1H, br s),
7.85(1H, d, J=8 Hz) MASS(ESI): m/z 414(M+1),mp 150-155.degree.
C.
5-Bromo-1-(2-chloro-4-phenylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine
[0744] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 5.44(2H, s), 6.57(1H,
d, J=8 Hz), 7.24-7.55(8H, m), 7.69(1H, s) MASS(ESI): m/z 414(M+1)
mp 181-185.degree. C.
Preparation Example 28-2
Methyl
3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[0745] In the same manner as in Preparation Example 26-2, the
objective compound (504 mg) was obtained as pale yellow crystals
from
5-bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(822 mg).
[0746] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 4.00(3H, s), 5.73(2H,
s), 6.71(1H, d, J=8 Hz), 7.30-7.54(6H, m), 7.67(1H, br s), 8.10(1H,
d, J=8 Hz), 8.18(1H, d, J=8 Hz) MASS(ESI): m/z 392(M+1) mp
200-201.degree. C.
Preparation Example 28-3
3-(2-Chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[0747] In the same manner as in Preparation Example 4-7, the
objective compound (403 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (500 mg).
[0748] .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s), 5.65(2H, s),
6.60(1H, d, J=8 Hz), 7.33-7.55(3H, m), 7.65(2H, br d, J=8 Hz),
7.85(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz)
MASS(ESI): m/z 376(M-1) mp 238-243.degree. C.
Preparation Example 29-1
5-Bromo anisaldehyde
[0749] 5-Bromosalicylaldehyde (25 g, 124 mmol) was dissolved in
acetone (300 ml) and anhydrous potassium carbonate (17.2 g, 124
mmol) was added. The mixture was heated and dimethyl sulfate (15.7
g, 124 mmol) was dropwise added over 45 min with gentle reflux.
After the dropwise addition, the mixture was refluxed for 1 hr and
cooled. Acetone was evaporated under reduced pressure. Toluene and
water were added to the residue and the toluene layer was
separated. The aqueous layer was extracted with toluene. The
combined organic layer was washed with water and dried over
anhydrous sodium sulfate. The desiccant was filtered off and the
filtrate was concentrated under reduced pressure to give the
objective compound (27.3 g, quantitative) as colorless
crystals.
Preparation Example 29-2
(5-Bromo-2-methoxyphenyl)acetone
[0750] A mixture of 5-bromoanisaldehyde (19.4 g, 90 mmol), toluene
(25 ml), nitroethane (8.1 g, 108 mmol) and butylamine (2.0 g, 27
mmol) was vigorously refluxed under heating while removing water
generated by the reaction with a Dean-Stark distilling tube. During
the reflux, N-butylamine (4.5 ml) and nitroethane (4 ml) were added
in several portions and the reaction proceeded for 6 hr. Then, the
reaction mixture was cooled and extracted with toluene and 3N
hydrochloric acid. The organic layer was washed with saturated
brine, and dried over anhydrous sodium sulfate. The desiccant was
filtered off and the filtrate was concentrated under reduced
pressure to give a brown oil containing
3-(2-nitropropen-1-yl)-4-methoxybromobenzene. The oil was dissolved
in toluene (30 ml) and an aqueous solution (30 ml) of iron(III)
chloride hexahydrate (1.0 g) was added. Thereto was added iron
powder (15.1 g, 270 mmol) and the mixture was heated to 75.degree.
C. While vigorously stirring the mixture, concentrated hydrochloric
acid (37.5 ml, 450 mmol) was dropwise added over 2 hr. After the
dropwise addition, the mixture was stirred for 1 hr at 75.degree.
C. After cooling, the insoluble matter was filtered off and the
filtrate was partitioned. The aqueous layer was extracted with
toluene. The organic layers were combined, washed with 3N
hydrochloric acid, and dried over anhydrous sodium sulfate. The
desiccant was filtered off and the filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography (eluent: hexane/ethyl acetate=4/1) to give the
objective compound (6.9 g, 33 %) as a colorless oil.
[0751] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 7.36(1H, dd, J=2.4 and
8.7 Hz), 7.24(1H, d, J=2.4 Hz), 6.75(1H, d, J=9.0 Hz), 3.78(3H, s),
3.63(2H, s), 2.15(3H, s)
Preparation Example 29-3
5-Bromo-2-methylbenzo[b]furan
[0752] (5-Bromo-2-methoxyphenyl)acetone (6.6 g, 28.6 mmol) was
dissolved in methylene chloride (50 ml) and cooled to -70.degree.
C. Thereto was dropwise added a 1 M solution (28.6 ml, 28.6 mmol)
of boron tribromide in methylene chloride over 15 min. After the
dropwise addition, the mixture was heated to room temperature and
stirred for 1.5 hr. Then, the reaction mixture was ice-cooled and
water (50 ml) was added. The insoluble matter was filtered off and
the filtrate was partitioned. The aqueous layer was extracted with
methylene chloride. The organic layers were combined, and dried
over anhydrous sodium sulfate. The desiccant was filtered off and
the filtrate was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (eluent:
hexane/ethyl acetate=30/1) to give the objective compound (3.45 g,
57%) as a colorless liquid.
[0753] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 7.58(1H, d, J=1.8 Hz),
7.29(1H, dd, J=1.8 and 8.6 Hz), 7.26(1H, d, J=8.3 Hz), 6.31(1H, d,
J=0.7 Hz), 2.45(3H, s).
Preparation Example 29-4
5-Carboxy-2-methylbenzo[b]furan
[0754] Magnesium (2.34 g, 97 mmol) was suspended in diethyl ether
and a solution of 5-bromo-2-methylbenzo[b]furan (3.4 g, 16.1 mmol)
and methyl iodide (6.86 g, 48.3 mmol) in diethyl ether (50 ml) was
dropwise added over about 50 min in such a manner that mild reflux
could be maintained. After the dropwise addition, the mixture was
refluxed under heating for 30 min and cooled in a dry ice--acetone
bath. The reaction mixture was slowly added with stirring into
diethyl ether containing pulverized dry ice. 2N Hydrochloric acid
was added to the reaction mixture and the mixture was stirred. The
partitioned organic layer was extracted with a 2N aqueous sodium
hydroxide solution (100 ml). The aqueous layer was acidified with
concentrated hydrochloric acid and precipitated crystals were
dissolved in diethyl ether. The organic layer was washed with
saturated brine, and dried over anhydrous sodium sulfate. The
desiccant was filtered off and the filtrate was concentrated under
reduced pressure to give the objective compound (1.9 g, 67%)
colorless crystals.
[0755] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 8.28(1H, d, J=1.5
Hz), 8.01(1H, dd, J=1.7 and 8.5 Hz), 7.45(1H, d, J=8.6 Hz),
6.46(1H, s), 2.48(3H, s)
Preparation Example 29-5
5-(Methoxycarbonyl)-2-methylbenzo[b]furan
[0756] 5-Carboxy-2-methylbenzo[b]furan (1.9 g, 10.7 mmol) was
suspended in methanol (50 ml) and concentrated sulfuric acid (0.1
ml) was added, which was followed by refux under heating for 14 hr.
After cooling, a saturated aqueous sodium hydrogencarbonate
solution was added. Methanol was evaporated under reduced pressure,
and the residue was extracted with methyl t-butyl ether. The
organic layer was washed with saturated brine, and dried over
anhydrous sodium sulfate. The desiccant was filtered off and the
filtrate was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography (eluent: hexane/ethyl
acetate=9/1) to give the objective compound (1.66 g, 81%) as
colorless crystals.
[0757] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.20(1H, d, J=1.4 Hz),
7.93(1H, dd, J=1.5 and 8.5 Hz), 7.42(1H, d, J=8.5 Hz), 6.43(1H, d,
J<1 Hz), 3.93(3H, s), 2.47(3H, d, J=0.6 Hz)
Preparation Example 29-6
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
[0758] Aluminum chloride (2.52 g, 18.9 mmol) was suspended in
methylene chloride (25 ml) and 2,4-dichlorobenzoyl chloride (1.98
g, 9.5 mmol) was added. Then,
5-(methoxycarbonyl)-2-methylbenzo[b]furan (1.5 g, 7.9 mmol) was
added and the mixture was stirred at room temperature for 1.5 hr.
The reaction mixture was poured into ice water and extracted with
ethyl acetate. The organic layer was washed with a saturated
aqueous solution of sodium hydrogencarbonate (twice) and then
saturated brine, and dried over anhydrous sodium sulfate. The
desiccant was filtered off and the filtrate was concentrated under
reduced pressure to give the objective compound (2.9 g,
quantitative) as colorless crystals.
[0759] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.28(1H, d, J=1.4 Hz),
8.04(1H, dd, J=1.5 and 8.4 Hz), 7.54(1H, d, J=1.8 Hz), 7.49(1H, dd,
J=0.6 and 8.3 Hz), 7.43(1H, dd, J=1.9 and 7.9 Hz), 7.37(1H, d,
J=8.1 Hz), 3.91(3H, s), 2.43(3H, s)
Preparation Example 29-7
3-((2,4-Dichlorophenyl)hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]-
furan
[0760]
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
(0.84 g, 2.31 mmol) was dissolved in tetrahydrofuran (20 ml) and a
solution (1.0 M, 5 ml, 5 mmol) of a borane-tetrahydrofuran complex
in tetrahydrofuran was added. The mixture was stirred at room
temperature for 30 min and then at 50.degree. C. for 2 hr. The
reaction mixture was concentrated under reduced pressure and a
saturated aqueous ammonium chloride solution was added to the
residue. The mixture was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and dried over anhydrous
magnesium sulfate. The desiccant was filtered off and the filtrate
was concentrated under reduced pressure to give the objective
compound (0.8 g) as a colorless oil. This crude product was used in
the next reaction as it was.
[0761] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.27(1H, s), 7.92(1H,
dd, J=1.6 and 8.4 Hz), 7.86(1H, d, J=9.2 Hz), 7.39(1H, d, J=8.9
Hz), 7.36(2H, m), 6.27(1H, d, J=2.9 Hz), 3.90(3H, s), 2.46(3H, s),
2.04(1H, brs)
Preparation Example 29-8
3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
[0762] Trifluoroacetic acid (50 ml) was ice-cooled and sodium
borohydride (873 mg, 23.1 mmol) was gradually added over 20 min
under a nitrogen atmosphere at 5-7.degree. C. Thereto was dropwise
added a solution of
3-((2,4-dichlorophenyl)-hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[-
b]furan in methylene chloride over 20 min, and the mixture was
stirred at room temperature for 45 min. After the completion of the
reaction, the reaction mixture was poured into ice water and a 25%
aqueous sodium hydroxide solution was added to make an alkali
solution. The solution was extracted with ethyl acetate. The
organic layer was washed with saturated brine, and dried over
anhydrous magnesium sulfate. The desiccant was filtered off and the
filtrate was concentrated under reduced pressure. The crystalline
residue was purified by silica gel column chromatography to give
the objective compound (0.58 g, 72% in 2 steps) as colorless
crystals.
[0763] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 7.98(1H, d, J=1.5 Hz),
7.95(1H, dd, J=1.8 and 8.7 Hz), 7.43(1H, d, J=8.2 Hz), 7.42(1H, d,
J=2.2 Hz), 7.10(1H, dd, J=2.2 and 8.3 Hz), 6.96(1H, d, J=8.3 Hz),
4.03(2H, s), 3.89(3H, s), 2.40(3H, s)
Preparation Example 29-9
5-Carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan
[0764] A mixture of
3-(2,4-dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbe- nzo[b]furan
(0.57 g, 1.6 mmol), methanol (6 ml), tetrahydrofuran (6 ml) and a
2M aqueous sodium hydroxide solution (8.5 ml) was refluxed under
heating for 40 min. The reaction mixture was concentrated under
reduced pressure and water was added to the residue. The mixture
was acidified with 3N hydrochloric acid and the precipitated solid
was extracted with hot ethyl acetate. The organic layer was washed
with saturated brine, and dried over anhydrous magnesium sulfate.
The desiccant was filtered off and the filtrate was concentrated
under reduced pressure to give the objective compound (0.54 g,
quantitative) as colorless crystals.
[0765] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 12.70(1H, brs),
7.88(1H, d, J=1.6 Hz), 7.81(1H, dd, J=1.8 and 8.7 Hz), 7.62(1H, d,
J=2.1 Hz), 7.55(1H, d, J=8.8 Hz), 7.34(1H, dd, J=2.1 and 8.3 Hz),
7.25(1H, d, J=8.3 Hz), 4.09(2H, s), 2.44(3H, s).
Preparation Example 30-1
Ethyl 5-methylsalicylate
[0766] To a solution of 5-methyl salicylic acid (9.90 g) in ethanol
(100 ml) was added concentrated sulfuric acid (1.0 g) and the
mixture was refluxed under heating for 21 hr. The reaction mixture
was concentrated to give an oil mainly containing the objective
compound.
[0767] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.40 (3H, t, J=7.1
Hz), 2.26(3H, s), 4.38(2H, quartet, J=7.1 Hz), 6.86(1H, d, J=8.5
Hz), 7.23(1H, dd, J=8.4 and 2.3 Hz), 7.61(1H, d, J=1.8 Hz),
Preparation Example 30-2
Ethyl 2-acetoxy-5-methylbenzoate
[0768] To this oil were added acetic acid (40 ml) and acetic
anhydride (40 ml), and the mixture was heated at 100.degree. C. for
20 min. After concentration, ether was added, and the mixture was
washed with water and a saturated aqueous solution of sodium
hydorgencarbonate, and dried over magnesium sulfate. Concentration
of the residue gave the objective compound (9.66 g) as a yellow
oil.
[0769] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.37(3H, t, J=7.2 Hz),
2.33(3H, s), 2.38(3H, s), 4.33(2H, quartet, J=7.4 Hz), 6.98(1H, d,
J=8.2 Hz), 7.34(1H, d, J=8.6 Hz), 7.82(1H, s)
Preparation Example 30-3
Ethyl 3-acetyl-5-methylsalicylate
[0770] Aluminum chloride (8.80 g) was added to a solution of ethyl
2-acetoxy-5-methylbenzoate (8.50 g) in 1,2-dichloroethane (25 ml),
and the mixture was stirred at room temperature for 30 min. Ice was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The extract was washed with water, dried over
magnesium sulfate and concentrated. The residue was purified by
silica gel column chromatography to give the objective compound
(2.28 g) as a white solid.
[0771] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.43(3H, t, J=7.2 Hz),
2.32(3H, s), 2.69(3H, s), 3.92(2H, quartet, J=7.2 Hz), 7.79(1H, s),
7.86(1H, d, J=2.3 Hz), 12.08(1H, s)
Preparation Example 30-4
2-(2,4-Dichlorobenzoyl)-7-(ethoxycarbonyl)-3,5-dimethylbenzo[b]furan
[0772] Ethyl 3-acetyl-5-methyl salicylate (2.40 g), 2,
2',4'-trichloro acetophenone (2.10 g), potassium iodide (1.50 g)
and potassium carbonate (2.76 g) were stirred in acetone (70 ml) at
room temperature for 7 hr. Acetone (ca. 50 ml) was evaporated from
the reaction mixture. Water (20 ml) was added and the precipitated
solid was collected by filtration. The solid was washed with
diisopropyl ether and dried to give the objective compound (0.80 g)
as a white solid.
[0773] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.20(3H, t, J=7.2 Hz),
2.52(3H, s), 2.65(3H, s), 4.32(2H, quartet, J=7.2 Hz), 7.39(1H, d,
J=8.4 Hz), 7.50(1H, s), 7.53 (1H, d, J=8.3 Hz), 7.67(1H, s),
7.99(1H, s)
Preparation Example 30-5
7-Carboxy-2-(2,4-dichlorobenzyl)-3,5-dimethylbenzo[b]furan
[0774]
2-(2,4-Dichlorobenzoyl)-7-(ethoxycarbonyl)-3,5-dimethylbenzo[b]fura-
n (0.78 g) and hydrazine monohydrate (0.70 g) were stirred in
ethylene glycol (6.5 ml) at 140.degree. C. for 2 hr. After cooling,
potassium hydoroxide (0.75 g) was added and the mixture was stirred
at 150.degree. C. for 4 hr. After cooling, ice and concentrated
hydrochloric acid were added and precipitate was collected by
filtration. The precipitate was washed with water and diisopropyl
ether and dried to give the objective compound (0.66 g) as white
crystals.
[0775] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.16(3H, s),
2.42(3H, s), 4.23(2H, s), 7.27(1H, d, J=8.3 Hz), 7.38(1H, dd, J=8.3
and 2.1 Hz), 7.57 (2H, 2s), 7.63(1H, d, J=2.1 Hz)
Preparation Example 31-1
5-(Methoxycarbonyl)-2-methylbenzo[b]furan
[0776] Methyl 4-hydroxybenzoate (25.51 g), 2,3-dichloropropene
(22.33 g) and potassium carbonate (27.65 g) were heated in
2-butanone (150 ml) at 70.degree. C. for 20 hr. The reaction
mixture was concentrated, and water was added, which was followed
by extraction with toluene. The extract was washed with saturated
brine and concentrated. To the concentrate (34.5 g) was added
diethyl aniline (100 ml) and the mixture was stirred at 200.degree.
C. for 89 hr. After cooing, toluene and concentrated hydrochloric
acid were added and the toluene layer was washed with saturated
brine, and dried over sodium sulfate. After concentration, formic
acid (80 ml) was added to the residue (34.5 g) and the mixture was
refluxed for 25 hr. After concentration, ethyl acetate and water
were added. The separated toluene layer was washed with a saturated
aqueous solution of sodium hydrogencarbonate, dried over magnesium
sulfate and concentrated. The residue was purified by silica gel
column chromatography to give the objective compound (3.30 g).
[0777] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.47(3H, s), 3.93(3H,
s), 6.44(1H, s), 7.41 (1H, d, J=8.8 Hz), 7.94(1H, dd, J=8.6 and 1.7
Hz), 8.20(1H, d, J=1.6 Hz)
Preparation Example 31-2
5-(Methoxycarbonyl)-2-methyl-3-(4-phenylbenzoyl)benzo[b]furan
[0778] Aluminum chloride (0.80 g) was stirred in methylene chloride
(10 ml) at room temperature. Thereto was added 4-phenylbenzoyl
chlodide (0.67 g), and then a solution of
5-(methoxycarbonyl)-2-methylbenzo[b]furan (0.67 g) in methylene
chloride (5 ml), and the mixture was stirred for 4 hr. Ice was
added to the reaction mixture and the mixture was extracted with
ethyl acetate. The extract was washed with a saturated aqueous
solution of sodium hydrogencarbonate (twice) and saturated brine
(once), dried over sodium sulfate and concentrated to give the
objective compound (1.36 g).
[0779] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.58(3H, s), 3.88(3H,
s), 7.39-8.28(12H, m)
Preparation Example 31-3
5-(Methoxycarbonyl)-2-methyl-3-(4-phenylbenzyl)benzo[b]furan
[0780] While a 1 M borane-tetrahydrofuran solution (8 ml) was
stirred at room temperature, a solution of
5-(methoxycarbonyl)-2-methyl-3-(4-phenylb- enzoyl)benzo[b]furan
(1.36 g) in tetrahydrofuran (20 ml) was dropwise added thereto over
20 min, which was followed by stirring at 50.degree. C. for 50 min.
After cooling, ethyl acetate and a 10% aqueous solution of ammonium
chloride were added and the separated organic layer was dried over
sodium sulfate and concentrated.
[0781] In a different container, sodium borohydride (1.51 g) was
added to trifluoroacetic acid (50 ml) over 10 min under cooling in
an ice water bath. Then, a solution of the residue (1.51 g) after
the above-mentioned concentration in methylene chloride (20 ml) was
dropwise added over 40 min. After the dropwise addition, the bath
was removed and the reaction mixture was stirred at room
temperature for 15 min. Ethyl acetate and a 10% aqueous sodium
hydroxide solution were added to the reaction mixture and the
separated ethyl acetate layer was washed with a 10% aqueous
solution of sodium hydroxide to basify the solution. The solution
was dried over sodium sulfate and concentrated to give the
objective compound (1.31 g).
[0782] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.46(3H, s), 3.89(3H,
s), 4.04(2H, s), 7.22-7.58(10H, m), 7.94(1H, d, J=8.6 Hz), 8.09(1H,
s)
Preparation Example 31-4
5-Carboxy-2-methyl-3-(4-phenylbenzyl)benzo[b]furan
[0783] 5-(Methoxycarbonyl)-2-methyl-3-(4-phenylbenzyl)benzo[b]furan
(1.31 g) was refluxed for 1 hr in a mixed solution of a 10% aqueous
solution (10 ml) of sodium hydroxide, methanol (10 ml) and
tetrahydrofuran (10 ml). The reaction mixture was concentrated and
concentrated hydrochloric acid was added to acidify the solution.
The precipitated solid was collected by filtration, washed with
water and diisopropyl ether and dried to give the objective
compound (0.68 g).
[0784] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.52(3H, s),
4.07(2H, s), 7.29-7.36(3H, m), 7.42 (2H, t, J=7.8 Hz),
7.53-7.63(5H, m), 7.81(1H, d, J=8.6 Hz), 7.99(1H, s)
Preparation Example 32-1
2-Acetyl-5-bromobenzo[b]furan
[0785] 5-Bromo salicylaldehyde (10.05 g), bromo acetone (8.0 g) and
potassium carbonate (13.80 g) were refluxed for 1 hr in 2-butanone
(100 ml). 2-Butanone (ca. 50 ml) was evaporated and ice was added.
The precipitate was collected by filtration and washed with water
and hexane to give the objective compound (10.50 g).
[0786] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.62(3H, s), 7.44(1H,
s), 7.47(1H, d, J=8.9 Hz), 7.57(1H, dd, J=8.9 and 2.0 Hz), 7.86(1H,
d, J=2.0 Hz)
Preparation Example 32-2
5-Bromo-2-ethylbenzo[b]furan
[0787] 2-Acetyl-5-bromobenzo[b]furan (10.00 g) and hydrazine
monohydrate (8.00 g) were stirred in ethylene glycol (60 ml) at
150.degree. C. for 2 hr. After cooling, potassium hydroxide (9.00
g) was added and the mixture was stirred at 150.degree. C. for 2
hr. After cooling, toluene (200 ml) and water (100 ml) were added
and the separated toluene layer was washed with 10% aqueous
solution (100 ml) of ammonium chloride, dried over magnesium
sulfate and concentrated to give the objective compound (8.30
g).
[0788] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.33(3H, t, J=7.5 Hz),
2.79(2H, quartet, J=7.5 Hz), 6.32(1H, s), 7.24-7.31(2H, m),
7.59(1H, d, J=1.8 Hz)
Preparation Example 32-3
5-Carboxy-2-ethylbenzo[b]furan
[0789] Magnesium (1.50 g) was stirred in ether (30 ml) at room
temperature. Thereto was dropwise added a solution of
5-bromo-2-ethylbenzo[b]furan (8.30 g) and methyl iodide (0.55 g) in
ether (30 ml) over 30 min. Then, the mixture was refluxed for 50
min and cooled in an ice water bath. In a different container,
pulverized dry ice was stirred in ether and the Grignard reagent
prepared above was transferred over about 5 min. 2N Hydrochloric
acid was added to the reaction mixture to acidify the solution, and
the ether layer was separated. The solution was basified with a 5%
aqueous solution of sodium hydroxide and the separated aqueous
layer was acidified with 2N hydrochloric acid. After extraction
with ether, the extract was dried over sodium sulfate and
concentrated to give the objective compound (2.48 g).
[0790] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.26(3H, t, J=7.6
Hz), 2.80(2H, quartet, J=7.5 Hz), 6.69(1H, s), 7.56(1H, dd, J=8.6
Hz), 7.83(1H, dd, J=8.6 and 1.8 Hz), 8.16(1H, d, J=1.7 Hz),
12.73(1H, s)
Preparation Example 32-4
2-Ethyl-5-(methoxycarbonyl)benzo[b]furan
[0791] 5-Carboxy-2-ethylbenzo[b]furan (2.48 g) and concentrated
sulfuric acid (0.30 g) were stirred with heating in methanol (50
ml) at 60.degree. C. for 16 hr. The reaction mixture was
concentrated and chloroform was added. The mixture was washed with
a saturated aqueous solution of sodium-hydrogencarbonate. The
chloroform layer was separated, dried over magnesium sulfate and
concentrated to give the objective compound (2.40 g).
[0792] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.35(3H, t, J=7.6 Hz),
2.82(2H, quartet, J=7.6 Hz), 3.93(3H, s), 6.44(1H, s), 7.42(1H, dd,
J=8.8 Hz), 7.94(1H, dd, J=8.6 and 1.8 Hz), 8.22(1H, d, J=1.6
Hz)
Preparation Example 32-5
3-(2,4-Dichlorobenzoyl)-2-ethyl-5-(methoxycarbonyl)benzo[b]furan
[0793] In the same manner as in Preparation Example 31-2, the
objective compound (2.28 g) was obtained from
2-ethyl-5-(methoxycarbonyl)benzo[b]fu- ran (2.40 g), aluminum
chloride (3.33 g) and 2,4-dichlorobenzoyl chloride (2.80 g).
[0794] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.30(3H, t, J=7.6 Hz),
2.79(2H, quartet, J=7.5 Hz), 3.91(3H, s), 7.38(1H, d, J=8.2 Hz),
7.42(1H, dd, J=8.1 and 1.9 Hz), 7.50(1H, d, J=8.8 Hz), 7.54(1H, d,
J=1.8 Hz), 8.05(1H, dd, J=8.6 and 1.8 Hz), 8.18(1H, d, J=1.8
Hz)
Preparation Example 32-6
3-(2,4-Dichlorobenzyl)-2-ethyl-5-(methoxycarbonyl)benzo[b]furan
[0795] In the same manner as in Preparation Example 31-3, the
objective compound (2.20 g) was obtained from
3-(2,4-dichlorobenzoyl)-2-ethyl-5-(me- thoxycarbonyl)benzo[b]furan
(2.28 g).
[0796] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.28(3H, t, J=7.6 Hz),
2.76(2H, quartet, J=7.6 Hz), 3.90(3H, s), 4.04(2H, s), 6.92(1H, d,
J=8.4 Hz), 7.09 (1H, dd, J=8.4 and 2.2 Hz), 7.42-7.46(2H, m),
7.96(1H, dd, J=8.6 and 1.7 Hz), 7.98(1H, d, J=1.5 Hz)
Preparation Example 32-7
5-Carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]furan
[0797] In the same manner as in Preparation Example 31-4, the
objective compound (1.50 g) was obtained from
3-(2,4-dichlorobenzyl)-2-ethyl-5-(met- hoxycarbonyl)benzo[b]furan
(2.20 g).
[0798] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.20(3H, t, J=7.5
Hz), 2.81(2H, quartet, J=7.5 Hz), 4.11(2H, s), 7.20(1H, d, J=8.4
Hz), 7.34 (1H, dd, J=8.3 and 2.2 Hz), 7.58 (1H, d, J=8.5 Hz),
7.63(1H, d, J=2.2 Hz), 7.83(1H, dd, J=8.6 and 1.7 Hz), 7.89(1H, d,
J=1.6 Hz), 12.78(1H, brs)
Preparation Example 33-1
5-Bromo-2-propionylbenzo[b]furan
[0799] In the same manner as in Preparation Example 32-1, the
objective compound (7.10 g) was obtained from 5-bromo
salicylaldehyde (5.50 g), 1-bromo-2-butanone (5.00 g) and potassium
carbonate (8.00 g).
[0800] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.26(3H, t, J=7.3 Hz),
3.00(2H, quartet, J=7.3 Hz), 7.42(1H, s), 7.46(1H, d, J=8.9 Hz),
7.56(1H, dd, J=8.8 and 2.0 Hz), 7.84(1H, d, J=2.0 Hz)
Preparation Example 33-2
5-Bromo-2-propylbenzo[b]furan
[0801] In the same manner as in Preparation Example 32-2, the
objective compound (5.85 g) was obtained from
5-bromo-2-propylbenzo[b]furan (7.00 g), hydrazine monohydrate (5.00
g) and potassium hydroxide (6.00 g).
[0802] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.01(3H, t, J=7.4 Hz),
1.72-1.81(2H, m), 2.73(2H, t, J=7.3 Hz), 6.32(1H, s), 7.25-7.30(2H,
m), 7.59(1H, d, J=1.8 Hz)
Preparation Example 33-3
5-Carboxy-2-propylbenzo[b]furan
[0803] In the same manner as in Preparation Example 32-3, the
objective compound (3.01 g) was obtained from
5-bromo-2-propylbenzo[b]furan (5.85 g), methyl iodide (10.0 g),
magnesium (2.67 g) and dry ice.
[0804] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.95(3H, t, J=7.4
Hz), 1.67-1.75(2H, m), 2.76(2H, t, J=7.4 Hz), 6.70(1H, d, J=0.70
Hz), 7.56(1H, d, J=8.5 Hz), 7.83(1H, dd, J=8.6 and 1.7 Hz),
8.15(1H, d, J=1.5 Hz)
Preparation Example 33-4
5-(Methoxycarbonyl)-2-propylbenzo[b]furan
[0805] In the same manner as in Preparation Example 32-4, the
objective compound (3.22 g) was obtained from
5-carboxy-2-propylbenzo[b]furan (3.00 g).
[0806] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.02(3H, t, J=7.4 Hz),
1.76-1.81(2H, m), 2.76(2H, t, J=7.5 Hz), 3.93(3H, s), 6.44(1H, s),
7.42(1H, dd, J=8.2 Hz), 7.94(1H, dd, J=8.6 and 1.7 Hz), 8.21 (1H,
s),
Preparation Example 33-5
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-propylbenzo[b]furan
[0807] In the same manner as in Preparation Example 31-2, the
objective compound (4.29 g) was obtained from
5-(methoxycarbonyl)-2-propylbenzo[b]f- uran (3.20 g), aluminum
chloride (4.00 g) and 2,4-dichlorobenzoyl chloride (3.84 g).
[0808] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.91(3H, t, J=7.4 Hz),
1.72-1.80(2H, m), 2.76(2H, t, J=7.5 Hz), 3.91(3H, s), 7.38(1H, d,
J=8.1 Hz), 7.42(1H, dd, J=8.2 and 1.9 Hz), 7.50(1H, d, J=8.3 Hz),
7.54(1H, d, J=2.0 Hz), 8.04(1H, dd, J=8.7 and 1.8 Hz), 8.15(1H, d,
J=1.9 Hz)
Preparation Example 33-6
3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-propylbenzo[b]furan
[0809] In the same manner as in Preparation Example 31-3, the
objective compound (2.27 g) was obtained from
3-(2,4-dichlorobenzoyl)-5-(methoxycar- bonyl)-2-propylbenzo[b]furan
(2.42 g).
[0810] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.94(3H, t, J=7.4 Hz),
1.69-1.77(2H, m), 2.71(2H, t, J=7.5 Hz), 3.89(3H, s), 4.04(2H, s),
6.91(1H, d, J=8.4 Hz), 7.08 (1H, dd, J=8.3 and 2.1 Hz),
7.43-7.46(2H, m), 7.94-7.98(2H, m)
Preparation Example 33-7
5-Carboxy-3-(2,4-dichlorobenzyl)-2-propylbenzo[b]furan
[0811] In the same manner as in Preparation Example 31-4, the
objective compound (2.04 g) was obtained from
3-(2,4-dichlorobenzyl)-5-(methoxycarb- onyl)-2-propylbenzo[b]furan
(2.25 g).
[0812] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.87(3H, t, J=7.4
Hz), 1.60-1.68(2H, m), 2.76(2H, t, J=7.4 Hz), 4.11(2H, s), 7.18(1H,
d, J=8.4 Hz), 7.34 (1H, dd, J=8.3 and 2.2 Hz), 7.58 (1H, d J=8.7
Hz), 7.63(1H, d, J=2.1 Hz), 7.83(1H, dd, J=8.6 and 1.7 Hz),
7.89(1H, d, J=1.6 Hz), 12.75(1H, brs).
Preparation Example 34-1
Methyl 4-((2,2-dimethoxy)ethoxy)benzoate
[0813] Methyl 4-hydroxybenzoate (15.52 g), bromoacetaldehyde
dimethyl acetal (16.90 g) and 60% sodium hydride (5.00 g) were
heated in dimethyl formamide (50 ml) at 80.degree. C. for 18 hr.
Dimethyl formamide was distilled away from the reaction mixture,
and toluene and water were added. The separated toluene layer was
dried over magnesium sulfate, and the solvent was distilled away to
give the objective compound (16.00 g).
[0814] .sup.1H-NMR(CDCl3, .delta. ppm): 3.47(6H, s), 3.89(3H, s),
4.06(1H, d, J=5.3 Hz), 4.73(1H, d, J=5.2 Hz), 6.94(2H, d, J=8.9
Hz), 7.99(2H, d, J=8.9 Hz)
Preparation Example 34-2
5-(Methoxycarbonyl)benzo[b]furan
[0815] Methyl 4-((2,2-dimethoxy)ethoxy)benzoate (10.00 g) and
polyphosphoric acid (20.00 g) were refluxed in 1,2-dichloroethane
(50 ml) for 1 hr. After cooling, ice was added, and the separated
organic layer was washed with 10% hydrochloric acid. The mixture
was dried over magnesium sulfate, concentrated and purified by
column chromatography to give the objective compound (0.86 g).
[0816] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.94(3H, s), 6.85(1H,
dd, J=2.4 and 0.8 Hz), 7.53(1H, d, J=8.6 Hz), 7.69(1H, d, J=2.2
Hz), 8.03(1H, dd, J=8.7 and 1.7 Hz), 8.35(1H, d, J=1.7 Hz),
Preparation Example 34-3
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-propylbenzo[b]furan
[0817] In the same manner as in Preparation Example 31-2, the
objective compound (0.34 g) was obtained from
5-(methoxycarbonyl)benzo[b]furan (0.85 g), aluminum chloride (1.11
g) and 2,4-dichlorobenzoyl chloride (1.00 g).
[0818] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.96(3H, s), 7.38(1H,
dd, J=8.3 and 1.9 Hz), 7.46(1H, d, J=8.2 Hz), 7.50(1H, d, J=2.0
Hz), 7.57(1H, d, J=8.9 Hz), 7.94(1H, s), 8.13(1H, dd, J=8.7 and 1.8
Hz), 8.94(1H, d, J=1.4 Hz)
Preparation Example 34-4
3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)benzo[b]furan
[0819] In the same manner as in Preparation Example 16-2, the
objective compound (0.28 g) was obtained from
3-(2,4-dichlorobenzoyl)-5-(methoxycar- bonyl)benzo[b]furan (0.34
g).
[0820] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.93(3H, s), 4.11(2H,
s), 7.13-7.18(2H, m), 7.41 (1H, s), 7.50(1H, d, J=8.8 Hz), 8.03(1H,
dd, J=8.7 and 1.8 Hz), 8.21(1H, d, J=1.7 Hz).
Preparation Example 34-5
5-Carboxy-3-(2,4-dichlorobenzyl)benzo[b]furan
[0821] In the same manner as in Preparation Example 35-5 to be
mentioned below, the objective compound (0.26 g) was obtained from
3-(2,4-dichlorobenzyl)-5-(methoxycarbonyl)benzo[b]furan (0.28
g).
[0822] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 4.13(2H, s),
7.17-7.18(2H, m), 7.43-7.55 (2H, m), 7.54 (1H, d, J=8.8 Hz),
8.10(1H, dd, J=8.7 and 1.7 Hz), 8.30(1H, d, J=1.6 Hz).
Preparation Example 35-1
5-Bromo-2-methylbenzo[b]thiophene
[0823] 4-Bromobenzenethiol (10.0 g, 52.8 mmol) was dissolved in
acetone (100 ml), and anhydrous potassium carbonate (8.8 g, 63
mmol), and 2,3-dichloropropene (7.0 g, 63 mmol) were added. The
mixture was stirred at room temperature for 14 hr. Acetone was
distilled away under reduced pressure and toluene and water were
added to the residue. The toluene layer was separated. The organic
layer was washed with water, and dried over anhydrous sodium
sulfate. The desiccant was filtered away and the filtrate was
concentrated under reduced pressure to give a pale-yellow oil (13.9
g). This oil was dissolved in diethyl aniline (45 ml), and the
mixture was stirred at 205.degree. C. for 50 hr with heating.
Diethyl aniline was distilled away under reduced pressure, and 3N
hydrochloric acid and toluene were added to the residue. After the
toluene layer was separated, the organic layer was dried over
anhydrous sodium sulfate. The desiccant was filtered off, and the
filtrate was concentrated under reduced pressure. The residual
crystalline oil was dissolved in hexane, and the insoluble oil was
removed by decantation. After concentration under reduced pressure,
the residue was recrystallized from a small amount of hot hexane to
give the objective compound (5.9 g, 58%) as colorless crystals.
[0824] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 7.77(1H, d, J=1.9 Hz),
7.58(1H, d, J=8.4 Hz), 7.33(1H, dd, J=1.9 8.4 Hz), 6.90(1H, s),
2.58(1H, d, J=1.0 Hz)
Preparation Example 35-2
5-Carboxy-2-methylbenzo[b]thiophene
[0825] Magnesium (1.93 g, 79 mmol) was dispersed in diethyl ether,
and diethyl ether (50 ml) solution of
5-bromo-2-methylbenzo[b]thiophene (3.0 g, 13.2 mmol) and methyl
iodide (5.62 g, 40 mmol) was added dropwise thereto over about 30
min in such a manner that mild refluxing could be maintained. After
the completion of the addition, the mixture was refluxed under
heating for about 50 min, and the reaction mixture was cooled with
ice. The reaction mixture was gradually added with stirring to
diethyl ether containing pulverized dry ice. The reaction mixture
containing oil was extracted with 2N hydrochloric acid, and the
organic layer was extracted with 1M aqueous sodium hydroxide
solution. The aqueous layer was acidified with 3M hydrochloric
acid, and the precipitated crystals were extracted with diethyl
ether. The organic layer was washed with saturated brine and dried
over anhydrous magnesium sulfate. The desiccant was filtered off,
and the filtrate was concentrated under reduced pressure to give
the objective compound (2.1 g, 82%) as colorless crystals.
[0826] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 12.84(1H, brs),
8.30(1H, d, J=1.3 Hz), 7.96(1H, d, J=8.4 Hz), 7.80(1H, dd, J=1.6
and 8.4 Hz), 7.26(1H, s), 2.57(1H, d, J=1.1 Hz)
Preparation Example 35-3
5-(Methoxycarbonyl)-2-methylbenzo[b]thiophene
[0827] 5-Carboxy-2-methylbenzo[b]thiophene (2.1 g, 10.9 mmol) was
dispersed in methanol (50 ml), and concentrated sulfuric acid was
added. The mixture was refluxed with heating for 6 hr. After
cooling, a saturated aqueous solution of sodium hydrogencarbonate
was added, and methanol was distilled away under reduced pressure.
The residue was extracted with methyl t-butyl ether. The organic
layer was washed with saturated brine, and dried over anhydrous
sodium sulfate. The desiccant was filtered off, and the filtrate
was concentrated under reduced pressure to give the objective
compound (2.0 g, 89%) as colorless crystals.
[0828] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.35(1H, d, J=1.5 Hz),
7.91(1H, dd, J=1.5 and 8.4 Hz), 7.78(1H, d, J=8.4 Hz), 7.04(1H, m),
3.94(3H, s), 2.60 (3H, d, J=1.2 Hz)
Preparation Example 35-4
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene
[0829] Aluminum chloride (1.24 g, 9.3 mmol) was dispersed in
methylene chloride (10 ml), and 2,4-dichlorobenzoyl chloride (0.97
g, 4.7 mmol) and then
5-(methoxycarbonyl)-2-methylbenzo[b]thiophene(0.8 g, 3.9 mml) were
added thereto. The mixture was stirred at room temperature for 4
hr. The reaction mixture was poured into ice water and ethyl
acetate was added. The mixture was extracted. The organic layer was
washed twice with a saturated aqueous solution of sodium
hydrogencarbonate and once with brine, and dried over anhydrous
sodium sulfate. The desiccant was filtered off, and the filtrate
was concentrated under reduced pressure to give the objective
compound (1.5 g, quantitative) as pale yellow crystals.
[0830] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 8.49(1H, d, J=1.3
Hz), 8.00(1H, dd, J=1.4 and 8.4 Hz), 7.81(1H, d, J=8.4 Hz),
7.49(1H, d, J=1.8 Hz), 7.47(1H, d, J=8.3 Hz), 7.40(1H, dd, J=1.9
and 8.3 Hz), 3.90(3H, s), 2.43(3H, s)
Preparation Example 35-5
3-((2,4-Dichlorophenyl)hydroxymethyl)-5-(methoxycarbonyl)
-2-methylbenzo[b]thiophene
[0831]
3-(2,4-Dichlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophe-
ne (600 mg, 1.58 mmol) was dissolved in a mixed solvent of
tetrahydrofuran (10 ml) and methanol (1 ml), and sodium borohydride
(72 mg, 1.9 mmol) was added thereto under ice-cooling. The mixture
was stirred for 40 min under ice-cooling. Water was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, and dried over
anhydrous magnesium sulfate. The desiccant was filtered off, and
the filtrate was concentrated under reduced pressure to give the
objective compound (580 mg, 96%) as colorless crystals.
[0832] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.46(1H, d, J=1.3 Hz),
7.90(1H, dd, J=1.5 and 8.4 Hz), 7.77(1H, d, J=8.4 Hz), 7.70(1H, d,
J=8.4 Hz), 7.37(1H, d, J=2.1 Hz), 7.29(1H, dd, J=2.1 and 8.4 Hz),
6.44(1H, d, J=2.8 Hz), 3.90(3H, s), 2.52(3H, s), 2.04(1H, brs)
Preparation Example 35-6
3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene
[0833] Trifluoroacetic acid (30 ml) was cooled with ice, and sodium
borohydride (537 mg, 14.2 mmol) was gradually added at 5-7.degree.
C. for 20 min under a nitrogen atmosphere. A solution of
3-((2,4-dichlorophenyl)-
hydroxymethyl)-5-(methoxycarbonyl)-2-methylbenzo[b]thiophene in
methylene chloride was added dropwise for 50 min and the mixture
was stirred at room temperature for 70 min. After the completion of
the reaction, the reaction mixture was poured into ice water, and
trifluoroacetic acid was neutralized with 25% aqueous solution of
sodium hydroxide to make the solution alkaline. The solution was
extracted with ethyl acetate, and the organic layer was washed with
saturated brine and dried over anhydrous magnesium sulfate. The
desiccant was filtered off, and the filtrate was concentrated under
reduced pressure to give the objective compound (0.52 g) as
colorless crystals.
[0834] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.13(1H, d, J=1.4 Hz),
7.94(1H, dd, J=1.5 and 8.3 Hz), 7.83(1H, d, J=8.3 Hz), 7.44(1H, d,
J=2.2 Hz), 7.01(1H, dd, J=2.1 and 8.3 Hz), 6.61(1H, J=8.3 Hz),
4.20(2H, s), 3.90(3H, s). 2.46(3H, s)
Preparation Example 35-7
5-Carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene
[0835] A mixture of
3-(2,4-Dichlorobenzyl)-5-(methoxycarbonyl)-2-methylben-
zo[b]thiophene (0.52 g, 1.42 mmol), methanol (5 ml),
tetrahydrofuran (5 ml) and 2M aqueous sodium hydroxide solution (7
ml) was refluxed under heating for 1 hr. The reaction mixture was
concentrated under reduced pressure, and water was added to the
residue. Then, the mixture was acidified with 3N hydrochloric acid
and the precipitate was extracted from hot ethyl acetate. The
organic layer was washed with saturated brine, and dried over
anhydrous magnesium sulfate. The desiccant was filtered off, and
the filtrate was concentrated under reduced pressure to give the
objective compound (0.45 g, 90% by two steps) as colorless
crystals.
[0836] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 12.91((1H, brs),
8.01(1H, d, J=8.5 Hz), 8.00(1H, s), 7.82(1H, dd, J=1.7 and 8.3 Hz),
7.66(1H, d, J=2.0 Hz), 7.25(1H, dd, J=2.1 and 8.4 Hz), 6.77(1H, d,
J=8.4 Hz), 4.24(2H, s), 2.50(3H, s)
Preparation Example 36-1
2-Bromophenyl (n-butane-2-on-1-yl)thioether
[0837] 2-Bromothiophenol (3.5 ml), 1-bromo-2-butanone (3.1 ml) and
potassium carbonate (6.90 g) were stirred in acetone at room
temperature for 30 min. The reaction mixture was added to water
(100 ml). The mixture was extracted with toluene (100 ml), dried
over magnesium sulfate, and concentrated to give the objective
compound (8.46 g) as an oil.
[0838] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.07 (3H, t, J=7.3
Hz), 2.66(2H, quartet, J=7.3 Hz), 7.05-7.09(1H, m), 7.27-7.29(2H,
m), 7.55(1H, d, J=8.4 Hz)
Preparation Example 36-2
7-Bromo-3-ethylbenzo[b]thiophene
[0839] Polyphosphoric acid (15.0 g) was added to
2-bromophenyl(n-butane-2-- on-1-yl)thioether (6.81 g), and the
mixture was stirred at 160.degree. C. for 2 hr. Ice was added to
the reaction mixture and the mixture was extracted with toluene.
The extract was washed with 10% aqueous ammonium chloride and a
saturated aqueous solution of sodium hydrogencarbonate, dried over
magnesium sulfate and concentrated to give the objective compound
(4.43 g) as an oil.
[0840] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.36(3H, t, J=7.5 Hz),
2.84(2H, quartet, J=7.5 Hz), 7.16(1H, s), 7.27(1H, t, J=7.8 Hz),
7.50(1H, d, J=7.6 Hz), 7.70(1H, d, J=7.9 Hz)
Preparation Example 36-3
7-Carboxy-3-ethylbenzo[b]thiophene
[0841] Magnesium (2.67 g) was stirred in ether (15 ml) at room
temperature. A solution of 7-bromo-3-ethylbenzo[b]thiophene (4.40
g) and methyl iodide (7.76 g) in ether (50 ml) were added dropwise
over 30 min. Then, refluxing was conducted for 50 min and the
reaction mixture was cooled in ice water bath. Using a separate
reaction vessel, pulverized dry ice was stirred in ether, and the
Grignard reagent prepared above was transferred to the vessel for
about 5 min. To the reaction mixture was added 2N hydrochloric acid
to acidify the solution, and the ether layer was separated. The
solution was made alkaline with a 5% aqueous sodium hydroxide
solution. The separated aqueous layer was acidified with 2N
hydrochloric acid. After extraction with ether, the extract was
dried over sodium sulfate and concentrated to give the objective
compound (3.22 g) as crystals.
[0842] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.40(3H, t, J=7.3 Hz),
2.91(2H, quartet, J=7.5 Hz), 7.25(1H, s), 7.52(1H, t, J=7.6 Hz),
8.02(1H, dd, J=7.9 and 0.9 Hz), 8.25(1H, d, J=7.4 Hz)
Preparation Example 36-4
3-Ethyl-7-(methoxycarbonyl)benzo[b]thiophene
[0843] 7-Carboxy-3-ethylbenzo[b]thiophene (3.20 g) and concentrated
sulfuric acid were stirred in methanol (100 ml) at 60.degree. C.
for 16 hr. The reaction mixture was concentrated and chloroform was
added thereto. The mixture was washed with a saturated aqueous
solution of sodium hydrogencarbonate. The chloroform was separated,
and the residue was dried over magnesium sulfate, and concentrated
to give the objective compound (3.04 g).
[0844] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.39(3H, t, J=7.5 Hz),
2.89(2H, quartet, J=7.5 Hz), 4.02(3H, s), 7.22(1H, s), 7.47(1H, t,
J=7.8 Hz), 7.95(1H, dd, J=7.9 and 0.9 Hz), 8.12(1H, d, J=7.5
Hz)
Preparation Example 36-5
2-(2,4-Dichlorobenzoyl)-3-ethyl-7-(methoxycarbonyl)benzo[b]thiophene
[0845] Aluminum chloride (2.48 g) was stirred in methylene chloride
(10 ml) and a solution of 2,4-dichlorobenzoyl chloride (1.94 g) in
methylene chloride (10 ml) was added dropwise over 5 min. After
stirring for 2 hr, ice was added to the reaction mixture, and the
mixture was extracted with ethyl acetate. The extract was washed
twice with a saturated aqueous solution of sodium hydrogencarbonate
and once with a saturated aqueous solution of ammonium chloride and
sodium sulfate. The concentration gave the objective compound (3.12
g).
[0846] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.32(3H, t, J=7.5 Hz),
3.28(2H, quartet, J=7.5 Hz), 3.99(3H, s), 7.37(1H, dd, J=8.3 and
2.0 Hz), 7.45(1H, d, J=8.2 Hz), 7.49(1H, d, J=1.9 Hz), 7.56(1H, t,
J=7.9 Hz), 8.16(1H, d, J=8.2 Hz), 8.26(1H, d, J=7.4 Hz)
Preparation Example 36-6
7-Carboxy-2-(2,4-dichlorobenzyl-3-ethylbenzo[b]thiophene
[0847]
2-(2,4-Dichlorobenzoyl)-3-ethyl-7-(methoxycarbonyl)benzo[b]thiophen-
e (2.85 g) and hydrazine hydrate (3.50 g) were stirred in ethylene
glycol (30 ml) at 160.degree. C. for 1 hr. After cooling, potassium
hydroxide (3.30 g) was added, and the mixture was stirred at
160.degree. C. for 2 hr. After cooling, ice and concentrated
hydrochloric acid were added, and the mixture was extracted with
ethyl acetate. The extract was dried over sodium sulfate and
concentrated, and the residue was purified by silica gel column
chromatography to give the objective compound (1.98 g) as white
crystals.
[0848] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.20(3H, t, J=7.6 Hz),
2.88(2H, quartet, J=7.6 Hz), 4.31(2H, s), 7.12(1H, d, J=8.4 Hz),
7.17(1H, dd, J=8.4 and 2.1 Hz), 7.42(1H, d, J=2.1 Hz), 7.50(1H, t,
J=7.8 Hz), 7.95 (1H, dd, J=7.9 and 0.8 Hz), 8.16(1H, dd, J=7.8 and
0.8 Hz).
Preparation Example 37-1
Ethyl 3-(2,4-dichlorobenzylamino)-4-nitrobenzoate
[0849] A mixture of 3-fluoro-4-nitrobenzoic acid (5.20 g),
2,4-dichlorobenzyl-amine (14.8 g) and toluene (35 ml) was refluxed
under heating for 24 hr. The mixture was heated to room
temperature, and water and ethyl acetate were added. The mixture
was stirred and precipitated crystals were collected by filtration.
The chloroform layer of the filtrate was separated and the solvent
was distilled away. Ether was added to the residue and the
precipitated crystals were collected by filtration. The crystals
were combined, washed with ether and dried to give
3-(2,4-dichlorobenzylamino)-4-nitrobenzoic acid. Sulfuric acid (2.3
g) was added thereto, and the mixture was refluxed under heating in
ethanol for 6 hr. The reaction mixture was concentrated and poured
into a saturated aqueous solution of sodium hydrogencarbonate. The
mixture was extracted with ethyl acetate, washed with saturated
brine and dried. The solvent was distilled away and the residue was
crystallized from a mixed solvent of ethyl acetate and hexane. The
crystals were collected by filtration and dried to give the
objective compound (4.0 g).
[0850] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.38(3H, t, J=7.1 Hz),
4.37(2H, q, J=7.1 Hz), 4.66(2H, d, J=5.9 Hz), 7.22-7.32(3H, m),
7.46(1H, d, J=2.0 Hz), 7.48(1H, d, J=1.7 Hz), 8.25(1H, d, J=8.8
Hz), 8.37(1H, brs).
Preparation Example 37-2
Ethyl 4-amino3-(2,4-dichlorobenzylamino)benzoate
[0851] Ethanol (7 ml), tetrahydrofuran (7 ml) and water (28 ml)
were added to ethyl 3-(2,4-dichlorobenzylamino)-4-nitrobenzoate
(1.40 g), and sodium hydrosulfite (4.50 g) was added at room
temperature. The mixture was stirred at 50.degree. C. for 20 min.
The reaction mixture was extracted with chloroform and water, and
the organic layer was washed with saturated brine, dried and
concentrated to give the objective compound (1.4 g, as a crude
product). The crude product was used in the following reaction as
it was.
Preparation Example 37-3
1-(2,4-Dichlorobenzylamino)-2-hydroxy-6-(ethoxycarbonyl)benzimidazol
[0852] A solution of crude ethyl
4-amino-3-(2,4-dichlorobenzylamino)benzoa- te (1.4 g) and
tetramethoxymethane (2.60 g) in acetic acid (4 ml) was stirred at
60.degree. C. for 5 hr. The reaction mixture was concentrated, and
ethanol (10 ml) and concentrated hydrochloric acid (0.5 g) were
added to the residue obtained. The mixture was refluxed under
heating for 2 hr. The mixture was heated to room temperature, and
neutralized with a saturated aqueous solution of sodium
hydrogencarbonate. The solvent was distilled away under reduced
pressure. Precipitated gum was gathered, and suspended in ethanol,
filtered and dried to give the objective compound (0.400 g).
[0853] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.27(3H, t, J=7.1
Hz), 4.24(2H, q, J=7.1 Hz), 5.12(2H, s), 7.04(1H, d, J=8.4 Hz),
7.12(1H, d, J=8.2 Hz), 7.37(1H, dd, J=2.1 and 8.4 Hz), 7.51(1H, s),
7.67-7.72(2H, m), 11.37(1H, brs)
Preparation Example 37-4
1-(2,4-Dichlorobenzylamino)-6-(ethoxycarbonyl)-3-methyl-2-benzimidazolone
[0854] Sodium hydrite (0.080 g, 60% suspension in oil) was added to
a solution of
1-(2,4-dichlorobenzylamino)-2-hydroxy-6-(ethoxycarbonyl)benzi-
midazole (0.396 g) in N,N'-dimethylformamide (4 ml), and the
mixture was stirred at room temperature for 1 hr. Methyl iodide
(0.307 g) was added, and the mixture was stirred for 2 hr. The
precipitated crystals were collected by filtration, washed with
water and ethanol and dried to give the objective compound (0.348
g).
[0855] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.28(3H, t, J=7.1
Hz), 3.41(3H, s), 4.25(2H, q, J=7.1 Hz), 5.17(2H, s), 7.05(1H, d,
J=8.4 Hz), 7.32(1H, d, J=8.3 Hz), 7.36(1H, d, J=8.4 Hz), 7.57(1H,
s), 7.69(1H, s), 7.76(1H, d, J=8.3 Hz)
Preparation Example 37-5
6-Carboxy-1-(2,4-dichlorobenzylamino)-3-methyl-2-benzimidazolone
[0856] Ten percent sodium hydroxide (0.650 g) was added to a
mixture of
1-(2,4-dichlorobenzylamino)-6-(ethoxycarbonyl)-3-methyl-2-benzimidazolone
(0.308 g), ethanol (4 ml), tetrahydrofuran (8 ml) and water (4 ml),
and the mixture was stirred at 60.degree. C. for 2.5 hr. A part of
the reaction mixture was concentrated, and neutralized with a
saturated aqueous solution of sodium hydrogencarbonate. The
crystals precipitated were filtered and dried to give the objective
compound (0.276 g).
[0857] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.41(3H, s),
5.16(2H, s), 7.03(1H, d, J=8.4 Hz), 7.29(1H, d, J=8.2 Hz), 7.36(1H,
dd, J=2.1 and 8.4 Hz), 7.55(1H, d, J=1.4 Hz), 7.69(1H, d, J=2.1
Hz), 7.75(1H, dd, J=1.4 and 8.3 Hz)
Preparation Example 38-1
1-(2,4-Dichlorobenzyl)-6-(ethoxycarbonyl)benzotriazole
[0858] Ethyl 4-amino-3-(2,4-dichlorobenzylamino)benzoate (0.89 g),
concentrated sulfuric acid (1.0 g) were stirred in a mixed solvent
of acetic acid (20 ml), water (10 ml) and tetrahydrofuran (20 ml).
Sodium nitrite (3.0 g) was added thereto, and the mixture was
stirred at room temperature for 30 min. The solvent was distilled
away, and water was added to separate the toluene layer. The
mixture was washed with a saturated aqueous solution of sodium
hydrogencarbonate. The toluene layer was concentrated to give the
objective compound (0.64 g) as a crude product.
[0859] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.43(3H, t, J=7.2 Hz),
4.43(2H, quartet, J=7.1 Hz), 5.97(2H, s), 6.94 (1H, d, J=8.4 Hz),
7.18(1H, dd, J=8.4 and 2.1 Hz), 7.48(1H, d, J=2.0 Hz), 8.06(1H, dd,
J=8.7 and 1.3 Hz), 8.12(1H, dd, J=8.9 and 0.9 Hz), 8.23(1H, d,
J=1.0 Hz)
Preparation Example 38-2
6-Carboxy-1-(2,4-dichlorobenzyl)benzotriazole
[0860] 1-(2,4-Dichlorobenzyl)-6-(ethoxycarbonyl)benzotriazole (0.60
g) was refluxed under heating in a mixed solvent of 5% aqueous
solution of sodium hydroxide (6 g) and ethanol (20 g) for 0.5 hr.
After cooling, concentrated hydrochloric acid (4 ml) and water (10
ml) were added to the reaction mixture, and the mixture was
extracted with ethyl acetate, concentrated and dried to give the
objective compound (0.50 g) as a crude product.
[0861] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 6.13(2H, s),
7.24(1H, d, J=8.3 Hz), 7.43-7.46(1H, m), 7.70-7.72(1H, m), 7.95(1H,
d, J=8.8 Hz), 8.14(1H, d, J=8.6 Hz), 8.47(1H, s)
Preparation Example 39-1
4-Ethyl-3-nitrobenzoic acid
[0862] 4-Ethylbenzoic acid (20 g, 133 mmol) was ice-cooled and
fuming nitric acid (94%, d=1.50, 50 ml) was dropwise added thereto
for 40 min. The mixture was stirred at 4-5.degree. C. for 1.25 hr.
The resulting yellow suspension was poured into ice-water and the
precipitated crystals were collected by filtration. The crystals
were dissolved in ethanol, and water was added for
recrystallization to give the objective compound (24.6 g, 94.8%) as
colorless crystals.
[0863] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.59(1H, d, J=1.6 Hz),
8.24(1H, dd, J=1.6 and 8.0 Hz), 7.52(1H, d, J=8.0 Hz), 3.00(2H,
quartet, J=7.5 Hz), 1.33(3H, t, J=7.5 Hz)
Preparation Example 39-2
3-Amino-4-ethylbenzoic acid
[0864] 4-Ethyl-3-nitrobenzoic acid (5.0 g, 27.4 mmol) was dissolved
in methanol (50 ml) and a Pd--C catalyst (5%, 250 mg) was added
thereto. The mixture was stirred under a hydrogen atmosphere from
0.degree. C. to room temperature for 1 hr. After the completion of
the reaction, the catalyst was filtered off and the filtrate was
concentrated under reduced pressure. The obtained crystals were
washed with methyl t-butyl ether/hexane and dried to give the
object compound (3.2 g, 70.6%).
[0865] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 12.40(1H, brs),
7.21(1H, d, J=1.6 Hz), 7.07(1H, dd, J=1.6 and 7.6 Hz), 6.99(1H, d,
J=7.7 Hz), 5.06(2H, brs), 2.45(2H, quartet, J=7.4 Hz), 1.11(3H, t,
J=7.4 Hz).
Preparation Example 39-3
6-Carboxy-3-methyl-1H-indazole
[0866] To chloroform (75 ml), which had been passed through an
alumina column, was added boron trifluoride diethyl ether complex
(3.75 g, 26.4 mmol) and the mixture was cooled at -12.degree. C. A
solution of 3-amino-4-ethylbenzoic acid (2.5 g, 15.1 mmol) in
tetrahydrofuran (25 ml) was dropwise added thereto for 20 min.
After the completion of the addition, t-butyl nitrite (1.87 g, 18.1
mmol) was added and the mixture was heated to 5.degree. C. The
mixture was stirred at 5.degree. C. for 1.5 hr. Then potassium
acetate (7.4 g, 75.4 mmol) and 18-crown-6-ether (400 mg, 1.51 mmol)
were added and the mixture was stirred at room temperature for 40
hr. The brown reaction mixture was concentrated under reduced
pressure. Ethyl acetate/acetone (7/3, 100 ml) and 1N hydrochloric
acid (25 ml) was added to the residue and the mixture was stirred
at room temperature for 1 hr. Saturated brine (25 ml) was added
thereto. The insoluble matter was filtered off and the filtrate was
partitioned. The water layers were extracted with ethyl
acetate/acetone (7/3, 40 ml) and the combined organic layer was
dried over anhydrous magnesium sulfate. The drying agent was
filtered off and the filtrate was concentrated under reduced
pressure. The obtained brown oil (4.3 g) was dissolved in ethyl
acetate, and then hydrogen chloride-diethyl ether (61 of hydrogen
chloride in 40 ml of ether) and diethyl ether (100 ml) were added.
The precipitated solid was collected by filtration. The obtained
solid was extracted with ethyl acetate/acetone (7/3, 100 ml) and
saturated brine (25 ml), and the aqueous layer was further
extracted with ethyl acetate. The combined organic layers were
dried over anhydrous magnesium sulfate. The drying agent was
filtered off and the filtrate was concentrated under reduced
pressure. The obtained solid was washed with diethyl ether to give
the objective compound (0.46 g, 17%) as brown crystals.
[0867] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 12.94(2H, brs),
8.04(1H, s), 7.77(1H, d, J=8.3 Hz), 7.62(1H, dd, J=1.1 and 8.4 Hz),
2.48(3H, s).
Preparation Example 39-4
6-(Methoxycarbonyl)-3-methyl-1H-indazole
[0868] 6-Carboxy-3-methyl-1H-indazole (359 mg, 2.11 mmol) was
dissolved in methanol (50 ml), and concentrated sulfuric acid (0.1
ml) was added. The mixture was heated under reflux for 22 hr. After
cooling, a saturated aqueous sodium hydrogencarbonate solution was
added and the methanol was distilled away under reduced pressure.
The residue was extracted with ethyl acetate, and the organic layer
was washed with saturated brine and dried over anhydrous sodium
sulfate. The drying agent was filtered off and the filtrate was
concentrated under reduced pressure to give the objective compound
(340 mg, 87%) as brown crystals.
[0869] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.18(1H, s), 7.82(1H,
d, J=8.4 Hz), 7.72(1H, d, J=8.4 Hz), 3.96(3H, s), 2.61(3H, s).
Preparation Example 39-5
1-(2,4-Dichlorobenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole
[0870] 6-(Methoxycarbonyl)-3-methyl-1H-indazole (0.40 g, 2.1 mmol)
was dissolved in dimethylformamide (15 ml) and the mixture was
ice-cooled. Sodium hydride (85 mg, 60% suspension in oil, 2.1 mmol
as NaH) was added and the mixture was stirred at 0.degree. C. for
30 min. 2,4-Dichlorobenzyl chloride (0.45 g, 2.31 mmol) was added
and the mixture was stirred at room temperature for 18 hr. The
reaction mixture was extracted with ethyl acetate/water. The
organic layer was washed with saturated brine and dried over
anhydrous sodium sulfate. The drying agent was filtered off and the
filtrate was concentrated under reduced pressure. The obtained
crystalline residue was separated and purified by silica gel column
chromatography (eluent: hexane/ethyl acetate=9/1) to give the
objective compound (0.54 g, 74%) as colorless crystals.
[0871] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 8.06(1H, d, J=1.1 Hz),
7.82(1H, dd, J=1.1 and 8.4 Hz), 7.72(1H, d, J=8.3 Hz), 7.42(1H, d,
J=2.0 Hz), 7.08(1H, dd, J=2.0 and 8.3 Hz), 6.60(1H, d, J=8.4 Hz),
5.63(2H, s), 3.94(3H, s), 2.61(3H, s)
Preparation Example 39-6
6-Carboxy-1-(2,4-dichlorobenzyl)-3-methyl-1H-indazole
[0872]
1-(2,4-Dichlorobenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole
(0.2 g, 0.57 mmol) was suspended in ethanol (10 ml), and a 1M
aqueous sodium hydroxide solution (2 ml) was added. The mixture was
stirred under heating at 90.degree. C. for 40 min. After the
stating compound disappeared, the ethanol was distilled away under
reduced pressure. The residue was acidified with 1N hydrochloric
acid (3 ml) and extracted with ethyl acetate. The organic layer was
washed with saturated brine and dried over anhydrous sodium
sulfate. The drying agent was filtered off and the filtrate was
concentrated under reduced pressure to give the objective compound
(0.19 g, 99%) as colorless crystals. .sup.1H-NMR(CDCl.sub.3,
.delta. ppm): 8.14(1H, s), 7.87(1H, dd, J=1.1 and 8.4 Hz), 7.76(1H,
d, J=8.2 Hz), 7.43(1H, d, J=2.1 Hz), 7.10(1H, dd, J=2.1 and 8.3
Hz), 6.67(1H, d, J=8.3 Hz), 5.65(2H, s), 2.63(3H, s)
Preparation Example 40-1
3-Ethyl-7-(methoxycarbonyl)-2,4-(1H,3H)-quinazolinedione
[0873] A mixture of dimethyl 2-aminoterephthalate (4.18 g), ethyl
isocyanate (2.58 ml) and triethylamine (1.0 ml) in toluene (20 ml)
was heated at 70.degree. C. for 15 hr. After concentration,
methanol (50 ml) and concentrated hydrochloric acid (10 ml) was
added and the mixture was stirred at room temperature for 5 hr.
After concentration, the residue was washed with water (50 ml) and
methanol (50 ml) and dried to give the object compound (2.23
g).
[0874] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.14(3H, t, J=7.1
Hz), 3.88(3H, s), 3.92(2H, quartet, J=7.1 Hz), 7.69(1H, dd, J=8.3
and 1.4 Hz), 7.75(1H, d, J=1.2 Hz), 8.03(1H, d, J=8.2 Hz),
11.58(1H, brs)
Preparation Example 40-2
1-(2,4-Dichlorobenzyl)-3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolined-
ione
[0875] A mixture of
3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolinedion- e (2.17 g),
2,4-dichlorobenzyl chloride (2.05 g), potassium iodide (1.45 g) and
potassium carbonate (5.0 g) in acetone (80 ml) was heated under
reflux for 1.5 hr. After cooling, water (50 ml) was added to the
reaction mixture and the precipitate was collected by filtration.
The precipitate was washed with water (30 ml) and methyl t-butyl
ether (30 ml) and dried to give the object compound (2.60 g).
[0876] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.20(3H, t, J=7.0
Hz), 3.83(3H, s), 4.02(2H, quartet, J=7.0 Hz), 5.38(2H, s),
7.16(1H, d, J=8.5 Hz), 7.29-7.31(1H, m), 7.51(1H, s), 7.75(1H, d,
J=2.0 Hz), 7.80(1H, d, J=8.1 Hz), 8.22(1H, d, J=8.1 Hz)
Preparation Example 40-3
7-Carboxy-1-(2,4-dichlorobenzyl)-3-ethyl-2,4-(1H,3H)-quinazolinedione
[0877]
1-(2,4-Dichlorobenzyl)-3-ethyl-7-(methoxycarbonyl)-2,4(1H,3H)-quina-
zolinedione (2.36 g) in a mixture of a 5% aqueous sodium hydroxide
solution (10 g) and methanol (30 g) was heated under reflux for 1
hr. After cooling, concentrated hydrochloric acid (3.9 g) was added
to the reaction mixture and the precipitate was collected by
filtration. The precipitate was washed with water (100 g) and
toluene (20 ml) and dried to give the objective compound (2.27 g)
as white crystals.
[0878] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.19(3H, t, J=7.0
Hz), 4.02(2H, quartet, J=7.0 Hz), 5.37(2H, s), 7.14(1H, d, J=8.4
Hz), 7.30(1H, dd, J=8.4 and 2.1 Hz), 7.48(1H, s), 7.75(1H, d, J=2.1
Hz), 7.78(1H, d, J=8.0 Hz), 8.20(1H, d, J=8.1 Hz) IR(Nujol): 1724,
1704, 1662 cm.sup.-1 mp: 238-240.degree. C.
Preparation Example 41-1
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-2,4(1H,3H)-quinazolinedione
[0879] A mixture of dimethyl 2-aminoterephthalate (4.18 g),
N,N'-carbonyldiimidazole (3.89 g) and N-methylmorpholine (4.0 ml)
in tetrahydrofuran (30 ml) was stirred at room temperature for 21
hr. After concentration of the reaction mixture, acetonitrile (70
ml) and 2,4-dichlorobenzylamine (5.47 g) were added and the mixture
was stirred at reflux temperature for 2 hr. The precipitated solid
was washed with water (50 ml) and acetonitrile (50 ml) and dried to
give the objective compound (4.64 g).
[0880] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.90(3H, s),
5.09(2H, s), 7.15(1H, d, J=8.4 Hz), 7.30(1H, dd, J=8.4 and 2.1 Hz),
7.65(1H, d, J=2.2 Hz), 7.71(1H, dd, J=8.3 and 1.4 Hz), 7.81(1H, s),
8.06(1H, d, J=8.4 Hz), 11.8(1H, brs).
Preparation Example 41-2
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-1-methyl-2,4(1H,3H)-quinazoline-
dione
[0881] A mixture of
3-(2,4-dichlorobenzyl)-7-(methoxycarbonyl)-2,4-(1H,3H)-
-quinazolinedione (2.30 g), methyl iodide (2.13 g) and potassium
carbonate (2.07 g) in acetone (30 ml) was heated under reflux for 2
hr. After cooling, the reaction mixture was concentrated, and the
residue was washed with water (60 ml) and methyl t-butyl ether (20
ml) and dried to give the objective compound (2.25 g) as white
crystals.
[0882] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.58(3H, s),
3.93(3H, s), 5.14(2H, s), 7.17(1H, d, J=8.4 Hz), 7.29 (1H, dd,
J=8.4 and 2.0 Hz), 7.65(1H, d, J=2.0 Hz), 7.84(1H, dd, J=8.2 and
1.2 Hz), 7.91(1H, s), 8.18(1H, d, J=8.2 Hz)
Preparation Example 41-3
7-Carboxy-3-(2,4-dichlorobenzyl)-1-methyl-2,4(1H,3H)-quinazolinedione
[0883]
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-1-methyl-2,4-(1H,3H)-qui-
nazolinedione (2.02 g) in a mixture of a 5% aqueous sodium
hydroxide solution (10 g) and methanol (30 g) was heated under
reflux for 1 hr. After cooling, concentrated hydrochloric acid (5.5
g) was added to the reaction mixture and the precipitate was
collected by filtration. The precipitate was washed with water (50
g) and methanol (50 g) and dried to give the objective compound
(1.90 g) as white crystals.
[0884] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.58(3H, s),
5.14(2H, s), 7.16(1H, d, J=8.5 Hz), 7.29 (1H, dd, J=8.4 and 2.1
Hz), 7.65(1H, d, J=2.1 Hz), 7.82(1H, d, J=8.2 Hz), 7.91(1H, s),
8.16(1H, d, J=8.2 Hz) IR(Nujol): 1712, 1691, 1667 cm.sup.-1 mp:
308-310.degree. C.
Preparation Example 42-1
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-4(3H)-quinazolinone
[0885] A solution of dimethyl 2-aminoterephthalate (4.18 g) and
N,N-dimethylformamide dimethyl acetal (4.77 g) in dimethylformamide
(20 ml) was heated at 135.degree. C. for 2 hr. The reaction mixture
was concentrated to give an oil (5.40 g). To 2.70 g of the oil,
2,4-dichlorobenzylamine (3.52 g) was added and the mixture was
heated for at 100.degree. C. for 5 min. After cooling, the residue
was washed with water (50 ml) and 2-propanol (50 ml) and dried to
give the objective compound (3.10 g) as white crystals.
[0886] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.99(3H, s),
5.26(2H, s), 7.24-7.27(2H, m), 7.42 (1H, d, J=8.4 Hz), 7.44(1H, d,
J=2.2 Hz), 8.12(1H, dd, J=8.3 and 1.7 Hz), 8.25(1H, s), 8.35(1H, d,
8.4 Hz), 8.39(1H, d, 1.4 Hz)
Preparation Example 42-2
7-Carboxy-3-(2,4-dichlorobenzyl)-4(3H)-quinazolinone
[0887]
3-(2,4-Dichlorobenzyl)-7-(methoxycarbonyl)-4(3H)-quinazolinone
(2.00 g) in a mixture of a 5% aqueous sodium hydroxide solution (20
ml) and methanol (20 ml) was heated under reflux for 1 hr. After
cooling, concentrated hydrochloric acid was added to the reaction
mixture and the precipitate was collected by filtration. The
precipitate was washed with water (50 g) and toluene (30 ml) and
dried to give the objective compound (1.50 g) as white
crystals.
[0888] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 5.25(2H, s),
7.19(1H, d, J=8.4 Hz), 7.37(1H, dd, J=8.4 and 2.3 Hz), 7.68(1H, d,
J=2.1 Hz), 8.03(1H, dd, J=8.2 and 1.5 Hz), 8.18(1H, s), 8.23(1H, d,
J=8.4 Hz), 8.58(1H, s) IR(Nujol): 1724, 1679, 1660 cm.sup.-1. mp:
244-246.degree. C.
Preparation Example 43-1
Dimethyl 2-((2,4-dichlorophenyl)acetylamino)terephthalate
[0889] A mixture of dimethyl 2-aminoterephthalate (2.09 g),
2,4-dichlorophenylacetic acid (2.05 g), N,N-dimethylaminopyridine
(1.32 g) and dicyclohexylcarbodiimide (2.22 g) in tetrahydrofuran
(20 ml) was stirred at room temperature for 2 hr and then at
80.degree. C. for 4 hr. After cooling, the precipitate was filtered
off and the filtrate was washed with 1 N hydrochloric acid.
Chloroform was added to the obtained organic layer, and the mixture
was washed with a saturated aqueous sodium hydrogencarbonate
solution and dried over sodium sulfate. The solvent was distilled
away and the residue was washed with water and methanol to give the
object compound (2.54 g) as white crystals.
[0890] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.81(3H, s),
3.86(3H, s), 3.93(2H, s), 7.45 (1H, dd, J=8.3 and 2.1 Hz), 7.51(1H,
d, J=8.3 Hz), 7.73(1H, dd, J=8.2 and 1.7 Hz), 7.97(1H, d, J=8.2
Hz), 8.74(1H, d, 1.7 Hz), 10.64(1H, s).
Preparation Example 43-2
2-(2,4-Dichlorobenzyl)-3-methyl-7-(methylcarbamoyl)-4(3H)-quinazolinone
[0891] Dimethyl 2-((2,4-dichlorophenyl)acetylamino)terephthalate
(0.96 g) and a 40% aqueous methylamine solution (5 ml) in a mixture
of methanol (20 ml) and tetrahydrofuran (20 ml) were stirred at
room temperature for 1 hr. After concentration of the reaction
mixture, methanol (20 ml) and concentrated hydrochloric acid (5 ml)
were added to the residue and the mixture was stirred at 50.degree.
C. for 30 min. The reaction mixture was concentrated to give the
objective compound (0.90 g) as white crystals.
[0892] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.05(3H, d, J=4.9 Hz),
3.56(3H, s), 4.28(2H, s), 6.24(1H, brs), 7.12(1H, d, J=8.4 Hz),
7.22(1H, dd, J=8.3 and 2.1 Hz), 7.48(1H, d, J=2.2 Hz), 7.86(1H, dd,
J=8.2 and 1.7 Hz), 7.90(1H, d, J=1.6 Hz), 8.32(1H, d, J=8.4
Hz).
Preparation Example 43-3
7-Carboxy-2-(2,4-dichlorobenzyl)-3-methyl-4(3H)-quinazolinone
[0893]
2-(2,4-Dichlorobenzyl)-3-methyl-7-(methylcarbamoyl)-4(3H)-quinazoli-
none (0.88 g) in a mixture of concentrated sulfuric acid (2.0 g)
and water (2.0 g) was stirred at 100.degree. C. for 7 hr. After
cooling of the reaction mixture, water (5 ml) was added. The
precipitate was collected by filtration, washed with methanol and
dried to give the objective compound (0.69 g) as white
crystals.
[0894] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.58(3H, s),
4.37(2H, s), 7.37-7.44(2H, m), 7.66(1H, d, J=2.0 Hz), 7.87(1H, d,
J=1.4 Hz), 7.94(1H, dd, J=8.2 and 1.6 Hz), 8.20(1H, d, J=8.3 Hz)
IR(Nujol): 1719, 1676 cm.sup.-1 mp: 266-271.degree. C.
Preparation Example 44-1
6-(Ethoxycarbonyl)-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-methylquinazoline
hydrochloride
[0895] A mixture of ethyl 3-methyl-4-nitrobenzoate (2.09 g),
N-bromosuccinimide (2.78 g) and AIBN (0.12 g) in carbon
tetrachloride (10 ml) was heated under reflux for 12 hr. After
cooling, precipitate was filtered off and the filtrate was
concentrated. 2,4-Dichlorobenzylamine (2.76 g), the potassium
carbonate (2.76 g) and toluene (20 ml) were added to the residue
and the mixture was stirred under heating at 100.degree. C. for 1.5
hr. After cooling, the reaction mixture was washed with water and
concentrated hydrochloric acid (5 ml) was added to the toluene
layer. The resulting solid was collected by filtration, washed with
water and toluene and dried to give a crude product of ethyl
3-(2,4-dichlorobenzylamino)methyl-4-nitrobenzoate hydrochloride
(2.74 g).
[0896] To the crude product were added sodium hydrosulfite (17 g),
tetrahydrofuran (20 ml), ethanol (20 ml) and water (80 ml) and the
mixture was heated under reflux for 1 hr. After cooling, the
tetrahydrofuran layer was separated and concentrated. To the
residue containing ethyl
4-amino-3-(2,4-dichlorobenzyl-amino)methylbenzoate as a main
component, acetic acid (20 ml) and acetic anhydride (20 ml) were
added and the mixture was heated at 100.degree. C. for 1 hr. After
concentration of the reaction mire containing ethyl
4-acetylamino-3-(2,4-dichlorobenzylamino)methylbenzoate as a main
component, methanol (20 ml) and concentrated hydrochloric acid (5
ml) were added and the mixture was heated under reflux for 1 hr.
The reaction mixture was concentrated to give a crude product of
the object compound (0.68 g).
Preparation Example 44-2
6-Carboxy-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-methylquinazoline
hydrochloride
[0897]
6-(Ethoxycarbonyl)-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-methylquina-
zoline hydrochloride (0.68 g) in a mixture of a 10% aqueous sodium
hydroxide solution (5 ml) and ethanol (10 ml) was stirred at
60.degree. C. for 1 hr. After standing cool the reaction mixture,
concentrated hydrochloric acid (5 ml) was added and the precipitate
was collected by filtration. The precipitated was washed with
toluene and 2-propanol and dried to give the objective compound
(0.41 g) as white crystals.
[0898] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.55(3H, s),
4.74(2H, s), 4.90(2H, s), 7.31(1H, d, J=8.3 Hz), 7.49 (1H, dd,
J=8.4 and 2.2 Hz), 7.64(1H, d, J=8.4 Hz), 7.71(1H, s), 7.76(1H, d,
J=2.0 Hz), 7.89(1H, d, J=8.3 Hz), 12.96(1H, brs) IR(Nujol): 1718
cm.sup.-1 mp: 277.degree. C. (decomposition)
Preparation Example 45-1
Dimethyl 2-((2,4-dichlorobenzyl)amino)terephthalate
[0899] Dimethyl 2-aminoterephthalate (10.45 g), 2,4-dichlorobenzyl
chloride (11.74 g), potassium iodide (8.33 g) and potassium
carbonate (13.82 g) in a mixed solvent of toluene (50 ml) and water
(30 ml) were heated under reflux for 20 hr. After cooling, toluene
(50 ml) was added and the precipitated yellow crystals were
collected by filtration. The crystals were washed with water and
toluene and dried to give the objective compound (7.87 g). The
mother liquor was concentrated and crystallized from ethyl acetate
to give the second crystals (4.43 g).
[0900] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.88(3H, s), 3.90(3H,
s), 7.19-7.27(4H, m), 7.42(1H, d, J=2.0 Hz), 7.99(1H, d, J=8.8 Hz),
8.20-8.28(1H, m)
Preparation Example 45-2
Dimethyl 2-((N-acetyl)-(2,4-dichlorobenzyl)amino)terephthalate
[0901] A mixture of dimethyl
2-(2,4-dichlorobenzyl)aminoterephthalate (12.00 g),
N,N-dimethylaniline (7.92 g) and acetyl chloride (5.5 ml) in
toluene (140 ml) was heated at 50.degree. C. for 15 hr. After
cooling, ice and concentrated hydrochloric acid were added to
acidify the reaction mixture and the toluene layer was separated.
The toluene layer was washed successively with water and a
saturated aqueous sodium hydrogencarbonate solution, dried over
sodium sulfate and concentrated. The residue was crystallized from
2-propanol to give the objective compound (8.40 g) as white
crystals.
[0902] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 3.88(3H, s), 3.90(3H,
s), 7.19-7.27(4H, m), 7.42(1H, d, J=2.0 Hz), 7.99(1H, d, J=8.8 Hz),
8.20-8.28(1H, m)
Preparation Example 45-3
2-((N-Acetyl)-(2,4-dichlorobenzyl)amino)terephthalic acid
[0903] A mixture of dimethyl
2-((N-acetyl)-(2,4-dichlorobenzyl)amino)terep- hthalate (2.05 g)
and 10% aqueous sodium hydroxide solution (8.00 g) in methanol (20
ml) was heated at 60.degree. C. for 1 hr. After cooling,
concentrated hydrochloric acid was added to acidify the reaction
mixture and the precipitated solid was collected by filtration. The
solid was washed with water (60 ml) and dried to give the objective
compound (1.87 g) as white crystals.
[0904] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.73(3H, s),
4.30(1H, d, J=10.30 Hz), 5.28(1H, d, J=10.30 Hz), 7.37(1H, dd,
J=8.3 and 2.0 Hz), 7.41(1H, d, J=8.4 Hz), 7.52(1H, d, J=2.0 Hz),
7.55(1H, s), 7.97-7.99(2H, m)
Preparation Example 45-4
2-((N-Acetyl)-(2,4-dichlorobenzyl)amino)-1,4-dicarbamoylbenzene
[0905] A mixture of
2-((N-acetyl)-(2,4-dichlorobenzyl)amino)terephthalic acid (1.80 g)
and N,N'-carbonyldiimidazole (1.62 g) in tetrahydrofuran (10 ml)
was stirred at room temperature for 1 hr. Thereto was added 25%
ammonia water (50 ml). The mixture was stirred for 10 min and
concentrated. The residue was washed with water and 2-propanol and
dried to give the object compound (1.56 g) as white crystals.
[0906] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.80(3H, s),
4.27(1H, d, J=15.75 Hz), 5.28(1H, d, J=15.75 Hz), 7.37(1H, dd,
J=8.4 and 2.1 Hz), 7.44(1H, d, J=8.4 Hz), 7.50(1H, brs), 7.54(1H,
d, J=2.1 Hz), 7.55(1H, d, J=1.5 Hz), 7.59(1H, d, J=8.0 Hz),
7.66(1H, brs), 7.88(1H, d, J=7.9 Hz), 8.01(1H, brs), 8.04(1H,
brs)
Preparation Example 45-5
7-Carbamoyl-1-(2,4-dichlorobenzyl)-2-methylquinazoline-4-one
[0907]
2-((N-Acetyl)-(2,4-dichlorobenzyl)amino)-1,4-dicarbamoylbenzene
(1.50 g) in a mixture of concentrated hydrochloric acid (10 ml) and
methanol (30 ml) was heated under reflux for 30 min. After
concentration, the object compound (1.46 g) was obtained as white
crystals.
[0908] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.70(3H, s),
5.70(2H, s), 7.16(1H, d, J=8.4 Hz), 7.35(1H, dd, J=8.4 and 2.1 Hz),
7.77(1H, brs), 7.86(1H, brs), 8.09(1H, d, J=8.2 Hz), 8.32(1H, d,
J=8.2 Hz), 8.37(1H, brs)
Preparation Example 45-6
7-Carboxy-1-(2,4-dichlorobenzyl)-2-methyl-4(1H)-quinazolinone
[0909]
7-Carbamoyl-1-(2,4-dichlorobenzyl)-2-methyl-4(1H)-quinazolinone
(1.40 g) in a mixture of concentrated sulfuric acid (6 ml) and
water (6 ml) was heated at 100.degree. C. for 1 hr. After cooling,
the precipitated solid was collected by filtration, washed with
water, dried and concentrated to give the object compound (1.46 g)
as white crystals.
[0910] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.54(3H, s), 5.56
(2H, s), 6.94(1H, d, J=8.5 Hz), 7.32(1H, d, J=8.5 Hz), 7.74(1H, s),
7.81(1H, d, J=1.9 Hz), 7.96(1H, d, J=8.2 Hz), 8.20(1H, d, J=8.2
Hz).
Preparation Example 46-1
Methyl 4-bromomethyl-3-nitrobenzoate
[0911] A mixture of methyl 3-nitro-4-methylbenzoate (4.147 g),
N-bromosuccinimide (7.12 g) and AIBN (0.40 g) in carbon
tetrachloride (30 ml) was stirred at 70.degree. C. for 42 hr. After
cooling, the insoluble matter was filtered off and the filtrate was
concentrated to give an oil (7.40 g) containing the object
compound.
Preparation Example 46-2
2-((N-Acetyl)aminomethyl)-5-((N-acetyl)carbamoyl)-1-nitrobenzene
[0912] The crude methyl 4-bromomethyl-3-nitrobenzoate (7.40 g)
obtained above in 25% aqueous ammonia water (140 ml) and methanol
(70 ml) was stirred at 50.degree. C. for 1 hr. The reaction mixture
was concentrated, and acetic acid (50 ml) and acetic anhydride (50
ml) were added. After refluxing for 30 min, the reaction mixture
was cooled and a saturated aqueous sodium hydrogencarbonate
solution was added. The mixture was extracted with ethyl acetate,
dried over magnesium sulfate and concentrated. The residue was
washed with chloroform to give the object compound.
[0913] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.91(3H, s),
2.34(3H, s), 4.57(2H, d, J=5.9 Hz), 7.63(1H, d, J=8.3 Hz), 8.19(1H,
d, J=8.2 Hz), 8.48-8.53(2H, m), 11.26(1H, brs)
Preparation Example 46-3
2-((N-Acetyl)aminomethyl)-5-((N-acetyl)carbamoyl)aniline
[0914]
2-((N-Acetyl)aminomethyl)-5-((N-acetyl)carbamoyl)-1-nitrobenzene
(1.00 g) and sodium hydrosulfite (7.0 g) in a mixture of
tetrahydrofuran (5 ml), ethanol (5 ml) and water (20 ml) were
heated under reflux for 1 hr. After cooling, the organic layer was
separated, dried over sodium sulfate and concentrated. The residue
was purified by silica gel column chromatography to give the
objective compound (1.06 g).
Preparation Example 46-4
7-(Acetylcarbamoyl)-1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methylquinazoline
hydrochloride
[0915] 5-(Acetylcarbamoyl)-2-(acetylaminomethyl)aniline (1.06 g),
potassium carbonate (1.40 g), potassium iodide (0.8 g) and
2,4-dichlorobenzyl chloride (1.40 g) in a mixture of
dimethylformamide (15 ml) and water (10 ml) were stirred at
90.degree. C. for 15 hr. After concentration of the reaction
mixture, water was added and the mixture was extracted with ethyl
acetate. The extract was concentrated, and methanol (5 ml) and
concentrated hydrochloric acid (5 ml) were added. The mixture was
refluxed for 1 hr. The reaction mixture was concentrated and
purified by thin-layer chromatography to give the objective
compound (0.46 g).
Preparation Example 46-5
7-Carboxy-1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methylquinazoline
1/2 sulfate
[0916] To
7-(acetylcarbamoyl)-1-(2,4-dichlorobenzyl)-1,4-dihydro-2-methylq-
uinazoline hydrochloride (0.46 g) were added water (1.2 g) and
concentrated sulfuric acid (1.0 g) and the mixture was heated at
70.degree. C. for 90 min. After cooling, ice was added and the
precipitated solid was collected by filtration. The precipitate was
washed with water and 2-propanol and dried to give the objective
compound (0.145 g).
[0917] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.24(3H, s),
4.67(2H, s), 5.14(2H, s), 7.14(1H, s), 7.23(2H, t, J=7.2 Hz),
7.38(1H, d, J=8.4 Hz), 7.65(1H, d, J=7.2 Hz), 7.75(1H, s)
Preparation Example 47-1
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-3-methyl-2(1H)-quinoxalinone
[0918] A mixture of ethyl
4-amino-3-(2-4-dichlorobenzylamino)benzoate (1.90 g) and methyl
pyruvate (0.55 ml) in toluene (15 ml) was heated under reflux for 1
hr. The reaction mixture was concentrated. The residue was washed
with methanol and dried to give the object compound (0.50 g) as
yellow crystals.
[0919] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.28(3H, t, J=7.2
Hz), 2.53(3H, s), 4.28(2H, quartet, J=7.1 Hz), 5.49(2H, s),
6.99(1H, d, J=8.6 Hz), 7.27 (1H, dd, J=8.4 and 2.1 Hz), 7.63(1H,
s), 7.76(1H, d, J=2.1 Hz), 7.84-7.91(1H, m)
Preparation Example 47-2
7-Carboxy-1-(2,4-dichlorobenzyl)-3-methyl-2(1H)-quinoxalinone
[0920]
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-3-methyl-2(1H)-quinoxalin-
one (0.50 g) in a mixture of a 5% aqueous sodium hydroxide solution
(3 g) and methanol (20 ml) was heated under reflux for 1 hr. After
cooling, concentrated hydrochloric acid (4 ml) and water (10 ml)
were added to the reaction mixture and the precipitate was
collected by filtration. The precipitate was washed with water (30
g) and dried to give the object compound (0.36 g) as yellow
crystals.
[0921] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.52(3H, s),
5.47(2H, s), 6.92(1H, d, J=8.4 Hz), 7.26(1H, dd, J=8.4 and 2.0 Hz),
7.62(1H, s), 7.76(1H, d, J=2.0 Hz), 7.84-7.89(1H, m)
Preparation Example 48-1
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-2,3(1H,4H)-quinoxalinedione
[0922] To a solution of ethyl
4-amino3-(2,4-dichlorobenzylamino)benzoate (1.53 g) and
dimethylaniline (0.71 g) in toluene was added oxalyl dichloride
(0.51 ml). After stirring at room temperature for 1.5 hr, ice was
added to the reaction mixture. The toluene layer was separated and
washed with 6N hydrochloric acid. The toluene layer was
concentrated, and the residue was washed with methyl t-butyl ether
and dried to give the object compound (1.03 g) as white
crystals.
[0923] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.24(3H, t, J=7.2
Hz), 4.21(2H, quartet, J=7.1 Hz), 5.34(2H, s), 7.24-7.32 (3H, m),
7.30(1H, d, J=2.1 Hz), 7.73(1H, dd, J=8.3 and 1.7 Hz), 7.75(1H, d,
J=2.1 Hz), 12.38(1H, brs)
Preparation Example 48-2
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-4-methyl-2,3(1H,4H)-quinoxalined-
ione
[0924] A mixture of
1-(2,4-dichlorobenzyl)-7-(ethoxycarbonyl)quinoxaline-2- ,3-dione
(0.90 g), methyl iodide (0.49 g) and potassium carbonate (0.63 g)
in acetone (20 ml) was heated under reflux for 2 hr. After cooling,
the reaction mixture was concentrated. The residue was washed with
water (150 ml) and methyl t-butyl ether (100 ml) and dried to give
the object compound (0.84 g) as white crystals.
[0925] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.25(3H, t, J=7.1
Hz), 3.59(3H, s), 4.23(2H, quartet, J=7.1 Hz), 5.37(2H, s), 7.24
(1H, d, 8.5 Hz), 7.30(1H, dd, J=8.5 and 2.1 Hz), 7.42(1H, d, J=1.6
Hz), 7.56(1H, d, J=8.6 Hz), 7.76(1H, d, J=2.1 Hz), 7.80(1H, dd,
J=8.6 and 1.6 Hz).
Preparation Example 48-3
7-Carboxy-1-(2,4-dichlorobenzyl)-4-methyl-2,3(1H,4H)-quinoxalinedione
[0926]
1-(2,4-Dichlorobenzyl)-7-(ethoxycarbonyl)-4-methyl-2,4(1H,4H)-quino-
xalinedione (0.80 g) in a mixture of a 3% aqueous sodium hydroxide
solution (10 g) and methanol (15 g) was heated under reflux for 1
hr. After cooling, concentrated hydrochloric acid (4 ml) and water
(10 ml) were added to the reaction mixture and the precipitate was
collected by filtration. The precipitate was washed with water (50
g) and methyl t-butyl ether (30 ml) and dried to give the object
compound (0.56 g) as yellow crystals.
[0927] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 3.59 (3H, s),
5.35(2H, s), 7.20(1H, d, J=8.5 Hz), 7.29(1H, dd, J=8.5 and 2.2Hz),
7.41(1H, d, J=1.6Hz), 7.54(1H, d, J=8.7 Hz), 7.76(1H, d, J=2.2 Hz),
7.80(1H, dd, J=8.6 and 1.7 Hz). IR(Nujol): 1716, 1681, 1659
cm.sup.-1 mp: 320-322.degree. C.
Preparation Example 49-1
4-(2,4-Dichlorobenzyl)-3-(ethoxycarbonyl)-5-ethylimidazo[1,2-b]pyrazole
[0928] To a solution of ethyl
3-(ethoxycarbonyl)-5-ethylimidazo[1,2-b]pyra- zole (0.348 g), which
was prepared by a method described in Japanese Patent Unexamined
Publication No. 163267/1993, in N,N-dimethylformamide was added
sodium hydride (60% in oil, 0.100 g) and the mixture was stirred at
room temperature for 30 min. 2,4-Dichlorobenzyl chloride (0.870 g)
was added to the reaction mixture and the mixture was stirred at
room temperature for 6 hr. The reaction mixture was concentrated to
dryness and the residue was dissolved in ethyl acetate. The organic
layer was washed with water and dried. The solvent was evaporated
and the residue was purified by silica gel column chromatography
(eluent: chloroform/ethyl acetate=2/1) to give the object compound
(0.510 g).
[0929] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.19-1.25(6H, m),
2.45(2H, q), 4.18(2H, q, J=7.1 Hz), 5.73(2H, s), 6.57(1H, d, J=8.4
Hz), 7.12(1H, dd, J=8.4 and 2.0 Hz), 7.18(1H, s), 7.41(1H, d, J=2.0
Hz), 8.02(1H, s)
Preparation Example 49-2
3-Carboxy-4-(2,4-dichlorobenzyl)-5-ethylimidazo[1,2-b]pyrazole
[0930] The objective compound (0.445 g) was obtained from
4-(2,4-dichlorobenzyl)-3-(ethoxycarbonyl)-5-ethylimidazo[1,2-b]pyrazole
(0.510 g).
[0931] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.13(3H, dt, J=7.3
and 1.7 Hz), 2.45(2H, q, J=7.3 Hz), 5.75(2H, s), 6.50(1H, d, J=8.3
Hz), 7.34(1H, d, J=8.4 Hz), 7.66(2H, d, J=8.3 Hz), 7.83(1H, s),
11.82(1H, brs)
Preparation Example 50-1
5-(4-Cyanophenylamino)methylidene-2,2-dimethyl-1,3-dioxane-4,6-dione
[0932] A mixture of p-aminobenzonitrile (2.00 g), Meldrum's acid
(2.56 g), ethyl orthoformate (2.76 g) and ethanol (10 ml) was
heated at 120.degree. C. (bath temperature) to evaporate the
ethanol. Ethyl acetate was added to the obtained orange solid. The
solid was pulverized, collected by filtration and washed with ethyl
acetate to give the object compound (3.28 g) as a white powder.
[0933] .sup.1H-NMR(CDCl.sub.3): 1.77 (6H, s), 7.34 (2H, d, J=8 Hz),
7.73 (2H, d, J=8 Hz), 8.67 (1H, d, J=15 Hz), 11.24 (1H, br)
Preparation Example 50-2
4-Hydroxy-6-quinolinecarbonitrile
[0934] A mixture of biphenyl (10 ml) and diphenyl ether (30 ml) was
heated at 250.degree. C. and
5-(4-cyanophenylamino)methylidene-2,2-dimethyl-1,3--
dioxane-4,6-dione (3.28 g) was added thereto. The mixture was
stirred for 1 hr. The reaction mixture was cooled to 80.degree. C.
while stirring and hexane (100 ml) was added. The mixture was
stirred in an ice bath for 0.5 hr. The resulting solid was
collected by filtration and washed with hexane to give the object
compound (1.86 g) as a yellow-brown powder.
[0935] .sup.1H-NMR(DMSO-d.sub.6): 6.15 (1H, d, J=7 Hz), 7.67 (1H,
d, J=8 Hz), 7.96-8.04 (2H, m), 8.42 (1H, d, J=4 Hz)
Preparation Example 50-3
4-Chloro-6-quinolinecarbonitrile
[0936] Phosphorus oxychloride (0.518 ml) was added to DMF (9 ml) at
an inner temperature of 5-7.degree. C. while stirring under
ice-cooling, and the mixture was stirred at room temperature for
0.5 hr. 4-Hydroxy-6-quinolinecarbonitrile (860 mg) was added while
stirring under ice-cooling and the mixture was stirred under
ice-cooling for 1 hr. 1N aqueous sodium hydroxide solution (18 ml)
was added and the mixture was stirred at room temperature for 10
min. The precipitate was collected by filtration and washed with
water to give a pale brown powder. The obtained powder was purified
by silica gel column chromatography (eluent:
chloroform-methanol=50/1) to give the object compound (800 mg) as a
pale yellow powder.
[0937] .sup.1H-NMR(CDCl.sub.3): 7.62 (1H, d, J=7 Hz), 7.93 (1H, d,
J=8 Hz), 8.23 (1H, d, J=8 Hz), 8.65 (1H, d, J=4 Hz), 8.92 (1H, d,
J=7 Hz)
Preparation Example 50-4
Methyl 4-methoxy-6-quinolinecarboxylate
[0938] To a suspension of 4-chloro-6-quinolinecarbonitrile (910 mg)
in methanol (50 ml) was dropwise added slowly concentrated sulfuric
acid (5 ml) while stirring under ice-cooling. The mixture was
heated under reflux for 15 hr and concentrated sulfuric acid (10
ml) was added. The mixture was further heated under reflux for 24
hr. An aqueous sodium hydrogencarbonate solution was added thereto
under ice-cooling to make the reaction mixture basic. The reaction
mixture was extracted once with chloroform. The organic layer was
washed once with water and saturated brine, respectively, and dried
over magnesium sulfate. The organic layer was concentrated to
dryness under reduced pressure to give a white solid. The solid was
pulverized by IPE to give the object compound (910 mg) as a white
powder.
[0939] .sup.1H-NMR(CDCl.sub.3): 3.98 (3H, s), 4.08 (3H, s), 6.80
(1H, d, J=7 Hz), 8.05 (1H, d, J=8 Hz), 8.29 (1H, d, J=8 Hz), 8.83
(1H, d, J=7 Hz), 8.97 (1H, d, J=4 Hz)
Preparation Example 50-5
Methyl 4-bromo-6-quinolinecarboxylate
[0940] To a solution of methyl 4-methoxy-6-quinolinecarboxylate
(910 mg) in DMF (7 ml) was added phosphorus tribromide (1.57 ml)
while stirring under ice-cooling. DMF (7 ml) was added and the
mixture was heated at 80.degree. C. for 3 hr. To the reaction
mixture was added water (50 ml) and the reaction mixture was made
weak basic with a 1N aqueous sodium hydroxide solution. The
resulting precipitate was collected by filtration and purified by
silica gel column chromatography (eluent:
chloroform-methanol=100/0-100/1) to give the object compound (420
mg) as a yellow powder.
[0941] .sup.1H-NMR(CDCl.sub.3): 4.03 (s, 3H), 7.78 (1H, d, J=7 Hz),
8.15 (1H, d, J=8 Hz), 8.36 (1H, d, J=8 Hz), 8.77 (1H, d, J=7 Hz),
8.95 (1H, d, J=4 Hz)
Preparation Example 50-6
4-(4-Phenylphenyloxy)-6-quinolinecarboxylic acid
[0942] 60% Sodium hydride (38 mg) was suspended in
dimethylimidazolinone (1 ml). 4-Phenylphenol (160 mg) was added
while stirring under water-cooling, and the mixture was stirred
under water-cooling for 0.5 hr. Methyl
4-bromo-6-quinolinecarboxylate (100 mg) was added under
water-cooling and the mixture was stirred at 100.degree. C. for 5
hr, and then at 140.degree. C. for 3 hr. Water (10 ml) was added to
the reaction mixture and the mixture was extracted once with ethyl
acetate. The aqueous layer was made adjusted to pH 4 with 1N
hydrochloric acid and the resulting solid was collected by
filtration to give the object compound (73 mg) as a pale brown
powder.
[0943] .sup.1H-NMR(DMSO-d.sub.6): 6.78 (1H, d, J=7 Hz), 7.37-7.53
(5H, m), 7.72 (2H, d, J=8 Hz), 7.84 (2H, d, J=8 Hz), 8.11 (1H, d,
J=8 Hz), 8.29 (1H, d, J=8 Hz), 8.82 (1H, d, J=7 Hz), 8.97 (1H,
s)
Preparation Example 50-7
4-Bromo-6-quinolinecarboxylic acid
[0944] Methyl 4-bromo-6-quinolinecarboxylate (6.00 g) was dissolved
in methanol (60 ml) and tetrahydrofuran (40 ml). A 1N aqueous
sodium hydroxide solution (30 ml) was added to the solution while
stirring at room temperature and the mixture was stirred at room
temperature for 3 hr. A1N aqueous sodium hydroxide solution (20 ml)
was added and the mixture was heated under reflux for 2 hr. The
reaction mixture was adjusted to pH 4 with 1N hydrochloric acid.
The resulting solid was collected by filtration and washed with
water and ether to give 4-bromo-6-quinolinecarboxylic acid (4.65 g)
as a white powder.
[0945] .sup.1H-NMR(DMSO-d.sub.6): 8.06 (1H, d, J=7 Hz), 8.18 (1H,
d, J=8 Hz), 8.30 (1H, d, J=8 Hz), 8.77 (1H, s), 8.83 (1H, d, J=7
Hz)
Preparation Example 50-8
4-(4-Phenylbenzyloxy)-6-quinolinecarboxylic acid
[0946] In the same manner as in Preparation Example 50-6, the
object compound (1.04 g) was obtained as a white powder from
4-bromo-6-quinolinecarboxylic acid (731 mg).
[0947] .sup.1H-NMR(DMSO-d.sub.6): 5.49 (2H, s), 7.26 (1H, d, J=7
Hz), 7.35-7.51 (3H, m), 7.64-7.79 (6H, m), 8.04 (1H, d, J=8 Hz),
8.21 (1H, d, J=8 Hz), 8.80 (1H, s), 8.86 (1H, d, J=7 Hz)
Preparation Example 51-1
Methyl
3-(4-phenylbenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0948] In the same manner as in Preparation Example 1-1, the object
compound (263 mg) was obtained as pale yellow crystals from methyl
2-methylbenzo[b]thiophene-5-carboxylate (200 mg).
[0949] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 3.87(3H, s),
7.39-7.51(3H, m), 7.63-7.72(4H, m), 7.84(1H, d, J=8 Hz),
7.92-7.97(2H, m), 8.00(1H, dd, J=2, 8 Hz), 8.30(1H, s)
Preparation Example 51-2
Methyl
3-((4-phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0950] In the same manner as in Preparation Example 1-2, the object
compound (177 mg) was obtained as white crystals from methyl
3-(4-phenylbenzyl)-2-methylbenzo[b]thiophene-5-carboxylate (240
mg).
[0951] .sup.1H-NMR(CDCl.sub.3): 2.55(3H, s), 3.90(3H, s), 4.23(2H,
s), 7.20-7.24(2H, m), 7.28-7.57(7H, m), 7.80(1H, d, J=8 Hz),
7.92(1H, dd, J=2, 8 Hz), 8.30(1H, s)
Preparation Example 51-3
3-((4-Phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0952] In the same manner as in Preparation Example 4-7, the object
compound (134 mg) was obtained as pale yellow crystals from methyl
3-((4-phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-carboxylate
(153 mg).
[0953] .sup.1H-NMR(DMSO-d.sub.6): 2.59(3H, s), 4.23(2H, s),
7.23-7.34(3H, m), 7.42(2H, t, J=7 Hz), 7.52-7.61(4H, m), 7.83(1H,
d, J=8 Hz), 7.92(1H, d, J=8 Hz), 8.20(1H, s)
Preparation Example 52-1
Methyl
3-(2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0954] In the same manner as in Preparation Example 16-2, the
object compound (220 mg) was obtained as pale yellow crystals from
methyl 2-methylbenzo-[b]thiophene-5-carboxylate (200 mg).
[0955] .sup.1H-NMR(CDCl.sub.3): 2.40(3H, s), 3.89(3H, s),
7.38-7.52(4H, m), 7.80(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz),
8.52(1H, s)
Preparation Example 52-2
Methyl
3-((2-chlorophenyl)hydroxymethyl)-2-methylbenzo[b]thiophene-5-carbo-
xylate
[0956] In the same manner as in Preparation Example 35-5, the
object compound (189 mg) was obtained as pale yellow crystals from
methyl 3-(2-chlorobenzoyl)-2-methylbenzo[b]thiophene-5-carboxylate
(207 mg).
[0957] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 3.89(3H, s), 6.51(1H,
s), 7.20-7.38(3H, m), 7.68(1H, dd, J=2, 8 Hz), 7.76(1H, dd, J=2, 8
Hz), 7.90(1H, s), 8.51(1H, s)
Preparation Example 52-3
Methyl
3-(2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
[0958] In the same manner as in Preparation Example 35-6, the
object compound (162 mg) was obtained as white crystals from methyl
3-((2-chlorophenyl)-hydroxymethyl)-2-methylbenzo[b]thiophene-5-carboxylat-
e (170 mg).
[0959] .sup.1H-NMR(CDCl.sub.3): 2.47(3H, s), 3.89(3H, s), 4.26(2H,
s), 6.69(1H, d, J=7 Hz), 7.02(1H, t, J=7 Hz), 7.13(1H, t, J=7 Hz),
7.42(1H, d, J=7 Hz), 7.82(1H, d, J=8 Hz), 7.93(1H, d, J=8 Hz),
8.17(1H, s)
Preparation Example 52-4
3-(2-Chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid
[0960] In the same manner as in Preparation Example 4-7, the object
compound (137 mg) was obtained as white crystals from methyl
3-(2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate (145
mg).
[0961] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 4.27(2H, s),
6.80(1H, d, J=7 Hz), 7.17(1H, t, J=7 Hz), 7.23(1H, t, J=7 Hz),
7.51(1H, d, J=8 Hz), 7.83(1H, dd, J=2, 8 Hz), 8.02(1H, d, J=8 Hz),
8.04(1H, s)
Preparation Example 53-1
3-Nitro-4-propylbenzoic acid
[0962] In the same manner as in Preparation Example 39-1, the
object compound (31.0 g) was obtained as white crystals from
4-propylbenzoic acid (25.0 g) and fuming nitric acid (60 ml).
[0963] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.02(3H, t, J=7.4 Hz),
1.67-1.76(2H, m), 2.94(2H, t, J=7.8 Hz), 7.49(1H, d, J=8.0 Hz),
8.22(1H, dd, J=8.0 and 1.7 Hz), 8.59(1H, d, J=1.8 Hz)
Preparation Example 53-2
Methyl 3-amino-4-propylbenzoate
[0964] To 3-nitro-4-propylbenzoic acid (31.0 g) were added sulfuric
acid (1.0 g) and methanol (300 ml) and the mixture was heated under
reflux for 24 hr. After cooling, 5% Pd--C (0.60 g) was added to the
reaction mixture and the mixture was stirred under a hydrogen
atmosphere (normal pressure) for 6 hr. The reaction mixture was
filtered through Celite and concentrated. To the residue was added
a saturated aqueous sodium hydrogencarbonate solution, and the
mixture was extracted with toluene. The toluene layer was dried
over sodium sulfate and concentrated to give the object compound
(28.7 g) as an brown oil.
[0965] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.00(3H, t, J=7.4 Hz),
1.62-1.71(2H, m), 2.50(2H, t, J=7.7 Hz), 3.72(2H, brs), 3.88(3H,
s), 7.09(1H, d, J=7.8 Hz), 7.34(1H, d, J=1.7 Hz), 7.39(1H, dd,
J=7.8 and 1.7 Hz)
Preparation Example 53-3
3-Ethyl-6-(methoxycarbonyl)-1H-indazole
[0966] To a solution of methyl 3-amino-4-propylbenzoate (5.07 g) in
acetic acid (150 ml) was dropwise added a solution of sodium
nitrite (2.07 g) in water (5 ml) for 5 min. After stirring for 20
min, the reaction mixture was concentrated, and then toluene and a
saturated aqueous sodium hydrogencarbonate solution were added to
the residue. The separated toluene layer was dried over sodium
sulfate and concentrated. The residue was allowed to stand and
partially solidified. The solid was washed with hexane and dried to
give the object compound (2.44 g) as a brown solid.
[0967] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.43(3H, t, J=7.6 Hz),
3.04(2H, quartet, J=7.6 Hz), 3.97(3H, s), 7.75(1H, dd, J=8.4 and
0.8 Hz), 7.81(1H, dd, J=8.4 and 1.3 Hz), 8.19(1H, d, J=0.9 Hz)
Preparation Example 53-4
1-(2,4-Dichlorobenzyl)-3-ethyl-6-(methoxycarbonyl)-1H-indazole
[0968] In the same manner as in Preparation Example 39-5, a crude
product of the object compound (3.73 g) was obtained from
3-ethyl-6-(methoxycarbo- nyl)-1H-indazole (1.84 g), 60% sodium
hydride (0.36 g) and 2,4-dichlorobenzyl chloride. The crude product
was used in the next step without purification.
[0969] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.42(3H, t, J=7.6 Hz),
3.04(2H, quartet, J=7.6 Hz), 3.94(3H, s), 5.65(2H, s), 6.56(1H, d,
J=8.4 Hz), 7.07(1H, dd, J=8.4 and 2.0 Hz), 7.43(1H, d, J=2.1 Hz),
7.76(1H, d, J=8.4 Hz), 7.81(1H, dd, J=8.4 and 1.0 Hz), 8.05(1H, d,
J=1.0 Hz)
Preparation Example 53-5
6-Carboxy-1-(2,4-dichlorobenzyl)-3-ethyl-1H-indazole
[0970] In the same manner as in Preparation Example 39-6, the
object compound (2.10 g) was obtained as brown crystals from the
unpurified
1-(2,4-dichlorobenzyl)-3-ethyl-6-(methoxycarbonyl)-1H-indazole
(3.70 g).
[0971] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.29(3H, t, J=7.6
Hz), 2.94(2H, quartet, J=7.5 Hz), 5.73(2H, s), 6.77(1H, d, J=8.4
Hz), 7.33(1H, dd, J=8.4 and 2.0 Hz), 7.65-7.69(2H, m), 7.87(1H, d,
J=8.4 Hz), 8.23(1H, s)
Preparation Example 54-1
6-Carbamoyl-3-(2,4-dichlorobenzyl)-2-methylimidazo[1,2-a]pyridine
[0972] A mixture of 3-bromo-4-(2,4-dichlorophenyl)-2-butanone (2.14
g), which was synthesized according to a method described in
GB205177A, and 6-aminonicotinamide (2.10 g) in dimethylformamide (5
ml) was stirred at 100.degree. C. for 64 hr. After concentration of
the reaction mixture, the residue was washed with water and toluene
and dried to give a crude product of the object compound (2.00 g)
as a brown solid. The crude product was used in the next step
without further purification.
Preparation Example 54-2
6-Carboxy-3-(2,4-dichlorobenzyl)-2-methylimidazo[1,2-a]pyridine
[0973] The crude product of
6-carbamoyl-3-(2,4-dichlorobenzyl)-2-methylimi- dazo[1,2-a]pyridine
(2.00 g) in a mixture of concentrated sulfuric acid (8.0 g) and
water (8.0 g) was stirred at 100.degree. C. for 1 hr. After cooling
of the reaction mixture, ice was added and the precipitate was
collected by filtration. The precipitate was washed with water and
dried to give a crude product of the object compound (1.50 g) as a
brown solid. The crude product was used in the next step without
further purification.
[0974] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.31(3H, s),
4.45(2H, s), 6.88(1H, d, J=8.4 Hz), 7.30(1H, dd, J=8.3 and 2.1 Hz),
7.56(1H, d, J=8.8 Hz), 7.61-7.66(1H, m), 7.67(1H, d, J=2.2 Hz),
8.63(1H, s)
Preparation Example 55
Methyl 2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
[0975] In the same manner as in Preparation Example 26-2, the
object compound (330 mg) was obtained as white crystals from
5-bromo-2-methyl-3H-imidazo[4,5-b]pyridine (1.06 g).
[0976] .sup.1H-NMR(CDCl.sub.3): 2.80(3H, s), 4.03(3H, s), 8.07(2H,
d, J=8 Hz)
Preparation Example 56-1
Methyl
3-(2,3-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late
[0977] In the same manner as in Preparation Example 14-2, the
object compound (70 mg) was obtained as white crystals from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate.
[0978] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 4.00(3H, s), 5.72(2H,
s), 6.50(1H, d, J=8 Hz), 7.07(1H, t, J=8 Hz), 7.43(1H, d, J=8 Hz),
8.17(2H, q, J=8 Hz)
Preparation Example 56-2
Methyl
3-((3-chlorobenzo[b]thiophene-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylate
[0979] In the same manner as in Preparation Example 14-2, the
object compound (111 mg) was obtained as white crystals from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (106 mg).
[0980] .sup.1H-NMR(CDCl.sub.3): 2.68(3H, s), 4.03(3H, s), 5.88(2H,
s), 7.35-7.48(2H, m), 7.68(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz),
8.04(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz)
Preparation Example 57-1
3-(2,3-Dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[0981] In the same manner as Preparation Example 4-7, the object
compound (55 mg) was obtained as white crystals from methyl
3-(2,3-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
(63 mg).
[0982] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.65(2H, s),
6.46(1H, d, J=8 Hz), 7.25(1H, t, J=8 Hz), 7.63(1H, d, J=8 Hz),
8.02(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz)
Preparation Example 57-2
3-((3-Chlorobenzo[b]thiophene-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylic acid
[0983] In the same manner as in Preparation Example 4-7, the object
compound (82 mg) was obtained as white crystals from methyl
3-((3-chlorobenzo[b]thiophene-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate (95 mg).
[0984] .sup.1H-NMR(DMSO-d.sub.6): 2.65(3H, s), 5.90(2H, s),
7.42-7.55(2H, m), 7.81(1H, d, J=8 Hz), 7.93(1H, d, J=8 Hz),
8.02(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz)
Preparation Example 58-1
Methyl
3-((2-chloro-4-phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-car-
boxylate
[0985] The object compound (288 mg) was obtained as white crystals
from methyl
3-(4-bromo-2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylate
(484 mg).
Preparation Example 58-2
3-((2-Chloro-4-phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid
[0986] In the same manner as in Preparation Example 4-7, the object
compound (237 mg) was obtained as white crystals from methyl
3-((3-chloro-4-phenylphenyl)methyl)-2-methylbenzo[b]thiophene-5-carboxyla-
te (273 mg).
[0987] .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s), 4.31(2H, s),
6.84(1H, d, J=8 Hz), 7.32-7.48(4H, m), 7.62-7.66(2H, m), 7.81(1H,
s), 7.83(1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz), 8.08(1H, s)
Preparation Example 59
3-Chlorobenzo[b]thiophene-2-methylene chloride
[0988] In the same manner as in Preparation Example 14-1, the
object compound (220 mg) was obtained as white crystals from
3-chlorobenzo[b]thiophene-2-methanol (200 mg).
[0989] .sup.1H-NMR(CDCl.sub.3): 4.92(2H, s), 7.39-7.50(2H, m),
7.78-7.83(2H, m)
Preparation Example 60-1
1-(2-Chloro-4-phenylbenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole
[0990] In the same manner as in Preparation Example 39-5, a crude
product of the object compound (1.10 g) was obtained from
6-(methoxycarbonyl)-3-m- ethyl-1H-indazole (0.475 g), 60% sodium
hydride (0.10 g) and 2-chloro-4-phenylbenzyl bromide (0.70 g). The
crude product was used in the next step without purification.
[0991] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.64(3H, s), 3.94(3H,
s), 5.73(2H, s), 6.74(1H, d, J=8.1 Hz), 7.31(1H, dd, J=8.1 and 1.8
Hz), 7.33-7.38(1H, m), 7.42(2H, t, J=7.5 Hz), 7.50-7.53(2H, m),
7.64-7.67(2H, m), 7.74(1H, d, J=8.4 Hz), 7.82(1H, dd, J=8.4 and 1.3
Hz), 8.13(1H, s)
Preparation Example 60-2
6-Carboxy-1-(2-chloro-4-phenylbenzyl)-3-methyl-1H-indazole
[0992] In the same manner as in Preparation Example 39-6, the
object compound (0.85 g) was obtained from
1-(2-chloro-4-phenylbenzyl)-6-(methox-
ycarbonyl)-3-methyl-1H-indazole (1.10 g).
[0993] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.67(3H, s),
5.77(2H, s), 6.91(1H, d, J=8.1 Hz), 7.37(1H, t, J=7.3 Hz), 7.44(2H,
t, J=7.5 Hz), 7.54(1H, dd, J=8.2 and 1.7 Hz), 7.65(2H, d, J=7.5
Hz), 7.67-7.71(1H, m), 7.77(1H, d, J=1.7 Hz), 7.84(1H, d, J=8.4
Hz), 8.28(1H, s)
Preparation Example 61-1
1-(4-Bromo-2-chlorobenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole
[0994] In the same manner as in Preparation Example 39-5, a crude
product of the object compound (2.00 g) was obtained from
6-(methoxycarbonyl)-3-m- ethyl-1H-indazole (0.63 g), 60% sodium
hydride (0.13 g) and 4-bromo-2-chlorobenzyl chloride (1.30 g). The
crude product was used in the next step without purification.
Preparation Example 61-2
1-(4-Bromo-2-chlorobenzyl)-6-carboxy-3-methyl-1H-indazole
[0995] In the same manner as in Preparation Example 39-6, the
object compound (1.00 g) was obtained from the unpurified
1-(4-bromo-2-chlorobenzyl)-6-(methoxycarbonyl)-3-methyl-1H-indazole
(2.00 g).
[0996] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.50(3H, s),
5.70(2H, s), 6.77(1H, d, J=8.4 Hz), 7.46(1H, dd, J=8.3 and 2.0 Hz),
7.68(1H, dd, J=8.4 and 1.0 Hz), 7.77(1H, d, J=2.0 Hz), 7.82(1H, d,
J=8.5 Hz), 8.24(1H, s)
Preparation Example 62-1
3-(4-Bromo-2-chlorobenzoyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
[0997] In the same manner as in Preparation Example 31-2, the
object compound (3.09 g) was obtained as pale yellow crystals from
5-(methoxycarbonyl)-2-methylbenzo[b]furan (1.90 g),
4-bromo-2-chlorobenzoyl chloride (2.80 g) and aluminum chloride
(2.67 g).
[0998] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.43(3H, s), 3.924(3H,
s), 7.31(1H, d, J=8.2 Hz), 7.49(1H, d, J=8.6 Hz),7.59(1H, d, J=8.1
Hz), 7.70(1H, d, J=1.4 Hz), 8.05(1H, d, J=8.5 Hz), 8.28(1H, s)
Preparation Example 62-2
3-(4-Bromo-2-chlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
[0999] In the same manner as in Preparation Example 31-3, a pale
yellow oil (4.00 g) containing the object compound as a main
component was obtained from
3-(4-bromo-2-chlorobenzoyl)-5-(methoxycarbonyl)-2-methylben-
zo[b]furan (3.09 g). The oil was used in the next step without
purification.
[1000] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.40(3H, s), 3.89(3H,
s), 4.01(2H, s), 6.89(1H, d, J=8.5 Hz), 7.25(1H, d, J=8.3 Hz),
7.42(1H, d, J=8.7 Hz), 7.57(1H, d, J=1.9 Hz), 7.94(1H, dd, J=8.5
and 1.5 Hz), 7.98(1H,s)
Preparation Example 62-3
3-(2-Chloro-4-phenylbenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
[1001] To unpurified
3-(4-bromo-2-chlorobenzyl)-5-(methoxycarbonyl)-2-meth-
ylbenzo[b]furan (4.00 g) were added a solution of phenylboric acid
(1.34 g) in ethanol (3 ml), tetrakis(triphenylphosphine)palladium
(0.40 g), sodium carbonate (1.59 g), water (7.50 g) and toluene (30
ml) and the mixture was heated under reflux for 80 min. After
cooling, the insoluble matter was removed by filtration through
Celite and the filtrate was washed with ethyl acetate and water.
Saturated brine was added to the filtrate. The organic layer was
separated, dried over anhydrous magnesium sulfate and concentrated
to give an oil (3.50 g) containing the object compound as main
component. The oil was used in the next step without
purification.
[1002] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.44(3H, s), 3.89(3H,
s), 4.12(2H, s), 7.09-8.09(11H, m)
Preparation Example 62-4
5-Carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylbenzo[b]furan
[1003] In the same manner as in Preparation Example 31-4, the
object compound (1.22 g) was obtained as pale yellow crystals from
the unpurified
3-(2-chloro-4-phenylbenzyl)-5-(methoxycarbonyl)-2-methylbenzo[-
b]furan (3.50 g).
[1004] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.48(3H, s),
4.15(2H, s), 7.30(1H, d, J=8.1 Hz), 7.36(1H, t, J=7.3 Hz), 7.44(2H,
t, J=7.6 Hz), 7.56(1H, dd, J=8.0 and 1.9 Hz), 7.57(1H, d, J=8.6
Hz), 7.66(2H, d, J=7.4 Hz), 7.75(1H, d, J=1.9 Hz), 7.82(1H, dd,
J=8.6 and 1.7 Hz), 7.95(1H, d, J=1.5 Hz)
Preparation Example 63
3-(4-Bromo-2-chlorobenzyl)-5-carboxy-2-methylbenzo[b]furan
[1005] In the same manner as in Preparation Example 31-4, the
object compound (0.67 g) was obtained as pale yellow crystals from
3-(4-bromo-2-chlorobenzyl)-5-(methoxycarbonyl)-2-methylbenzo[b]furan
(1.15 g).
[1006] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.44(3H, s),
4.08(2H, s), 7.18(1H, d, J=8.3 Hz), 7.47(1H, dd, J=8.3 and 2.0 Hz),
7.56(1H, d, J=8.5 Hz), 7.74(1H, d, J=2.1 Hz), 7.82(1H, dd, J=8.6
and 1.7 Hz), 7.89(1H, d, J=1.6 Hz)
Preparation Example 64-1
Methyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late and methyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine--
5-carboxylate
[1007] In the same manner as in Preparation Example 14-2, methyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
(2.20 g) and methyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyri-
dine-5-carboxylate (2.00 g) were obtained as a pale yellow powder
from methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (2.68
g) and 2,4-dichlorobenzyl chloride (3.29 g).
Methyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late:
[1008] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 3.99(3H, s), 5.63(2H,
s), 6.60(1H, d, J=8 Hz), 7.10(1H, dd, J=8 and 2 Hz), 7.47(1H, d,
J=2 Hz), 8.07(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass(ESI): m/e
350 (M+H).sup.+
Methyl
1-(2,4-dichlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxy-
late:
[1009] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 4.02(3H, s), 5.41(2H,
s), 6.43(1H, d, J=8 Hz), 7.14(1H, dd, J=8 and 2 Hz), 7.50(1H, d,
J=2 Hz), 7.54(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz) Mass(ESI): m/e
350 (M+H).sup.+
Preparation Example 64-2
3-(2,4-Dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1010] In the same manner as in Preparation Example 4-7, the object
compound (1.98 g) was obtained as a white powder from methyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
(2.17 g).
[1011] .sup.2H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.60(2H, s),
6.60(1H, d, J=8 Hz), 7.32(1H, d, J=8 Hz), 7.76(1H, s), 8.00(1H, d,
J=8 Hz), 8.13(1H, d, J=8 Hz) Mass(ESI): m/e 334 (M-H).sup.-
Preparation Example 65-1
2-Chloro-4-(thiophene-2-yl)benzyl alcohol
[1012] In the same manner as in Preparation Example 11-2, the
object compound (196 mg) was obtained as a pale yellow oil from
4-bromo-2-chlorobenzyl alcohol (500 mg) and 2-thiopheneboronic acid
(318 mg).
[1013] .sup.1H-NMR(CDCl.sub.3): 1.93(1H, t, J=8 Hz), 4.79(2H, d,
J=8 Hz), 7.09(1H, t, J=3 Hz), 7.29-7.34(2H, m), 7.46-7.54(2H, m),
7.61(1H, s)
Preparation Example 65-2
2-Chloro-1-((methanesulfonyloxy)methyl)-4-(thiophen-2-yl)benzene
[1014] In the same manner as in Preparation Example 14-1, the
object compound was obtained from 2-chloro-4-(thiophen-2-yl)benzyl
alcohol (196 mg). This compound was used in the next step without
purification.
Preparation Example 65-3
Methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate and methyl
1-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methy-
l-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1015] In the same manner as in Preparation Example 14-2, methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate was obtained as an amorphous (120 mg), and methyl
1-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-1H-imidazo[4,5-b]pyridine-5-
-carboxylate was obtained as an amorphous (86 mg) from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (148 mg) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-(thiophen-2-yl)benzene
(210 mg).
Methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate:
[1016] .sup.1H-NMR(CDCl.sub.3): 2.58(3H, s), 4.00(2H, s), 5.69(2H,
s), 6.65(1H, d, J=8 Hz), 7.08(1H, t, J=4 Hz), 7.25-7.36(3H, m),
7.69(1H, d, J=2 Hz), 8.08(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz)
Mass(ESI): m/z 398 (M+1)
Methyl
1-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-1H-imidazo[4,5-b]pyri-
dine-5-carboxylate:
[1017] .sup.1H-NMR(CDCl.sub.3): 2.68(3H, s), 4.01(2H, s), 5.45(2H,
s), 6.50(1H, d, J=8 Hz), 7.09(1H, t, J=4 Hz), 7.28-7.39(3H, m),
7.58(1H, d, J=8 Hz), 7.70(1H, br s), 8.08(1H, d, J=8 Hz) Mass(ESI):
m/z 398 (M+1)
Preparation Example 65-4
3-[2-Chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylic acid
[1018] In the same manner as in Preparation Example 4-2, the object
compound (61 mg) was obtained as colorless crystals from methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (70 mg).
[1019] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.62(2H, s),
6.60(1H, d, J=8 Hz), 7.14(1H, t, J=4 Hz), 7.49(1H, d, J=8 Hz),
7.59(2H, d, J=4 H), 7.87(1H, d, J=2 Hz), 8.01(1H, d, J=8 Hz),
8.14(1H, d, J=8 Hz) Mass(ESI): m/z 382 (M-1) mp 247-248.degree.
C.
Preparation Example 66-1
Methyl
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,-
5-b]pyridine-5-carboxylate
[1020] To a suspension of methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (50 mg, 0.126 mmol) in
acetic acid (1 ml) was added N-chlorosuccinimide (19 mg, 0.138
mmol) at room temperature. Thirty minutes later, dichloromethane
(0.5 ml) was added to the reaction mixture to give a clear
transparent solution. Four hours later, N-chlorosuccinimide (19 mg,
0.138 mmol) was further added. The reaction mixture was left
standing overnight and concentrated. The residue was purified by
p-TLC (chloroform/methanol=40/1) to give the object compound (52
mg, 95.7%) as a colorless oil.
[1021] .sup.1H-NMR(CDCl.sub.3): 2.56(3H, s), 3.99(2H, s), 5.69(2H,
s), 6.64(1H, d, J=8 Hz), 6.89(1H, t, J=4 Hz), 7.06(1H, d, J=4 Hz),
7.22(1H, d, J=8 Hz), 7.58(1H, s), 8.08(1H, d, J=8 Hz), 8.16(1H, d,
J=8 Hz) Mass(ESI): m/z 432 (M+1)
Preparation Example 66-2
3-[2-Chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid
[1022] In the same manner as in Preparation Example 4-7, the object
compound (33 mg) was obtained as colorless crystals from methyl
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate (50 mg).
[1023] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.62(2H, s),
6.59(1H, d, J=8 Hz), 7.18(1H, d, J=4 Hz), 7.42(1H, d, J=8 Hz),
7.49(1H, d, J=4 Hz), 7.87(1H, s), 8.01(1H, d, J=8 Hz), 8.14(1H, d,
J=8 Hz) Mass(ESI): m/z 416 (M-1) mp 242-243.degree. C.
Preparation Example 67-1
2-Chloro-4-vinylbenzyl alcohol
[1024] In the same manner as in Preparation Example 11-1, the
object compound (1.23 g) was obtained as a colorless solid from
4-bromo-2-chlorobenzyl alcohol (2.0 g) and tributyl(vinyl)tin (3.32
g).
[1025] .sup.1H-NMR(CDCl.sub.3): 1.91(1H, t, J=7 Hz), 4.78(2H, d,
J=7 Hz), 5.30(1H, d, J=10 Hz), 5.76(1H, d, J=16 Hz), 6.65(1H, dd,
J=16, 10 Hz), 7.30(1H, d, J=8 Hz), 7.39-7.47(2H, m)
Preparation Example 67-2
2-Chloro-1-((methanesulfonyloxy)methyl)-4-vinylbenzene
[1026] In the same manner as in Preparation Example 14-1 the object
compound was obtained from 2-chloro-4-vinylbenzyl alcohol (600 mg).
This compound was used in the next step without purification.
Preparation Example 67-3
Methyl
3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate and methyl
1-(2-chloro-4-vinylbenzyl)-2-methyl-1H-imidazo[4,5-b]p-
yridine-5-carboxylate
[1027] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te was obtained as pale yellow crystals (387 mg), and methyl
1-(2-chloro-4-vinylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyla-
te was obtained as an amorphous (264 mg) from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (478 mg) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-vinylbenzene (678
mg).
Methyl
3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1028] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 4.00(2H, s), 5.30(1H,
d, J=10 Hz), 5.67(2H, s), 5.73(1H, d, J=16 Hz), 6.56-6.67(2H, m),
7.13(1H, d, J=8 Hz), 7.47(1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz),
8.16(1H, d, J=8 Hz) Mass(ESI): m/z 342 (M+1) mp 185-186.degree.
C.
Methyl
1-(2-chloro-4-vinylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1029] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 4.01(2H, s), 5.34(1H,
d, J=10 Hz), 5.43(2H, s), 5.76(1H, d, J=16 Hz), 6.47(1H, d, J=10
Hz), 6.61(1H, dd, J=16, 10 Hz), 7.15(1H, d, J=8 Hz), 7.50(1H, s),
7.56(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz) Mass(ESI): m/z 342
(M+1)
Preparation Example 67-4
Methyl
3-(2-chloro-4-ethylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1030] To a solution of methyl
3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine-5-carboxylate (230 mg, 0.67 mmol) in 1,4-dioxane
(4.6 ml) was added platinum dioxide (23 mg) and the mixture was
subjected to catalytic reduction at normal temperature. Six hours
later, the reaction mixture was filtered through Celite and the
filtrate was concentrated to give black crystals. The obtained
crystals were subjected to flash silica gel chromatography (silica
gel 40 ml, eluent: chloroform/ethyl acetate=5/1-4/1) and
crystallized from diisopropyl ether to give the object compound
(213 mg) as colorless crystals.
[1031] .sup.1H-NMR(CDCl.sub.3): 1.20(3H, d, J=8 Hz), 2.53(3H, s),
2.60(2H, q, J=8 Hz), 3.99(3H, s), 5.65(2H, s), 6.53(1H, d, J=8 Hz),
6.92(1H, d, J=8 Hz), 7.28(1H, s), 8.05(1H, d, J=8 Hz), 8.14(1H, d,
J=8 Hz) Mass(ESI): m/z 344 (M+1) mp 172-173.degree. C.
Preparation Example 67-5
3-(2-Chloro-4-ethylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1032] In the same manner as in Preparation Example 4-7, the object
compound (61 mg) was obtained as pale yellow crystals from methyl
3-(2-chloro-4-ethylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (209 mg).
[1033] .sup.1H-NMR(DMSO-d.sub.6): 1.14(3H, d, J=8 Hz), 2.50(3H, s),
2.59(2H, q, J=8 Hz), 5.59(2H, s), 6.45(1H, d, J=8 Hz), 7.06(1H, d,
J=8 Hz), 7.14(1H, s), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz)
Mass(ESI): m/z 328 (M-1) mp 194-196.degree. C.
Preparation Example 68
3-(2-Chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1034] In the same manner as in Preparation Example 4-7, the object
compound (128 mg) was obtained as colorless crystals from methyl
3-(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (150 mg).
[1035] .sup.1H-NMR(DMSO-d.sub.6): 2.5(3H, s), 5.32(1H, d, J=10 Hz),
5.60(2H, s), 5.89(1H, d, J=16 Hz), 6.54(1H, d, J=8 Hz), 6.70(1H,
dd, J=16, 10 Hz), 7.32(1H, d, J=8 Hz), 7.71(1H, s), 8.01(1H, d, J=8
Hz), 8.14(1H, d, J=8 Hz) Mass(ESI): m/z 326 (M-1) mp
229-230.degree. C.
Preparation Example 69-1
2-Chloro-1-((methanesulfonyloxy)methyl)-4-methylbenzene
[1036] In the same manner as in Preparation Example 14-1, the
objective compound (383 mg) was obtained as a colorless oil from
2-chloro-4-methylbenzyl alcohol (259 mg).
[1037] .sup.1H-NMR(CDCl.sub.3): 2.35(3H, s), 2.98(3H, s), 5.31(2H,
s), 7.11(1H, d, J=8 Hz), 7.26(1H, s), 7.36(1H, d, J=8 Hz)
Preparation Example 69-2
Methyl
3-(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate and methyl
1-(2-chloro-4-methylbenzyl)-2-methyl-1H-imidazo[4,5-b-
]pyridine-5-carboxylate
[1038] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (74 mg) and methyl
1-(2-chloro-4-methylbenzyl)-2-methyl-1H-imidazo[4,5-
-b]pyridine-5-carboxylate (80 mg) were obtained as white powders
from methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (152
mg) and 2-chloro-1-((methane-sulfonyloxy)methyl)-4-methylbenzene
(230 mg).
Methyl
3-(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1039] .sup.1H-NMR(CDCl.sub.3): 2.29(3H, s), 2.51(3H, s), 3.99(3H,
s), 5.64(2H, s), 6.51(1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.24(1H,
s), 8.05(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). Mass(ESI): m/E 330
(M+H).sup.+
Methyl
1-(2-chloro-4-methylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1040] .sup.1H-NMR(CDCl.sub.3): 2.32(3H, s), 2.65(3H, s), 4.01(3H,
s), 5.40(2H, s), 6.41(1H, d, J=8 Hz), 6.94(1H, d, J=8 Hz), 7.28(1H,
s), 7.54(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz). Mass(ESI): m/E 330
(M+H).sup.+
Preparation Example 69-3
3-(2-Chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[1041] In the same manner as in Preparation Example 4-7, the
objective compound (98 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (68 mg).
[1042] .sup.1H-NMR(DMSO-d.sub.6): 2.26(3H, s), 2.49(3H, s),
5.59(2H, s), 6.41(1H, d, J=8 Hz), 7.02(1H, d, J=8 Hz), 7.39(1H, s),
8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz) Mass(ESI): m/E 314
(M-H).sup.-
Preparation Example 70-1
4-Bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene
[1043] To a solution of 4-bromo-2-chlorobenzyl alcohol (14.48 g) in
N,N-dimethylformamide (72 ml) were added imidazole (5.34 g) and
tert-butylchlorodiphenylsilane (19.8 g) under ice-cooling and the
mixture was stirred for 1 hr. Water was added to the reaction
mixture and the resulting product was extracted twice with hexane.
The organic layers were combined, and washed successively with
water, a saturated aqueous solution of sodium hydrogen-carbonate
and saturated brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated and the residue was subjected to silica gel
column chromatography (hexane) to give the objective compound
(29.22 g) as colorless oil.
[1044] .sup.1H-NMR(CDCl.sub.3): 1.10(9H, s), 4.75(2H, s),
7.32-7.50(8H, m), 7.55-7.72(5H, m)
Preparation Example 70-2
1-((tert-Butyldiphenylsilyloxy)methyl)-2-chloro-4-(n-pentyl)benzene
[1045] Tetrahydrofuran (5 ml) was added to magnesium (438 mg,
turnings) under a nitrogen atmosphere and a small amount of a
solution of
4-bromo-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene (7.92
g) in tetrahydrofuran (10 ml) was dropwise added. Upon confirmation
of the initiation of the reaction, the reaction mixture was diluted
with tetrahydrofuran (6.5 ml) and heated to 60.degree. C. The
remaining starting material was dropwise added over 45 min. After
completion of the dropwise addition, the reaction mixture was
refluxed under heating for 30 min to give a solution (ca. 0.6 M) of
4-((tert-butyldiphenyl-silyloxy)met- hyl)-3-chlorophenyl magnesium
bromide in tetrahydrofuran.
[1046] Then, 1-iodopentane (910 mg) was added to a suspension of
copper bromide-dimethyl sulfide complex (62 mg) in
hexamethylphosphoric triamide (0.3 ml) under a nitrogen atmosphere,
and the mixture was heated to 60.degree. C. Thereto was dropwise
added the above-mentioned solution (5 ml) of
4-((tert-butyldiphenylsilyloxy)methyl)-3-chlorophenyl magnesium
bromide in tetrahydrofuran over 10 min after removal of unreacted
magnesium. After completion of the dropwise addition, the reaction
mixture was refluxed under heating for 2 hr. Aqueous ammonium
chloride was added to the reaction mixture and the resulting
product was extracted three times with hexane. The organic layers
were combined, washed successively with water and saturated brine,
and dried over anhydrous magnesium sulfate. The solvent was
evaporated and the residue was subjected to silica gel column
chromatography (hexane) to give the objective compound (914 mg) as
a colorless oil.
[1047] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.11(9H, s),
1.22-1.40(4H, m), 1.52-1.68(2H, m), 2.52-2.62(2H, m), 4.80(2H, s),
7.07-7.16(2H, m), 7.31-7.48(6H, m), 7.61(1H, d, J=8 Hz),
7.64-7.74(4H, m), 7.64-7.74(4H, m).
Preparation Example 70-3
2-Chloro-4-(n-pentyl)benzyl alcohol
[1048] A solution (1.0 M, 2.4 ml) of tetrabutylammonium
fluoride/tetrahydrofuran was added to a solution of
1-((tert-butyldiphenylsilyloxy)methyl)-2-chloro-4-(n-pentyl)benzene
(890 mg) in tetrahydrofuran (4.5 ml) under ice-cooling, and the
mixture was stirred for 2 hr. Water was added to the reaction
mixture and the resulting product was extracted three times with
ethyl acetate. The organic layers were combined and washed
successively with diluted hydrochloric acid, a saturated aqueous
solution of sodium hydrogencarbonate and saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was evaporated and
the residue was purified by silica gel column chromatography
(hexane/ethyl acetate=7/1) to give the objective compound (345 mg)
as a colorless oil.
[1049] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.21-1.41(4H,
m), 1.51-1.66(2H, m), 1.90(1H, br t, J=7 Hz), 2.51-2.63(2H, m),
4.74(2H, d, J=7 Hz), 7.08(1H, d, J=8 Hz), 7.19(1H, s), 7.35(1H, d,
J=8 Hz)
Preparation Example 70-4
2-Chloro-1-((methanesulfonyloxy)methyl)-4-(n-pentyl)benzene
[1050] In the same manner as in Preparation Example 14-1, the
objective compound (530 mg) was obtained as a colorless oil from
2-chloro-4-(n-pentyl)benzyl alcohol (333 mg).
[1051] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.22-1.44(4H,
m), 1.51-1.67(2H, m), 2.52-2.64(2H, m), 2.99(3H, s), 5.31(2H, s),
7.12(1H, d, J=8 Hz), 7.25(1H, s), 7.38(1H, d, J=8 Hz), 7.38(1H, d,
J=8 Hz)
Preparation Example 70-5
Methyl
3-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate and methyl
1-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-1H-imida-
zo[4,5-b]pyridine-5-carboxylate
[1052] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylate (147 mg) and methyl
1-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-1H-imid-
azo[4,5-b]pyridine-5-carboxylate (176 mg) were obtained as
pale-yellow powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (230 mg) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-(n-pentyl)benzene (440
mg).
Methyl
3-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1053] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.19-1.40(4H,
m), 1.48-1.64(2H, m), 2.48-2.59(2H, m), 2.53(3H, s), 3.99(3H, s),
5.65(2H, s), 6.52(1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.25(1H, s),
8.07(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). Mass(ESI): m/E 386
(M+H).sup.+
Methyl
1-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridine--
5-carboxylate
[1054] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.19-1.40(4H,
m), 1.50-1.64(2H, m), 2.49-2.61(2H, m), 2.65(3H, s), 4.01(3H, s),
5.40(2H, s), 6.42(1H, d, J=8 Hz), 6.93(1H, d, J=8 Hz), 7.29(1H, s),
7.55(1H, d, J=8 Hz), 8.07(1H, d, J=8 Hz) Mass(ESI): m/E 386
(M+H).sup.+
Preparation Example 70-6
3-(2-Chloro-4-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1055] In the same manner as in Preparation Example 4-7, the
objective compound (119 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (135 mg).
[1056] .sup.1H-NMR(DMSO-d.sub.6): 0.84(3H, t, J=7 Hz),
1.13-1.37(4H, m), 1.43-1.60(2H, m), 2.44-2.60(2H, m), 2.50(3H, s),
5.58(2H, s), 6.45(1H, d, J=8 Hz), 7.03(1H, d, J=8 Hz), 7.39(1H, s),
8.01(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz). Mass(ESI): m/E 370
(M-H).sup.-
Preparation Example 71-1
1-((tert-Butyldiphenylsilyloxy)methyl)-2-chloro-4-isobutylbenzene
[1057] In the same manner as in Preparation Example 70-2, the
objective compound (1.644 g, 76%) was obtained as a colorless oil
from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene
and isobutyl iodide.
[1058] .sup.1H-NMR(CDCl.sub.3): 0.90(6H, d, J=7 Hz), 1.10(9H, s),
1.75-1.96(1H, m), 2.44(2H, d, J=7 Hz), 4.80(2H, s), 7.03-7.11(2H,
m), 7.30-7.46(6H, m), 7.56-7.74(5H, m).
Preparation Example 71-2
2-Chloro-4-isobutylbenzyl alcohol
[1059] In the same manner as in Preparation Example 70-3, the
objective compound (568 mg) was obtained as a colorless oil from
1-((tert-butyl-diphenylsilyloxy)methyl)-2-chloro-4-isobutylbenzene
(1.71 g).
[1060] .sup.1H-NMR(CDCl.sub.3): 0.90(6H, d, J=7 Hz), 1.74-1.95(1H,
m), 1.18(1H, br t, J=7 Hz), 2.44(2H, d, J=7 Hz), 4.75(2H, d, J=7
Hz), 7.05(1H, d, J=8 Hz), 7.16(1H, s), 7.35(1H, d, J=8 Hz)
Preparation Example 71-3
2-Chloro-4-isobutyl-1-((methanesulfonyloxy)methyl)benzene
[1061] In the same manner as in Preparation Example 14-1, the
objective compound (458 mg) was obtained as a colorless oil from
2-chloro-4-isobutylbenzyl alcohol (293 mg).
[1062] .sup.1H-NMR(CDCl.sub.3): 0.90(6H, d, J=7 Hz), 1.75-1.96(1H,
m), 2.48(2H, d, J=7 Hz), 3.00(3H, s), 5.31(2H, s), 7.09(1H, d, J=8
Hz), 7.22(1H, s), 7.39(1H, d, J=8 Hz)
Preparation Example 71-4
Methyl
3-(2-chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate and methyl
1-(2-chloro-4-isobutylbenzyl)-2-methyl-1H-imidazo[4-
,5-b]pyridine-5-carboxylate
[1063] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylate (124 mg) and methyl
1-(2-chloro-4-isobutylbenzyl)-2-methyl-1H-imidaz-
o[4,5-b]pyridine-5-carboxylate (152 mg) were obtained as
pale-yellow powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (212 mg) and
2-chloro-4-isobutyl-1-((methanesulfonyloxy)methyl)benzene (390
mg).
Methyl
3-(2-chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate
[1064] .sup.1H-NMR(CDCl.sub.3): 0.88(6H, d, J=7 Hz), 1.71-1.90(1H,
m), 2.40(2H, d, J=7 Hz), 2.52(3H, s), 3.99(3H, s), 5.64(2H, s),
6.53(1H, d, J=8 Hz), 6.87(1H, d, J=8 Hz), 7.21(1H, s), 8.05(1H, d,
J=8 Hz), 8.13(1H, d, J=8 Hz) Mass(ESI): m/E 372 (M+H).sup.+
Methyl
1-(2-chloro-4-isobutylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5--
carboxylate
[1065] .sup.1H-NMR(CDCl.sub.3): 0.88(6H, d J=7 Hz), 1.71-1.92(1H,
m), 2.42(2H, d J=7 Hz), 2.65(3H, s), 4.00(3H, s), 5.41(2H, s),
6.41(1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.24(1H, s), 7.55(1H, d,
J=8 Hz), 8.07(1H, d, J=8 Hz). Mass(ESI): m/E 372 (M+H).sup.+
Preparation Example 71-5
3-(2-Chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
lic acid
[1066] In the same manner as in Preparation Example 4-7, the
objective compound (122 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylate (116 mg).
[1067] .sup.1H-NMR(DMSO-d.sub.6): 0.82(6H, d, J=7 Hz),
1.68-1.89(1H, m), 2.42(2H, d, J=7 Hz), 2.50(3H, s), 5.59(2H, s),
6.44(1H, d, J=8 Hz), 7.01(1H, d, J=8 Hz), 7.36(1H, s), 8.00(1H, d,
J=8 Hz), 8.12 d, J=8H). Mass(ESI): m/E 356 (M-H).sup.-
Preparation Example 72-1
1-((tert-Butyldiphenylsilyloxy)methyl)-2-chloro-4-(cyclohexylmethyl)benzen-
e
[1068] In the same manner as in Preparation Example 70-2, the
objective compound (797 mg, 56%) was obtained as a colorless oil
from 4-bromo-1-((tert-butyldiphenylsilyloxy)methyl)-2-chlorobenzene
and cyclohexylmethyl iodide.
[1069] .sup.1H-NMR(CDCl.sub.3): 0.82-1.75(11H, m), 1.11(9H, s),
2.45(2H, d, J=7 Hz), 4.79(2H, s), 7.03-7.11(2H, m), 7.31-7.48(6H,
m), 7.61(1H, d, J=8 Hz), 7.63-7.73(4H, m)
Preparation Example 72-2
2-Chloro-4-(cyclohexylmethyl)benzyl alcohol
[1070] In the same manner as in Preparation Example 70-3, the
objective compound (378 mg) was obtained as a colorless oil from
1-((tert-butyldiphenylsilyloxy)methyl)-2-chloro-4-(cyclohexylmethyl)benze-
ne (1.03 g).
[1071] .sup.1H-NMR(CDCl.sub.3): 0.82-1.74(11H, m), 1.87(1H, br t,
J=7 Hz), 2.44(2H, d, J=7 Hz), 4.74(2H, d, J=7 Hz), 7.04(1H, d, J=8
Hz), 7.15(1H, s), 7.34(1H, d, J=8 Hz)
Preparation Example 72-3
2-Chloro-4-(cyclohexylmethyl)-1-((methanesulfonyloxy)methyl)benzene
[1072] In the same manner as in Preparation Example 14-1, the
objective compound (543 mg) was obtained as a colorless oil from
2-chloro-4-(cyclohexylmethyl)benzylalcohol (365 mg).
[1073] .sup.1H-NMR(CDCl.sub.3): 0.80-1.75(11H, m), 2.46(2H, d, J=7
Hz), 2.99(3H, s), 5.30(2H, s), 7.08(1H, d, J=8 Hz), 7.20(1H, s),
7.38(1H, d, J=8 Hz)
Preparation Example 72-4
Methyl
3-(2-chloro-4-(cycohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate(170 mg) and methyl
1-(2-chloro-4-(cyclohexylmethyl)-b-
enzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1074] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (170 mg) and methyl
1-(2-chloro-4-(cyclohexylmethyl)benzyl-
)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (222 mg) were
obtained as pale-yellow powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-c- arboxylate (229 mg) and
2-chloro-4-(cyclohexylmethyl)-1-((methanesulfonylo-
xy)methyl)benzene (469 mg).
Methyl 3-(
2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1075] .sup.1H-NMR(CDCl.sub.3): 0.80-1.74(11H, m), 2.40(2H, d, J=7
Hz), 2.53(3H, s), 3.99(3H, s), 5.64(2H, s), 6.52(1H, d, J=8 Hz),
6.86(1H, d, J=8 Hz), 7.21(1H, s), 8.05(1H, d, J=8 Hz), 8.13(1H, d,
J=8 Hz). Mass(ESI): m/E 412 (M+H).sup.+
Methyl
1-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-1H-imidazo[4,5-b]p-
yridine-5-carboxylate
[1076] .sup.1H-NMR(CDCl.sub.3): 0.80-1.75(11H, m), 2.43(2H, d, J=7
Hz), 2.65(3H, s), 4.01(3H, s), 5.04(2H, s), 6.40(1H, d, J=8 Hz),
6.89(1H, d, J=8 Hz), 7.24(1H, s), 7.56(1H, d, J=8 Hz), 8.07(1H, d,
J=8 Hz) Mass(ESI): m/E 412 (M+H).sup.+
Preparation Example 72-5
3-(2-Chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid
[1077] In the same manner as in Preparation Example 4-7, the
objective compound (180 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (156 mg).
[1078] .sup.1H-NMR(DMSO-d.sub.6): 0.78-1.68(11H, m), 2.42(2H, d,
J=7 Hz), 2.50(3H, s), 5.58(2H, s), 6.44(1H, d, J=8 Hz), 7.00(1H, d,
J=8 Hz), 7.35(1H, s), 8.01(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz)
Mass(ESI): m/E 396 (M-H).sup.-
Preparation Example 73-1
4-Bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzene
[1079] In the same manner as in Preparation Example 70-1, the
objective compound (6.10 g) was obtained as a colorless oil from
4-bromo-2-chlorobenzyl alcohol (4.42 g).
[1080] .sup.1H-NMR(CDCl.sub.3): 0.12(6H, s), 0.95(9H, s), 4.71(2H,
s), 7.37-7.50(3H, m).
Preparation Example 73-2
4-((tert-Butyldimethylsilyloxy)methyl)-3-chlorobenzaldehyde
[1081] A solution (1.6 M, 8.3 ml) of n-butyl lithium/hexane was
added to a solution of
4-bromo-1-((tert-butyldimethylsilyloxy)methyl)-2-chlorobenzen- e
(4.03 g) in tetrahydrofuran (10 ml) under a nitrogen atmosphere at
-60.degree. C. and the mixture was stirred for 45 min. The reaction
mixture was once heated to 0.degree. C. and then cooled to
-40.degree. C. and 1-formyl piperidine (1.63 g) was dropwise added
over 3 min. Then, the reaction mixture was heated to 0.degree. C.
over 2 hr. Aqueous ammonium chloride was added to the reaction
mixture and the resulting product was extracted twice with hexane.
The organic layers were combined, washed successively with diluted
hydrochloric acid, a saturated aqueous solution of sodium
hydrogencarbonate and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the residue was
subjected to silica gel column chromatography (hexane/ethyl
acetate=30/1) to give the objective compound (2.49 g) as a
colorless oil.
[1082] .sup.1H-NMR(CDCl.sub.3): 0.16(6H, s), 0.98(9H, s), 4.83(2H,
s), 7.70-7.86(3H, m), 9.96(1H, s). Mass(ESI): m/E 283
(M-H).sup.-
Preparation Example 73-3
(E)-1-((tert-Butyldimethylsilyloxy)methyl)-2-chloro-4-(2-phenylethenyl)ben-
zene
[1083] Sodium hydride (70% in mineral oil, 81 mg) was added to a
mixture of
4-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzaldehyde (571
mg) and diethyl benzylphosphonate (502 mg) in N,N-dimethylformamide
(2 ml) under a nitrogen atmosphere at room temperature and the
mixture was stirred at 40.degree. C. for 2 hr. Water was added to
the reaction mixture and the resulting product was extracted three
times with ether. The organic layers were combined, washed with
water and saturated brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated and the residue was subjected
to silica gel column chromato-graphy (hexane/ethyl acetate=50/1) to
give the objective compound (448 mg) as a colorless oil.
[1084] .sup.1H-NMR(CDCl.sub.3): 0.14(6H, s), 0.97(9H, s), 4.80(2H,
s), 7.03(1H, d, J=16 Hz), 7.10(1H, d, J=16 Hz), 7.26-7.58(8H,
m).
Preparation Example 73-4
(E)-2-Chloro-4-(2-phenylethenyl)benzyl alcohol
[1085] In the same manner as in Preparation Example 70-3, the
objective compound (422 mg) was obtained as a white powder from
(E)-1-((tert-butyldimethylsilyloxy)methyl)-2-chloro-4-(2-phenylethenyl)be-
nzene (745 mg).
[1086] .sup.1H-NMR(CDCl.sub.3): 1.91(1H, br t, J=7 Hz), 4.79(2H, d,
J=7 Hz), 7.02(1H, d, J=16 Hz), 7.12(1H, d, J=16 Hz), 7.24-7.55(8H,
m).
Preparation Example 73-5
(E)-2-Chloro-1-((methanesulfonyloxy)methyl)-4-(2-phenylethenyl)benzene
[1087] In the same manner as in Preparation Example 14-1, the
objective compound (583 mg) was obtained as a white solid from
(E)-2-chloro-4-(2-phenylethenyl)benzyl alcohol (412 mg).
[1088] .sup.1H-NMR(CDCl.sub.3): 3.01(3H, s), 5.34(2H, s), 7.02(1H,
d, J=16 Hz), 7.14(1H, d, J=16 Hz), 7.27-7.61(8H, m).
Preparation Example 73-6
Methyl
(E)-3-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine-5-carboxylate and methyl
(E)-1-(2-chloro-4-(2-phenylethenyl)ben-
zyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1089] In the same manner as in Preparation Example 14-2, methyl
(E)-3-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate (163 mg) and methyl
(E)-1-(2-chloro-4-(2-phenylethenyl)-
benzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (194 mg)
were obtained as white powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-- 5-carboxylate (250 mg) and
(E)-2-chloro-1-((methanesulfonyloxy)methyl)-4-(-
2-phenylethenyl)benzene (518 mg).
Methyl
(E)-3-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine-5-carboxylate
[1090] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.99(3H, s), 5.68(2H,
s), 6.61(1H, d, J=8 Hz), 6.97(1H, d, J=16 Hz), 7.08(1H, d, J=16
Hz), 7.16-7.62(7H, m), 8.08(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).
Mass(ESI): m/E 418 (M+H).sup.+
Methyl
(E)-1-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-1H-imidazo[4,5--
b]pyridine-5-carboxylate
[1091] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 4.01(3H, s), 5.44(2H,
s), 6.48(1H, d, J=8 Hz), 6.97(1H, d, J=16 Hz), 7.10(1H, d, J=16
Hz), 7.19-7.64(8H, m), 8.08(1H, d, J=8 Hz). Mass(ESI): m/E 418
(M+H).sup.+
Preparation Example 73-7
(E)-3-(2-Chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylic acid
[1092] In the same manner as in Preparation Example 4-7, the
objective compound (149 mg) was obtained as a white powder from
methyl
(E)-3-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate (158 mg).
[1093] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.63(2H, s),
6.59(1H, d, J=8 Hz), 7.16-7.48(6H, m), 7.53-7.63(2H, m), 7.84(1H,
s), 8.01(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). Mass(ESI): m/E 402
(M-H).sup.-
Preparation Example 74-1
2-Chloro-4-hydroxybenzoic acid
[1094] 4-Amino-2-chlorobenzoic acid (10.01 g) was homogeneously
dissolved in 12.5% sulfuric acid (400 ml) by heating the mixture to
70.degree. C. and cooled with ice. An aqueous solution of sodium
nitrite (4.24 g/water 12 ml) was dropwise added to this suspension
over 5 min at a temperature of not more than 8.degree. C. Five
minutes later, this solution was gradually poured into water (500
ml) at 80.degree. C., upon which vigorous bubbling occurred and the
solution turned red. The reaction mixture was further stirred at
80.degree. C. for 1 hr. After cooling, the resulting product was
extracted three times with ether. The organic layers were combined,
washed successively with diluted hydrochloric acid, water and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated and a small amount of diisopropyl ether was
added to allow crystallization, whereby the objective compound
(6.32 g) was obtained as an orange powder.
[1095] .sup.1H-NMR(DMSO-d.sub.6): 6.79(1H, dd, J=8 and 2 Hz),
6.88(1H, d, J=2 Hz), 7.77(1H, d, J=8 Hz). Mass(ESI): m/E 171
(M-H).sup.-
Preparation Example 74-2
Benzyl 4-benzyloxy-2-chlorobenzoate
[1096] Potassium carbonate (1.67 g) and benzyl bromide (1.73 g)
were added to a solution of 2-chloro-4-hydroxybenzoic acid (695 mg)
in N,N-dimethylformamide (3.5 ml) and the mixture was stirred for
14 hr at room temperature. To the reaction mixture was added 1N
hydrochloric acid and the resulting product was extracted three
times with ether. The organic layers were combined, washed
successively with water, a saturated aqueous solution of sodium
hydrogen-carbonate and saturated brine, and dried over anhydrous
magnesium sulfate. The solvent was evaporated and the residue was
recrystallized from diisopropyl ether/hexane to give the objective
compound (1.13 g) as a pale-yellow powder.
[1097] .sup.1H-NMR(CDCl.sub.3): 5.09(2H, s), 5.32(2H, s), 6.87(1H,
dd, J=8 and 2 Hz), 7.05(1H, d, J=2 Hz), 7.29-7.50(10H, m), 7.91(1H,
d, J=8 Hz). Mass(ESI): m/E 353 (M+H).sup.+
Preparation Example 74-3
4-Benzyloxy-2-chlorobenzoic acid
[1098] Ethanol (8.8 ml), 1,4-dioxane (2.2 ml) and a 1N aqueous
sodium hydroxide solution (4.7 ml) were added to benzyl
4-benzyloxy-2-chlorobenz- oate (1.12 g). The mixture was stirred at
70.degree. C. for 1.5 hr. The solvent was evaporated and water was
added to the residue to dissolve the same. After washing with
ether, the aqueous layer was acidified with 1N hydrochloric acid,
and the resulting precipitate was collected by filtration to give
the objective compound (810 mg) as a pale-yellow powder.
[1099] .sup.1H-NMR(DMSO-d.sub.6): 5.20(2H, s), 7.06(1H, dd, J=8 and
2 Hz), 7.18(1H, d, J=2 Hz), 7.29-7.50(5H, m), 7.82(1H, d, J=8 Hz).
Mass(ESI): m/E 261 (M-H).sup.-
Preparation Example 74-4
4-Benzyloxy-2-chlorobenzyl alcohol
[1100] To a solution of 4-benzyloxy-2-chlorobenzoic acid (788 mg)
in tetrahydrofuran (7.9 ml) was dropwise added a boran-dimethyl
sulfide complex (10.0 M, 0.6 ml) at room temperature under a
nitrogen atmosphere, and the mixture was refluxed under heating for
2.5 hr. The reaction mixture was allowed to cool to room
temperature and 1N hydrochloric acid (1.5 ml) was dropwise added
carefully, which was followed by stirring for 30 min. Water was
added to the reaction mixture and the resulting product was
extracted three times with ethyl acetate. The organic layers were
combined, washed successively with a saturated aqueous solution of
sodium hydrogencarbonate and saturated brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated to give the
objective compound (778 mg) as a white powder.
[1101] .sup.1H-NMR(CDCl.sub.3): 1.83(1H, br t, J=7 Hz), 4.70(2H, d,
J=7 Hz), 5.05(2H, s), 6.88(1H, dd, J=8 and 2 Hz), 7.01(1H, d, J=2
Hz), 7.28-7.46(6H, m).
Preparation Example 74-5
4-Benzyloxy-2-chlorobenzyl chloride
[1102] In the same manner as in Preparation Example 14-1, the
objective compound (639 mg) was obtained as a colorless oil from
4-benzyloxy-2-chlorobenzyl alcohol (523 mg).
[1103] .sup.1H-NMR(CDCl.sub.3): 4.67(2H, s), 5.05(2H, s), 6.87(1H,
dd, J=8 and 2 Hz), 7.02(1H, d, J=2 Hz), 7.28-7.44(6H, m).
Preparation Example 74-6
Methyl
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate and methyl
1-(4-benzyloxy-2-chlorobenzyl)-2-methyl-1H-imidazo-
[4,5-b]pyridine-5-carboxylate
[1104] In the same manner as in Preparation Example 14-2, methyl
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (130 mg) and methyl
1-(4-benzyloxy-2-chlorobenzyl)-2-methyl-1H-imid-
azo[4,5-b]pyridine-5-carboxylate (141 mg) were obtained as
pale-yellow powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (229 mg) and
4-benzyloxy-2-chlorobenzyl chloride (509 mg).
Methyl
3-(4-benzyloxy2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate
[1105] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 4.00(3H, s), 5.01(2H,
s), 5.62(2H, s), 6.63(1H, d, J=8 Hz), 6.72(1H, dd, J=8 and 2 Hz),
7.06(1H, d, J=2 Hz), 7.30-7.42(5H, m), 8.04(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz). Mass(ESI): m/E 422 (M+H).sup.+
Methyl
1-(4-benzyloxy-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1106] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 4.01(3H, s), 5.02(2H,
s), 5.38(2H, s), 6.48(1H, d, J=8 Hz), 6.75(1H, dd, J=8 and 2 Hz),
7.08(1H, d, J=2 Hz), 7.28-7.47(5H, m), 7.54(1H, d, J=8 Hz),
8.06(1H, d, J=8 Hz). Mass(ESI): m/E 422 (M+H).sup.+
Preparation Example 74-7
3-(4-Benzyloxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylic acid
[1107] In the same manner as in Preparation Example 4-7, the
objective compound (110 mg) was obtained as a white powder from
methyl
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (116 mg).
[1108] .sup.1H-NMR(DMSO-d.sub.6): 2.39(3H, s), 5.08(2H, s),
5.51(2H, s), 6.41(1H, d, J=8 Hz), 6.88(1H, dd, J=8 and 2 Hz),
7.23(1H, d, J=2 Hz), 7.28-7.45(5H, m), 7.85(2H, s). Mass(ESI): m/E
406 (M-H).sup.-
Preparation Example 75-1
Methyl
3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate (62 mg) and methyl
1-(2-chloro-4-methoxybenzyl)-2-methyl-1H-imi-
dazo[4,5-b]pyridine-5-carboxylate
[1109] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (62 mg) and methyl
1-(2-chloro-4-methoxybenzyl)-2-methyl-1H-imidazo[4-
,5-b]pyridine-5-carboxylate (62 mg) were obtained as white powders
from methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (145
mg) and 2-chloro-4-methoxybenzyl bromide (215 mg).
Methyl
3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate
[1110] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 3.77(3H, s), 4.00(3H,
s), 5.61(2H, s), 6.65(2H, s), 6.97(1H, s), 8.04(1H, d, J=8 Hz),
8.12(1H, d, J=8 Hz). Mass(ESI): m/E 346 (M+H).sup.+
Methyl
1-(2-chloro-4-methoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine5-ca-
rboxylate
[1111] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 3.78(3H, s), 4.01(3H,
s), 5.38(2H, s), 6.51(1H, d, J=8 Hz), 6.68(1H, dd, J=8 and 2 Hz),
7.00(1H, d, J=2 Hz), 7.54(1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz).
Mass(ESI): m/E 346 (M+H).sup.+
Preparation Example 75-2
3-(2-Chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ic acid
[1112] In the same manner as in Preparation Example 4-7, the
objective compound (83 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (78 mg).
[1113] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 3.55(3H, s),
5.53(2H, s), 6.58(1H, d, J=8 Hz), 6.81(1H, dd, J=8 and 2 Hz),
7.13(1H, d, J=2 Hz), 7.99(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).
Mass(ESI): m/E 330 (M-H).sup.-
Preparation Example 76-1
Isopropyl 2-chloro-4-isopropoxy benzoate
[1114] In the same manner as in Preparation Example74-2, the
objective compound (839 mg) was obtained as a pale-brown oil from
2-chloro-4-hydroxybenzoic acid (500 mg) and isopropyl iodide (1.18
g).
[1115] .sup.1H-NMR(CDCl.sub.3): 1.36(12H, m), 4.59(1H, m), 4.59(1H,
m), 5.24(1H, m), 6.78(1H, d, J=8 Hz), 6.93(1H, s), 7.82(1H, d, J=8
Hz).
Preparation Example 76-2
2-Chloro-4-isopropoxybenzyl alcohol
[1116] Lithium aluminum hydride (100 mg) was added to a solution of
isopropyl 2-chloro-4-isopropoxybenzoate (675 mg) in ether (6.8 ml)
and the mixture was stirred for 2 hr. To the reaction mixture were
dropwise added successively water (0.8 ml), a 1N aqueous sodium
hydroxide solution (0.8 ml) and water (2.4 ml) under ice-cooing,
and the mixture was stirred for 30 min at room temperature. Then
ether and water were added and the organic layer was separated. The
resulting product was extracted with ether from the aqueous layer.
The organic layers were combined, washed with saturated brine, and
dried over anhydrous magnesium sulfate. The solvent was evaporated
to give the objective compound (513 mg) as a brown oil.
[1117] .sup.1H-NMR(CDCl.sub.3): 1.32(6H, d, J=6 Hz), 1.97(1H, t,
J=6 Hz), 4.52(1H, m), 4.70(2H, d, J=6 Hz), 6.78(1H, dd, J=2 Hz),
6.92(1H, d, J=2 Hz), 7.33(1H, d, J=8 Hz).
Preparation Example 76-3
2-Chloro-4-isopropoxybenzyl chloride
[1118] Pyridine (0.5 ml) and thionyl chloride (0.18 mg) were
successively added to a solution of
2-chloro-4-isopropoxybenzylalcohol (401 mg) in dichloromethane (2
ml) under ice-cooling, and the mixture was stirred for 1 hr. Water
was added to the reaction mixture and the resulting product was
extracted three times with hexane. The organic layers were
combined, washed successively with 1N hydrochloric acid, a
saturated aqueous solution of sodium hydrogencarbonate and
saturated brine, and dried over anhydrous magnesium sulfate. The
solvent was evaporated to give the objective compound (353 mg) as a
yellow oil.
[1119] .sup.1H-NMR(CDCl.sub.3): 1.32(6H, d, J=7 Hz), 4.52(1H, sept,
J=7 Hz), 4.65(2H, s), 6.76(1H, dd, J=8 and 2 Hz), 6.91(1H, d, J=2
Hz), 7.32(1H, d, J=8.5 Hz).
Preparation Example 76-4
Methyl
3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate and methyl
1-(2-chloro-4-isopropoxybenzyl)-2-methyl-1H-imida-
zo[4,5-b]pyridine-5-carboxylate
[1120] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (73 mg) and methyl
1-(2-chloro-4-isopropoxybenzyl)-2-methyl-1H-imi-
dazo[4,5-b]pyridine-5-carboxylate (80 mg) as white powders from
methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (194 mg)
and 2-chloro-4-isopropoxybenzyl chloride (340 mg).
Methyl
3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1121] .sup.1H-NMR(CDCl.sub.3): 1.29(6H, d, J=7 Hz), 2.54(3H, s),
4.00(3H, s), 4.47(1H, sept, J=7 Hz), 5.61(2H, s), 6.62(2H, s),
6.95(1H, s), 8.05(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). Mass(ESI):
m/E 374 (M+H).sup.+
Methyl
1-(2-chloro-4-isopropoxybenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine--
5-carboxylate
[1122] .sup.1H-NMR(CDCl.sub.3): 1.30(6H, d, J=7 Hz), 2.65(3H, s),
4.00(3H, s), 4.48(1H, sept, J=7 Hz), 5.35(2H, s), 6.47(1H, d, J=8
Hz), 6.64(1H, dd, J=8 and 2 Hz), 6.98(1H, d, J=2 Hz), 7.54(1H, d,
J=8 Hz), 8.06(1H, d, J=8 Hz). Mass(ESI): m/E 374 (M+H).sup.+
Preparation Example 76-5
3-(2-Chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1123] In the same manner as in Preparation Example 4-7, the
objective compound (66 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (67 mg).
[1124] .sup.1H-NMR(DMSO-d.sub.6): 1.23(6H, d, J=7 Hz), 2.50(3H, s),
4.60(1H, sept, J=7 Hz), 5.53(2H, s), 6.52(1H, d, J=8 Hz), 6.79(1H,
dd, J=8 and 2 Hz), 7.11(1H, d, J=2 Hz), 8.01(1H, d, J=8 Hz),
8.12(1H, d, J=8 Hz). Mass(ESI): m/E 358 (M-H).sup.-
Preparation Example 77-1
n-Butyl 4-(n-butoxy)-2-chlorobenzoate
[1125] In the same manner as in Preparation Example 74-2, the
objective compound (839 mg) was obtained as a pale-brown oil from
2-chloro-4-hydroxybenzoic acid (500 mg) and n-butyl iodide (1.28
g).
[1126] .sup.1H-NMR(CDCl.sub.3): 0.98(6H, t, J=6 Hz), 1.48(4H, m),
1.76(4H, m), 3.99(2H, t, J=6 Hz), 4.30(2H, t, J=6 Hz), 6.80(1H, d,
J=8 Hz), 6.95(1H, s), 7.86(1H, d, J=8 Hz).
Preparation Example 77-2
4-(n-Butoxy)-2-chlorobenzyl alcohol
[1127] In the same manner as in Preparation Example 80-2 to be
mentioned later, the objective compound (513 mg) was obtained as a
pale-brown oil from n-butyl 4-(n-butoxy)-2-chlorobenzoate (835
mg).
[1128] .sup.1H-NMR(CDCl.sub.3): 0.98(3H, t, J=6 Hz), 1.48(2H, m),
1.76(2H, m), 1.86(1H, t, J=6 Hz), 3.95(2H, t, J=6 Hz), 4.71(2H, d,
J=6 Hz), 6.80(1H, d, J=8 Hz), 6.93(1H, s), 7.34(1H, d, J=8 Hz).
Preparation Example 77-3
4-(n-Butoxy)-2-chlorobenzyl chloride
[1129] In the same manner as in Preparation Example 14-1, the
objective compound (505 mg) was obtained as a colorless oil from
4-(n-butoxy)-2-chlorobenzyl alcohol (475 mg).
[1130] .sup.1H-NMR(CDCl.sub.3): 0.98(3H, t, J=7 Hz), 1.38-1.56(2H,
m), 1.68-1.82(2H, m), 3.95(2H, t, J=7 Hz), 4.67(2H, s), 6.78(1H,
dd, J=8 and 2 Hz), 6.92(1H, d, J=2 Hz), 7.33(1H, d, J=8 Hz).
Preparation Example 77-4
Methyl
3-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate and methyl
1-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-1H-imida-
zo[4,5-b]pyridine-5-carboxylate
[1131] In the same manner as in Preparation Example 14-2, methyl
3-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (105 mg) and methyl
1-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-1H-im-
idazo[4,5-b]pyridine-5-carboxylate (111 mg) were obtained as
pale-yellow powders from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (230 mg) and
4-(n-butoxy)-2-chlorobenzyl chloride (443 mg).
Methyl
3-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1132] .sup.1H-NMR(CDCl.sub.3): 0.96(3H, t, J=7 Hz), 1.38-1.54(2H,
m), 1.65-1.81(2H, m), 2.52(3H, s), 3.90(2H, t, J=7 Hz), 4.00(3H,
s), 5.60(2H, s), 6.63(2H, s), 6.95(1H, s), 8.04(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz). Mass(ESI): m/E 388 (M+H).sup.+
Methyl
1-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine--
5-carboxylate
[1133] .sup.1H-NMR(CDCl.sub.3): 0.95(3H, t, J=7 Hz), 1.38-1.53(2H,
m), 1.66-1.81(2H, m), 2.65(3H, s), 3.92(2H, t, J=7 Hz), 4.01(3H,
s), 5.37(2H, s), 6.48(1H, d, J=8 Hz), 6.67(1H, dd, J=8 and 2 Hz),
6.99(1H, d, J=2 Hz), 7.55(1H, d, J=8 Hz), 8.06(1H, d, J=8 Hz).
Mass(ESI): m/E 388 (M+H).sup.+
Preparation Example 77-5
3-(4-(n-Butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1134] In the same manner as in Preparation Example 4-7, the
objective compound (90 mg) was obtained as a pale-yellow powder
from methyl
3-(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (90 mg).
[1135] .sup.1H-NMR(DMSO-d.sub.6): 0.90(3H, t, J=7 Hz),
1.30-1.48(2H, m), 1.57-1.71(2H, m), 2.50(3H, s), 3.94(2H, t, J=7
Hz), 5.54(2H, s), 6.53(1H, d, J=8 Hz), 6.80(1H, dd, J=8 and 2 Hz),
7.13(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).
Mass(ESI): m/E 372 (M-H).sup.-
Preparation Example 78-1
Cyclohexylmethyl 2-chloro-4-((cyclohexylmethyl)oxy)benzoate
[1136] In the same manner as in Preparation Example 74-2, the
objective compound (1.14 g) was obtained as a pale-brown oil from
2-chloro-4-hydroxybenzoic acid (500 mg) and cyclohexylmethyl
bromide (1.23 g).
[1137] .sup.1H-NMR(CDCl.sub.3): 1.08(4H, m), 1.26(6H, m), 1.78(12H,
m), 3.78(2H, d, J=6 Hz), 4.12(2H, d, J=6 Hz), 6.80(1H, d, J=8 Hz),
6.96(1H, s), 7.88(1H, d, J=8 Hz).
Preparation Example 78-2
2-Chloro-4-((cyclohexylmethyl)oxy)benzyl alcohol
[1138] In the same manner as in Preparation Example 80-2 to be
mentioned later, the objective compound (903 mg) was obtained as a
pale-brown oil from cyclohexylmethyl
2-chloro-4-((cyclohexylmethyl)oxybenzoate (1.13 g).
[1139] .sup.1H-NMR(CDCl.sub.3): 0.85-1.90(11H, m), 3.44(1H, t, J=6
Hz), 3.73(2H, d, J=6 Hz), 4.70(2H, d, J=6 Hz), 6.79(1H, dd, J=8, 1
Hz), 6.92(1H, d, J=1 Hz), 7.33(1H, d, J=8 Hz).
Preparation Example 78-3
2-Chloro-4-((cyclohexyl)methyloxy)benzyl chloride
[1140] In the same manner as in Preparation Example 76-3, the
objective compound (844 mg) was obtained as a colorless oil from
2-chloro-4-((cyclohexylmethyl)-oxy)benzyl alcohol (855 mg).
[1141] .sup.1H-NMR(CDCl.sub.3): 0.82-1.91(11H, m), 3.72(2H, d, J=7
Hz), 4.66(2H, s), 6.78(1H, dd, J=8 and 2 Hz), 6.92(1H, d, J=2 Hz),
7.32(1H, d, J=8 Hz).
Preparation Example 78-4
Methyl
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,-
5-b]pyridine-5-carboxylate (58 mg) and methyl
1-(2-chloro-4-((cyclohexylme-
thyl)-oxy)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1142] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate (58 mg) and methyl
1-(2-chloro-4-((cyclohexylmethyl)o-
xy)-benzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (36
mg) were obtained as colorless oils from methyl
2-methyl-1H-imidazo[4,5-b]pyridine- -5-carboxylate (194 mg) and
2-chloro-4-((cyclohexylmethyl)oxy)benzyl chloride (403 mg).
Methyl
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,-
5-b]pyridine-5-carboxylate
[1143] .sup.1H-NMR(CDCl.sub.3): 0.90-1.90(11H, m), 2.52(3H, s),
3.69(2H, d, J=7 Hz), 3.99(3H, s), 5.61(2H, s), 6.62(2H, s),
6.95(1H, s), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). Mass(ESI):
m/E 428 (M+H).sup.+
Methyl
1-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-1H-imidazo[4,-
5-b]pyridine-5-carboxylate
[1144] .sup.1H-NMR(CDCl.sub.3): 0.92-1.92(11H, m), 2.64(3H, s),
3.69(2H, d, J=7 Hz), 4.00(3H, s), 5.37(2H, s), 6.48(1H, d, J=8 Hz),
6.65(1H, dd, J=8 and 2 Hz), 6.98(1H, d, J=2 Hz), 7.53(1H, d, J=8
Hz), 8.04(1H, d, J=8 Hz). Mass(ESI): m/E 428 (M+H).sup.+
Preparation Example 78-5
3-(2-Chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid
[1145] In the same manner as in Preparation Example 4-7, the
objective compound (53 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate (53 mg).
[1146] .sup.1H-NMR(DMSO-d.sub.6): 0.90-1.82(11H, m), 2.50(3H, s),
3.76(1H, d, J=7 Hz), 5.53(2H, s), 6.54(1H, d, J=8 Hz), 6.80(1H, dd,
J=8 and 2 Hz), 7.12(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz), 8.11(1H,
d, J=8 Hz). Mass(ESI): m/E 412 (M-H).sup.-
Preparation Example 79-1
2-Chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzaldehyde
[1147] To a solution of
2-[N-(2-hydroxyethyl)-N-methylamino]pyridine (3.87 g) in dry
N,N-dimethylformamide (39 ml) was added sodium hydride (60% in oil,
1.12 g), and the reaction mixture was stirred at room temperature
for 30 min. 2-Chloro-4-fluorobenzaldehyde (4.43 g) was added to the
reaction mixture and the mixture was stirred for 3 days. The
mixture was diluted with ethyl acetate and washed with water. The
aqueous layer was extracted twice with ethyl acetate. The organic
layers were combined, dried over magnesium sulfate and concentrated
to dryness under reduced pressure. The residue was purified by
silica gel column chromatography (hexane/ethyl acetate=9/1) to give
the objective compound (3.30 g) as a pale-yellow oil.
[1148] .sup.1H-NMR(CDCl.sub.3): 3.13(3H, s), 4.01(2H, t, J=6 Hz),
4.28(2H, t, J=6 Hz), 6.52(1H, d, J=8 Hz), 6.60(1H, dd, J=8, 5 Hz),
6.90(1H, dd, J=8, 2 Hz), 7.02(1H, d, J=8, 2 Hz), 7.48(1H, t, J=8
Hz), 7.87(1H, d, J=8 Hz), 8.18(1H, d, J=5 Hz), 10.00(1H, s).
Preparation Example 79-2
2-Chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl
alcohol
[1149] Sodium borohydride (58 mg) was added to a solution of
2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzaldehyde
(438 mg) in ethanol (3 ml) at room temperature and the mixture was
stirred for 2 hr. 1N Hydrochloric acid (1.5 ml) was dropwise added
to the reaction mixture to decompose the redundant reagent and the
whole mixture was diluted with ethyl acetate. A saturated aqueous
solution of sodium hydrogencarbonate was added to neutralize the
mixture and the resulting product was extracted twice with ethyl
acetate. The organic layers were combined, washed with saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated to give the objective compound (437 mg) as a colorless
oil.
[1150] .sup.1H-NMR(CDCl.sub.3): 3.12(3H, s), 3.97(2H, t, J=5 Hz),
4.17(2H, t, J=5 Hz), 4.70(2H, s), 6.51(1H, d, J=8 Hz), 6.58(1H, dd,
J=8 and 5 Hz), 6.79(1H, dd, J=8 and 2 Hz), 6.97(1H, d, J=2 Hz),
7.32(1H, d, J=8 Hz), 7.46(1H, t, J=8 Hz), 8.16(1H, d, J=5 Hz).
Mass(ESI): m/E 293 (M+H).sup.+
Preparation Example 79-3
2-Chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl
chloride
[1151] In the same manner as in Preparation Example 76-3, the
objective compound (662 mg) was obtained as a pale-yellow oil from
2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl
alcohol (557 mg).
[1152] .sup.1H-NMR(CDCl.sub.3): 3.13(3H, s), 3.99(2H, t, J=5 Hz),
4.19(2H, t, J=5 Hz), 4.65(2H, s), 6.51(1H, d, J=8 Hz), 6.58(1H, dd,
J=8 and 5 Hz), 6.79(1H, dd, J=8 and 2 Hz), 7.00(1H, d, J=2 Hz),
7.31(1H, d, J=8 Hz), 7.47(1H, t, J=8 Hz), 8.17(1H, d, J=5 Hz).
Preparation Example 79-4
Methyl
3-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)--
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate and methyl
1-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-meth-
yl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1153] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine-5-carboxylate (156 mg) and methyl
1-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-meth-
yl-1H-imidazo[4,5-b]pyridine-5-carboxylate (160 mg) were obtained
as colorless oils from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyla- te (290 mg) and
2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)be- nzyl
chloride (577 mg).
Methyl
3-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)--
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
[1154] .sup.1H-NMR(CDCl.sub.3): 2.51(3H, s), 3.11(3H, s), 3.95(2H,
t, J=5 Hz), 3.99(3H, s), 4.14(2H, t, J=5 Hz), 5.60(2H, s), 6.49(1H,
d, J=8 Hz), 6.55(1H, dd, J=8 and 5 Hz), 6.63(2H, s), 7.02(1H, s),
7.44(1H, t, J=8 Hz), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz),
8.15(1H, d, J=5 Hz). Mass(ESI): m/E 466 (M+H).sup.+
Methyl
1-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)--
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1155] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 3.11(3H, s), 3.95(2H,
t, J=5 Hz), 4.01(3H, s), 4.15(2H, t, J=5 Hz), 5.35(2H, s),
6.45-6.60(3H, m), 6.68(1H, dd, J=8 and 2 Hz), 7.08(1H, d, J=2 Hz),
7.44(1H, t, J=8 Hz), 7.52(1H, d, J=8 Hz), 8.01(1H, d, J=2 Hz),
8.04(1H, d, J=8 Hz). Mass(ESI): m/E 466 (M+H).sup.+
Preparation Example 79-5
3-(2-Chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-methy-
l-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
[1156] In the same manner as in Preparation Example 4-7, the
objective compound (114 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine-5-carboxylate (143 mg).
[1157] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 3.03(3H, s),
3.87(2H, t, J=5 Hz), 4.13(2H, t, J=5 Hz), 5.53(2H, s),
6.50-6.65(3H, m), 6.82(1H, dd, J=8 and 2 Hz), 7.20(1H, d, J=2 Hz),
7.49(1H, t, J=8 Hz), 7.99(1H, d, J=8 Hz), 8.06(1H, d, J=5 Hz),
8.10(1H, d, J=8 Hz). Mass(ESI): m/E 450 (M-H).sup.-
Preparation Example 80-1
Methyl 2-chloro-4-(methylthio)benzoate
[1158] Sodium thiomethoxide (459 mg) was added to a solution of
methyl 4-bromo-2-chlorobenzoate (1.25 g) in N,N-dimethylformamide
(10 ml) under ice-cooling, and the mixture was stirred for 2 hr. 1N
Hydrochloric acid was added to the reaction mixture and the
resulting product was extracted three times with ether. The organic
layers were combined, washed successively with water and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated and the residue was subjected to silica gel column
chromatography (hexane/ethyl acetate=10/1) to give the objective
compound (835 mg) as a colorless oil.
[1159] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 3.90(3H, s), 7.11(1H,
d, J=8 Hz), 7.23(1H, s), 7.78(1H, d, J=8 Hz).
Preparation Example 80-2
2-Chloro-4-(methylthio)benzyl alcohol
[1160] Methyl 2-chloro-4-(methylthio)benzoate (806 mg) was dropwise
added to a suspension of lithium aluminum hydride (139 mg) in
tetrahydrofuran (8 ml) under ice-cooling, and the mixture was
stirred for 1 hr. The reaction mixture was diluted with ether and
1N hydrochloric acid (10 ml) was dropwise added. The resulting
product was extracted three times with ether. The organic layers
were combined, washed successively with a saturated aqueous
solution of sodium hydrogencarbonate and saturated brine, and dried
over anhydrous magnesium sulfate. The solvent was evaporated to
give the objective compound (725 mg) as a colorless oil.
[1161] .sup.1H-NMR(CDCl.sub.3): 1.92(1H, br t, J=7 Hz), 2.48(3H,
s), 4.73(2H, d, J=7 Hz), 7.15(1H, d, J=8 Hz), 7.23(1H, s), 7.37(1H,
d, J=8 Hz).
Preparation Example 80-3
2-Chloro-1-((methanesulfonyloxy)methyl)-4-(methylthio)benzene
[1162] In the same manner as in Preparation Example 14-1, the
objective compound (1.02 g) was obtained as a colorless oil from
2-chloro-4-(methylthio)benzyl alcohol (687 mg).
[1163] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 3.00(3H, s), 5.30(2H,
s), 7.15(1H, dd, J=8 and 2 Hz), 7.26(1H, d, J=2 Hz), 7.38(1H, d,
J=8 Hz).
Preparation Example 80-4
Methyl
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate and methyl
1-(2-chloro-4-(methylthio)benzyl)-2-methyl-1H-i-
midazo[4,5-b]pyridine-5-carboxylate
[1164] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (457 mg) and methyl
1-(2-chloro-4-(methylthio)benzyl)-2-methyl-1-
H-imidazo[4,5-b]pyridine5-carboxylate (402 mg) were obtained as
white powder from methyl
2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (573 mg) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-(methylthio)benzene (955
mg).
Methyl
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1165] .sup.1H-NMR(CDCl.sub.3): 2.44(3H, s), 2.53(3H, s), 4.00(3H,
s), 5.63(2H, s), 6.58(1H, d, J=8 Hz), 6.96(1H, dd, J=8 and 2 Hz),
7.28(1H, d, J=2 Hz), 8.06(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).
Mass(ESI): m/e 362 (M+H).sup.+
Methyl
1-(2-chloro-4-(methylthio)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1166] .sup.1H-NMR(CDCl.sub.3): 2.45(3H, s), 2.65(3H, s), 4.01(3H,
s), 5.39(3H, s), 6.42(1H, d, J=8 Hz), 6.98(1H, dd, J=8 and 2 Hz),
7.30(1H, d, J=2 Hz), 7.54(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz).
Mass(ESI): m/e 362 (M+H).sup.+
Preparation Example 80-5
3-(2-Chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylic acid
[1167] In the same manner as in Preparation Example 4-7, the
objective compound (184 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (146 mg).
[1168] .sup.1H-NMR(DMSO-d.sub.6): 2.45(3H, s), 2.50(3H, s),
5.60(2H, s), 6.44(1H, d, J=8 Hz), 7.10(1H, d, J=8 Hz), 7.42(1H, s),
8.00(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz). Mass(ESI): m/e 346
(M-H).sup.-
Preparation Example 81-1
Methyl
3-(2-chloro-4-(methylsulfinyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1169] To a solution of methyl
3-(2-chloro-4-(methylthio)benzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylate (148 mg) in dichloromethane
(2.8 ml) was added m-chloroperbenzoic acid (81 mg) under
ice-cooling, and the mixture was stirred for 1 hr. The reaction
mixture was diluted with chloroform, washed successively with a
saturated aqueous sodium hydrogencarbonate solution and saturated
brine, and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and acetonitrile was added to the residue for
crystallization, whereby the objective compound (118 mg) was
obtained as a white powder.
[1170] .sup.1H-NMR(CDCl.sub.3): 2.55(3H, s), 2.71(3H, s), 3.99(3H,
s), 5.71(2H, s), 6.78(1H, d, J=8 Hz), 7.32(1H, d, J=8 Hz), 7.80(1H,
s), 8.09(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz). Mass(ESI): m/e 378
(M+H).sup.+
Preparation Example 81-2
3-(2-Chloro-4-(methylsulfinyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1171] In the same manner as in Preparation Example 4-7, the
objective compound (112 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-(methylsulfinyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (112 mg).
[1172] .sup.1H-NMR(DMSO-d.sub.6): 2.54(3H, s), 2.76(3H, s),
5.67(2H, s), 6.75(1 H, d, J=8 Hz), 7.52(1H, d, J=8 Hz), 7.88(1H,
s), 8.01(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). Mass(ESI): m/e 362
(M-H).sup.-
Preparation Example 82-1
2-Chloro-4-(methanesulfonyl)-1-((methanesulfonyloxy)methyl)benzene
[1173] In the same manner as in Preparation Example 14-1, the
objective compound (737 mg) was obtained as a white powder from
2-chloro-4-(methanesulfonyl)benzyl alcohol (457 mg) and
methanesulfonyl chloride (261 mg).
[1174] .sup.1H-NMR(DMSO-d.sub.6): 3.31(3H, s), 3.33(3H, s),
5.42(2H, s), 7.85(1H, d, J=8 Hz), 7.79(1H, d, J=8 Hz), 8.07(1H,
s).
Preparation Example 82-2
Methyl
3-(2-chloro-4-(methanesulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate and methyl
1-(2-chloro-4-(methanesulfonyl)benzyl)-2-m-
ethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1175] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-(methanesulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate (233 mg) was obtained as white crystals and methyl
1-(2-chloro-4-(methane-sulfonyl)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e-5-carboxylmethylate (25 mg) was obtained as white crystals, from
methyl 2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg)
and
2-chloro-4-((methanesulfonyl)-1-((methane-sulfonyloxy)methyl)benzene
(344 mg).
Methyl
3-(2-chloro-4-(methanesulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1176] .sup.1H-NMR(CDCl.sub.3): 2.56(3H, s), 3.03(3H, s), 3.99(3H,
s), 5.72(2H, s), 6.80(1H, d, J=8 Hz), 7.08(1H, d, J=8 Hz), 8.05(1H,
s), 8.10(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz).
Methyl
1-(2-chloro-4-(methanesulfonyl)benzyl)-2-methyl-1H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1177] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 3.10(3H, s), 4.03(3H,
s), 5.62(2H, s), 6.62-6.70(1H, m), 7.75-8.12(4H, m).
Preparation Example 82-3
3-(2-Chloro-4-(methylsulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1178] In the same manner as in Preparation Example 4-7, the
objective compound (199 mg) was obtained as white crystals from
methyl
3-(2-chloro-4-(methylsulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate.
[1179] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 3.25(3H, s),
5.70(2H, s), 6.80(1H, d, J=8 Hz), 7.75(1H, d, J=8 Hz), 8.00(1H, d,
J=8 Hz), 8.10(1H, s), 8.13(1H, d, J=8 Hz).
Preparation Example 83-1
2-Chloro-1-((methanesulfonyloxy)methyl)4-nitrobenzene
[1180] In the same manner as in Preparation Example 14-1, the
objective compound (3.56 g) was obtained as brown crystals from
2-chloro-4-nitrobenzyl alcohol (2.5 g) and methanesulfonyl chloride
(1.68 g).
[1181] .sup.1H-NMR(DMSO-d.sub.6): 3.12(3H, s), 5.40(2H, s),
7.73(1H, d, J=8 Hz), 8.18(1H, dd, J=2, 8 Hz), 8.79(1H, d, J=2
Hz).
Preparation Example 83-2
Methyl
3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate and methyl
1-(2-chloro-4-nitrobenzyl)-2-methyl-1H-imidazo[4,5-b]p-
yridine-5-carboxylate.
[1182] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (1.02 g) was obtained as white crystals, and methyl
1-(2-chloro-4-nitrobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyla-
te (330 mg) was obtained as pale-brown crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.00 g) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-nitrobenzene (3.06
g).
Methyl
3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1183] .sup.1H-NMR(CDCl.sub.3): 2.55(3H, s), 3.99(3H, s), 5.73(2H,
s), 6.80(1H, d, J=8 Hz), 7.97(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz),
8.16(1H, d, J=8 Hz), 8.33(1H, s).
Methyl
1-(2-chloro-4-nitrobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1184] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 4.03(3H, s), 5.51(2H,
s), 6.62(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz), 8.01(1H, dd, J=2, 8
Hz), 8.10(1H, d, J=8 Hz), 8.39(1H, d, J=2 Hz).
Preparation Example 83-3
Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1185] Methyl
3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (705 mg) was suspended in ethanol (6 ml), and
reduced iron (437 mg) and acetic acid (1.01 ml) were added. The
mixture was refluxed under heating for 2 hr. Then, reduced iron
(218 mg) and acetic acid (1.01 ml) were further added, and the
mixture was refluxed under heating for 1 hr. The reaction mixture
was filtered through Celite, the insoluble matter was washed with
ethanol and the filtrate was concentrated under reduced pressure.
To the concentrate were added a saturated aqueous sodium
hydrogencarbonate solution and ethyl acetate to make the aqueous
layer alkaline. At this stage, part of the objective compound was
precipitated. The precipitate was collected by filtration and the
filtrate was partitioned. The organic layer was washed successively
with a saturated aqueous sodium hydrogencarbonate solution and
saturated brine, dried over anhydrous magnesium sulfate, and
filtrated. The objective compound that precipitated during
neutralization was dissolved in a mixed solvent of
methanol/chloroform (1/4), and the mixture was filtrated. Both
filtrates were combined and concentrated under reduced pressure to
give the objective compound (608 mg) as a white powder.
[1186] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 3.75(2H, s), 4.00(3H,
s), 5.67(2H, s), 6.40(1H, dd, J=2, 8 Hz), 6.54(1H, dd, J=1, 8 Hz),
6.72(1H, d, J=1 Hz), 8.02(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz).
Preparation Example 834
Methyl
3-(4-(benzylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate
[1187] Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (100 mg) was dissolved in methanol (1 ml), and
benzaldehyde (39 mg), zinc chloride (49 mg) and sodium
cyanoborohydride (23 mg) were added. The mixture was stirred at
room temperature for 2 hr and refluxed under heating for 15 min.
Benzaldehyde (16 mg), zinc chloride (21 mg) and sodium
cyanoborohydride (10 mg) were added and the mixture was stirred at
room temperature for 1 hr. To the reaction mixture was added ice
water, and then a saturated aqueous sodium hydrogencarbonate
solution. The mixture was extracted with ethyl acetate, and the
organic layer was washed successively with a saturated aqueous
sodium hydrogencarbonate solution and saturated brine, dried over
anhydrous magnesium sulfate, and filtrated. The filtrate was
concentrated under reduced pressure. Hexane was added to the
residue and the precipitated pale-yellow crystals were washed,
collected by filtration and dried under reduced pressure to give
the objective compound (120 mg).
[1188] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 3.98(3H, s), 4.17(1H,
t, J=7 Hz), 4.27(2H, d, J=6 Hz), 5.56(2H, s), 6.34(1H, dd, J=2, 8
Hz), 6.55(1H, d, J=8 Hz), 6.66(1H, d, J=2 Hz), 7.25-7.37(5H, m),
8.02(1H, d, J=8 Hz), 8. 10(1H, d, J=8 Hz).
Preparation Example 83-5
3-(4-(Benzylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylic acid
[1189] In the same manner as in Preparation Example 4-7, the
objective compound (82 mg) was obtained as white crystals from
methyl
3-(4-(benzylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5
carboxylate.
[1190] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 4.22(2H, d, J=6 Hz),
5.44(2H, s), 6.43(2H, s), 6.58-6.63(1H, m), 6.68(1H, s),
7.17-7.25(1H, m), 7.27-7.30(4H, m), 7.98(1H, d, J=8 Hz), 8.08(1H,
d, J=8 Hz).
Preparation Example 84-1
Methyl
3-(4-(n-butylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylate
[1191] In the same manner as in Preparation Example 84-4, the
objective compound (87 mg) was obtained as pale-yellow crystals
from methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (100 mg) and n-butyl aldehyde (37 mg).
[1192] .sup.1H-NMR(CDCl.sub.3): 0.93(3H, t, J=8 Hz), 1.37-1.48(2H,
m), 1.52-1.62(2H, m), 2.55(3H, s), 4.00(2H, q, J=7 Hz), 3.72(1H, br
s), 4.01(3H, s), 5.57(2H, s), 6.32(1H, dd, J=2, 8 Hz), 6.57(1H, d,
J=8 Hz), 6.60(1H, d, J=2 Hz), 8.02(1H, d, J=8 Hz), 8.12(1H, d, J=8
Hz).
Preparation Example 84-2
3-(4-(n-Butylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylic acid
[1193] In the same manner as in Preparation Example 4-7, the
objective compound (54 mg) was obtained as a white powder from
methyl
3-(4-(n-butylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate (75 mg).
[1194] .sup.1H-NMR(DMSO-d.sub.6): 0.88(3H, t, J=8 Hz),
1.23-1.40(2H, m), 1.42-1.53(2H, m), 2.49(3H, s), 2.92(2H, q, J=7
Hz), 5.45(2H, s), 5.93(1H, t, J=7 Hz), 6.38(1H, d, J=8 Hz),
6.44(1H, d, J=8 Hz), 6.63(1H, s), 8.00(1H, d, J=8 Hz), 8.10(1H, d,
J=8 Hz).
Preparation Example 85-1
Methyl
3-(2-chloro-4-(N,N-dimethylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1195] Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (100 mg) was dissolved in acetonitrile (1 ml), and
a 37% aqueous formaldehyde solution (0.123 ml) and sodium
cyanoborohydride (29 mg) were added, and the mixture was stirred at
room temperature for 1 hr. Then, a 37% aqueous formaldehyde
solution (0.123 ml) and sodium cyanoborohydride (29 mg) were added,
and acetic acid was added to neutralize the reaction mixture, which
was followed by stirring at room temperature overnight. The
reaction mixture was concentrated under reduced pressure, and ice
water was added to the residue. A saturated aqueous sodium
hydrogencarbonate solution was added and the mixture was extracted
with ethyl acetate. The organic layer was washed successively with
an aqueous sodium hydrogencarbonate solution and saturated brine,
dried over anhydrous magnesium sulfate, dried and filtrated. The
filtrate was concentrated under reduced pressure. Hexane was added
to the residue and the precipitated pale-yellow crystals were
washed, filtered, and dried under reduced pressure to give the
objective compound (97 mg).
[1196] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 2.90(6H, s), 4.00(3H,
s), 5.59(2H, s), 6.42(1H, dd, J=2, 8 Hz), 6.62(1H, d, J=8 Hz),
6.70(114, d, J=2 Hz), 8.03(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).
Preparation Example 85-2
3-(2-Chloro-4-(N,N-dimethylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid
[1197] In the same manner as in Preparation Example 4-7, the
objective compound (65 mg) was obtained as white crystals from
methyl
3-(2-chloro-4-(N,N-dimethylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (90 mg).
[1198] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 2.87(6H, s),
5.48(2H, s), 6.78(1H, s), 7.98(1H, d, J=8 Hz), 8.10(1H, d, J=8
Hz).
Preparation Example 86-1
Methyl
3-(4-(acetylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate
[1199] Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (150 mg) was dissolved in 1,2-dichloroethane (1.5
ml), and acetic anhydride (148 mg) and acetic acid (87 mg) were
added at room temperature. The mixture was refluxed under heating
for 1 hr. The reaction mixture was concentrated under reduced
pressure, and ice water, a saturated aqueous sodium
hydrogencarbonate solution were successively added to the residue.
The precipitated white crystals were collected by filtration,
washed with water, and dried under reduced pressure to give the
objective compound (139 mg).
[1200] .sup.1H-NMR(CDCl.sub.3): 2.12(3H, s), 2.52(3H, s), 3.40(1H,
s), 3.99(3H, s), 5.60(2H, s), 6.51(1H, d, J=8 Hz), 7.13(1H, d, J=8
Hz), 7.83(1H, s), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).
Preparation Example 86-2
3-(4-(Acetylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylic acid
[1201] In the same manner as in Preparation Example 4-7, the
objective compound (116 mg) was obtained as white crystals from
methyl
3-(4-(acetylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine5-ca-
rboxylate (123 mg).
[1202] .sup.1H-NMR(DMSO-d.sub.6): 2.03(3H, s), 2.50(3H, s),
5.55(2H, s), 6.57(1H, d, J=8 Hz), 7.23(1H, d, J=8 Hz), 7.95(1H, s),
7.98(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).
Preparation Example 87-1
Methyl
3-(2-chloro-4-(methanesulfonylamino)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate
[1203] Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (150 mg) was dissolved in pyridine (1.5 ml), and a
solution of methanesulfonyl chloride (114 mg) in pyridine (0.5 ml)
was added at room temperature. The mixture was refluxed under
heating for 1 hr. Thereto was added a solution of methanesulfonyl
chloride (114 mg) in pyridine (0.5 ml) at room temperature, and the
mixture was left standing overnight at room temperature. The
reaction mixture was concentrated under reduced pressure and ice
water was added to the residue. The resulting product was extracted
with chloroform. The organic layer was washed successively with a
saturated aqueous sodium hydrogencarbonate solution and saturated
brine, dried over anhydrous magnesium sulfate, and filtrated. The
filtrate was concentrated under reduced pressure. Ethanol was added
to the residue, and the crystals were washed, filtrated and dried
under reduced pressure to give the objective compound. (101 mg) as
pale-yellow crystals.
[1204] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 3.04(3H, s), 3.97(3H,
s), 5.60(2H, s), 6.10(1H, d, J=8 Hz), 6.90(1H, d, J=8 Hz), 7.20(1H,
d, J=3 Hz), 8.07(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz), 8.87(1H,
s).
Preparation Example 87-2
3-(2-Chloro-4-(methanesulfonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]-pyr-
idine-5-carboxylic acid
[1205] In the same manner as in Preparation Example 4-7, the
objective compound (88 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-(methanesulfonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate.
[1206] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 3.01(3H, s),
5.55(2H, s), 6.60(1H, d, J=8 Hz), 7.03(1H, d, J=8 Hz), 7.33(1H, s),
7.97(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).
Preparation Example 88
3-(2-Chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1207] In the same manner as in Preparation Example 4-7, the
objective compound (258 mg) was obtained as white crystals from
methyl
3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (300 mg).
[1208] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.70(2H, s),
6.82(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz), 8.04(1H, dd, J=2, 8 Hz),
8.12(1H, d, J=8 Hz), 8.40(1H, s).
Preparation Example 89-1
3-Chloro-4-(hydroxymethyl)benzaldehyde
[1209] In the same manner as in Preparation Example 70-3, the
objective compound (112 mg) was obtained as a pale-yellow powder
from 4-((tert-butyldimethylsilyloxy)methyl)-3-chlorobenzaldehyde
(228 mg).
[1210] .sup.1H-NMR(CDCl.sub.3): 2.04(1H, br.s), 4.88(2H, br.s),
7.76(1H, d, J=8 Hz), 7.82(1H, d, J=8 Hz), 7.88(1H, s), 9.98(1H,
s).
Preparation Example 89-2
3-Chloro-4-((methanesulfonyloxy)methyl)benzaldehyde
[1211] In the same manner as in Preparation Example 14-1, the
objective compound (577 mg) was obtained as pale-yellow oil from
3-chloro-4-(hydroxymethyl)benzaldehyde (393 mg).
[1212] .sup.1H-NMR(CDCl.sub.3): 3.12(3H, s), 5.40(2H, s), 7.72(1H,
d, J=8 Hz), 7.84(1H, d, J=8 Hz), 7.94(1H, s), 9.98(1H, s).
Preparation Example 89-3
Methyl
3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate and methyl
1-(2-chloro-4-formylbenzyl)-2-methyl-1H-imidazo[4,5-b-
]pyridine-5-carboxylate
[1213] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate was obtained as colorless crystals (1.71 g) and methyl
1-(2-chloro-4-formylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine5-carboxyla-
te was obtained as amorphous (1.40 g), from methyl
2-methyl-3H-imidazo[4,5- -b]pyridine-5-carboxylate (2.60 g) and
3-chloro-4-((methanesulfonyloxy)met- hyl)benzaldehyde (3.72 g).
Methyl
3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1214] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.99(3H, s), 5.73(2H,
s), 6.77(1H, d, J=8 Hz), 7.61(1H, d, J=8 Hz), 7.98(1H, s), 8.10(1H,
d, J=8 Hz), 8.18(1H, d, J=8 Hz), 9.94(1H, s) Mass(ESI): m/z 344
(M+1) mp 189-191.degree. C.
Methyl
1-(2-chloro-4-formylbenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1215] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 4.00(3H, s), 5.50(2H,
s), 6.61(1H, d, J=8 Hz), 7.55(1H, d, J=8 Hz), 7.64(1H, br d, J=8
Hz), 8.00(1H, s), 8.09(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz),
9.95(1H, s) Mass(ESI): m/z 344 (M+1)
Preparation Example 89-4
3-(2-Chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[1216] In the same manner as in Preparation Example 4-7, the
objective compound (202 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (200 mg).
[1217] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.70(2H, s),
6.78(1H, d, J=8 Hz), 7.75(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz),
8.09(1H, s), 8.16(1H, d, J=8 Hz), 9.96(1H, s). Mass(ESI): m/z 328
(M-1) mp 188-192.degree. C.
Preparation Example 90-1
Methyl
3-[2-chloro-4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]-benzyl]-
-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
[1218] A suspension of methyl
3-(2-chloro-4-formylbenzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine-5-carboxylate (200 mg, 0.582 mmol),
thiazolidine-2,4-dione (82 mg, 0.698 mmol) and piperidine (25 mg,
0.291 mmol) in ethanol (4 ml) was refluxed under heating overnight.
The reaction mixture was cooled, and the precipitated crystals were
filtrated to give the objective compound (189 mg) as pale-yellow
crystals.
[1219] .sup.1H-NMR(DMSO-d.sub.6): 2.54(3H, s), 3.85(3H, s),
5.64(2H, s), 6.71(1H, d, J=8 Hz), 7.42(1H, d, J=8 Hz), 7.74(1H, s),
7.82(1H, s), 8.02(1H, d, J=8 Hz), 8.17(1H, d, J=8 Hz). Mass(ESI):
m/z 441 (M-1) mp>300.degree. C.
Preparation Example 90-2
3-[2-Chloro-4-[(2,4-dioxo-1,3-thiazolidin-5-ylidene)methyl]benzyl]-2-methy-
l-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
[1220] In the same manner as in Preparation Example 4-7, the
objective compound (63 mg) was obtained from methyl
3-[2-chloro-4-[(thiazolidine-2,-
4-dione-5-ylidene)methyl]benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (80 mg).
[1221] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.67(2H, s),
6.70(1H, d, J=8 Hz), 7.42(1H, d, J=8 Hz), 7.75(1H, s), 7.84(1H, s),
8.01(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz). Mass(ESI): m/z 427 (M-1)
mp>300.degree. C.
Preparation Example 91-1
2-Chloro-4-fluorobenzyl alcohol
[1222] In the same manner as in Preparation Example 74-4, the
objective compound (4.20 g) was obtained as white crystals from
2-chloro-4-fluorobenzoic acid (5.00 g).
[1223] .sup.1H-NMR(CDCl.sub.3): 1.92(1H, br s), 4.75(2H, br d),
6.99(1H, dt, J=2, 8 Hz), 7.12(1H, dd, J=2, 8 Hz), 7.47(1H, t, J=7
Hz).
Preparation Example 91-2
2-Chloro-4-fluoro-1-((methanesulfonyloxy)methyl)benzene
[1224] In the same manner as in Preparation Example 14-1, the
objective compound (572 mg) was obtained as a colorless oil from
2-chloro-4-fluorobenzyl alcohol (400 mg) and methanesulfonyl
chloride (314 mg).
[1225] .sup.1H-NMR(CDCl.sub.3): 3.02(3H, s), 5.30(2H, s), 7.03(1H,
dt, J=2, 8 Hz), 7.20(1H, dd, J=2, 8 Hz), 7.49(1H, t, J=8 Hz).
Preparation Example 91-3
Methyl
3-(2-chloro-4-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate and methyl
1-(2-chloro-4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b-
]pyridine-5-carboxylate
[1226] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (100 mg) was obtained as white crystals and methyl
1-(2-chloro-4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (55 mg) was obtained as pale-yellow crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) and
2-chloro-4-fluoro-1-((methanesulfonyloxy)methyl)benzene (206
mg).
Methyl
3-(2-chloro-4-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1227] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 4.00(3H, s), 5.62(2H,
s), 6.70(1H, dt, J=1, 8 Hz), 6.85(1H, dt, J=2, 8 Hz), 7.20(1H, dd,
J=2, 8 Hz), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz).
Methyl
1-(2-chloro-4-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1228] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 4.02(3H, s), 5.40(2H,
s), 6.50(1H, dt, J=1, 8 Hz), 6.87(1H, dt, J=2, 8 Hz), 7.23(1H, dd,
J=2, 8 Hz), 7.53(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz).
Preparation Example 91-4
3-(2-Chloro-4-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[1229] In the same manner as in Preparation Example 4-7, the
objective compound (75 mg) was obtained as white crystals from
methyl
3-(2-chloro-4-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (90 mg).
[1230] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.59(2H, s),
6.67(1H, dt, J=1, 8 Hz), 7.11(1H, dt, J=1, 8 Hz), 7.60(1H, dd, J=2,
8 Hz), 8.01(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).
Preparation Example 92-1
2,4,6-Trichlorobenzyl alcohol
[1231] In the same manner as in Preparation Example 74-4, the
objective compound (4.14 g) was obtained as white crystals from
2,4,6-trichlorobenzoic acid (5.00 g).
[1232] .sup.1H-NMR(CDCl.sub.3): 2.04(1H, br s), 4.91(2H, s),
7.36(2H, s).
Preparation Example 92-2
2,4,6-Trichloro-1-((methanesulfonyloxy)methyl)benzene
[1233] In the same manner as in Preparation Example 14-1, the
objective compound (407 mg) was obtained as white crystals from
2,4,6-trichlorobenzyl alcohol (300 mg) and methanesulfonyl chloride
(179 mg).
[1234] .sup.1H-NMR(CDCl.sub.3): 3.08(3H, s), 5.48(2H, s), 7.42(2H,
s).
Preparation Example 92-3
Methyl
2-methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate and methyl
2-methyl-1-(2,4,6-trichlorobenzyl)-1H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1235] In the same manner as in Preparation Example 14-2, methyl
2-methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (129 mg) was obtained as white crystals and methyl
2-methyl-1-(2,4,6-trichlorobenzyl)-1H-imidazo[4,5-b]pyridine-5-carboxylat-
e (100 mg) was obtained as pale-yellow crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) and
2,4,6-trichloro-1-((methanesulfonyloxy)methyl)benzene (250 mg).
Methyl
2-methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[1236] .sup.1H-NMR(CDCl.sub.3): 2.46(3H, s), 4.00(3H, s), 5.79(2H,
s), 7.39(2H, s), 7.97(1H, d, J=1, 8 Hz), 8.07(1H, d, J=1, 8
Hz).
Methyl
2-methyl-1-(2,4,6-trichlorobenzyl)-1H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[1237] .sup.1H-NMR(CDCl.sub.3): 2.73(3H, s), 4.00(3H, s), 5.56(2H,
s), 7.34(1H, d, J=8 Hz), 7.44(2H, s), 7.98(1H, d, J=8 Hz).
Preparation Example 92-4
2-Methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1238] In the same manner as in Preparation Example 4-7, the
objective compound (83 mg) was obtained as white crystals from
2-methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (94 mg).
[1239] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.71(2H, s),
7.72(2H, s), 7.92(1H, d, J=8 Hz), 8.03(1H, d, J=8 Hz).
Preparation Example 93-1
2,3,4-trichlorobenzyl-bromide
[1240] 2,3,4-Trichlorotoluene (2.00 g) was dissolved in carbon
tetrachloride (20 ml), and
2,2'-azobis(2,4-dimethyl-4-methoxyvaleronitril- e) (158 mg) and
N-bromosuccinimide (2.00 g) were added thereto. The mixture was
refluxed under heating for 2 hr, and hexane was added, which was
followed by stirring under cooling for 30 min. The mixture was
filtrated and an insoluble matter on a filter paper was washed with
small amounts of hexane. The filtrates were combined and
concentrated under reduced pressure. Diisopropyl ether was added to
the residue and the mixture was washed successively with a
saturated aqueous sodium hydrogencarbonate solution and saturated
brine, dried over anhydrous magnesium sulfate and filtrated. The
filtrate was concentrated under reduced pressure to give a mixture
(2.40 g) of the objective compound and 2,3,4-trichlorotoluene as
brown crystals.
[1241] .sup.1H-NMR(CDCl.sub.3): 4.57(2H, s), 7.29(1H, d, J=8 Hz),
7.37(1H, d, J=8 Hz).
Preparation Example 93-2
Methyl
2-methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate and methyl
2-methyl-1-(2,3,4-trichlorobenzyl)-1H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1242] In the same manner as in Preparation Example 14-2, methyl
2-methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (196 mg) was obtained as white crystals and methyl
2-methyl-1-(2,3,4-trichlorobenzyl)-1H-imidazo[4,5-b]pyridine-5-carboxylat-
e (82 mg) was obtained as pale-brown crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg) and
2,3,4-trichlorobenzyl-bromide (1.44 g).
Methyl
2-methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.98(3H, s), 5.65(2H,
s), 6.43(1H, d, J=8 Hz), 7.23(1H, d, J=9 Hz), 8.07(1H, d, J=8 Hz),
8.15(1H, d, J=8 Hz).
Methyl
2-methyl-1-(2,3,4-trichlorobenzyl)-1H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[1243] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 4.03(3H, s), 5.42(2H,
s), 6.26(1H, d, J=8 Hz), 7.26(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz),
8.10(1H, d, J=8 Hz).
Preparation Example 93-3
2-Methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1244] In the same manner as in Preparation Example 4-7, the
objective compound (156 mg) was obtained as white crystals from
methyl
2-methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (185 mg).
[1245] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.62(2H, s),
6.52(1H, d, J=8 Hz), 7.52(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz).
Preparation Example 94-1
2,4-Dichloro-5-fluorobenzyl alcohol
[1246] In the same manner as in Preparation Example 74-4, the
objective compound (1.00 g) was obtained as white crystals from
2,4-dichloro-5-fluorobenzoic acid (1.25 g).
[1247] .sup.1H-NMR(CDCl.sub.3): 1.96(1H, t, J=7 Hz), 4.73(2H, d,
J=7 Hz), 7.35(1H, d, J=9 Hz), 7.40(1H, d, J=7 Hz).
Preparation Example 94-2
2,4-Dichloro-5-fluoro-1-((methanesulfonyloxy)methyl)benzene
[1248] In the same manner as in Preparation Example 14-1, the
objective compound (404 mg) was obtained as a colorless oil from
2,4-dichloro-5-fluorobenzyl alcohol (300 mg) and methanesulfonyl
chloride (194 mg).
[1249] .sup.1H-NMR(CDCl.sub.3): 3.08(3H, s), 5.27(2H, s), 7.32(1H,
d, J=9 Hz), 7.49(1H, d, J=7 Hz).
Preparation Example 94-3
Methyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (234 mg) and methyl
1-(2,4-dichloro-5-fluorobenzyl)-2-methyl-
-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1250] In the same manner as in Preparation Example 14-2, methyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine5-carbo-
xylate (234 mg) was obtained as white crystals, and methyl
1-(2,4-dichloro-5-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carb-
oxylate (86 mg) was obtained as pale-yellow crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg) and
2,4-dichloro-5-fluoro-1-((methanesulfonyloxy)methyl)benzene (314
mg).
Methyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1251] .sup.1H-NMR(CDCl.sub.3): 2.57(3H, s), 4.00(3H, s), 5.60(2H,
s), 6.53(1H, d, J=9 Hz), 7.52(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz),
8.17(1H, d, J=8 Hz).
Methyl
1-(2,4-dichloro-5-fluorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine--
5-carboxylate
[1252] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 4.03(3H, s), 5.38(2H,
s), 6.28(1H, d, J=9 Hz), 7.55(1H, d, J=8 Hz), 7.56(1H, d, J=8 Hz),
8.12(1H, d, J=8 Hz).
Preparation Example 94-4
3-(2,4-Dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1253] In the same manner as in Preparation Example 4-7, the
objective compound (198 mg) was obtained as white crystals from
methyl
3-(2,4-dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (215 mg).
[1254] .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s), 5.58(2H, s),
6.82(1H, d, J=9 Hz), 7.95(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz),
8.12(1H, dd, J=1, 8 Hz).
Preparation Example 95-1
2-Chloro-4-iodobenzyl-bromide
[1255] In the same manner as in Preparation Example 93-1, the the
objective compound (5.83 g) was obtained as a pale-yellow oil from
2-chloro-4-iodotoluene (5.10g).
[1256] .sup.1H-NMR(CDCl.sub.3): 4.52(2H, s), 7.17(1H, d, J=8 Hz),
7.60(1H, d, J=8 Hz), 7.76(1H, s).
Preparation Example 95-2
Methyl
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate and methyl
1-(2-chloro-4-iodobenzyl)-2-methyl-1H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1257] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (163 mg) and methyl
1-(2-chloro-4-iodobenzyl)-2-methyl-1H-imidazo[4,5-b]-
pyridine-5-carboxylate (108 mg) were obtained as pale-brown powder,
from methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate (150
mg) and 2-chloro-4-iodobenzyl bromide (780 mg).
Methyl
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[1258] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.99(3H, s), 5.62(2H,
s), 6.37(1H, d, J=8 Hz), 7.43(1H, d, J=8 Hz), 7.80(1H, s), 8.08(1H,
d, J=8 Hz), 8.16(1H, d, J=8 Hz).
Methyl
1-(2-chloro-4-iodobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carb-
oxylate
[1259] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 4.03(3H, s), 5.38(2H,
s), 6.20(1H, d, J=8 Hz), 7.48(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz),
7.83((1H, s), 8.09(1H, d, J=8 Hz).
Preparation Example 95-3
3-(2-Chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1260] In the same manner as in Preparation Example 4-7, the
objective compound (115 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (160 mg).
[1261] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.57(2H, s),
6.34(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz), 7.97(1H, s), 8.02(1H, d,
J=8 Hz), 8.12(1H, d, J=8 Hz).
Preparation Example 96-1
2,5-Dichloro-3-(hydroxymethyl)thiophene
[1262] In the same manner as in Preparation Example 76-2, the
objective compound (718 mg) was obtained as a pale-yellow oil from
methyl 2,5-dichlorothiophene-3-carboxylate (835 mg).
[1263] .sup.1H-NMR(CDCl.sub.3): 1.70 (1H, t, J=6 Hz), 4.58(2H, d,
J=6 Hz), 6.88(1H, s).
Preparation Example 96-2
2,5-Dichloro-3-((methanesulfonyloxy)methyl)thiophene
[1264] In the same manner as in Preparation Example 14-1, the
objective compound (384 mg) was obtained as a colorless oil from
2,5-dichloro-3-(hydroxymethyl)thiophene (300 mg) and
methanesulfonyl chloride (206 mg).
[1265] .sup.1H-NMR(CDCl.sub.3): 3.02(3H, s), 5.12(2H, s), 6.90(1H,
s).
Preparation Example 96-3
Methyl
3-((2,5-dichlorothiophen-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate and methyl
1-((2,5-dichlorothiophen-3-yl)methyl)-2-met-
hyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1266] In the same manner as in Preparation Example 14-2, methyl
3-((2,5-dichlorothiophen-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (87 mg) was obtained as white crystals and methyl
1-((2,5-dichlorothiophene-3-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-
-5-carboxylate (59 mg) was obtained as pale-yellow crystals, from
methyl 2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg)
and 2,5-dichloro-3-((methane-sulfonyloxy)methyl)thiophene (225
mg).
Methyl
3-((2,5-dichlorothiophene-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate:
[1267] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 4.03(3H, s), 5.42(2H,
s), 6.66(1H, s), 8.02(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz).
Methyl
1-((2,5-dichlorothiophene-3-yl)methyl)-2-methyl-1H-imidazo[4,5-b]py-
ridine-5carboxylate
[1268] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 4.02(3H, s), 5.20(2H,
s), 6.30(1H, s), 7.64(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz).
Preparation Example 96-4
3-((2,5-Dichlorothiophen-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1269] In the same manner as in Preparation Example 4-7, the
objective compound (67 mg) was obtained as white crystals from
methyl
3-((2,5-dichlorothiophen-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (77 mg).
[1270] .sup.1H-NMR(DMSO-d.sub.6): 2.60(3H, s), 5.43(2H, s),
6.94(1H, s), 7.99(1H, d, J=8 Hz), 8.07(1H, d, J=8 Hz).
Preparation Example 97-1
Methyl
3-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylate and methyl
1-(2-chloro-4,5-(methylenedioxy)benzyl)-2-
-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1271] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (169 mg) was obtained as white crystals and methyl
1-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e-5-carboxylate (75 mg) was obtained as white crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg) and
6-chloropiperonyl chloride (236 mg).
Methyl
3-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylate
[1272] .sup.1H-NMR(CDCl.sub.3): 2.56(3H, s), 4.00(3H, s), 5.59(2H,
s), 5.91(2H, s), 6.23(1H, s), 6.89(1H, s), 8.04 (1H, d, J=8 Hz),
8.14(1H, d, J=8 Hz).
Methyl
1-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-1H-imidazo[4,5-b]p-
yridine 5-carboxylate
[1273] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 4.02(3H, s), 5.33(2H,
s), 5.94(2H, s), 5.99(1H, s), 6.92(1H, s), 7.57 (1H, d, J=8 Hz),
8.08(1H, d, J=8 Hz).
Preparation Example 97-2
3-(2-Chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid
[1274] In the same manner as in Preparation Example 4-7, the
objective compound (144 mg) was obtained as yellow crystals from
methyl
3-(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (160 mg).
[1275] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 5.47(2H, s),
6.00(2H, s), 6.11(1H, s), 7.19(1H, s), 7.88(1H, d, J=8 Hz),
7.92(1H, d, J=8 Hz).
Preparation Example 98-1
[1276] In the same manner as in Preparation Example 14-1, a mixture
(377 mg) of 2-chloro-3-((methanesulfonyloxy)methyl)quinoline and
2-chloro-3-(chloromethyl)quinoline was obtained as a pale-yellow
powder from 2-chloro-3-(hydroxymethyl)quinoline (300 mg) and
methanesulfonyl chloride (89 mg). This compound was used in the
next reaction without purification.
Preparation Example 98-2
Methyl
3-((2-chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate and methyl
1-((2-chloroquinolin-3-yl)methyl)-2-methyl-1H-i-
midazo[4,5-b]pyridine-5-carboxylate
[1277] In the same manner as in Preparation Example 14-2, methyl
3-((2-chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (112 mg) was obtained as pale-yellow crystals and methyl
1-((2-chloroquinoline-3-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-c-
arboxylate (100 mg) was obtained as pale-yellow crystals, from
methyl 2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (200 mg)
and 2-chloro-3-((methanesulfonyloxy)methyl)quinoline (313 mg,
mixture with 2-chloro-3-(chloromethyl)quinoline).
Methyl
3-((2-chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1278] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 3.97(3H, s), 5.80(2H,
s), 7.39(1H, s), 7.50(1H, t, J=7 Hz), 7.58(1H, d, J=8 Hz), 7.72(1H,
t, J=8 Hz), 8.03(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz), 8.18(1H, dd,
J=1, 8 Hz).
Methyl
1-((2-chloroquinolin-3-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1279] .sup.1H-NMR(CDCl.sub.3): 2.70(3H, s), 4.03(3H, s), 5.59(2H,
s), 7.10(1H, s), 7.49-7.62(3H, m), 7.70-7.78(1H, m), 8.02-8.20(2H,
m).
Preparation Example 98-3
3-((2-Chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylic acid
[1280] In the same manner as in Preparation Example 4-7, the
objective compound (90 mg) was obtained as white crystals from
methyl
3-((2-chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (100 mg).
[1281] .sup.1H-NMR(DMSO-d.sub.6): 2.60(3H, s), 5.74(2H, s),
7.58(1H, t, J=7 Hz), 7.70(1H, s), 7.80(1H, t, J=8 Hz), 7.91(1H, d,
J=8 Hz), 8.00(2H, t, J=8 Hz), 8.16(1H, d, J=8 Hz).
Preparation Example 99-1
Methyl
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate and methyl
1-(2-chloro-4-(trifluoromethyl)benzyl)-2-m-
ethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1282] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate (129 mg) was obtained as white crystals and methyl
1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-
-5-carboxylate (129 mg) was obtained as white crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)benzene
(226 mg).
Methyl
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1283] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.99(3H, s), 5.71(2H,
s), 6.73(1H, d, J=8 Hz), 7.38(1H, d, J=8 Hz), 7.72(1H, s), 8.08(1H,
d, J=8 Hz), 8.17(1H, d, J=8 Hz).
Methyl
1-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-1H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1284] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 4.03(3H, s), 5.49(2H,
s), 6.57(1H, d, J=8 Hz), 7.40(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz),
7.76(1H, s), 8.10(1H, d, J=8 Hz).
Preparation Example 99-2
3-(2-Chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid
[1285] In the same manner as in Preparation Example 4-7, the
objective compound (103 mg) was obtained as white crystals from
methyl
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate (119 mg).
[1286] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.69(2H, s),
6.75(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz), 8.02(1H, d, J=8 Hz),
8.03(1H, s), 8.15(1H, d, J=8 Hz).
Preparation Example 100-1
Methyl
3-(1-bromonaphthalen-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate and methyl
1-(1-bromonaphthalen-2-ylmethyl)-2-methyl-1H-imi-
dazo[4,5-b]pyridine-5-carboxylate
[1287] In the same manner as in Preparation Example 14-2, methyl
3-(1-bromonaphthalen-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate (1122 mg) was obtained as white crystals and methyl
1-(1-bromonaphthalen-2-ylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-car-
boxylate (198 mg) was obtained as white crystals, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (150 mg) and
1-bromonaphthalen-2-ylmethyl bromide (259 mg).
Methyl
3-(1-bromonaphthalene-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1288] .sup.1H-NMR(CDCl.sub.3): 2.50(3H, s), 3.97(3H, s), 5.92(2H,
s), 6.65(1H, d, J=8 Hz), 7.56(1H, t, J=8 Hz), 7.64(2H, dt, J=1, 8
Hz), 7.77(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.17(1H, d, J=8 Hz),
8.37(1H, d, J=8 Hz).
Methyl
1-(1-bromonaphthalene-2-ylmethyl)-2-methyl-1H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1289] .sup.1H-NMR(CDCl.sub.3): 2.68(3H, s), 4.02(3H, s), 5.67(2H,
s), 6.52(1H, d, J=8 Hz), 7.53-7.60(2H, m), 7.68(2H, dt, J=2, 7 Hz),
7.81(1H, d), 8.07(1H, d), 8.36(1H, d, J=7 Hz).
Preparation Example 100-2
3-(1-Bromonaphthalen-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylic acid
[1290] In the same manner as in Preparation Example 4-7, the
objective compound (81 mg) was obtained as white crystals from
methyl
3-(1-bromonaphthalen-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate (105 mg).
[1291] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 5.83(2H, s),
6.62(1H, d, J=8 Hz), 7.62(1H, t, J=8 Hz), 7.75(1H, t, J=8 Hz),
7.86(1H, d, J=8 Hz), 7.96(1H, d, J=8 Hz), 8.03(1H, d, J=8 Hz),
7.17(1H, d, J=8 Hz), 8.31(1H, d, J=8 Hz).
Preparation Example 101
Methyl
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate and methyl
1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]p-
yridine-5-carboxylate
[1292] In the same manner as in Preparation Example 14-2, methyl
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (400 mg) was obtained as a white powder and methyl
1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxyla-
te (250 mg) was obtained as a pale-yellow powder, from methyl
2-methylimidazo[4,5-b]pyridine-5-carboxylate (400 mg) and
4-bromo-2-chloro-1-((methanesulfonyloxy)methyl)benzene (689
mg).
Methyl
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1293] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 4.00(3H, s), 5.62(2H,
s), 6.53(1H, d, J=8 Hz), 7.25(1H, d, J=8 Hz), 7.61(1H, s), 8.08(1H,
d, J=8 Hz), 8.16(1H, d, J=8 Hz). Mass(ESI): m/z 396 (M+1)
Methyl
1-(4-bromo-2-chlorobenzyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1294] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 4.01(3H, s), 5.49(2H,
s), 6.36(1H, d, J=8 Hz), 7.29(1H, d, J=8 Hz), 7.53(1H, d, J=8 Hz),
7.65(1H, s), 8.09(1H, d, J=8 Hz). Mass(ESI): m/z 396 (M+1)
Preparation Example 102-1
2,7-Dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide
[1295] To a solution of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine
(4.29 g) in chloroform (43 ml) was added m-chloroperbenzoic acid
(80%, 7.55 g) at room temperature, and the mixture was refluxed
under heating for 1 hr. After cooling to room temperature, the
reaction mixture was directly purified by silica gel column
chromatography (chloroform/methanol=9/1) and pulverized in ethyl
acetate to give the objective compound (4.61 g) as a brown
powder.
[1296] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 2.52(3H, s),
6.93(1H, d, J=5 Hz), 7.98(1H, d, J=5 Hz).
Preparation Example 102-2
5-Chloro-2,7-dimethyl-1H-imidazo[4,5-b]pyridine
[1297] A mixture of 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-4-oxide
(4.45 g) in chloroform (4.5 ml) and phosphorous oxychloride (25.4
ml) was stirred at 80.degree. C. for 3 hr and concentrated to
dryness under reduced pressure. The residue was poured to ice (75
g), and which was neutralized with aqueous ammonia under
ice-cooling. The mixture was stirred at room temperature for 30 min
and the precipitated solid was washed with water to give the
objective compound (3.66 g) as a gray powder.
[1298] .sup.1H-NMR(DMSO-d.sub.4): 2.49(3H, s), 2.52(3H, s),
7.08(1H, s).
Preparation Example 102-3
5-Bromo-2,7-dimethyl-1H-imidazo[4,5-b]pyridine
[1299] In the same manner as in Preparation Example 9-1, the
objective compound (4.07 g) was obtained as a brown solid from
6-chloro-2,7-dimethyl-1H-imidazo[4,5-b]pyridine (3.6 g).
[1300] .sup.1H-NMR(DMSO-d.sub.6): 2.44-2.57(6H, overlapped with
DMSO-d 6), 7.20(1H, s). Mass(ESI): m/z 226 (M-1)
Preparation Example 102-4
Methyl 2,7-dimethyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1301] In the same manner as in Preparation Example 110-4 to be
described later, the objective compound (2.44 g) was obtained as a
white powder from 5-bromo-2,7-dimethyl-1H-imidazo[4,5-b]pyridine
(4.02 g).
[1302] .sup.1H-NMR(CDCl.sub.3): 2.72(3H, s), 2.80(3H, s), 3.49(1H,
br s), 4.02(3H, s), 7.91(1H, s). Mass(ESI): m/e 206 (M+1).sup.+
Preparation Example 102-5
Methyl
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate
[1303] To a suspension of methyl
2,7-dimethyl-1H-imidazo[4,5-b]pyridine-5-- carboxylate (625 mg) in
N,N-dimethylformamide (6 ml) was added sodium hydride (70% in
mineral oil, 125 mg) under ice-cooling, and the mixture was stirred
for 30 min. 1-Bromonaphthalen-2-ylmethyl bromide (1.05 g) was added
to the reaction mixture, and the mixture was stirred under
ice-cooling for 3 hr. Diisopropyl ether (12 ml) was added to the
reaction mixture and the precipitate was collected by filtration to
give the objective compound (1.35 g) as a white powder.
[1304] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 2.75(3H, s), 3.98(3H,
s), 5.91(2H, s), 6.64(1H, d, J=8 Hz), 7.49-7.83(4H, m), 8.00 (1H,
s), 8.38 (1H, d, J=8 Hz). Mass(ESI): m/e 426 (M+1).sup.+
Preparation Example 102-6
3-(1-Bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5--
carboxylic acid
[1305] In the same manner as in Preparation Example 4-7, the
objective compound (1.01 g) was obtained as a white powder from
methyl
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (1.34 g).
[1306] .sup.1H-NMR(DMSO-d.sub.6): 2.49(3H, s), 2.62(3H, s),
5.82(2H, s), 6.53(1H, d, J=8 Hz), 7.55-8.00(5H, m), 8.29(1H, d, J=8
Hz). Mass(ESI): m/e 408, 410 (M-1).sup.-
Preparation Example 103-1
Methyl
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1307] In the same manner as in Preparation Example 102-6, the
objective compound (950 mg) was obtained as colorless crystals from
methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (550
mg) and 4-bromo-2-chloro-1-((methanesulfonyloxy)methyl)benzene (963
mg).
[1308] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, s), 2.73(3H, s), 3.98(3H,
s), 5.59(2H, s), 6.49(1H, d, J=8 Hz), 7.22(1H, d, J=8 Hz), 7.60(1H,
s), 7.99(1H, d, J=8 Hz).
Preparation Example 103-2
3-(4-Bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine5-carboxy-
lic acid
[1309] In the same manner as in Preparation Example 4-7, the
objective compound (870 mg) was obtained as colorless crystals from
methyl
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (950 mg).
[1310] .sup.1H-NMR(DMSO-d.sub.6): 2.49(3H, s), 2.62(3H, s),
5.55(2H, s), 6.47(1H, d, J=8 Hz), 7.43(1H, dd, J=8, 1 Hz), 7.85(1H,
d, J=1 Hz).
Preparation Example 104
Methyl
3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late
[1311] In the same manner as in Preparation Example 26-2, the
objective compound was obtained as a pale-yellow powder from
5-bromo-3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine.
[1312] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 3.99(3H, s), 5.63(2H,
s), 6.60(1H, d, J=8 Hz), 7.10(1H, dd, J=8 and 2 Hz), 7.47(1H, d,
J=2 Hz), 8.07(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz). Mass(ESI): m/e
350 (M+H).sup.+
Preparation Example 105-1
Methyl
3-(2-chloro-4-nitrobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1313] In the same manner as in Preparation Example 102-6, the
objective compound (759 mg) was obtained as a pale-brown powder
from methyl 2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (500
mg) and 2-chloro-1-((methanesulfonyloxy)methyl)-4-nitrobenzene (777
mg).
[1314] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 2.65(3H, s), 3.83(3H,
s), 5.68(2H, s), 6.82(1H, d, J=8 Hz), 7.90(1H, s), 8.08(1H, dd,
J=8, 2 Hz), 8.42(1H, d, J=2 Hz).
Preparation Example 105-2
3-(2-Chloro-4-nitrobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylic acid
[1315] In the same manner as in Preparation Example 4-7, the
objective compound (681 mg) was obtained as a pale-brown powder
from methyl
3-(2-chloro-4-nitrobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (755 mg).
[1316] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 2.62(3H, s),
5.69(2H, s), 6.77(1H, d, J=8 Hz), 7.85(1H, s), 8.05(1H, dd, J=8, 2
Hz), 8.40(1H, d, J=2 Hz).
Preparation Example 106-1
2-Amino-6-bromo-3-nitropyridine
[1317] To a suspension of 2,6-dibromo-3-nitropyridine (5.00 g) in
ethanol (10 ml) was added an ammonia/ethanol solution (6.8 M, 15
ml) at room temperature, and the mixture was placed in a closed
reaction vessel and stirred at room temperature for 19 hr. To the
reaction mixture was added water (25 ml), and the precipitate was
collected by filtration. The precipitate was washed with ethanol,
suspended in ethanol (55 ml), heated and cooled. The precipitate
was collected by filtration to give the objective compound (3.19 g)
as a yellow powder.
[1318] .sup.1H-NMR(DMSO-d.sub.6): 6.89(1H, d, J=8 Hz), 8.24(1H, d,
J=8 Hz), 8.25(2H, br s). Mass(ESI): m/e 216, 218 (M-H).sup.-
Preparation Example 106-2
2-(Acetamido)-6-bromo-3-nitropyridine
[1319] To a suspension of 2-amino-6-bromo-3-nitropyridine (23.9 g)
in acetic acid (48 ml) were added acetic anhydride (48 ml) and
sulfuric acid (2.9 ml), and the mixture was heated at 65.degree. C.
for 40 min. The mixture was uniform so that it quickly became a
suspension containing a precipitate. After cooling, the reaction
mixture was poured into cold water (480 ml) and the mixture was
stirred for 30 min. The precipitate was collected by filtration and
washed with water to give a crude product. The crude product was
suspended in ether (60 ml) and collected by filtration to give the
objective compound (27.2 g) as a pale-yellow powder.
[1320] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 7.33(1H, d, J=8 Hz),
8.33(1H, d, J=8 Hz), 9.95(1H, br s). Mass(ESI): m/e 258, 260
(M-H).sup.-
Preparation Example 106-3
6-Bromo-2-(N-(2-chloro-4-cyanobenzyl)acetamido)-3-nitropyridine
[1321] 2-(Acetamido)-6-bromo-3-nitropyridine (3.21 g) was dissolved
in dry N,N-dimethylformamide (16 ml), and sodium hydride (60% in
oil, 326 mg) was added under ice-cooling. The mixture was stirred
for 30 min. A solution of 2-chloro-4-cyanobenzyl bromide (2.34 g)
in dry N,N-dimethylformamide (4 ml) was dropwise added at the same
temperature, and the mixture was stirred at room temperature for 1
hr. The reaction mixture was poured into ice water and the mixture
was extracted with ethyl acetate. The organic layer was dried over
magnesium sulfate and concentrated to dryness under reduced
pressure. The residue was purified by silica gel column
chromatography (hexane/ethyl acetate=5/1) to give the objective
compound (4.17 g) as a pale-yellow powder.
[1322] .sup.1H-NMR(CDCl.sub.3): 2.17(3H, s), 5.39(2H, s), 7.54(1H,
d, J=8 Hz), 7.58(1H, d, J=8 Hz), 7.69(1H, s), 7.79(1H, d, J=8 Hz),
8.14(1H, d, J=8 Hz).
Preparation Example 106-4
5-Bromo-3-(2-chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[1323] To a solution of
6-bromo-2-(N-(2-chloro-4-cyanobenzyl)acetamido)-3-- nitropyridine
(21.8 g) in ethanol (33 ml)-acetic acid (8.3 ml) was added iron
powder (2.29 g) at room temperature, and the mixture was refluxed
under heating for 2 hr. The reaction mixture was cooled, the
insoluble matter was removed by filtration, and the solvent was
evaporated. To the residue was added dichloromethane, and the
product was extracted. The solvent was evaporated and the residue
was purified by silica gel column chromatography
(dichloromethane/methanol=30/1) to give the objective compound
(1.90 g) as a pale-yellow powder.
[1324] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 5.58(2H, s), 6.67(1H,
d, J=8 Hz), 7.41(1H, d, J=8 Hz), 7.44(1H, d, J=8 Hz), 7.75(1H, s),
7.87(1H, d, J=8 Hz). Mass(ESI): m/e 361, 363 (M+H).sup.+
Preparation Example 106-5
Methyl
3-(2-chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate
[1325] In the same manner as in Preparation Example 26-2, the
objective compound (482 mg) was obtained as a white powder from
5-bromo-3-(2-chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(546 mg).
[1326] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.98(3H, s), 5.70(2H,
s), 6.73(1H, d, J=8 Hz), 7.42(1H, d, J=8 Hz), 7.76(1H, s), 8.09(1H,
d, J=8 Hz), 8.16(1H, d, J=8 Hz). Mass(ESI): m/e 341 (M+H).sup.+
Preparation Example 106-6
3-(2-Chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid
[1327] In the same manner as in Preparation Example 4-7, the
objective compound (39 mg) was obtained as a pale-brown powder from
methyl
3-(2-chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (67 mg).
[1328] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.68(2H, s),
6.72(1H, d, J=8 Hz), 7.69(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz),
8.14(1H, d, J=8 Hz), 8.20(1H, s). Mass(ESI): m/e 325
(M-H).sup.-
Preparation Example 107-1
2-Chloro-4-phenyltoluene
[1329] In the same manner as in Preparation Example 11-2, the
objective compound (1.9 g) was obtained as a pale-brown oil from
2-chloro-4-iodotoluene (2.3g).
[1330] .sup.1H-NMR(CDCl.sub.3): 2.40(3H, s), 7.23-7.60(8H, m).
Preparation &le 107-2
2-Chloro-4-phenylbenzyl-bromide
[1331] In the same manner as in Preparation Example 93-1, the
objective compound (3.22 g) was obtained as colorless crystals from
2-chloro-4-phenyltoluene (3.6 g).
[1332] .sup.1H-NMR(CDCl.sub.3): 4.64(2H, s), 7.35-7.63(8H, m). mp
73-74.degree. C.
Preparation Example 107-3
6-Bromo-2-(N-(2-chloro-4-phenylbenzyl)acetamido)-3-nitropyridine
[1333] In the same manner as in Preparation Example 106-3, the
objective compound (1.6 g) was obtained as amorphous from
2-(acetamido)-6-bromo-3-n- itropyridine (1.0 g) and
2-chloro-4-phenylbenzyl bromide (1.1 g).
[1334] .sup.1H-NMR(CDCl.sub.3): 2.25(3H, br s), 5.42(2H, br s),
7.32-7.70(9H, m), 8.11(1H, d, J=8 Hz). Mass(ESI): m/z 458 (M-H)
Preparation Example 107-4
5-Bromo-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[1335] In the same manner as in Preparation Example 106-4, the
objective compound (2.80 g) was obtained as pale-yellow crystals
from
6-bromo-2-(N-(2-chloro-4-phenylbenzyl)acetamido)-3-nitropyridine
(3.56 g).
[1336] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.62(2H, s), 6.71(1H,
d, J=8 Hz), 7.32-7.55(7H, m), 7.68(1H, s), 7.92(1H, d, J=8 Hz).
Mass(ESI): m/z 414 (M+1)
Preparation Example 108-1
6-Bromo-2-(N-(2-chloro-4-(trifluoromethyl)benzyl)acetamido)-3-nitropyridin-
e
[1337] In the same manner as in Preparation Example 106-3, the
objective compound (2.60 g) was obtained from
2-(acetamido)-6-bromo-3-nitropyridine (2.00 g) and
2-chloro-1-((methanesulfonyloxy)methyl)-4-(trifluoromethyl)b-
enzene (2.33 g).
[1338] .sup.1H-NMR(CDCl.sub.3): 2.20(3H, br s), 5.40(2H, br s),
7.53(2H, d, J=8 Hz), 7.66(1H, br s), 7.78(1H, d, J=8 Hz), 8.12(1H,
d, J=8 Hz).
Preparation Example 108-2
5-Bromo-3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine
[1339] In the same manner as in Preparation Example 106-4, the
objective compound (1.55 g) was obtained as pale-yellow crystals
from
6-bromo-2-(N-(2-chloro-4-(trifluoromethyl)benzyl)acetamido)-3-nitropyridi-
ne (2.60 g).
[1340] .sup.1H-NMR(CDCl.sub.3): 2.51(3H, s), 5.59(2H, s), 6.68(1H,
d, J=8 Hz), 7.39(1H, br d, J=8 Hz), 7.41(1H, d, J=8 Hz), 7.73(1H,
br s), 7.88(1H, d, J=8 Hz). Mass(ESI): m/z 406 (M+1) mp
106-107.degree. C.
Preparation Example 108-3
Methyl
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1341] In the same manner as in Preparation Example 26-2, the
objective compound (1.47 g) was obtained as pale-brown crystals
from
5-bromo-3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine (1.50 g).
[1342] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.99(3H, s), 5.71(2H,
s), 6.73(1H, d, J=8 Hz), 7.38(1H, d, J=8 Hz), 7.72(1H, s), 8.08(1H,
d, J=8 Hz), 8.17(1H, d, J=8 Hz).
Preparation Example 109-1
2-Amino-6-bromo-3-nitropyridine hydrobromide
[1343] 2-Amino-6-chloro-3-nitropyridine (20.2 g) was suspended in a
30% hydrobomide/acetic acid solution (100 ml), and the suspension
was stirred at 90.degree. C. After 4 hours, a 30%
hydrobomide/acetic acid solution (100 ml) was added, and the
mixture was stirred for another 1 hour at 90.degree. C. Then, the
reaction mixture was stirred at 100.degree. C. for 8 hr while a
hydrobromic acid gas was introduced little by little.. The reaction
mixture was cooled, and the precipitate was collected by filtration
and washed with hexane to give the objective compound (33.0 g) as a
pale-yellow powder.
[1344] .sup.1H-NMR(DMSO-d.sub.6): 7.63(1H, d, J=8 Hz), 8.01(1H, d,
J=8 Hz).
Preparation Example 109-2
2-(Acetamido)-6-bromo-3-nitropyridine
[1345] In the same manner as in Preparation Example 106-2, the
objective compound (40.7 g) was obtained as a pale-yellow powder
from 2-amino-6-bromo-3-nitropyridine hydrobromide (50.0 g) and
acetic anhydride (100 ml).
[1346] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 7.34(1H, d, J=8 Hz),
8.34(1H, d, J=8 Hz), 9.98(1H, br s) Mass(ESI): m/e 260
(M-1).sup.-
Preparation Example 109-3
5-Bromo-2-methyl-1H-imidazo[4,5-b]pyridine
[1347] In the same manner as in Preparation Example 106-4, the
objective compound (2.48 g) was obtained as pale-yellow crystals
from 2-(acetamido)-6-bromo-3-nitropyridine (4.0 g).
[1348] .sup.1H-NMR(DMSO-d.sub.6): 2.51(3H, s), 7.32(1H, d, J=8 Hz),
7.83(1H, d, J=8 Hz). Mass(ESI): m/z 210(M-1) mp 239-241.degree.
C.
Preparation Example 109-4
Methyl 2-methyl-1H-imidazo[4,5-b]pyridine-5-carboxylate
[1349] Palladium acetate (1.18 g),
1,3-bis(diphenylphosphino)propane (2.31 g) and
5-bromo-2-methyl-1H-imidazo[4,5-b]pyridine (3.72 g) were placed in
an autoclave, and N,N-dimethylformamide (18.6 ml), methanol (14.9
ml) and triethylamine (5.4 ml) were added thereto. The mixture was
stirred at 85.degree. C. for 14 hr at 10 atm under a carbon
monoxide atmosphere. The reaction mixture was cooled and the
solvent was evaporated. To the residue was added methanol (60 ml),
and the mixture was heated. The insoluble matter was filtered off
while the mixture was hot. The filtrate was concentrated to give
the objective compound (2.95 g) as a white powder.
[1350] .sup.1H-NMR(CDCl.sub.3): 2.82(3H, s), 4.05(3H, s), 8.04(1H,
d, J=8 Hz), 8.10(1H, d, J=8 Hz). Mass(ESI): m/e 192 (M+1).sup.+
Preparation Example 110-1
6-Bromo-2-(N-(2,4-dichlorobenzyl)acetamido)-3-nitropyridine
[1351] In the same manner as in Preparation Example 106-3, the
objective compound (11.71 g) was obtained as a pale-yellow powder
from 2-(acetmaido)-6-bromo-3-nitropyridine (10.0 g) and
2,4-dichlorobenzyl chloride (8.3 g).
[1352] .sup.1H-NMR(CDCl.sub.3): 2.20(3H, br s), 5.33(2H, br s),
7.24(2H, d, J=8 Hz), 7.30-7.68(3H, m), 8.11(1H, d, J=8 Hz).
Preparation Example 110-2
5-Bromo-3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[1353] In the same manner as in Preparation Example 106-4, the
objective compound (4.27 g) was obtained as a pale-yellow powder
from 6-bromo-2-(N-(2,4-dichlorobenzyl)acetamido)-3-nitropyridine
(11.7 g).
[1354] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 5.50(2H, s), 6.54(1H,
d, J=8 Hz), 7.12(1H, dd, J=8 and 2 Hz), 7.39(1H, d, J=8 Hz),
7.47(1H, d, J=2 Hz), 7.86(1H, d, J=8 Hz). Mass(ESI): m/e 370, 372
(M+H).sup.+
Preparation Example 111-1
3-Chloro-4-methylbenzyl alcohol
[1355] In the same manner as in Preparation Example 74-4, the
objective compound (23.0 g) was obtained as a colorless oil from
3-chloro-4-methylbenzoic acid (25.0 g).
[1356] .sup.1H-NMR(CDCl.sub.3): 2.36(3H, s), 4.65(2H, s), 7.14(1H,
d, J=8 Hz), 7.23(1H, d, J=8 Hz), 7.36(1H, S)
Preparation Example 111-2
3-chloro-4-methylbenzaldehyde
[1357] To a solution of 3-chloro-4-methylbenzyl alcohol (2.00 g)
and triethylamine (8.9 ml) in a dimethyl sulfoxide (10 ml) was
added sulfur trioxide-pyridine complex (4.47 g) under ice-cooling,
and the mixture was stirred at room temperature for 3 hr. The
reaction mixture was poured into ice water, and extracted with
ether. The organic layer was washed with 1N hydrochloric acid,
saturated brine and a saturated aqueous sodium hydrogencarbonate
solution, dried over magnesium sulfate, and concentrated to dryness
under reduced pressure to give the objective compound (1.40 g) as a
pale-yellow oil.
[1358] .sup.1H-NMR(CDCl.sub.3): 2.46(3H, s), 4.65(2H, s), 7.40(1H,
d, J=8 Hz), 7.68(1H, d, J=8 Hz), 9.92(1H, s)
Preparation Example 111-3
2-Chloro-4-(E)-(2-phenylethenyl)toluene
[1359] In the same manner as in Preparation Example 73-3, the
objective compound (1.55 g) was obtained as a white powder from
3-chloro-4-methylbenzaldehyde (1.40 g) and diethyl benzyl
phosphonate(2.27 g).
[1360] .sup.1H-NMR(CDCl.sub.3): 2.38(3H, s), 7.00(1H, d, J=16 Hz),
7.08(11H, d, J=16 Hz), 7.18-7.53(8H)
Preparation Example 111-4
2-Chloro-4-(E)-(2-phenylethenyl)benzyl bromide
[1361] In the same manner as in Preparation Example 93-1, the
objective compound (309 mg) was obtained as a white powder from
2-chloro-4-(E)-(2-phenylethenyl)toluene (1.35 g).
[1362] .sup.1H-NMR(CDCl.sub.3): 4.61(2H, s), 7.01(1H, d, J=16 Hz),
7.14(1H, d, J=16 Hz), 7.24-7.57(8H)
Preparation Example 112-1
Methyl
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate
[1363] Methyl
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imida-
zo[4,5-b]pyridine-5-carboxylate (2.37 g) was dissolved in
methanol/chloroform=1/4 (24 ml), and platinum(IV) oxide (169 mg)
was added. The mixture was stirred under a hydrogen atmosphere at
normal pressure for 4 hours. Platinum(IV) oxide (169 mg) was added,
and the mixture was further stirred under a hydrogen atmosphere at
normal pressure for 6 hr. The reaction mixture was filtered through
Celite and the filtrate was concentrated to dryness under reduced
pressure. The obtained residue was subjected to silica gel column
chromatography (eluent: ethyl acetate/chloroform=1/3). The fraction
containing the objective compound was concentrated under reduced
pressure to give the objective compound (1.92 g) as a white
powder.
[1364] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 2.88(4H, s), 4.01(3H,
s), 5.64(2H, s), 6.53(1H, d, J=8 Hz), 6.89(1H, dd, J=2, 8 Hz),
7.12-7.30(6H, m), 8.04(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz)
Preparation Example 112-2
3-(2-Chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine5-c-
arboxylic acid
[1365] In the same manner as in Preparation Example 4-7, the
objective compound (1.79 g) was obtained as white crystals from
methyl
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (1.89 g).
[1366] .sup.1H-NMR(DMSO-d.sub.6): 2.50(4H, s), 2.84(3H, s),
5.57(2H, s), 6.45(1H, d, J=8 Hz), 7.09(1H, dd, J=2, 8 Hz),
7.15-7.20(5H, m), 7.43(1H, s) 7.99(1H, d, J=8 Hz), 8.12(1H, d, J=8
Hz)
Preparation Example 113-1
Ethyl 3-chloro4-methylbenzoate
[1367] In the same manner as in Preparation Example 74-2, the
objective compound (28.7 g) was obtained as a pale-yellow oil from
3-chloro-4-methylbenzoic acid (28.7 g).
[1368] .sup.1H-NMR(CDCl.sub.3): 1.39(3H, t, J=6 Hz), 2.43(3H, s),
4.38(2H, q, J=6 Hz), 7.29(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz),
8.02(1H, s)
Preparation Example 113-2
Ethyl 4-bromomethyl-3-chlorobenzoate
[1369] In the same manner as in Preparation Example 93-1, the
objective compound (39.9 g) was obtained as pale-yellow oil from
ethyl 3-chloro-4-methylbenzoate (28.7 g).
[1370] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=6 Hz), 4.39(2H, q,
J=6 Hz), 4.60(2H, s), 7.52(1H, d, J=8 Hz), 7.92(1H, d, J=8 Hz),
8.06(1H, s)
Preparation Example 113-3
6-Bromo-2-(N-(4-carboethoxy-2-chlorobenzyl)acetamido)-3-nitropyridine
[1371] In the same manner as in Preparation Example 106-3, the
objective compound (40.91 g) was obtained from
2-acetamido-6-bromo-3-nitropyridine (24.7 g) and ethyl
4-bromomethyl-3-chlorobenzoate (44.8 g).
[1372] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=6 Hz), 2.20(3H, s),
4.40(2H, q, J=6 Hz), 5.40(2H, s), 7.16-8.22(5H)
Preparation Example 113-4
5-Bromo-3-(2-chloro-4-(ethoxycarbonyl)benzyl)
-2-methyl-3H-imidazo[4,5-b]p- yridine
[1373] In the same manner as in Preparation Example 106-4, the
objective compound (32.0 g) was obtained as pale-yellow crystals
from
2-[N-acetyl-N-(2-chloro-4-(ethoxycarbonyl)benzyl)]amino-6-bromo-3-nitropy-
ridine (40.8 g).
[1374] .sup.1H-NMR(CDCl.sub.3): 1.38(3H, t, J=7.5 Hz), 4.36(2H, q,
J=7.5 Hz), 5.57(2H, s), 6.61(1H, d, J=8 Hz), 7.40(1H, d, J=8 Hz),
7.77(1H, d, J=8 Hz), 7.88(1H, d, J=8 Hz), 8.11(11H, s)
Preparation Example 113-5
3-(2-Chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1375] In a sealed tube,
5-bromo-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine (4.92 g) was dissolved in a mixture
of N,N-dimethylformamide (27.6 ml) and t-butanol (21.7 ml), and
triethylamine (2.84 g), 1,3-bis(diphenylphosphino)propane (1.59 g)
and palladium acetate (II) (865 mg) were added. After sealing, the
mixture was stirred under a carbon monoxide atmosphere at 10 atm
and 85.degree. C. for 24 hr. Triethylamine (1.42 g),
1,3-bis(diphenylphosphino)propane (795 mg) and palladium acetate
(II) (433 mg) were successively added. After sealing, the mixture
was stirred under a carbon monoxide atmosphere at 10 atm and
85.degree. C. for 12 hr. The reaction mixture was filtrated, and
the residue was washed with chloroform. The filtrate was
concentrated under reduced pressure. The residue was subjected to
silica gel column chromatography (eluent:
methanol/chloroform={fraction (1/49)}). The fraction containing the
objective compound was concentrated under reduced pressure. To the
residue was added ethyl acetate (50 ml), and the mixture was warmed
on a water bath. The reaction mixture was cooled with stirring at
room temperature. The precipitated crystals were collected by
filtration to give the objective compound (3.61 g) as pale-yellow
crystals.
[1376] .sup.1H-NMR(DMSO-d.sub.6): 1.30(3H, t, J=7 Hz), 2.50(3H, s),
4.28(2H, q, J=7 Hz), 5.08(2H, s), 6.70(1H, d, J=8 Hz), 7.76(1H, d,
J=8 Hz), 8.00-8.03(2H, m), 8.14(1H, d, J=8 Hz)
Preparation Example 114-1
5-Bromo-3-(2-chloro-4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine
[1377] In the same manner as in Preparation Example 76-2, the
objective compound (11.5 g) was obtained as pale-yellow crystals
from
5-bromo-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine (15.0 g).
[1378] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 4.47(2H, d, J=5 Hz),
5.32(1H, t, J=5 Hz), 5.50(2H, s), 6.55(1H, d, J=8 Hz), 7.16(1H, d,
J=8 Hz), 7.44(1H, d, J=8 Hz),7.48(1H, s), 7.99(1H, d, J=8 Hz)
MS(ESI) m/e: 366,368.
Preparation Example 114-2
Methyl
3-(2-chloro4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylate
[1379] In the same manner as in Preparation Example 26-2, the
objective compound (9.95 g) was obtained as pale-yellow crystals
from
5-bromo-3-(2-chloro-4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine (12.7 g).
[1380] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 3.86(3H, s),
4.46(2H, d, J=5 Hz), 5.31(1H, t, J=3 Hz), 5.59(2H, s), 6.53(1H, d,
J=8 Hz), 7.14(1H, d, J=8 Hz), 7.49(1H, s), 8.02(1H, d, J=8 Hz),
8.15(1H, d, J=8 Hz) MS(ESI) m/e: 346(M+H), 691(2M+H),
713(2M+Na).
Preparation Example 114-3
Methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imida-
zo[4,5-b]pyridine-5-carboxylate
[1381] In the same manner as in Preparation Example 14-1, the
objective compound (4.2 g) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-(hydroxymethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (3.6 g) and methanesulfonyl chloride (1.43 g).
[1382] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 3.00(3H, s), 4.00(3H,
s), 5.16(2H, s), 5.68(2H, s), 6.65(1H, d, J=8 Hz), 7.15(1H, d, J=8
Hz), 7.51(1H, s), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz) MS(ESI)
m/e: 424(M+H), 446(M+Na).
Preparation Example 114-4
Methyl
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1383] In the same manner as in Example 118 described later, the
objective compound (1.94 g) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (2.8 g).
[1384] .sup.1H-NMR(CDCl.sub.3): 2.54(3H, s), 4.00(3H, s), 5.01(2H,
s), 5.69(2H, s), 6.63(1H, d, J=8 Hz), 6.91-7.01(3H, m), 7.16(1H, d,
J=8 Hz), 7.25-7.34(2H, m), 7.55(1H, s), 8.07(1H, d, J=8 Hz),
8.15(1H, d, J=8 Hz) MS(ESI) m/e: 422(M+H).
Preparation Example 114-5
3-(2-Chloro-4-((phenyloxy)methyl)benzyl)-2
methyl-3H-imidazo[4,5-b]pyridin- e-5-carboxylic acid
[1385] In the same manner as in Preparation Example 4-7, the
objective compound (1.54 g) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (1.94 g).
[1386] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.08(2H, s),
5.64(2H, s), 6.52(1H, br peak), 6.89-7.03(3H, m), 7.23-7.34(3H, m),
7.64(1H, s), 7.98(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz) MS(ESI) m/e:
406(M-H).
Preparation Example 115-1
Methyl
3-(2-chloro-4-(dimethylaminomethyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine-5-carboxylate
[1387] In the same manner as in Preparation Example 116-1 described
later, the objective compound (128 mg) was obtained as pale-yellow
crystals from methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine-5-carboxylate (200 mg) and dimethylamine
hydrochloride (115 mg).
[1388] .sup.1H-NMR(CDCl.sub.3): 2.25(6H, s), 2.52(3H, s), 3.40(2H,
s), 3.99(3H, s), 5.67(2H, s), 6.58(1H, d, J=8 Hz), 7.06(1H, d, J=8
Hz), 7.45(1H, s), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz) MS(ESI)
m/e: 373(M+H)
Preparation Example 115-2
3-(2-Chloro-4-(dimethylaminomethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine5-carboxylic acid
[1389] In the same manner as in Preparation Example 4-7, the
objective compound (116 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-(dimethylaminomethyl)benzyl)-2-methyl-3H-idazo[4,5-b]pyridi-
ne-5-carboxylate (120 mg).
[1390] .sup.1H-NMR(DMSO-d.sub.6): 2.45-2.61(9H, m), 4.04(2H, br
peak), 5.63(2H, s), 6.62(1H, d, J=8 Hz), 7.33(1H, d, J=8 Hz),
7.74(1H, s), 8.01(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz) MS(ESI) m/e:
357(M-H)
Preparation Example 116-1
Methyl
3-(2-chloro4-((imidazol-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate
[1391] To a solution of methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)b-
enzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in
dichloromethane (6.0 ml) was added imidazole (193 mg), and the
mixture was stirred at room temperature overnight. The reaction
mixture was poured into water and extracted with chloroform. The
organic layer was washed with saturated brine, dried over magnesium
sulfate and concentrated to dryness under reduced pressure. The
residue was washed with diethyl ether, and collected by filtration
to give the objective compound (213 mg) as a pale-yellow
powder.
[1392] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 3.99(3H, s), 5.08(2H,
s), 5.65(2H, s), 6.62(1H, d, J=8 Hz), 6.84-6.93(2H, m), 7.11(1H,
s), 7.21(1H, s), 7.53(1H, s), 8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8
Hz) MS(ESI) m/e: 396(M+H).
Preparation Example 116-2
3-(2-Chloro-4-((imidazol-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid
[1393] In the same manner as in Preparation Example 4-7, the
objective compound (204 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((imidazol-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate (235 mg).
[1394] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.21(2H, s),
5.58(2H, s), 6.65(1H, d, J=8 Hz), 7.00(1H, s), 7. 10(1H, d, J=8
Hz), 7.26(1H, s), 7.47(1H, s), 7.93(1H, s), 7.99(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz) MS(ESI) m/e: 380.1(M-H).
Preparation Example 117-1
Methyl
3-(2-chloro-4-((piperidin-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine-5-carboxylate
[1395] In the same manner as in Preparation Example 116-1, the
objective compound (174 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (200 mg) and piperidine (80 mg).
[1396] .sup.1H-NMR(CDCl.sub.3): 1.36-1.48(2H, m), 1.48-1.64(4H,
m),2.27-2.40(4H, m), 2.54(3H, s), 3.40(2H, s), 4.00(3H, s),
5.66(2H, s), 6.54(1H, d, J=8 Hz), 7.04(1H, d, J=8 Hz), 7.43(1H, s),
8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz) MS(ESI) m/e:
413.2(M+H)
Preparation Example 117-2
3-(2-Chloro-4-((piperidin-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid
[1397] In the same manner as in Preparation Example 4-7, the
objective compound (153 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((piperidin-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylate (169 mg).
[1398] .sup.1H-NMR(DMSO-d.sub.6): 1.45(2H, br peak), 1.64(4H, br
peak), 2.54(3H, s), 2.79(4H, br peak), 4.02(2H, br peak), 5.62(2H,
s), 6.60(1H, d, J=8 Hz), 7.31(1H, d, J=8 Hz), 7.73(1H, s), 8.00(1H,
d, J=8 Hz), 8.15(1H, d, J=8 Hz) MS(ESI) m/e: 399.3(M+H).
Preparation Example 118-1
Methyl
3-(2-chloro4-(phenylthiomethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1399] In the same manner as in Example 118 described later, the
objective compound (182 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (200 mg) and thiophenol (62 mg).
[1400] .sup.1H-NMR(CDCl.sub.3): 2.50(3H, s), 4.00(3H, s), 4.01(2H,
s), 5.63(2H, s), 6.51(1H, d, J=8 Hz), 6.98(1H, d, J=8 Hz),
7.15-7.30(5H, m), 7.36(1H, s), 8.04(1H, d, J=8 Hz), 8.14(1H, d, J=8
Hz) MS(ESI) m/e: 438
Preparation Example 118-2
3-(2-Chloro-4-(phenylthiomethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
5-carboxylic acid
[1401] The objective compound (191 mg) was obtained as pale-yellow
crystals from methyl
3,(2-chloro-4-(phenylthiomethyl)benzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine-5-carboxylate (217 mg).
[1402] .sup.1H-NMR(DMSO-d.sub.6): 2.47(3H, s), 4.21(2H, s),
5.58(2H, s), 6.50(1H, d, J=8 Hz), 7.11-7.22(2H, m), 7.22-7.34(4H,
m), 7.53(1H, s), 8.00(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz) MS(ESI)
m/e: 422(M-H)
Preparation Example 119-1
Methyl
3-(4-((benzyloxy)methyl)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1403] To a suspension of methyl.
3-(2-chloro-4-(hydroxymethyl)benzyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (400 mg) in
dimethylformamide (8.0 ml) were added sodium hydride (51 mg) and
benzyl bromide (277 mg) under ice-cooling, and the mixture was
stirred at the same temperature for 4 hr. The reaction mixture was
concentrated under reduced pressure. Chloroform and sodium
hydrogencarbonate were added to the residue, and the mixture was
partitioned. The organic layer was washed with saturated brine and
dried over magnesium sulfate. The solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
(eluent: chloroform:methanol=50:1) to give the objective compound
(322 mg) as a pale-yellow powder.
[1404] .sup.1H-NMR(CDCl.sub.3): 2.53(3H, s), 3.99(3H, s), 4.48(2H,
s), 4.55(2H, s), 5.66(2H, s), 6.59(1H, d, J=8 Hz), 7.08(1H, d, J=8
Hz), 7.26-7.41(5H, m), 7.46(1H, s), 8.06(1H, d, J=8 Hz), 8.15(1H,
d, J=8 Hz) MS(ESI) m/e: 436.
Preparation Example 119-2
3-(4-((Benzyloxy)methyl)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid
[1405] In the same manner as in Preparation Example 4-7, the
objective compound (232 mg) was obtained as pale-yellow crystals
from methyl
3-(4-((benzyloxy)methyl)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (352 mg).
[1406] .sup.1H-NMR(DMSO-d.sub.6): 4.51(4H, s-like), 5.62(2H, s),
6.55(1H, d, J=8 Hz), 7.21(1H, d, J=8 Hz), 7.24-7.40(5H, m),
7.53(1H, 5), 8.01(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) MS(ESI) m/e:
420(M-H)
Preparation Example 120-1
5-Bromo-3-(4-carboxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
[1407] In the same manner as in Preparation Example 4-7, the
objective compound (5.3 g) was obtained as pale-yellow crystals
from
5-bromo-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine (6.0 g).
[1408] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.57(2H, s),
6.70(1H, d, J=8 Hz), 7.45(1H d, J=8 Hz), 7.79(1H, d, J=8 Hz),
7.95-8.09(2H, m) MS(ESI) m/e: 378, 380, 382.
Preparation Example 120-2
5-Bromo-3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine
[1409] To a solution of
5-bromo-3-(4-carboxy-2-chlorobenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine (2.75 g) in N,N-dimethylformamide (30 ml)
were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (1.66 g), 1-hydroxybenzotriazole (1.37 g) and
1,2-phenylenediamine (781 mg) at room temperature, and the mixture
was stirred for 1 hr. The reaction mixture was allowed to stand
under the same conditions overnight and concentrated to dryness
under reduced pressure. The residue was partitioned between
chloroform and a saturated aqueous sodium hydrogencarbonate
solution. The partially precipitated solid was collected by
filtration. The organic layer was dried over magnesium sulfate, and
the solvent was evaporated under reduced pressure. The
previously-collected solid and the residue were combined and washed
with ether to give the amide compound (2.97 g).
[1410] To the suspension of the obtained amide compound (2.97g) in
ethanol (100 ml) was added p-toluenesulfonic acid monohydrate (150
mg), and the mixture was refluxed under heating for 48 hr. The
residue was partitioned between chloroform and a saturated aqueous
sodium hydrogencarbonate solution. The aqueous layer was further
extracted with a mixture of chloroform and methanol (10:1). The
combined organic layers were dried over magnesium sulfate, and the
solvent was evaporated under reduced pressure. The residue was
washed with ethyl acetate and collected by filtration to give the
object compound (2.39 g) as a pale-yellow powder.
[1411] .sup.1H-NMR(DMSO-.sub.6): 2.52(3H, s), 5.59(2H, s),
6.81(11H, d, J=8 Hz), 7.17-7.26(2H, m), 7.47(1H, d, J=8 Hz),
7.55-7.65(2H, m), 7.97-8.06(2H, m), 8.33(1H, s) MS(ESI) m/e: 450,
452, 454
Preparation Example 120-3
Methyl
3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1412] In the same manner as in Preparation Example 26-2, the
objective compound (1.38 g) was obtained as pale-yellow crystals
from
5-bromo-3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5--
b]pyridine (1.85 g).
[1413] .sup.1H-NMR(DMSO-d.sub.6): 2.58(3H, s), 3.86(3H, s),
5.68(2H, s), 6.80(1H, d, J=8 Hz), 7.17-7.27(2H, m), 7.55-7.66(2H,
m), 7.98-8.09(2H, m), 8.19(1H, d, J=8 Hz), 8.35(1H, s) MS(ESI) m/e:
430(M-H).
Preparation Example 120-4
3-[4-(Benzimidazole-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid
[1414] In the same manner as in Preparation Example 4-7, the
objective compound (260 mg) was obtained as pale-yellow crystals
from methyl
3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (300 mg).
[1415] .sup.1H-NMR(DMSO-.sub.6): 2.58(3H, s), 5.70(2H, s), 6.81(1H,
d, J=8 Hz), 7.21-7.31(2H, m), 7.60-7.69(2H, m), 7.98-8.06(2H, m),
8.16(1H, d, J=8 Hz), 8.37(1H, s) MS(ESI) m/e: 416(M-H).
Preparation Example 121-1
Methyl
2-methyl-3-[4-(1-methylbenzimidazol-2-yl)-2-chlorobenzyl]-3H-imidaz-
o[4,5-b]pyridine-5-carboxylate
[1416] A mixture of
3-[4-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-i-
midazo[4,5-b]pyridine-5-carboxylate (325 mg), methyl iodide (107
mg), potassium carbonate (198 mg) and dimethylformamide (10 ml) was
stirred at room temperature overnight and concentrated to dryness
under reduced pressure. The residue was suspended in chloroform and
washed with a saturated aqueous sodium hydrogencarbonate solution
and then with saturated brine. The organic layer was dried over
magnesium sulfate and concentrated to dryness under reduced
pressure. The residue was pulverized in ether to give the objective
compound (282 mg) as a pale-yellow powder.
[1417] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 3.85(3H, s), 4.01(3H,
s), 5.78(2H, s), 6.77(1H, d, J=8 Hz), 7.27-7.44(3H, m), 7.50(1H, d,
J=8 Hz), 7.76-7.84(1H, m), 7.95( 1H, s), 8.10(1H, d, J=8 Hz),
8.17(1H, d, J=8 Hz) MS(ESI) m/e: 446(M+H)
Preparation Example 121-2
2-Methyl-3-[4-(
1-methylbenzimidazol-2-yl)-2-chlorobenzyl]-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid
[1418] In the same manner as in Preparation Example 4-7, the
objective compound (215 mg) was obtained as pale-yellow crystals
from methyl 2-methyl-3-[4-(
1-methylbenzimidazol-2-yl)-2-chlorobenzyl]-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (268 mg).
[1419] .sup.1H-NMR(DMSO-d.sub.6): 2.59(3H, s), 3.88(3H, s),
5.74(2H, s), 6.72(1H, d, J=8 Hz), 7.20-7.40(2H, m), 7.59-7.80(3H,
m), 7.98-8.13(2H, m), 8.18(1H, d, J=8 Hz) MS(ESI) m/e:
430(M-H).
Preparation Example 122-1
Methyl
3-((benzimidazol-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine5-c-
arboxylate and methyl
1-((benzimidazol-2-yl)methyl)-2-methyl-1H-imidazol4,-
5-b]pyridine-5-carboxylate
[1420] In the same manner as in Preparation Example 14-2, methyl
3-((benzimidazol-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylate (20 mg) and methyl
1-((benzimidazol-2-yl)methyl)-2-methyl-1H-imidazo-
[4,5-b]pyridine-5-carboxylate (20 mg) were obtained both as brown
powder from methyl 2-methylimidazo[4,5-b]pyridine-5-carboxylate
(100 mg).
Methyl
3-((benzimidazol-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate
[1421] .sup.1H-NMR(CDCl.sub.3): 2.88(3H, s), 4.10(3H, s), 5.69(2H,
s), 7.20-7.80(4H), 8.03(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz)
Methyl
1-((benzimidazol-2-yl)methyl)-2-methyl-1H-imidazo[4,5-b]pyridine-5--
carboxylate
[1422] .sup.1H-NMR(CDCl.sub.3): 2.30(3H, s), 3.83(3H, s), 5.66(2H,
s), 7.18-7.88(6H)
Preparation Example 122-2
Methyl
3-[(1-ethylbenzimidazol-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate
[1423] In the same manner as in Preparation Example 121-1, the
objective compound (192 mg) was obtained as yellow crystals from
methyl
3-[(benzimidazol-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylate (380 mg) and ethyl iodide (194 mg).
[1424] .sup.1H-NMR(CDCl.sub.3): 1.08(3H, t, J=7.5 Hz), 2.85(3H, s),
4.04(3H, s), 4.51(2H, q, J=7.5 Hz), 5.83(2H, s), 7.23-7.38(3H, m),
7.71-7.80(1H, m), 8.02(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) MS(ESI)
m/e: 350(M+H).
Preparation Example 122-3
3-[(1-Ethylbenzimidazol-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylic acid
[1425] In the same manner as in Preparation Example 4-7, the
objective compound (110 mg) was obtained as pale-yellow crystals
from methyl
3-[(1-ethylbenzimidazol-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (226 mg).
[1426] .sup.1H-NMR(DMSO-d.sub.6): 1.33(3H, t, J=7.5 Hz), 2.68(3H,
s), 4.53(2H, q, J=7.5 Hz), 5.91(2H, s), 7.14(1H, t, J=8 Hz),
7.24(1H, t, J=8 Hz), 7.50(1H, d, J=8 Hz), 7.60(1H, d, J=8 Hz),
8.00(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz) MS(ESI) m/e: 334(M-H)
Preparation Example 123-1
2-Chloro4-(thiophen-2-yl)toluene
[1427] In the same manner as in Preparation Example 11-2, the
objective compound (6.50 g) was obtained from
2-chloro-4-iodotoluene (7.89 g) and thiophene-2-boric acid (4.8
g).
[1428] .sup.1H-NMR(CDCl.sub.3): 2.38(3H, s), 7.07(1H, dd, J=5, 4
Hz), 7.22(1H, d, J=8 Hz), 7.24-7.30(2H), 7.39(1H, d, J=8 Hz),
7.60(1H, s)
Preparation Example 123-2
2-Chloro4-(thiophen-2-yl)benzyl bromide
[1429] In the same manner as in Preparation Example 93-1, the
objective compound (1.35 g) was obtained from
2-chloro-4-(thiophen-2-yl)toluene (1.00 g).
[1430] .sup.1H-NMR(CDCl.sub.3): 4.61(2H, s), 7.09(1H, t, J=4 Hz),
7.30-7.52(4H), 7.63(1H, s)
Preparation Example 123-3
6-Bromo-2-(N-(2-chloro-4-(thiophen-2-yl)benzyl)acetamido)
-3-nitropyridine
[1431] In the same manner as in Preparation Example 106-3, the
objective compound (1.60 g) was obtained from
2-acetamido-6-bromo-3-nitropyridine (1.24 g) and
2-chloro-4-(thiophen-2-yl)benzyl bromide (1.35 g).
[1432] .sup.1H-NMR(CDCl.sub.3): 2.24(3H, br. s), 5.39(2H, br. s),
7.09(1H, t, J=4 Hz), 7.29-7.34(2H), 7.50(1H, br. d, J=8 Hz),
7.62(1H, br. d, J=8 Hz), 8.11(1H, d, J=8 Hz)
Preparation Example 123-4
5-Bromo-3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine
[1433] In the same manner as in Preparation Example 106-4, the
objective compound (647 mg) was obtained from
6-bromo-2-(N-(2-chloro-4-(thiophen-2--
yl)benzyl)acetamido)-3-nitropyridine (836 mg).
[1434] .sup.1H-NMR(CDCl.sub.3): 2.52(3H, br. s), 5.56(2H, s),
6.60(11H, d, J=8 Hz), 7.08(1H, t, J=5 Hz), 7.26-7.42(4H), 7.67(1H,
s), 7.87(1H, d, J=8 Hz)
Preparation Example 123-5
Methyl
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-idazo[4,5-b]pyridi-
ne-5-carboxylate
[1435] In the same manner as in Preparation Example 26-2, the
objective compound (4.0 g) was obtained as pale-yellow crystals
from
5-bromo-3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine (4.7 g).
[1436] .sup.1H-NMR(CDCl.sub.3): 2.56(3H, s), 4.00(3H, s), 5.69(3H,
s), 6.64(1H, d, J=8 Hz), 7.07(1H, dd, J=5, 4 Hz), 7.22-7.37(3H, m),
7.67(1H, d, J=2 Hz), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz)
MS(ESI) m/e: 398.0(M+H).
Preparation Example 124-1
Methyl
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1437] In the same manner as in Preparation Example 102-5, the
objective F compound (1.48 g) was obtained as colorless crystals
from methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
(900 mg).
[1438] mp 202-204.degree. C. .sup.1H-NMR(CDCl.sub.3): 2.58(3H, s),
2.75(3H, s), 3.99(3H, s), 5.70(2H, s), 6.65(1H, d, J=8 Hz),
7.23-7.45(4H, m), 7.51(2H, d, J=8 Hz), 7.66(1H, s), 7.99(1H, s)
MS(ESI) m/z: 406(M+1)
Preparation Example 124-2
Methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1439] In the same manner as in Preparation Example 14-2, the
objective compound (4.60 g) was obtained as colorless crystals from
2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (2.85 g).
[1440] mp 160-164.degree. C. .sup.1H-NMR(CDCl.sub.3): 2.57(3H, s),
2.75(3H, s), 4.00(3H, s), 5.67(2H, s), 6.61(1H, d, J=8 Hz),
7.07(1H, t, J=4 Hz), 7.25-7.35(3H, m), 7.67(1H, d, J=1 Hz),
7.99(1H, d, J =8 Hz), 8.16(1H, d, J=8 Hz) MS(ESI) m/z:
412(M+1).
Preparation Example 125-1
3-(2-Chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1441] In the same manner as in Preparation Example 4-7, the
objective compound (1.33 g) was obtained as colorless crystals from
methyl
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylate (1.45 g).
[1442] mp>250.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 2.55(3H, s),
2.64(3H, s), 5.64(2H, s), 6.56(1H, d, J=8 Hz), 7.35-7.54(4H, m),
7.62-7.67(2H, m), 7.84-7.89(2H, m) MS(ESI) m/z: 392(M+1).
Preparation Example 125-2
3-[2-Chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid
[1443] In the same manner as in Preparation Example 4-7, the
objective compound (1.81 g) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (2.0 g).
[1444] mp>250.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s),
2.64(3H, s), 5.61(2H, s), 6.55(1H, d, J=8 Hz), 7.14(1H, t, J=4 Hz),
7.49(1H, dd, J=8, 1 Hz), 7.58(1H, s), 7.60(1H, br s), 7.87(2H, s)
MS(ESI) m/z: 396(M-1)
Preparation Example 126-1
Methyl
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidaz-
o[4,5-b]pyridine-5-carboxylate
[1445] In the same manner as in Preparation Example 66-1, the
objective compound (1.72 g) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (2.55 g).
[1446] .sup.1H-NMR(CDCl.sub.3): 2.55(3H, s), 2.74(3H, s), 3.98(3H,
s), 5.60(2H, s), 6.60(1H, d, J=8 Hz), 6.88(1H, d, J=4 Hz), 7.04(1H,
d, J=4 Hz), 7.21(1H, dd, J=8, 1 Hz), 7.57(1H, d, J=1 Hz), 7.98(1H,
s) MS(ESI) m/z: 446(M+1)
Preparation Example 126-2
3-[2-Chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylic acid
[1447] In the same manner as in Preparation Example 4-7, the
objective compound (1.08 g) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylate (1.23 g).
[1448] mp>250.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s),
2.63(3H, s), 5.60(2H, s), 6.54(1H, d, J=8 Hz), 7.17(1H, d, J=4 Hz),
7.42(1H, dd, J=8, 1 Hz), 7.49(1H, d, J=4 Hz), 7.84-7.88(2H, m)
MS(ESI) m/z: 430(M-1).
Preparation Example 127-1
Methyl 2-chloro-4-(n-pentanethio)benzoate
[1449] In the same manner as in Preparation Example 80-1, the
objective compound (438 mg) was obtained-as a colorless oil from
methyl 4-bromo-2-chlorobenzoate (1 g).
[1450] .sup.1H-NMR(CDCl.sub.3): 0.90(3H, t, J=8 Hz), 1.29-1.51(4H,
m), 1.64-1.76(2H, m), 2.96(2H, t, J=8 Hz), 3.90(3H, s), 7.14(1H,
dd, J=8, 1 Hz), 7.29(1H, d, J=1 Hz)
Preparation Example 127-2
Methyl 4-benzylthio-2-chlorobenzoate
[1451] In the same manner as in Preparation Example 80-1, the
objective compound (908 mg) was obtained as a colorless oil from
methyl 4-bromo-2-chlorobenzoate (1 g).
[1452] .sup.1H-NMR(CDCl.sub.3): 3.91(3H, s), 4.19(2H, s), 7.15(1H,
dd, J=8, 1 Hz), 7.23-7.43(6H, m), 7.75(1H, d, J=8 Hz)
Preparation Example 127-3
Methyl 2-chloro-4-ethylthiobenzoate
[1453] In the same manner as in Preparation Example 80-1, the
objective compound (2.01 g) was obtained as a colorless oil from
methyl 4-bromo-2-chlorobenzoate (3.65 g).
[1454] .sup.1H-NMR(CDCl.sub.3): 1.37(3H, t, J=7.5 Hz), 3.01(2H, q,
J=7.5 Hz), 3.91(3H, s), 7.15(1H, dd, J=8, 1 Hz), 7.29(1H, d, J=1
Hz), 7.78(1H, d, J=8 Hz)
Preparation Example 128-1
2-Chloro-4-(n-pentanethio)benzyl alcohol
[1455] In the same manner as in Preparation Example 80-2, the
objective compound (354mg) was obtained as a colorless oil from
methyl 2-chloro-4-(n-pentanethio)benzoate (430 mg).
[1456] .sup.1H-NMR(CDCl.sub.3): 0.90(3H, t, J=8 Hz), 1.29-1.49(4H,
m), 1.60-1.72(2H, m), 1.89(1H, t, J=5 Hz), 2.91(2H, t, J=8 Hz),
4.74(2H, d, J=5 Hz), 7.20(1H, d, J=8 Hz), 7.29(1H, br s), 7.38(1H,
d, J=8 Hz)
Preparation Example 128-2
4-Benzylthio-2-chlorobenzyl alcohol
[1457] In the same manner as in Preparation Example 80-2, the
objective compound (787 mg) was obtained as a colorless oil from
methyl 4-benzylthio-2-chlorobenzoate (900 mg).
[1458] .sup.1H-NMR(CDCl.sub.3): 1.88(1H, t, J=7 Hz), 4.11(3H, s),
4.73(2H, d, J=7 Hz), 4.19(2H, s), 7.19(1H, d, J=8 Hz),
7.21-7.32(6H, m), 7.36(1H, d, J=8 Hz)
Preparation Example 128-3
2-Chloro4-ethylthiobenzyl alcohol
[1459] In the same manner as in Preparation Example 80-2, the
objective compound (1.69 g) was obtained as a colorless oil from
methyl 2-chloro-4-ethylthiobenzoate (2.0 g).
[1460] .sup.1H-NMR(CDCl.sub.3): 1.32(3H, t, J=7.5 Hz), 1.92(1H, t,
J=7 Hz), 2.95(2H, q, J=7.5 Hz), 4.74(2H, d, J=7 Hz), 7.21(1H, dd,
J=8, 1 Hz), 7.30(1H, d, J=1 Hz), 7.38(1H, d, J=8 Hz)
Preparation Example 129-1
2-Chloro-1-((methanesulfonyloxy)methyl)-4-(n-pentanethio)benzene
[1461] In the same manner as in Preparation Example 14-1, the
objective compound was obtained from
2-chloro-4-(n-pentanethio)benzyl alcohol (350 mg). This compound
was used in the next reaction without purification.
Preparation Example 129-2
4-Benzylthio-1-((methanesulfonyloxy)methyl)-2-chlorobenzene
[1462] In the same manner as in Preparation Example 14-1, the
objective compound was obtained from 4-benzylthio-2-chlorobenzyl
alcohol (350 mg). The compound was used in the next reaction
without purification.
Preparation Example 129-3
2-Chloro-4-ethylthio-1-((methanesulfonyloxy)methyl)benzene
[1463] In the same manner as in Preparation Example 14-1, the
objective compound was obtained from 2-chloro4-ethylthiobenzyl
alcohol (1.66 g). The compound was used in the next reaction
without purification.
Preparation Example 130-1
Methyl
3-[2-chloro4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylate and methyl
1-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylate
[1464] In the same manner as in Preparation Example 14-2, methyl
3-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (207 mg) was obtained as pale-yellow crystals and
methyl
1-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (293 mg) was obtained as an amorphous, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (273 mg).
Methyl
3-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazol4,5-b]pyri-
dine-5-carboxylate
[1465] mp 64-65.degree. C. .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t,
J=7.5 Hz), 1.26-1.46(4H, m), 1.59-1.70(2H, m), 2.54(3H, s),
2.89(2H, t, J=7.5 Hz), 4.00(3H, s), 5.63(2H, s), 6.55(1H, d, J=8
Hz), 7.00(1H, d, J=8 Hz), 7.34(1H, d, J=1 Hz), 8.06(1H, d, J=8 Hz),
8.16(1H, d, J=8 Hz) MS(ESI) m/z : 418(M+1).
Methyl
1-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate
[1466] .sup.1H-NMR(CDCl.sub.3): 0.89(H, t, J=7.5 Hz), 1.26-1.47(4H,
m), 1.59-1.71(2H, m), 2.65(3H, s), 2.90(2H, t, J=7.5 Hz), 4.01(3H,
s), 5.39(2H, s), 6.40(1H, d, J=8 Hz), 7.01(1H, dd, J=8, 1 Hz),
7.35(1H, br s), 7.56(1H, d, J=8 Hz), 8.09(1H, d, J=8 Hz) MS(ESI)
m/z: 418(M+1).
Preparation Example 130-2
Methyl
3-[4-(benzylthio)-2-chloro]benzyl-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate and methyl
1-[4-(benzylthio)-2-chloro]benzyl-2-methyl-3H-i-
midazo[4,5-b]pyridine-5-carboxylate
[1467] In the same manner as in Preparation Example 14-2, methyl
3-[4-(benzylthio)-2-chloro]-benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate (592 mg) was obtained as pale-yellow crystals and methyl
1-[4-(benzylthio)-2-chloro]benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (495 mg) was obtained as an amorphous, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (554 mg).
Methyl
3-[4-(benzylthio)-2-chloro]-benzyl-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate
[1468] mp 140-142.degree. C. .sup.1H-NMR(CDCl.sub.3): 2.51(3H, s),
4.00(3H, s), 4.09(2H, s), 5.61(2H, s), 6.51(1H, d, J=8 Hz),
6.99(1H, d, J=8 Hz), 7.23-7.31(5H, m), 7.34(1H, br s), 8.05(1H, d,
J=8 Hz), 8.14(1H, d, J=8 Hz) MS(ESI) m/z: 438(M+1).
Methyl
1-[4-(benzylthio)-2-chloro]benzyl-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate
[1469] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 4.00(3H, s), 4.10(2H,
s), 5.38(2H, s), 6.38(1H, d, J=8 Hz), 7.01(1H, br d, J=8 Hz),
7.20-7.31(5H, m), 7.36(1H, br s), 7.51(1H, d, J=8 Hz), 8.07(1H, d,
J=8 Hz) MS(ESI) m/z: 438(M+1).
Preparation Example 130-3
Methyl
3-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-idazo[4,5-b]pyridine-5-c-
arboxylate and methyl
1-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine-5-carboxylate
[1470] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (1.21 g) was obtained as pale-yellow crystals and methyl
1-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (947 mg) was obtained as an amorphous, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (1.57 g).
Methyl
3-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1471] mp 116-117.degree. C. .sup.1H-NMR(CDCl.sub.3): 1.31(3H, t,
J=7.5 Hz), 2.54(3H, s), 2.92(2H, q, J=7.5 Hz), 4.00(3H, s),
5.63(2H, s), 6.55(1H, d, J=8 Hz), 7.01(1H, dd, J=8, 1 Hz), 7.34(1H,
d, J=1 Hz), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) MS(ESI) m/z:
376(M+1).
Methyl
1-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1472] mp 150-151.degree. C. .sup.1H-NMR(CDCl.sub.3): 1.32(3H, t,
J=7.5 Hz), 2.66(3H, s), 2.93(2H, q, J=7.5 Hz), 4.02(3H, s),
5.39(2H, s), 6.41(1H, d, J=8 Hz), 7.02(1H, dd, J=8, 1 Hz), 7.36(1H,
d, J=1 Hz), 7.55(1H, d, J=8 Hz), 8.07(1H, d, J=8 Hz) MS(ESI) m/z:
376(M+1).
Preparation Example 131-1
3-[2-Chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5--
carboxylic acid
[1473] In the same manner as in Preparation Example 4-7, the
objective compound (182 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (200 mg).
[1474] mp 178-179.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 0.83(3H, t,
J=7.5 Hz), 1.19-1.41(4H, m), 1.49-1.62(2H, m), 2.51(3H, s),
2.97(2H, t, J=7.5 Hz), 5.57(2H, s), 6.50(1H, d, J=8 Hz), 7.14(1H,
dd, J=8, 1 Hz), 7.46(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz), 8.13(1H,
d, J=8 Hz) MS(ESI) m/z: 404(M+1).
Preparation Example 131-2
3-[4-(Benzylthio)-2-chloro]benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylic acid
[1475] In the same manner as in Preparation Example 4-7, the
objective compound (413 mg) was obtained as colorless crystals from
methyl
3-[4-(benzylthio)-2-chloro]benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate (462 mg).
[1476] mp 177-185.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H,
s), 4.25(2H, s), 5.55(2H, s), 6.49(1H, d, J=8 Hz), 7.13-7.39(6H,
m), 7.50(1 H, d, J=1 Hz), 8.00(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz)
MS(ESI) m/e: 424(M+1).
Preparation Example 131-3
3-(2-Chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylic acid
[1477] In the same manner as in Preparation Example 4-7, the
objective compound (1.07 g) was obtained as colorless crystals from
methyl
3-(2-chloro-4-ethylthiobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (1.2 g).
[1478] mp 202-204.degree. C. .sup.1H-NMR(DMSO-d.sub.6): 1.21(3H, t,
J=7.5 Hz), 2.52(3H, s), 2.99(2H, q, J=7.5 Hz), 5.57(2H, s),
6.50(1H, d, J=8 Hz), 7.15(1H, dd, J=8, 1 Hz), 7.47(1H, d, J=1 Hz),
8.00(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz) MS(ESI) m/z: 360(M-1).
Preparation Example 132-1
Methyl
3-(2-chloro-4-((3-pyridyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate
[1479] In the same manner as in the following Example 118, the
objective compound (197 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (300 mg) and 3-hydroxypyridine (77
mg).
[1480] .sup.1H-NMR(CDCl.sub.3): 2.55(3H, s), 4.00(3H, s), 5.06(2H,
s), 5.69(2H, s), 6.65(1H, d, J=8 Hz), 7.16(1H, d, J=8 Hz),
7.19-7.30(2H, m), 7.55(1H, s), 8.07(1H, d, J=8 Hz), 8.15(1H, d, J=8
Hz), 8.21-8.19(1H, m), 8.36(1H, s) MS(ESI) m/e: 423.1(M+H).
Preparation Example 132-2
3-(2-Chloro4-((3-pyridyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylic acid
[1481] In the same manner as in Preparation Example 4-7, the
objective compound (162 mg) was obtained as pale-yellow crystals
from methyl 3-(2-chloro-4-((3-pyridyloxy)methyl)benzyl)
-2-methyl-3H-imidazo[4,5-b]py- ridine-5-carboxylate (210 mg).
[1482] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.17(2H, s),
5.63(2H, s), 6.59(1H, d, J=8 Hz), 7.26-7.36(2H, m), 7.43(1H, dd,
J=8, 2 Hz), 7.68(1H, s), 8.01(1H, d, J=8 Hz), 8.10-8.20(2H, m),
8.34(1H, d, J=2 Hz) MS(ESI) m/e: 407.2 (M-H).
Preparation Example 133-1
Methyl
3-(4-(N-butyrylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1483] In the same manner as in Preparation Example 133-2, the
objective compound (510 mg) was obtained as colorless crystals from
methyl
3-(4-amino2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylat-
e (500 mg) and benzenesulfonyl chloride (191 mg).
[1484] .sup.1H-NMR(CDCl.sub.3): 0.94(3H, t, J=7 Hz), 1.64-1.78(2H,
m), 2.32(2H, t, J=8 Hz), 2.48(3H, s), 3.98(3H, s), 5.48(2H, s),
6.17(1H, d, J=8 Hz), 7.04(1H, dd, J=8, 2 Hz), 7.86(1H, s), 8.07(1H,
d, J=8 Hz), 8.15(1H, d, J=8 Hz), 8.67(1H, s)
Preparation Example 133-2
Methyl
3-(4-(N-benzoylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1485] To a solution of methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine-5-carboxylate (300 mg) in dichloromethane (3 ml)
was added triethylamine (110 mg). Benzoyl chloride (134 mg) was
added under ice-cooling and the mixture was stirred at room
temperature for 12 hr. Water was added to the reaction mixture and
the mixture was extracted with chloroform. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. Hexane was added to the
residue for crystallization, and the crystals were collected by
filtration and dried under reduced pressure to give the objective
compound (317 mg) as colorless crystals.
[1486] .sup.1H-NMR(CDCl.sub.3): 2.50(3H, s), 3.49(3H, s), 5.55(2H,
s), 6.35(1H, d, J=8 Hz), 7.17(1H, d, J=8 Hz), 7.37-7.53(3H, m),
7.89(2H, d, J=8 Hz), 8.06-8.17(3H, m), 8.70(1H, s)
Preparation Example 134-1
3-(4-(N-Butyrylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1487] In the same manner as in Preparation Example 4-7, the
objective compound (228 mg) was obtained as colorless crystals from
methyl
3-(4-(N-butyrylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (239 mg).
[1488] .sup.1H-NMR(DMSO-d.sub.6): 0.89(3H, t, J=7 Hz),
1.52-1.63(2H, m), 2.26(2H, t, J=7 Hz), 2.50(3H, s), 5.56(2H, s),
6.57(1H, d, J=8 Hz), 7.28(1H, dd, J=8, 2 Hz), 7.97-8.02(2H, m),
8.12(1H, d, J=8 Hz)
Preparation Example 134-2
3-(4-(N-Benzoylamino)-2-chlorobenzyl)-2-methyl-3H-imidazol4,5-b]pyridine-5-
-carboxylic acid
[1489] In the same manner as in Preparation Example 4-7, the
objective compound (165 mg) was obtained as colorless crystals from
methyl 3-(4-(N-benzoylamino)-2-chlorobenzyl)
-2-methyl-3H-imidazo[4,5-b]pyridine- -5-carboxylate (200 mg).
[1490] .sup.1H-NMR(DMSO-d.sub.6): 2.52(3H, s), 5.60(2H, s),
6.63(1H, d, J=8 Hz), 7.50-7.62(4H, m), 7.92-8.15(5H, m)
Preparation Example 135-1
Methyl
3-(4-(N-benzoyl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine-5-carboxylate
[1491] To a solution of methyl
3-(4-(N-benzoylamino)-2-chlorobenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (300 mg) in
N,N-dimethylformamide (3 ml) was added 60% sodium hydride (in
mineral oil, 30.4 mg) at room temperature. After 15 min, methyl
iodide (108 mg) was added and the mixture was stirred at room
temperature for 2 hr. Ice water was poured thereinto and the
mixture was extracted with ethyl acetate. The organic layer was
successively washed with a saturated aqueous solution of sodium
hydrogencarbonate and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure to give
the objective compound (305 mg) as a pale-yellow powder.
[1492] .sup.1H-NMR(CDCl.sub.3): 2.45(3H, s), 3.45(3H, s), 4.00(3H,
s), 5.59(2H, s), 6.51(1H, d, J=8 Hz), 6.76(1H, d, J=8 Hz),
7.18-7.25(6H, m), 8.03(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz)
Preparation Example 135-2
3-(4-(N-Benzoyl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo4,5-b]py-
ridine-5-carboxylic acid
[1493] In the same manner as in Preparation Example 4-7, the
objective compound (257 mg) was obtained as a pale-yellow powder
from methyl
3-(4-(N-benzoyl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate (288 mg).
[1494] .sup.1H-NMR(DMSO-d.sub.6): 2.40(3H, s), 2.50(3H, s),
5.55(2H, s), 6.51(1H, d, J=8 Hz), 7.01(1H, dd, J=8, 2 Hz),
7.22-7.32(5H, m), 7.49(1H, s), 7.98(1H, d, J=8 Hz), 8.11(1H, d, J=8
Hz)
Preparation Example 136-1
Methyl
3-(4-(N-butyryl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine-5-carboxylate
[1495] In the same manner as in Preparation Example 135-1, the
objective compound (107 mg) was obtained as colorless crystals from
methyl
3-(4-(N-butyrylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (250 mg) and methyl iodide (97 mg).
[1496] .sup.1H-NMR (CDCl.sub.3): 0.85(3H, t, J=7 Hz), 1.56-1.64(2H,
m), 2.06(2H, br), 2.58(3H, s), 3.22(3H, s), 4.00(3H, s), 5.69(2H,
s), 6.68(1H, d, J=8 Hz), 6.94(1H, dd, J=8, 2 Hz), 7.31(1H, s),
8.07(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz)
Preparation Example 136-2
3-(4-(N-Butyryl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylic acid
[1497] In the same manner as in Preparation Example 4-7, the
objective compound (99 mg) was obtained as a pale-yellow powder
from methyl
3-(4-(N-butyryl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate (102 mg).
[1498] .sup.1H-NMR (DMSO-d.sub.6): 0.77(3H, t, J=7 Hz),
1.39-1.51(2H, m), 2.03(2H, br), 2.53(3H, s), 3.13(3H, s), 5.64(2H,
s), 6.57(1H, d, J=8 Hz), 7.17(1H, d, J=8 Hz), 7.64(1H, s), 8.01(1H,
d, J=8 Hz), 8.14(1H, d, J=8 Hz)
Preparation Example 137-1
Methyl
3-(2-chloro-4-(N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1499] In the same manner as in Preparation Example 83-4, the
objective compound (481 mg) was obtained as pale-yellow crystals
from methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyla-
te (500 mg) and valeraldehyde (169 mg).
[1500] .sup.1H-NMR (CDCl.sub.3): 0.91(3H, t, J=7 Hz), 1.30-1.40(4H,
m), 1.55-1.63(2H, m), 2.55(3H, s), 3.00-3.06(2H, m), 3.73(1H, br),
4.01(3H, s), 5.57(2H, s), 6.31(1H, d, J=8 Hz), 6.55-6.60(2H, m),
8.03(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz)
Preparation Example 137-2
3-(2-Chloro-4-(N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid
[1501] In the same manner as in Preparation Example 4-7, the
objective compound (186 mg) was obtained as a colorless powder from
methyl
3-(2-chloro-4-(N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (200 mg).
[1502] .sup.1H-NMR (DMSO-d.sub.6): 0.86(3H, t), 1.22-1.34(4H, m),
1.43-1.46(2H, m), 2.49(3H, s), 2.93(2H, m), 5.46(2H, s), 5.96(1H,
br), 6.37-6.43(2H, m), 6.64(1H, d, J=2 Hz), 7.99(1H, d, J=8 Hz),
8.09(1H, d, J=8 Hz)
Preparation Example 137-3
Methyl
3-(2-chloro-4-(N-methyl-N-(n-pentyl)amino)benzyl)-2-methyl-3H-imida-
zo[4,5-b]pyridine-5-carboxylate
[1503] In the same manner as in Preparation Example 85-1, the
objective compound (95 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-(N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (201 mg) and a 37% aqueous formaldehyde solution
(151 mg).
[1504] .sup.1H-NMR (CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.20-1.38(4H,
m), 1.46-1.56(2H, m), 2.85(3H, s), 2.91(3H, s), 3.26(2H, t, J=7
Hz), 4.05(3H, s), 5.72(2H, s), 6.43(1H, dd, J=8, 2 Hz), 6.63(1H, d,
J=2 Hz), 6.91(1H, d, J=8 Hz), 8.32(1H, d, J=8 Hz), 8.38(1H, d, J=8
Hz)
Preparation Example 137-4
3-(2-Chloro-4-(N-methyl-N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid
[1505] In the same manner as in Preparation Example 4-7, the
objective compound (50 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-(N-methyl-N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylate (85 mg).
[1506] .sup.1H-NMR (DMSO-d.sub.6): 0.84(3H, t, J=7 Hz),
1.15-1.32(4H, m), 1.38-1.48(2H, m), 2.77(3H, s), 2.86(3H, s),
5.66(2H, s), 6.55(1H, dd, J=8, 2 Hz), 6.71(1H, d, J=2 Hz), 6.90(1H,
d, J=8 Hz), 8.27(1H, d, J=8 Hz), 8.40(1H, d, J=8 Hz)
Preparation Example 138-1
Methyl
3-(4-(N-benzenesulfonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine-5-carboxylate
[1507] To a solution of methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine-5-carboxylate (200 mg) in dichloromethane (2 ml)
was added pyridine (95.7 mg). Benzenesulfonyl chloride (117 mg) was
added under ice-cooling and the mixture was stirred at room
temperature for 12 hr. Water was added to the reaction mixture and
the mixture was extracted with chloroform. The organic layer was
washed with saturated brine, dried over anhydrous magnesium sulfate
and concentrated under reduced pressure. Methanol was added to the
residue for crystallization, and the crystals were collected by
filtration, dried under reduced pressure to give the objective
compound (213 mg) as colorless crystals.
[1508] .sup.1H-NMR (CDCl.sub.3): 2.45(3H, s), 3.99(3H, s), 5.57(2H,
s), 6.45(1H, d, J=8 Hz), 6.83(1H, dd, J=8, 2 Hz), 7.24(1H, d, J=2
Hz), 7.44(2H, t, J=7 Hz), 7.54(1H, t, J=7Hz), 7.76-7.79(2H, m),
8.04(1H, d, J=8 Hz),8.13(1H, d, J=8 Hz)
Preparation Example 138-2
3-(4-(N-Benzenesulfonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid
[1509] In the same manner as in Preparation Example 4-7, the
objective compound (179 mg) was obtained as colorless crystals from
methyl
3-(4-(N-benzenesulfonylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylate (200 mg).
[1510] .sup.1H-NMR (DMSO-d.sub.6): 2.43(3H, s), 5.50(2H, s),
6.55(1H, d, J=8 Hz), 6.96(1H, dd, J=8, 2 Hz), 7.22(1H, d, J=2 Hz),
7.52-7.62(3H,m), 7.74-7.77(2H, m), 7.98(1H, d, J=8 Hz), 8.10(1H, d,
J=8 Hz)
Preparation Example 139-1
5-Bromo-3-(2-chloro-4-(isopropoxylcarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine
[1511] To a solution of
5-bromo-3-(2-chloro-4-carboxybenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine (400 mg) in N,N-dimethylformamide (4 ml) were
successively added potassium carbonate (218 mg) and isopropyl
iodide (197 mg), and the mixture was stirred at room temperature
for 24 hr. Water and ethyl acetate were added for partitioning. The
organic layer was successively washed with water and saturated
brine, dried over anhydrous magnesium sulfate and concentrated
under reduced pressure. Hexane was added to the residue and the
mixture was heated and allowed to cool. The precipitated crystals
were collected by filtration. The crystals were dried under reduced
pressure and by heating to give the objective compound (394 mg) as
gray-brown crystals.
[1512] .sup.1H-NMR (CDCl.sub.3): 1.34(3H, s), 1.36(3H, s), 2.48(3H,
s), 5.17-5.39(1H, m), 5.58(2H, s), 6.60(1H, d, J=8 Hz), 7.40(1H, d,
J=8 Hz), 7.78(1H, d, J=8, 2 Hz), 7.87(1H, d, J=8 Hz), 8.10(1H, d,
J=2 Hz)
Preparation Example 139-2
5-Bromo-3-(2-chloro-4-(cyclohexyloxycarbonyl)benzyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine
[1513] To a solution of
5-bromo-3-(2-chloro-4-carboxybenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine (525 mg) in dichloromethane (5 ml) were added
oxalyl chloride (0.36 ml) and N,N-dimethylformamide (0.03 ml), and
the mixture was stirred at room temperature for 1 hr and
concentrated under reduced pressure. Dichloromethane (5 ml) was
added and dissolved, and trimethylamine (698 mg),
4-dimethylaminopyridine (10 mg) and cyclohexanol (1.38 g) were
successively added under ice-cooling. The mixture was stirred under
ice-cooling for 30 min and at room temperature for 30 min. The
reaction mixture was concentrated under reduced pressure, and water
and ethyl acetate were added for partitioning. The organic layer
was successively washed with a saturated aqueous solution of sodium
hydrogencarbonate and saturated brine, dried over anhydrous
magnesium sulfate and concentrated under reduced pressure. Hexane
(20 ml) was added to the residue and the mixture was heated. The
black insoluble matter was removed by filtration and the filtrate
was allowed to cool. The precipitated crystals were collected by
filtration, dried under reduced pressure and by heating to give the
objective compound (533 mg) as colorless crystals.
[1514] .sup.1H-NMR (CDCl.sub.3): 1.15-1.90(10H, m), 2.48(3H, s),
4.96-5.04(1H, m), 5.58(2H, 6.61(1H, d, J=8 Hz), 7.40(1H, d, J=8
Hz), 7.79(1H, dd, J=8, 2 Hz), 7.86(1H, d, J=8 Hz), 8.10(1H, d, J=2
Hz) Mass (ESI): m/z 464(M+H).sup.+
Preparation Example 140-1
3-(2-Chloro-4-(isopropoxylcarbonyl)benzyl)
-2-methyl-3H-imidazo[4,5-b]pyri- dine-5-carboxylic acid
[1515] In the same manner as in Preparation Example 113-5, the
objective compound (282 mg) was obtained as a pale-yellow powder
from
5-bromo-3-(2-chloro-4-(isopropoxylcarbonyl)benzyl)-2-methyl-3H-imidazo[4,-
5-b]pyridine (370 mg).
[1516] .sup.1H-NMR (DMSO-d.sub.6): 1.29(3H, s), 1.31(3H, s),
2.52(3H, s), 5.06-5.18(1H, m), 5.69(2H, s), 6.72(1H, d, J=8 Hz),
7.78(1H, d, J=8, 2 Hz), 8.00-8.03(2H, m), 8.15(1H, d, J=8 Hz)
Preparation Example 140-2
3-(2-Chloro-4-(cyclohexyloxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid
[1517] In the same manner as in Preparation Example 113-5, the
objective compound (317 mg) was obtained as colorless crystals from
5-bromo-3-(2-chloro-4-(cyclohexyloxycarbonyl)benzyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine (514 mg).
[1518] .sup.1H-NMR (DMSO-d.sub.6): 1.28-1.58(6H, m), 1.69(2H, br
s), 1.83(2H, br s), 2.52(3H, s), 4.87-4.95(1H, m), 5.69(2H, s),
6.71(1H, d, J=8 Hz), 7.80(1H, dd, J=8, 2 Hz), 8.01-8.03(2H, m),
8.05(1H, d, J=8 Hz)
Preparation Example 141-1
Methyl
3-(2-chloro-4-(3-phenylureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate
[1519] Methyl
3-(4-amino-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylate (275 mg) was suspended in toluene (10 ml), and
phenyl isocyanate (218 mg) was added at room temperature. The
mixture was refluxed under heating for 5 hr and concentrated under
reduced pressure. Hexane (20 ml) was added, and the mixture was
heated and allowed to cool. The precipitated crystals were
collected by filtration. The crystals were suspended in ethyl
acetate (10 ml), heated and allowed to cool. The precipitated
crystals were collected by filtration and dried under reduced
pressure and by heating to give the objective compound (328 mg) as
colorless crystals.
[1520] .sup.1H-NMR (CDCl.sub.3): 2.49(3H, s), 4.01(3H, s), 5.46(2H,
s), 5.78(1H, d, J=8 Hz), 6.75(1H, d, J=8 Hz), 6.99(1H, t, J=7 Hz),
7.20-7.26(2H, m), 7.31-7.37(3H, m), 8.05(1H, s), 8.15(1H, d, J=8
Hz), 8.21(1H, d, J=8 Hz), 8.34(1H, s) Mass (ESI): m/z
448(M-H).sup.-
Preparation Example 141-2
3-(2-Chloro-4-(3-phenylureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid
[1521] In the same mariner as in Preparation Example 4-7, the
objective compound (222 mg) was obtained as a pale-yellow powder
from methyl
3-(2-chloro-4-(3-phenylureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate (300 mg).
[1522] .sup.1H-NMR (DMSO-d.sub.6): 2.52(3H, s),5.57(2H, s),5.66(1H,
d, J=8 Hz),6.98(1H, t, J=7 Hz),7.01(1H, dd, J=8, 2 Hz),7.28(2H, t,
J=8 Hz),7.43(2H, d, J=8 Hz),7.89(1H, d, J=2 Hz),8.01(1H, d, J=8
Hz),8.14(1H, d, J=8 Hz),8.72(1H, s),8.93(1H, s) Mass (ESI): m/z
434(M-H).sup.-
Preparation Example 142-1
4-Acetoxy-2-chlorotoluene
[1523] To a solution of 3-chloro-4-methylphenol (500 mg) in ether
(5.0 ml) were added acetic anhydride (430 mg) and pyridine (416
mg), and the mixture was stirred at room temperature for 2 hr. The
reaction mixture was washed with 1N hydrochloric acid (once) and
saturated brine (twice), dried over magnesium sulfate and
concentrated to dryness-under reduced pressure to give the
objective compound (645 mg) as a pale-yellow oil.
[1524] .sup.1H-NMR (CDCl.sub.3): 2.30(3H, s),2.36(3H, s),6.90(1H,
dd, J=8, 2 Hz),7.12(1H, d, J=2 Hz),7.22(1H, d, J=8 Hz)
Preparation Example 142-2
2-Bromomethyl-5-acetoxychlorobenzene
[1525] In the same manner as in Preparation Example 93-1, the
objective compound (18.4 g) was obtained as a pale-yellow oil from
4-acetoxy-2-chlorotoluene (13.4 g).
[1526] .sup.1H-NMR (CDCl.sub.3): 2.30(3H, s),4.58(2H, s),7.02(1H,
dd, J=8, 2 Hz),7.18(1H, d, J=2 Hz),7.44(1H, d, J=8 Hz)
Preparation Example 142-3
Methyl
3-(4-acetoxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate
[1527] In the same manner as in Preparation Example 14-2, the
objective compound (4.64 g) was obtained as a pale-brown powder
from methyl 2-methylimidazo[4,5-b]pyridine-5-carboxylate (5.00 g)
and 2-bromomethyl-5-acetoxychlorobenzene (6.89 g).
[1528] .sup.1H-NMR (CDCl.sub.3): 2.28(3H, s), 2.56(3H, s), 4.00(3H,
s), 5.64(2H, s), 6.64(1H, d, J=8 Hz), 6.86(1H, dd, J=8, 2 Hz),
7.24(1H, d, J=2 Hz), 8.06(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz)
[1529] A by-product, methyl
1-(4-acetoxy-2-chlorobenzyl)-2-methyl-1H-imida-
zo[4,5-b]pyridine-5-carboxylate (3.84 g), was obtained as a
pale-brown powder.
[1530] .sup.1H-NMR (CDCl.sub.3): 2.30(3H, s), 2.68(3H, s), 4.02(3H,
s), 5.43(2H, s), 6.48(1H, d, J=8 Hz), 6.88(1H, dd, J=8, 2 Hz),
7.28(1H, d, J=2 Hz), 7.56(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz)
Preparation Example 142-4
Methyl
3-(2-chloro-4-hydroxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylate
[1531] To a mixture of methyl
3-(4-acetoxy-2-chlorobenzyl)-2-methyl-3H-imi-
dazo[4,5-b]pyridine-5-carboxylate (2.87 g), methanol (29 ml),
1,4-dioxane (29 ml) and water (2.9 ml) was added sodium
hydrogencarbonate (968 mg), and the mixture was stirred at room
temperature for 2.5 hr. 1,4-Dioxane (29 ml) was added to dissolve
the insoluble matter, and the mixture was stirred for 2 hr. Sodium
hydrogencarbonate (968 mg) was added and the mixture was stirred at
room temperature for 2 days and at 60.degree. C. for 3 hr and stood
overnight. The reaction mixture was partitioned between ethyl
acetate and water, and the aqueous layer was again extracted with
ethyl acetate. The organic layers were combined and concentrated to
dryness under reduced pressure. The residue was pulverized in ether
to give the objective compound (1.94 g) as a pale-yellow
powder.
[1532] .sup.1H-NMR (DMSO-d.sub.6): 2.52(3H, s), 3.86(3H, s),
5.50(2H, s), 6.50(1H, d, J=8 Hz), 6.64(1H, dd, J=8, 2 Hz), 6.92(1H,
d, J=2 Hz), 8.04(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz), 10.00(1H, br
s)
Preparation Example 143-1
2-Methyl-5-ethoxychlorobenzene
[1533] In the same manner as in Preparation Example 74-2, the
objective compound (3.56 g) was obtained as a pale-yellow oil from
3-chloro-4-methylphenol (3.0 g).
[1534] .sup.1H-NMR (CDCl.sub.3): 1.40(3H, t, J=6 Hz), 2.28(3H, s),
4.00(3H, q, J=6 Hz), 6.72(1H, dd, J=8, 2 Hz), 6.90(1H, d, J=2 Hz),
7.10(1H, d, J=8 Hz)
Preparation Example 143-2
2-Bromomethyl-5-ethoxychlorobenzene
[1535] In the same manner as in Preparation Example 93-1, the
objective compound (3.99 g) was obtained as a pale-yellow oil from
2-methyl-5-ethoxychlorobenzene (3.56 g).
[1536] .sup.1H-NMR (CDCl.sub.3): 1.40(3H, t, J=6 Hz), 4.02(3H, q,
J=6 Hz),4.59(2H, s),6.78(1H, dd, J=8, 2 Hz),6.92(1H, d, J=2
Hz),7.32(1H, d, J=8 Hz)
Preparation Example 144-1
Methyl
3-[2-chloro4-propoxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1537] In the same manner as in Preparation Example 74-2, the
objective compound (220 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (240 mg).
[1538] .sup.1H-NMR (CDCl.sub.3): 1.01(3H, t, J=7 Hz), 1.70-1.85(2H,
m), 2.53(3H, s), 3.86(2H, t, J=7 Hz), 4.00(3H, s), 5.61(2H, s),
6.63(2H, s), 6.96(1H, br s), 8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8
Hz) Mass (ESI):m/z 374(M+1).
Preparation Example 144-2
Methyl
3-[2-chloro4-(n-pentoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1539] In the same manner as in Preparation Example 74-1, the
objective compound (247 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (240 mg).
[1540] .sup.1H-NMR (CDCl.sub.3): 0.92(3H, br t, J=7 Hz),
1.29-1.48(4H, m), 1.69-1.81(2H, m), 2.53(3H, s), 3.89(2H, t, J=7
Hz), 4.00(3H, s), 5.61(2H, s), 6.63(2H, s), 6.96(1H, br s),
8.04(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz) Mass (ESI):m/z
402(M+1)
Preparation Example 144-3
Methyl
3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazol4,5-b]pyridine-5-ca-
rboxylate and methyl
1-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylate
[1541] In the same manner as in Preparation Example 14-2, methyl
3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (380 mg) was obtained as pale-yellow crystals and methyl
1-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (415 mg) was obtained an amorphous, from methyl
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (554 mg).
Methyl
3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylate
[1542] .sup.1H-NMR (CDCl.sub.3): 1.39(3H, t, J=7 Hz), 2.53(3H, s),
3.93-4.03(5H, m), 5.62(2H, s), 6.63(1H, s), 6.64(1H, s), 6.96(1H,
br s), 8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass (ESI):m/z
360(M+1).
Methyl
1-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine5-car-
boxylate
[1543] .sup.1H-NMR (CDCl.sub.3): 1.40(3H, t, J=7 Hz),2.66(3H, s),
3.94-4.04(5H, m), 5.37(2H, s), 6.49(1H, d, J=8 Hz), 6.68(1H, dd,
J=8, 2 Hz), 6.99(1H, d, J=2 Hz), 7.54(1H, d, J=8 Hz), 8.06(1H, d,
J=8 Hz) Mass (ESI):m/z 360(M+1).
Preparation Example 144-4
Methyl
3-[2-chloro-4-(2-methoxyethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate
[1544] In the same manner as in Preparation Example 74-1, the
objective compound (216 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (240 mg).
[1545] .sup.1H-NMR (CDCl.sub.3): 2.53(3H, s), 3.43(3H, s),
3.69-3.74(2H, m), 4.00(3H, s), 4.04-4.09(2H, m), 5.62(2H, s),
6.63(1H, d, J=8 Hz), 6.69(1H, dd, J=8, 2 Hz), 7.01(1H, d, J=2 Hz),
8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass (ESI):m/z
390(M+1).
Preparation Example 144-5
Methyl
3-[2-chloro-4-[(thiophen-2-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo-
[4,5-b]pyridine-5-carboxylate
[1546] In the same manner as in Preparation Example 14-2, the
objective compound (220 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (240 mg).
[1547] .sup.1H-NMR (CDCl.sub.3): 2.53(3H, s), 4.00(3H, s), 5.17(2H,
s), 5.61(2H, s), 6.64(1H, d, J=8 Hz), 6.73(1H, dd, J=8, 2 Hz),
6.99(1H, dd, J=8, 5 Hz), 7.05-7.10(2H, m), 7.32(1H, d, J=5 Hz),
8.05(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz) Mass (ESI):m/z
428(M+1).
Preparation Example 144-6
Methyl
3-[2-chloro-4-[(thiophene-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidaz-
o[4,5-b]pyridine-5-carboxylate
[1548] To a suspension of methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H--
imidazo[4,5-b]pyridine-5-carboxylate (240 mg), 3-thiophenemethanol
(68 mg) and triphenylphosphine (218 mg) in dry dichloromethane were
added to diethyl azodicarboxylate (139 mg) under ice-cooling. After
2 hr, the reaction mixture was stirred at room temperature. After 6
hr, to a suspension of 3-thiophenemethanol (34 mg) and
triphenylphosphine (109 mg) in dry dichloromethane was added
diethyl azodicarboxylate (69 mg) under ice-cooling. After 20 hr,
the reaction mixture was subjected to flash silica gel
chromatography (silica gel 60 ml, eluent: chloroform). The eluate
was recrystallized from ethyl acetate to give the objective
compound (143 mg) as colorless crystals.
[1549] .sup.1H-NMR (CDCl.sub.3): 2.54(3H, s),4.00(3H, s), 5.02(2H,
s), 5.62(2H, s), 6.64(1H, d, J=8 Hz), 6.72(1H, dd, J=8, 2 Hz),
7.05(1H, d, J=2 Hz), 7.12(1H, br d, J=5 Hz), 7.26-7.38(2H,
m),8.05(1H, d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass (ESI):m/z
428(M+1).
Preparation Example 144-7
Methyl
3-[2-chloro-4-cyclopentylmethyloxybenzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylate
[1550] In the same manner as in Preparation Example 74-2, the
objective compound (83 mg) was obtained as a colorless amorphous
from methyl
3-[2-chloro-4-hydroxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (240 mg).
[1551] .sup.1H-NMR (CDCl.sub.3): 1.22-1.41(2H, m), 1.50-1.70(3H,
m), 1.75-1.90(2H, m), 2.33(1H, m), 2.53(3H, s), 3.77(2H, d, J=5
Hz), 4.00(3H, s), 5.62(2H, s), 6.64(2H, s) 6.97(1H, br s), 8.05(1H,
d, J=8 Hz), 8.14(1H, d, J=8 Hz) Mass (ESI):m/z 414(M+1).
Preparation Example 145-1
3-[2-Chloro-4-propoxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ic acid
[1552] In the same manner as in Preparation Example 4-7, the
objective compound (205 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-propoxybenzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxy-
late (247 mg).
[1553] .sup.1H-NMR (DMSO-d.sub.4): 0.93(3H, t, J=7 Hz),
1.62-1.76(2H, m), 2.51(3H, s), 3.91(2H, t, J=7 Hz), 5.54(2H, s),
6.56(1H, d, J=8 Hz), 6.81(1H, dd, J=8, 2 Hz), 7.13(1H, d, J=2 Hz),
8.00(11H, d, J=8 Hz), 8.11(1H, d, J=8 Hz) Mass (ESI):m/z
358(M-1).
Preparation Example 145-2
3-[2-Chloro-4-(n-pentoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylic acid
[1554] In the same manner as in Preparation Example 4-7, the
objective compound (208 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(n-pentoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate (247 mg).
[1555] .sup.1H-NMR (DMSO-d.sub.6): 0.87(3H, t, J=7 Hz),
1.27-1.41(6H, m), 1.61-1.72(2H, m), 2.50(3H, s), 3.94(2H, t, J=7
Hz), 5.53(2H, s), 6.55(1H, d, J=8 Hz), 6.80(1H, dd, J=8, 2 Hz),
7.13(1H, d, J=2 Hz), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) Mass
(ESI):m/z 386(M-1).
Preparation Example 145-3
3-(2-Chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyli-
c acid
[1556] In the same manner as in Preparation Example 4-7, the
objective compound (380 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-ethoxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ate (376 mg).
[1557] .sup.1H-NMR (DMSO-d.sub.6): 1.21(3H, t, J=7.5 Hz), 2.52(3H,
s), 2.99(2H, q, J=7.5 Hz), 5.57(2H, s), 6.50(1H, d, J=8 Hz),
7.15(1H, dd, J=8, 1 Hz), 7.47(1H, d, J=1 Hz), 8.00(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz)
Preparation Example 145-4
3-[2-Chloro-4-(2-methoxyethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid
[1558] In the same manner as in Preparation Example 4-7, the
objective compound (192 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(2-methoxyethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate (216 mg).
[1559] .sup.1H-NMR (CDCl.sub.3): 2.63(3H, s), 3.43(3H, s),
3.69-3.76(2H, m), 4.05-4.12(2H, m), 5.54(2H, s), 6.65(1H, d, J=8
Hz), 6.74(1H, dd, J=8, 2 Hz), 7.04(1H, d, J=2 Hz), 8.15(1H, d, J=8
Hz), 8.21(1H, d, J=8 Hz) Mass (ESI):m/z 374(M-1).
Preparation Example 145-5
3-[2-Chloro-4-[(thiophen-2-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid
[1560] In the same manner as in Preparation Example 4-7, the
objective compound (195 mg) was obtained as-colorless crystals from
methyl
3-[2-chloro-4-[(thiophen-2-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylate (243 mg).
[1561] .sup.1H-NMR (DMSO-d.sub.6): 2.50(3H, s), 5.29(2H, s),
5.55(2H, br s), 6.57(1H, d, J=8 Hz), 6.90(1H, dd, J=8, 2 Hz),
7.02(1H, dd, J=5, 3 Hz), 7.19(1H, d, J=3 Hz), 7.27(1H, d, J=2 Hz),
7.55(1H, d, J=5 Hz), 8.00(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) Mass
(ESI):m/z 412(M-1).
Preparation Example 145-6
3-[2-Chloro-4-1(thiophen-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid
[1562] In the same manner as in Preparation Example 4-7, the
objective compound (118 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-1(thiophen-3-yl)methyl]oxybenzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylate (140 mg).
[1563] .sup.1H-NMR (DMSO-d.sub.6): 2.50(3H, s), 5.09(2H, s),
5.55(2H, s), 6.57(1H, d, J=8 Hz), 6.89(1H, dd, J=8, 2 Hz), 7.15(1H,
d, J=5 Hz), 7.24(1H, d, J=2 Hz), 7.51-7.60(2H, m), 8.00(1H, d, J=8
Hz), 8.12(1H, d, J=8 Hz) Mass (ESI):m/z 412(M-1).
Preparation Example 145-7
3-[2-Chloro-4-(cyclopentylmethyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid
[1564] In the same manner as in Preparation Example 4-7, the
objective compound (72 mg) was obtained as colorless crystals from
methyl
3-[2-chloro-4-(cyclopentylmethyloxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylate (82 mg).
[1565] .sup.1H-NMR (CDCl.sub.3): 1.24-1.41(2H, m), 1.50-1.70(3H,
m), 1.75-1.90(2H, m), 2.33(1H, m), 2.64(3H, s), 3.79(2H, d, J=5
Hz), 5.53(2H, s), 6,67(1H, d, J=8 Hz), 6.70(1H, dd, J=8, 2 Hz),
7.00(1H, d, J=2 Hz), 8.15(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz) Mass
(ESI):m/z 398(M-1).
Preparation Example 146-1
Methyl
3-(2-chloro-4-iodobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate
[1566] In the same manner as in Preparation Example 14-2, the
objective compound (6.42 g) was obtained as a white powder from
methyl 2,7-dimethylimidazo[4,5-b]pyridine-5-carboxylate (3.00 g)
and 2-chloro-4-iodobenzyl bromide (7.00 g).
[1567] .sup.1H-NMR (DMSO): 2.51(3H, s), 2.63(3H, s), 3.85(3H, s),
5.50(2H, s), 6.30(1H, d, J=8 Hz), 7.58(1H, d, J=8 Hz), 7.88(1H, s),
7.95(1H, s)
Preparation Example 146-2
Methyl
3-(2-chloro-4-(2-phenylethynyl)benzyl)-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylate
[1568] In the same manner as in the following Preparation Example
147-1, the objective compound (386 mg) was obtained as a white
powder from methyl
3-(2-chloro-4-iodobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate (400 mg).
[1569] .sup.1H-NMR (CDCl.sub.3): 2.54(3H, s), 2.75(3H, s), 3.99(3H,
s), 5.67(2H, s), 6.56(1H, d, J=8 Hz), 7.21-7.72(7H), 7.99(1H,
s)
Preparation Example 146-3
3-(2-Chloro-4-(2-phenylethynyl)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylic acid
[1570] In the same manner as in Preparation Example 4-7, the
objective compound (348 mg) was obtained as a white powder from
methyl
3-(2-chloro-4-(2-phenylethynyl)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylate (383 mg).
[1571] .sup.1H-NMR (DMSO): 2.48(3H, s), 2.61(3H, s), 5.60(2H, s),
6.52(1H, d, J=8 Hz), 7.34-7.60(6H), 7.76(1H, s), 7.85(1H, s)
Preparation Example 147-1
Methyl
3-(2-chloro-4-(1-hexynyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylate
[1572] A mixture of methyl
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine-5-carboxylate (2.31 g), 1-hexyne (2.00 g),
palladium(II) acetate (235 mg), triphenylphosphine (549 mg),
copper(I) iodide (297 mg), tributylamine (2.91 g) and
dimethylformamide (23 ml) was stirred under an nitrogen atmosphere
at 60.degree. C. for 1.5 hr. The reaction mixture was partitioned
between ethyl acetate and water. The organic layer was washed with
water, dried and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=1:1-1:2) to give the objective compound (1.44 g) as a gray
powder.
[1573] .sup.1H-NMR (CDCl.sub.3): 0.94(3H, t, J=6 Hz),
1.38-1.64(4H), 2.38(2H, t, J=6 Hz), 2.52(3H, s), 4.00(3H, s),
5.65(2H, s), 6.52(1H, d, J=8 Hz), 7.10(1H, d, J=8 Hz), 7.47(1H, s),
8.06(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz)
[1574] Also, a by-product, methyl
3-(4-chloro-2-(1-hexynyl)benzyl)-2-methy-
l-3H-imidazo[4,5-b]pyridine-5-carboxylate (288 mg) was obtained as
a gray powder.
[1575] .sup.1H-NMR (CDCl.sub.3): 0.94(3H, t, J=6 Hz),
1.35-1.65(4H), 2.38(2H, t, J=6 Hz),2.65(3H, s), 4.00(3H,s),
5.67(2H, s), 6.56(1H, d, J=8 Hz), 7.12(1H, d, J=8 Hz), 7.47(1H, s),
8.15(1H, d, J=8 Hz), 8.35(1H, d, J=8 Hz)
Preparation Example 147-2
3-(2-Chloro-4-(1-hexynyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylic acid
[1576] In the same manner as in Preparation Example 4-7, the
objective compound (872 mg) was obtained as a gray powder from
methyl
3-(2-chloro-4-(1-hexynyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-car-
boxylate (1.0 g).
[1577] .sup.1H-NMR (DMSO): 0.86(3H, t, J=6 Hz), 1.30-1.54(4H),
2.38(2H, t, J=6 Hz), 2.48(3H, s), 5.58(2H, s), 6.47(1H, d, J=8 Hz),
7.20(1H, d, J=8 Hz), 7.54(1H, s), 7.98(1H, d, J=8 Hz),8.1 1(1H, d,
J=8 Hz)
Preparation Example 148-1
Methyl
3-(2-chloro-4-cyclohexylmethyloxybenzyl)-2,7-dimethyl-3H-imidazo[4,-
5-b]pyridine-5-carboxylate
[1578] In the same manner as in Preparation Example 102-5, the
objective compound (954 mg) was obtained as colorless crystals from
methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (513
mg) and 2-chloro-1-chloromethyl-4-cyclohexylmethyloxybenzene (751
mg).
[1579] .sup.1H-NMR (CDCl.sub.3): 0.95-1.34(5H, m), 1.68-1.84(6H,
m), 2.52(3H, s), 2.72(3H, s), 3.68(2H, d, J=7 Hz), 3.99(3H, s),
5.59(2H, s), 6.56-6.63(2H, m), 6.95(1H, d, J=1 Hz), 7.96(1H, s) MS
(ESI):m/z 442(M+1)
Preparation Example 148-2
3-(2-Chloro-4-cyclohexylmethyloxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid
[1580] In the same manner as in Preparation Example 4-7, the
objective compound (797 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-cyclohexylmethyloxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylate (900 mg).
[1581] .sup.1H-NMR (CDCl.sub.3): 0.97-1.35(5H, m), 1.67-1.85(6H,
m), 2.63(3H, s), 2.75(3H, s), 3.71(2H, d, J=7 Hz), 5.50(2H, s),
6.58-6.70(2H, m), 6.98-6.99(1H, m), 8.03(1H, s), MS (ESI):m/z
426(M-1)
Preparation Example 149-1
Methyl
3-(2-chloro-4-vinylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1582] In the same manner as in Preparation Example 11-1, the
objective compound (786 mg) was obtained as colorless crystals from
methyl
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (1.10 g) and vinyl tributyltin (853 mg).
[1583] .sup.1H-NMR (CDCl.sub.3): 2.53(3H, s), 2.73(3H, s), 3.98(3H,
s), 5.29(1H, d, J=10 Hz), 5.64(2H, s), 5.72(1H, d, J=15 Hz),
6.54(1H, d, J=7 Hz), 6.60(1H, dd, J=10, 15 Hz), 7.11(1H, d, J=8
Hz), 7.47(1H, d, J=1 Hz), 7.97(1H, s) MS (ESI):m/z 356(M+1)
Preparation Example 149-2
Methyl
3-(2-chloro-4-ethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylate
[1584] In the same manner as in Preparation Example 67-4, the
objective compound (502 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-vinylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (750 mg).
[1585] .sup.1H-NMR (CDCl.sub.3): 1.19(3H, t, J=7 Hz), 2.53(3H, s),
2.59(2H, q, J=7 Hz), 2.73(3H, s), 3.98(3H, s), 5.63(2H, s),
6.50(1H, d, J=8 Hz), 6.91(1H, d, J=8 Hz), 7.26(1H, overlapped with
CDCl.sub.3), 7.97(1H, s) MS (ESI):m/z 358(M+1)
Preparation Example 149-3
3-(2-Chloro-4-ethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbox-
ylic acid
[1586] In the same manner as in Preparation Example 4-7, the
objective compound (385 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-ethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylate (490 mg).
[1587] .sup.1H-NMR (CDCl.sub.3): 1.21(3H, t, J=7 Hz), 2.61(2H, q,
J=7 Hz), 2.62(3H, s), 3.76(3H, s), 5.54(2H, s), 6.54(1H, d, J=8
Hz), 6.96(1H, d, J=8 Hz), 7.30(1H,s), 8.04(1H, s) MS (ESI):m/z
342(M-1)
Preparation Example 150-1
Methyl
3-(2-chloro-4-trifluoromethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylate
[1588] In the same manner as in Preparation Example 102-5, the
objective compound (819 mg) was obtained as pale-yellow crystals
from methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate
(467 mg) and 1-bromomethyl-2-chloro-4-trifluoromethylbenzene.
[1589] .sup.1H-NMR (CDCl.sub.3): 2.54(3H, s), 2.74(3H, s), 3.98(3H,
s), 5.69(2H, s), 6.68(1H, d, J=8 Hz), 7.35(1H, br d, J=8 Hz),
7.70(1H, br s), 7.98(1H, s)
Preparation Example 150-2
3-(2-Chloro-4-trifluoromethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid
[1590] In the same manner as in Preparation Example 4-7, the
objective compound (566 mg) was obtained as pale-yellow crystals
from methyl
3-(2-chloro-4-trifluoromethylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylate (767 mg).
[1591] .sup.1H-NMR (CDCl.sub.3): 2.61(3H, s), 2.78(3H, s), 5.61(2H,
s), 6.67(1 H, d, J=8 Hz), 7.41(1H, br d, J=8 Hz), 7.76(1H, br s),
8.08(1H, s)
Preparation Example 151-1
Methyl
3-(2-chloro-4-ethoxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine--
5-carboxylate
[1592] In the same manner as in Preparation Example 102-5, the
objective compound (631 mg) was obtained as beige crystals from
methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (430
mg) and 1-bromomethyl-2-chloro-4-ethoxybenzene.
[1593] .sup.1H-NMR (CDCl.sub.3): 1.38(3H, t, J=7 Hz), 2.53(3H, s),
2.73(3H, s), 3.97(2H, q, J=7 Hz), 3.99(3H, s), 5.59(2H, s),
6.59(1H, d, J=8 Hz), 6.64(1H, dd, J=8, 2 Hz), 6.95(1H, d, J=2 Hz),
7.97(1H, s)
Preparation Example 151-2
3-(2-Chloro-4-ethoxybenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid
[1594] In the same manner as in Preparation Example 4-7, the
objective compound (530 mg).was obtained as colorless crystals from
methyl
3-(2-chloro-4-ethoxybenzyl)-2,7-dimethyl-3H-imidazol4,5-b]pyridine-5-carb-
oxylate (621 mg).
[1595] .sup.1H-NMR (CDCl.sub.3): 1.40(3H, t, J=7 Hz), 2.62(3H, s),
2.75(3H, s), 3.99(2H, q, J=7 Hz), 5.51(2H, s), 6.61(1H, d, J=8 Hz),
6.68(1H, dd, J=8, 2 Hz), 6.99(1H, d, J=2 Hz), 8.03(1H, s)
Preparation Example 152-1
2-(2-Chloro-4-phenylbenzyl)-6-(methoxycarbonyl)-3-methyl-2H-indazole
[1596] A mixture of 6-(methoxycarbonyl)-3-methyl-1H-indazole (1.90
g), 2-chloro-4-phenylbenzyl bromide (3.37 g), potassium carbonate
(2.76 g), ethyl acetate(10 ml) and water (5 ml) was stirred for 14
hr at 70.degree. C. Hexane and water were added, and the
precipitated solid was collected by filtration and washed with a
mixed solvent of ethyl acetate and hexane (2/3). This was dried
under reduced pressure to give the objective compound (1.02 g).
[1597] .sup.1H-NMR (CDCl.sub.3, .delta. ppm): 2.61(3H, s), 3.96(3H,
s), 5.77(2H, s), 6.66(1H, d, J=8.1 Hz), 7.33-7.39(2H, m), 7.43(2H,
t, J=7.6 Hz), 7.51(2H, d, J=7.5 Hz), 7.62-7.66(2H, m), 7.69(1H, d,
J=8.8 Hz), 8.49(1H, s)
Preparation Example 152-2
6-Carboxy-2-(2-chloro-4-phenylbenzyl)-3-methyl-2H-indazole
[1598] In the same manner as in Preparation Example 39-6, the
objective compound (1.80 g) was obtained from
2-(2-chloro-4-phenylbenzyl)-6-(methox-
ycarbonyl)-3-methyl-2H-indazole (3.00 g). This was immediately used
for the following reaction.
Preparation Example 153-1
Methyl
3-(2-chloro-4-methylthiobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylate
[1599] In the same manner as in Preparation Example 102-5, the
objective compound (904 mg) was obtained as colorless crystals from
methyl 2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (648
mg) and 2-chloro-1-chloromethyl-4-methylthiobenzene (767 mg).
[1600] .sup.1H-NMR (CDCl.sub.3): 2.45(3H, s), 2.53(3H, s), 2.73(3H,
s), 3.99(3H, s), 5.61(2H, s), 6.53(1H, d, J=8 Hz), 6.95(1H, dd,
J=1, 8 Hz), 7.28(1H, d, J=1 Hz), 7.97(1H, s), MS (ESI):m/z
376(M+1)
Preparation Example 153-2
3-(2-Chloro-4-methylthiobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylic acid
[1601] In the same manner as in Preparation Example 4-7, the
objective compound (797 mg) was obtained as colorless crystals from
methyl
3-(2-chloro-4-methylthiobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5--
carboxylate (879 mg).
[1602] .sup.1H-NMR (CDCl.sub.3): 2.46(3H, s), 2.62(3H, s), 2.76(3H,
s), 5.52(2H, s), 6.55(1H, d, J-8 Hz), 6.99(1H, dd, J=1, 8 Hz),
7.30(1H, d, J=1 Hz), 8.04(1H, s) MS (ESI):m/z 360(M-1)
Example 1
[1603]
3-(3,4-Dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid
(160 mg) was dissolved in dry dimethylformamide (2 ml).
Carbonyl-diimidazole (111 mg) was added and the mixture was stirred
at room temperature for 1 hr. To the reaction mixture were added
n-pentanesulfonamide (108 mg) and
1,8-diazabicyclo[5,4,0]undec-7-ene (122 mg) and the mixture was
stirred at 100.degree. C. for 1.5 hr. The reaction mixture was
cooled in ice, and the pH thereof was adjusted to pH 4 with 1N
hydrochloric acid. The mixture was partitioned between ethyl
acetate and water. The organic layer was washed twice with water,
dried over magnesium sulfate and concentrated to dryness under
reduced pressure. The residue was eluted by silica gel column
chromatography (hexane:ethyl acetate=1:1). The resulting residue
was crystallized from hexane-ethyl acetate to give
3-(3,4-dichlorobenzyl)-2-methyl-5-(n-pentane-
sulfonyl-carbamoyl)benzo[b]thiophene (118 mg).
[1604] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.20-1.51(4H,
m), 1.75-1.93(2H, m), 2.52(3H, s), 3.47-3.63(2H, m), 4.16(2H, s),
6.98(1H, d, J=8 Hz), 7.16(1H, s), 7.32(1H, d, J=8 Hz), 7.70(1H, d,
J=8 Hz), 7.89(1H, d, J=8 Hz), 8.01(1H, s), 8.59(1H, br s)
Mass(ESI): m/e 482(M-H).sup.- mp: 159-160.degree. C.
Example 2
[1605] In the same manner as in Example 1,
3-(2,3-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene was obtained from
3-(2,3-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid.
[1606] .sup.1H-NMR(CDCl.sub.3): 0.86(3H, t, J=7 Hz), 1.22-1.49(4H,
m), 1.74-1.92(2H, m), 2.48(3H, s), 3.48-3.61(2H, m), 4.27(2H, s),
6.56(1H, d, J=8 Hz), 6.99(1H, t, J=8 Hz), 7.33(1H, d, J=8
Hz),7.71(1H, d, J=8 Hz),7.89(1H, d, J=8 Hz),7.90(1H, s), 8.45(1H,
br s) Mass(ESI): m/e 482(M-H).sup.- mp: 196-197.degree. C.
Example 3
[1607] In the same manner as in Example 1,
3-(2,5-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene was obtained from
3-(2,5-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-carboxylic
acid.
[1608] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.22-1.48(4H,
m), 1.76-1.92(2H, m), 2.49(3H, s), 3.48-3.62(2H, m), 4.21(2H, s),
6.61(1H, d, J=2 Hz), 7.13(1H, dd, J=8 and 2 Hz), 7.37(1H, d, J=8
Hz), 7.72(1H, dd, J=8 and 2 Hz), 7.90(1H, d, J=8 Hz), 7.93(1H, d,
J=2 Hz), 8.52(1H, br s) Mass(ESI): m/e 482(M-H).sup.- mp:
147-148.degree. C.
Example 4-1
[1609] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)pyrazolo[1,5-a]pyridine (103 mg) was
obtained as a yellow-green powder from
3-(2,4-dichlorobenzyl)-2-methylpyr-
azolo[1,5-a]pyridine-5-carboxylic acid (102 mg).
[1610] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.24-1.46(4H,
m), 1.84(2H, m), 2.38(3H, s), 3.54(2H, t, J=7 Hz), 4.13(2H, s),
6.79(1H, d, J=8 Hz), 7.09(1H, t, J=8 Hz), 7.43(1H, s), 7.87(1H, s),
8.43(1H, d, J=8 Hz).
Example 4-2
[1611] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(benzenesulfonylcarbamoyl)pyrazolo[1,5-a]pyridine (139 mg) was
obtained as a yellow powder from
3-(2,4-dichlorobenzyl)-2-methylpyrazolo[1,5-a]pyr-
idine-5-carboxylic acid (101 mg).
[1612] .sup.1H-NMR(CDCl.sub.3): 2.32(3H, s), 4.06(2H, s), 6.70(1H,
d, J=8 Hz), 7.00-7.07(2H), 7.37(1H, s), 7.56(2H, t, J=8 Hz),
7.67(1H, t, J=8 Hz), 7.84(1H, s), 8.12(2H, d, J=8 Hz), 8.37(1H, d,
J=8 Hz).
Example 5-1
[1613] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-2-methyl-
-7-(n-pentanesulfonylcarbamoyl)indolizine (208 mg) was obtained as
a yellow-green powder from
1-(2,4-dichlorobenzyl)-2-methylindolizine-7-carb- oxylic acid (200
mg).
[1614] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=6 Hz), 1.23-1.45(4H),
1.82(2H, m), 2.14(3H, s), 3.53(2H, t, J=6 Hz), 4.17(2H, s),
6.68(1H, d, J=8 Hz), 6.86(1H, d, J=8 Hz), 7.06(1H, d, J=8 Hz),
7.42(1H, s), 7.82(1H, s), 7.86(1H, d, J=8 Hz), 8.51(1H, s).
Example 5-2
[1615] In the same manner as in Example 1,
7-(n-butanesulfonylcarbamoyl)-1-
-(2,4-dichlorobenzyl)-2-methylindolizine (151 mg) was obtained as a
yellow-green powder from
1-(2,4-dichlorobenzyl)-2-methylindolizine-7-carb- oxylic acid (200
mg).
[1616] .sup.1H-NMR(CDCl.sub.3): 0.92(3H, t, J=6 Hz), 1.46(2H, m),
1.82(2H, m), 2.14(3H, s), 3.53(2H, t, J=6 Hz), 4.17(2H, s),
6.68(1H, d, J=8 Hz), 6.86(1H, d, J=8 Hz), 7.06(1H, d, J=8 Hz),
7.41(1H, s), 7.82(1H, s), 7.86(1H, d, J=8 Hz), 8.54(1H, s).
Example 5-3
[1617] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-2-methyl-
-7-(benzenesulfonylcarbamoyl)indolizine (208 mg) was obtained as a
yellow-green powder from
1-(2,4-dichlorobenzyl)-2-methylindolizine-7-carb- oxylic acid (200
mg).
[1618] .sup.1H-NMR(DMSO-d.sub.6): 2.14(3H, s), 4.1.8(2H, s),
6.76(1H, d, J=8 Hz), 6.82(1H, d, J=8 Hz), 7.28(1H, d, J=8 Hz),
7.55-7.75(5H), 7.98(1H, d, J=8 Hz), 8.18(1H, d, J=8 Hz), 8.26(1H,
s).
Example 6
[1619] In the same manner as in Example 1,
2-methyl-7-(n-pentanesul-fonylc-
arbamoyl)-1-(4-phenylbenzyl)indolizine (329 mg) was obtained as a
yellow-green powder from
2-methyl-1-(4-phenylbenzyl)indolizine-7-carboxyl- ic acid (300
mg).
[1620] .sup.1H-NMR(DMSO-d.sub.6): 0.83(3H, t, J=6 Hz), 1.29(2H, m),
1.38(2H, m), 1.70(2H, m), 2.17(3H, s), 3.52(2H, t, J=6 Hz),
4.18(2H, s), 6.92(1H, d, J=8 Hz), 6.82(1H, d, J=8 Hz), 7.27(2H, d,
J=8 Hz), 7.33(1H, t, J=8 Hz), 7.43(2H, t, J=8 Hz), 7.52-7.64(5H),
8.20(1H, d, J=8 Hz), 8.44(1H, s).
Example 7
[1621] In the same manner as in Example 1,
6-(n-pentanesulfonylcarbamoyl)-- 4-(4-phenylbenzyl)quinoline (68
mg) was obtained as a white powder from
4-(4-phenylbenzyl)quinoline-6-carboxylic acid (81 mg).
[1622] .sup.1H-NMR(DMSO-d.sub.6): 0.80 (3H, t, J=7 Hz), 1.19-1.42
(4H, br), 1.64-1.76 (2H, br), 3.50 (2H, br), 4.61 (2H, s),
7.30-7.47 (6H, m), 7.64 (4H, m), 8.10 (1H, d, J=8 Hz), 8.22 (1H, d,
J=8 Hz), 8.89-8.96 (2H, m).
Example 8-1
[1623] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine(98 mg)
was obtained as a pale-yellow crystal from
3-(2,4-dichlorobenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine-5-carboxylic acid (115 mg).
[1624] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.28-1.50(4H,
m), 1.80-1.95(2H, m), 2.66(3H, s), 3.49-3.59(2H, m), 5.55(2H, s),
6.69(1H, d, J=8 Hz), 7.20(1H, dd, J=8, 1 Hz), 7.51(1H, d, J=1 Hz),
8.17(1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz), 9.77(1H, br s) MASS(ESI):
m/z 467(M-1) mp 174-175.degree. C.
Example 8-2
[1625] In the same manner as in Example 1,
5-(n-butanesulfonylcarbamoyl)-3-
-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (132 mg)
was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methyl-3H-im-
idazo[4,5-b]pyridine-5-carboxylic acid (150 mg).
[1626] .sup.1H-NMR(CDCl.sub.3): 0.94(3H, t, J=7 Hz), 1.42-1.54(2H,
m), 1.80-1.92(2H, m), 2.62(3H, s), 3.51-3.60(2H, m), 5.54(2H, s),
6.67(1H, d, J=8 Hz), 7.19(1H, dd, J=8, 2 Hz), 7.51(1H, d, J=2 Hz),
8.13(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz), 9.79(1H, br s).
MASS(ESI): m/z 455(M+1) mp 153-154.degree. C.
Example 8-3
[1627] In the same manner as in Example 1,
5-benzenesulfonylcarbamoyl-3-(2-
,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (128 mg) was
obtained as pale-yellow crystals from
3-(2,4-dichlorobenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine-5-carboxylic acid (150 mg).
[1628] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.55(2H, s), 6.69(1H,
d, J=8 Hz), 7.21(1H, dd, J=8, 2 Hz), 7.50-7.68(4H, m), 8.05(1H, d,
J=8 Hz), 8.10(1H, d, J=8 Hz), 8.17(2H, br d, J=8 Hz). MASS(ESI):
m/z 475(M+1) mp 193-194.degree. C.
Example 9
[1629] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (34
mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-phenylbenzyl)-2-methy-
l-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160 mg).
[1630] .sup.1H-NMR(CDCl.sub.3): 0.86(3H, t, J=7 Hz), 1.22-1.45(4H,
m), 1.79-1.91(2H, m), 2.69(3H, s), 3.50-3.58(2H, m), 5.62(2H, s),
6.80(1H, d, J=8 Hz), 7.34-7.48(4H, m), 7.50-7.58(2H, m), 7.70(1H,
br s), 8.14(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz), 9.83(1H, br s).
MASS(ESI): m/z 509(M-1) mp 155-156.degree. C.
Example 10
[1631] In the same manner as in Example 1,
3-(1-bromo-2-naphthyl)methyl-2--
methyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (40
mg) was obtained as pale-yellow crystals from
3-(1-bromo-2-naphthyl)methyl-2--
methyl-3H-imidazol4,5-b]pyridine-5-carboxylic acid (140 mg).
[1632] .sup.1H-NMR(CDCl.sub.3): 0.84(3H, t, J=7 Hz), 1.22-1.44(4H,
m), 1.74-1.87(2H, m), 2.65(3H, s), 3.46-3.55(2H, m), 5.81(2H, s),
6.81(1H, d, J=8 Hz), 7.57(1H, br t, J=8 Hz), 7.65(1H, br t, J=8
Hz), 7.74(1H, br d, J=8 Hz), 7.82(1H, br d, J=8 Hz), 8.13(1H, d,
J=8 Hz), 8.20(1H, d, J=8 Hz), 8.39(1H, br d, J=8 Hz), 9.81(1H, br
s). MASS(ESI): m/z 527(M-1) mp 200-201.degree. C.
Example 11
[1633] In the same manner as in Example 1,
2-methyl-5-(n-pentanesulfonyl-c-
arbamoyl)-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine (120 mg) was
obtained as colorless crystals from
2-methyl-3-(4-phenylbenzyl)-3H-imidaz-
o[4,5-b]pyridine-5-carboxylic acid (130 mg).
[1634] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.26-1.50(4H,
m), 1.83-1.98(2H, m), 2.65(3H, s), 3.52-3.62(2H, m), 5.55(2H, s),
7.20(2H, d, J=8 Hz), 7.30-7.48(3H, m), 7.51-7.61(4H, m), 8.15(1H,
d, J=8 Hz), 8.24(1H, d, J=8 Hz), 9.92(1H, br s). MASS(ESI): m/z
475(M-1) mp 170-171.degree. C.
Example 12-1
[1635] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2-me-
thyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (66
mg) was obtained as a white powder from
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-im-
idazo[4,5-b]pyridine-5-carboxylic acid (70 mg).
[1636] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.24-1.50(4H,
m), 1.78-1.94(2H, m), 2.63(3H, s), 3.49-3.60(2H, m), 5.53(2H, s),
6.60(1H, dd, J=8 and 2 Hz), 7.34(1H, d, J=8 Hz), 7.66(1H, d, J=2
Hz), 8.14(1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz), 9.76(1H, br s)
Mass(ESI): m/e 511, 513 (M-H).sup.- mp: 183-184.degree. C.
Example 12-2
[1637] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-5-(n-
-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine (63
mg) was obtained as a white powder from
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-im-
idazo[4,5-b]pyridine-5-carboxylic acid (70 mg).
[1638] .sup.1H-NMR(CDCl.sub.3): 0.93(3H, t, J=7 Hz), 1.39-1.56(2H,
m), 1.78-1.92(2H, m), 2.64(3H, s), 3.50-3.61(2H, m), 5.53(2H, s),
6.61(1H, d, J=8 Hz), 7.34(1H, dd, J=8 Hz), 7.67(1H, d, J=2 Hz),
8.15(1H, d, J=8 Hz), 8.22(1H, d, J=8 Hz), 9.78(1H, br s) Mass(ESI):
m/e 497, 499 (M-H).sup.- mp: 165-166.degree. C.
Example 12-3
[1639] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-bromo-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (68 mg)
was obtained as a white powder from
3-(4-bromo-2-chlorobenzyl)-2-methyl-3H-im-
idazo[4,5-b]pyridine-5-carboxylic acid (70 mg).
[1640] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.53(2H, s), 6.65(1H,
d, J=8 Hz), 7.37(1H, dd, J=8 and 2 Hz), 7.50-7.65(3H, m), 7.68(1H,
d, J=2 Hz), 8.09(2H, s), 8.17(2H, m), 10.08(1H, br s) Mass(ESI):
m/e 517, 519 (M-H).sup.- mp: 193-194.degree. C.
Example 13-1
[1641] In the same manner as in Example 1,
3-(2-bromo-4-chlorobenzyl)-2-me-
thyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (70
mg) was obtained as a pale-yellow powder from
3-(2-bromo-4-chlorobenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (81 mg).
[1642] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.22-1.50(4H,
m), 1.79-1.95(2H, m), 2.68(3H, s), 3.48-3.61(2H, m), 5.54(2H, s),
6.62(1H, d, J=8 Hz), 7.23(1H, dd, J=8 and 2 Hz), 7.70(1H, d, J=2
Hz), 8.13-8.29(2H, m), 9.76(1H, br s) Mass(ESI): m/e 511, 513
(M-H).sup.- mp: 167-168.degree. C.
Example 13-2
[1643] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-bromo-4-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (56 mg)
was obtained as a pale-yellow powder from
3-(2-bromo-4-chlorobenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (79 mg).
[1644] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 5.56(2H, s), 6.67(1H,
d, J=8 Hz), 7.27(1H, dd, J=8 and 2 Hz), 7.50-7.68(3H, m), 7.71(1H,
d, J=2 Hz), 8.07-8.22(4H, m), 10.06(1H, br s)Mass(ESI): m/e 517,
519 (M-H).sup.- mp: 189-190.degree. C.
Example 13-3
[1645] In the same manner as in Example 1,
3-(2-bromo-4-chlorobenzyl)-5-(n-
-butanesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine (27
mg) was obtained as a pale-yellow powder from
3-(2-bromo-4-chlorobenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (41 mg).
[1646] .sup.1H-NMR(CDCl.sub.3): 0.94(3H, t, J=7 Hz), 1.38-1.56(2H,
m), 1.76-1.93(2H, m), 2.67(3H, s), 3.48-3.62(2H, m), 5.55(2H, s),
6.62(1H, d, J=8 Hz), 7.24(1H, dd, J=8 and 2 Hz), 7.69(1H, d, J=2
Hz), 8.13-8.29(2H, m), 9.74(1H, br s) Mass(ESI): m/e 497, 499
(M-H).sup.- mp: 145-146.degree. C.
Example 14-1
[1647] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-6-(n-pentanesulfonylcarbamoyl)indolizine (90 mg) was obtained as a
yellow-green powder from
3-(2,4-dichlorobenzyl)-2-methylindolizine-6-carb- oxylic acid (150
mg).
[1648] .sup.1H-NMR(DMSO-d.sub.6): 0.82(3H, t, J=7 Hz),
1.21-1.35(4H, m), 1.53-1.62(2H, m), 2.19(3H, s), 3.12-3.18(2H, m),
4.32(2H, s), 6.37(1H, s), 6.48(1H, d, J=8 Hz), 7.15(1H, d, J=8 Hz),
7.25(1H, dd, J=8 and 3 Hz), 7.32(1H, d, J=8 Hz), 7.66(1H, d, J=3
Hz), 8.34(1H, s) Mass(ESI): m/e 465(M-H).sup.-
Example 14-2
[1649] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-6-(n-butanesulfonylcarbamoyl)indolizine (88 mg) was obtained as a
yellow-green powder from
3-(2,4-dichlorobenzyl)-2-methylindolizine-6-carb- oxylic acid (150
mg).
[1650] .sup.1H-NMR(DMSO-d.sub.6): 0.82(3H, t, J=8 Hz),
1.29-1.40(2H, m), 1.52-1.62(2H, m), 2.19(3H, s), 3.14-3.20(2H, m),
4.32(2H, s), 6.38(1H, s), 6.50(1H, d, J=8 Hz), 7.15(1H, d, J=8 Hz),
7.25(1H, dd, J=8 and 3 Hz), 7.32(1H, d, J=8 Hz), 7.66(1H, d, J=3
Hz), 8.37(1H, s) Mass(ESI): m/e 451(M-H).sup.-
Example 14-3
[1651] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-6-(benzenesulfonylcarbamoyl)indolizine (68 mg) was obtained as a
yellow-green powder from
3-(2,4-dichlorobenzyl)-2-methylindolizine-6-carb- oxylic acid (150
mg).
[1652] .sup.1H-NMR(DMSO-d.sub.6): 2.18(3H, s), 4.30(2H, s),
6.33(1H, s), 6.47(1H, d, J=8 Hz), 7.11(1H, d, J=8 Hz),
7.22-7.30(2H, m), 7.40-7.43(3H, m), 7.66(1H, s), 7.80-7.83(2H, m),
8.28(1H, s) Mass(ESI): m/e 471(M-H).sup.-
Example 15
[1653] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-ethyl--
7-methyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(211 mg) was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-ethyl-7--
methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (177 mg).
[1654] .sup.1H-NMR(CDCl.sub.3) 0.89(3H, t, J=7 Hz), 1.29-1.50(7H,
m), 1.80-1.95(2H, m), 2.76(3H, s), 2.87(2H, q, J=7 Hz),
3.50-3.60(2H, m), 5.53(2H, s), 6.67(1H, d, J=8 Hz), 7.15(1H, dd,
J=8, 2 Hz), 7.51(1H, d, J=2 Hz), 8.02(1H, s), 9.82(1H, br s).
Mass(ESI): m/e 495(M-1) mp: 178-180.degree. C.
Example 16
[1655] In the same manner as in Example 1,
2-ethyl-7-methyl-5-(n-pentane-s-
ulfonylcarbamoyl)-3-(4-phenylbenzyl)-3H-imidazo[4,5-b]pyridine (138
mg) was obtained as colorless crystals from
2-ethyl-7-methyl-3-(4-phenylbenzy-
l)-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (120 mg).
[1656] .sup.1H-NMR(CDCl.sub.3): 0.87(3H, t, J=7 Hz), 1.25-1.47(7H,
m), 1.80-1.92(2H, m), 2.75(3H, s), 2.90(2H, q, J=7 Hz),
3.50-3.59(2H, m), 5.52(2H, s), 7.15(1H, d, J=8 Hz), 7.28-7.47(3H,
m), 7.50-7.59(4H, m), 8.02(1H, s). Mass(ESI): m/e 503(M-1) mp:
210-211.degree. C.
Example 17-1
[1657] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(benzenesulfonylcarbamoyl)benzo[b]thiophene (117 mg) was
obtained as white crystals from
3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-ca- rboxylic
acid (150 mg).
[1658] .sup.1H-NMR(DMSO-d.sub.6): 2.42(3H, s), 4.25(2H, s),
6.71(1H, d, J=8 Hz), 7.24(1H, dd, J=2, 8 Hz), 7.60-7.78(5H, m),
7.97-8.04(3H, m), 8.11(1H, s) Mass(ESI): 488(M-H).sup.-
Example 17-2
[1659] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-butanesulfonylcarbamoyl)benzo[b]thiophene (117 mg) was
obtained as white crystals from
3-(2,4-dichlorobenzyl)-2-methylbenzo[b]thiophene-5-ca- rboxylic
acid (150 mg).
[1660] .sup.1H-NMR(DMSO-d.sub.6): 0.83(3H, t, J=8 Hz),
1.33-1.46(2H, m), 1.60-1.71(2H, m), 2.45(3H, s), 3.50(2H, t, J=8
Hz), 4.27(2H, s), 6.73(1H, d, J=8 Hz), 7.25(1H, dd, J=2, 8 Hz),
7.67(1H, d, J=2 Hz), 7.83(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz),
8.18(1H, s) Mass(ESI): 468(M-H).sup.-
Example 18
[1661] In the same manner as in Example 1,
3-(4-phenylbenzyl)-2-methyl-5-(-
n-pentanesulfonylcarbamoyl)benzo[b]thiophene (87 mg) was obtained
as white crystals from
3-(4-phenylbenzyl)-2-methylbenzo[b]thiophene-5-carboxylic acid (112
mg).
[1662] .sup.1H-NMR(DMSO-d.sub.6): 0.79(3H, t, J=7 Hz),
1.20-1.38(4H, m), 1.60-1.70(2H, m), 2.57(3H, s), 3.33-3.40(2H, m),
4.26(2H, s), 7.25-7.34(3H, m), 7.41(2H, t, J=8 Hz), 7.54-7.60(4H,
m), 7.83(1H, d, J=8 Hz), 7.97(1H, d, J=8 Hz), 8.33(1H, s)
Mass(ESI): 490(M-H).sup.-
Example 19
[1663] In the same manner as in Example 1,
3-(2-chlorobenzyl)-2-methyl-5-(-
n-pentanesulfonylcarbamoyl)benzo[b]thiophene (131 mg) was obtained
as white crystals from
3-(2-chlorobenzyl)-2-methylbenzo[b]thiophene-5-carbox- ylic acid
(120 mg).
[1664] .sup.1H-NMR(DMSO-d.sub.6): 0.80(3H, t, J=7 Hz),
1.20-1.42(4H, m), 1.63-1.73(2H, m), 2.47(3H, s), 3.48(2H, t, J=8
Hz), 4.29(2H, s), 6.74(1H, d, J=7 Hz), 7.17(1H, t, J=7 Hz),
7.24(1H, t, J=7 Hz), 7.51(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz),
8.06(1H, d, J=8 Hz), 8.18(1H, s) Mass(ESI): 448(M-H).sup.-
Example 20
[1665] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2-me-
thyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene (137 mg) was
obtained as white crystals from
3-(4-bromo-2-chlorobenzyl)-2-methylbenzo[b]thiophe- ne-5-carboxylic
acid (212 mg).
[1666] .sup.1H-NMR(DMSO-d.sub.6): 0.82(3H, t, J=7 Hz),
1.20-1.41(4H, m), 1.63-1.73(2H, m), 2.45(3H, s), 3.50(2H, t, J=8
Hz), 4.24(2H, s), 6.67(1H, d, J=8 Hz), 7.37(1H, dd, J=2, 8 Hz),
7.78(1H, s), 7.82(1H, d, J=8 Hz), 8.08(1H, d, J=8 Hz), 8.17(1H, s)
Mass(ESI): 528(M-H).sup.-
Example 21
[1667] In the same manner as in Example 1,
3-(2,4-dichloro-5-fluorobenzyl)-
-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene (204 mg)
was obtained as white crystals from
3-(2,4-dichloro-5-fluorobenzyl)-2-methylb-
enzo[b]-thiophene-5-carboxylic acid (222 mg).
[1668] .sup.1H-NMR(DMSO-d.sub.6): 0.80(3H, t, J=8 Hz),
1.22-1.40(4H, m), 1.03-1.73(2H, m), 2.48(3H, s), 3.51(2H, t, J=8
Hz), 4.27(2H, s), 6.70(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz),
7.88(1H, d, J=7 Hz), 8.08(1H, d, J=8 Hz), 8.17(1H, s) Mass(ESI):
500(M-H).sup.-
Example 22
[1669] In the same manner as in Example 1,
3-((3-chlorobenzo[b]thiophen-2--
yl)methyl)-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene
(176 mg) was obtained as white crystals from
3-((3-chlorobenzo[b]-thiophen-2-y-
l)methyl)-2-methylbenzo[b]thiophene-5-carboxylic acid (218 mg).
[1670] .sup.1H-NMR(DMSO-d.sub.6): 0.79(3H, t, J=7 Hz),
1.18-1.40(4H, m), 1.63-1.74(2H, m), 2.60(3H, s), 3.50(2H, t, J=8
Hz), 4.56(2H, s), 7.38(1H, t, J=7 Hz), 7.47(1H, t, J=7 Hz),
7.76(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz), 7.86(1H, d, J=7 Hz),
8.08(1H, d, J=8 Hz), 8.41(1H, s) Mass(ESI): 504(M-H).sup.-
Example 23
[1671] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-yl)methy-
l-2-methyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene (207 mg)
was obtained as white crystals from
3-(1-bromonaphthalen-2-yl)methyl-2-methyl-
benzo[b]thiophene-5-carboxylic acid (200 mg).
[1672] .sup.1H-NMR(DMSO-d.sub.6): 0.75(3H, t, J=7 Hz),
1.15-1.37(4H, m), 1.60-1.70(2H, m), 2.48(3H, s), 3.47(2H, t, J=8
Hz), 4.54(2H, s), 6.91(1H, d, J=8 Hz), 7.60(1H, t, J=7 Hz),
7.72(1H, t, J=7 Hz), 7.80(1H, d, J=8 Hz), 7.83(1H, d, J=8 Hz),
7.91(1H, d, J=8 Hz), 8.096(1H, d, J=8 Hz), 8.26(1H, s), 8.30(1H, d,
J=8 Hz) Mass(ESI): 544(M-H).sup.-
Example 24-1
[1673] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)-1H-thieno[2,3-d]imidazole (112 mg)
was obtained as a pale-yellow powder from
1-(2,4-dichlorobenzyl)-2-methyl-1H--
thieno[2,3-d]imidazole-5-carboxylic acid (120 mg).
[1674] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, 7 Hz), 1.27-1.47(4H,
m), 1.78-1.88(2H, m), 2.57(3H, s), 3.50-3.54(2H, m), 5.30(2H, s),
6.69(1H, d, 8 Hz), 7.18(1H, d, 8 Hz), 7.38(1H, s), 7.46(1H, d, 2
Hz) Mass(ESI): 472(M-H).sup.-
Example 24-2
[1675] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)-3H-thieno[2,3-d]imidazole (77 mg)
was obtained as a white powder from
3-(2,4-dichlorobenzyl)-2-methyl-3H-thieno-
[2,3-d]imidazole-5-carboxylic acid (90 mg).
[1676] .sup.1H-NMR(CDCl.sub.3): 0.87(3H, t, 8 Hz), 1.25-1.43(4H,
m), 1.68-1.85(2H, m), 2.60(3H, s), 3.32-3.53(2H, m), 5.27(2H, s),
7.38(2H, s), 7.48(1H, s), 7.84(1H, s) Mass(ESI): 472(M-H).sup.-
Example 25
[1677] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-2-methyl-
-6-(n-pentanesulfonylcarbamoyl)-1H-imidazo[4,5-b]pyridine (151 mg)
was obtained as colorless crystals from
1-(2,4-dichlorobenzyl)-2-methyl-1H-im-
idazo[4,5-b]pyridine-6-carboxylic acid (150 mg).
[1678] .sup.1H-NMR (DMSO-d.sub.6): 0.82(3H, t, J=7 Hz),
1.20-1.42(4H, m), 1.64-1.78(2H, m), 2.55(3H, s), 3.51(2H, t, J=7
Hz), 5.65(2H, s), 6.60(1H, d, J=8 Hz), 7.34(1H, dd, J=8, 2 Hz),
7.76(1H,d, J=2 Hz), 8.44(1H, s), 8.90(1H, s). MASS(ESI): m/z
467(M-1) mp 103-106.degree. C.
Example 26-1
[1679] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(n-pentanesulfonylcarbamoyl)pyrrolo[3,2-b]pyridine (87 mg) was
obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]p-
yridine-5-carboxylic acid (100 mg).
[1680] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.27-1.49(4H,
m), 1.81-1.95(2H, m), 2.50(3H, s), 3.49-3.57(2H, m), 4.19(2H, s),
7.14-7.22(2H, m), 7.39(1H, s), 7.65(1H, d, J=8 Hz), 7.94(1H, d, J=8
Hz), 8.32(1H, br s). MASS(ESI): m/z 466(M-1) mp 147-148.degree.
C.
Example 26-2
[1681] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(benzenesulfonylcarbamoyl)pyrrolo[3,2-b]pyridine (70 mg) was
obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methylpyrrolo[3,2-b]p-
yridine-5-carboxylic acid (60 mg).
[1682] .sup.1H-NMR(DMSO-d.sub.6): 2.39(3H, s), 4.25(2H, s),
7.29(1H, d, J=8 Hz), 7.33(1H, d, J=8 Hz), 7.58-7.74(5H, m),
7.79(1H, d, J=8 Hz), 8.04(1H, d, J=8 Hz). MASS(ESI): m/z 472(M-1)
mp>250.degree. C.
Example 27
[1683] In the same manner as in Example 1,
3-(4-chloro-2-methoxybenzyl)-2--
methyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (47
mg) was obtained as colorless crystals from
3-(4-chloro-2-methoxybenzyl)-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (50 mg).
[1684] .sup.1H-NMR (CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.28-1.50(4H,
m), 1.81-1.94(2H, m), 2.78(3H, s), 3.51-3.60(2H, m), 3.86(3H, s),
5.47(2H, s), 6.84-6.95(3H, m), 8.19(1H, d, J=8 Hz), 8.23(1H, d, J=8
Hz), 9.79(1H, br s). MASS(ESI): m/z 463(M-1) mp 168-170.degree.
C.
Example 28-1
[1685] In the same manner as in Example 1,
3-(4-chloro-2-methylbenzyl)-2-m-
ethyl-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (73
mg) was obtained as colorless crystals from
3-(4-chloro-2-methylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (70 mg).
[1686] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=7 Hz), 1.28-1.49(4H,
m), 1.79-1.95(2H, m), 2.42(3H, s), 2.69(3H, s), 3.51-3.60(2H, m),
5.45(2H, s), 6.43(1H, d, J=8 Hz), 7.09(1H, br d, J=8 Hz), 7.28(1H,
br s), 8.17(1H, d, J=8 Hz), 8.23(1H, d, J=8 Hz), 9.78(1H, br s).
MASS(ESI): m/z 447(M-1) mp 155-157.degree. C.
Example 28-2
[1687] In the same manner as in Example 1,
5-benzenesulfonylcarbamoyl-3-(4-
-chloro-2-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (85 mg)
was obtained as colorless crystals from
3-(4-chloro-2-methylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (70 mg).
[1688] .sup.1H-NMR(DMSO-d.sub.6): 2.40(3H, s), 2.42(3H, s),
5.72(2H, s), 6.60(1H, d, J=8 Hz), 7.17(1H, br d, J=8 Hz), 7.39(1H,
br s), 7.59-7.77(3H, m), 7.89(1H, d, J=8 Hz), 8.02(2H, br d, J=8
Hz), 8.12(1H, d, J=8 Hz). MASS(ESI): m/z 453(M-1) mp
235-237.degree. C.
Example 29-1
[1689] In the same manner as in Example 1,
5-benzenesulfonylcarbamoyl-3-(2-
-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (78 mg)
was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (130 mg).
[1690] .sup.1H-NMR(CDCl.sub.3): 2.40(3H, s), 2.76(3H, s), 5.64(2H,
s), 6.95(1H, d, J=8 Hz), 7.38-7.52(4H, m), 7.59(2H, d, J=8 Hz),
7.82(1H, br s), 8.07-8.16(3H, m). MASS(ESI): m/z 515(M-1) mp
204-214.degree. C. [broad]
Example 29-2
[1691] In the same manner as in Example 1,
5-(n-butanesulfonylcarbamoyl)-3-
-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (106
mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (130 mg).
[1692] .sup.1H-NMR(CDCl.sub.3): 0.90(3H, t, J=7 Hz), 1.38-1.51(2H,
m), 1.77-1.89(2H, m), 2.75(3H, s), 3.50-3.59(2H, m), 5.65(2H, s),
6.89(1H, br d, J=8 Hz), 7.35-7.49(4H, m), 7.55(2H, br d, J=8 Hz),
7.71(1H, br s), 8.20(1H, d, J=8 Hz), 8.26(1H, d, J=8 Hz), 9.80(1H,
br s). MASS(ESI): m/z 495(M-1) mp 199-200.degree. C.
Example 30-1
[1693] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(1-n-pentanesulfonylcarbamoyl)benzo[b]furan (260 mg, 62%) was
obtained as colorless crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo- [b]furan (300 mg,
0.90 mmol), N,N'-carbonyldiimidazole (218 mg, 1.34 mmol),
1,8-diazabicyclo[5,4,0]-7-undecene (DBU, 204 mg, 1.34 mmol) and
1-n-pentanesulfonamide (203 mg, 1.34 mmol).
[1694] mp: 149.1-149.9.degree. C. .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 11.94(1H, br s), 7.99(1H, d, J=1.3 Hz), 7.82(1H, dd, J=1.7
and 8.6 Hz), 7.63(1H, d, J=2.1 Hz), 7.61(1H, d, J=8.6 Hz), 7.33(1H,
dd, J=2.1 and 8.3 Hz), 7.19(1H, d, J=8.4 Hz), 4.09(2H, s), 3.48(2H,
m), 2.41(3H, s), 1.67(2H, quint., J=7.7 Hz), 1.35(2H, quint., J=7.4
Hz), 1.25(2H, sextet, J=7.6 Hz), 0.80(3H, t, J=7.3 Hz). IR(Nujol):
1687cm.sup.-1 Mass(FD): m/e 467(M).
Example 30-2
[1695] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (168 mg, 54%) was
obtained as colorless crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo-[b- ]furan (220 mg,
0.66 mmol), N,N'-carbonyldiimidazole (160 mg, 0.66 mmol), DBU (150
mg, 0.98 mmol) and benzenesulfonamide (155 mg, 0.98 mmol).
[1696] mp: 208.5-209.5.degree. C. .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 12.45(1H, br s), 7.97(2H, m), 7.93(1H, d, J=1.6 Hz), 7.75(1H,
dd, J=1.8 and 8.6 Hz), 7.70(1H, m), 7.62(3H, m), 7.57(1H, d, J=8.6
Hz), 7.32(1H, dd, J=2.1 and 8.3 Hz), 7.16(1H, d, J=8.4 Hz),
4.06(2H, s), 2.38(3H, s). IR(Nujol): 1702cm.sup.-1. Mass(FD): m/e
473(M).
Example 31-1
[1697] In the same manner as in Example 1,
2-(2,4-dichlorobenzyl)-3,5-dime-
thyl-7-(1-n-pentanesulfonylcarbamoyl)benzo[b]furan (0.26 g) was
obtained as white crystals from
7-carboxy-2-(2,4-dichlorobenzyl)-3,5-dimethylbenzo- [b]furan (0.30
g), N,N'-carbonyldiimidazole (0.28 g), DBU (0.26 ml) and
1-n-pentanesulfonamide (0.26 g).
[1698] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.79(3H, t, J=7.2
Hz), 1.20-1.28(2H, m), 1.30-1.37(2H, m), 1.64-1.71(2H, m), 2.19(3H,
s), 2.42(3H, s), 3.46(2H, t, J=7.7 Hz), 4.24(2H, s), 7.33-7.38(2H,
m), 7.46(1H, s), 7.59(1H, s), 7.62(1H, s), 11.57(1H, br s).
IR(Nujol): 1691cm.sup.-1. Mass(FD): m/e 481(M) mp:
164-165.5.degree. C.
Example 31-2
[1699] In the same manner as in Example 1,
7-(benzenesulfonylcarbamoyl)-2--
(2,4-dichlorobenzyl)-3,5-dimethylbenzo[b]furan (0.29 g) was
obtained as white crystals from
7-carboxy-2-(2,4-dichlorobenzyl)-3,5-dimethylbenzo-[b- ]furan (0.30
g), N,N'-carbonyldiimidazole (0.28 g), DBU (0.26 ml) and
benzenesulfonamide (0.27 g).
[1700] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.17(3H, s),
2.38(3H, s), 4.23(2H, s), 7.33-7.41(3H, m), 7.56(1H, s),
7.58-7.64(3H, m), 7.72(1H, t, J=7.3 Hz), 7.97-8.00(2H, m),
12.09(1H, br s). IR(Nujol): 1703cm.sup.-1. Mass(FD): m/e 487(M) mp:
214-215.degree. C.
Example 32-1
[1701] In the same manner as in Example 1,
2-methyl-5-(1-n-pentanesulfonyl-
carbamoyl)-3-(4-phenylbenzyl)benzo[b]furan (0.25 g) was obtained as
white crystals from
5-carboxy-2-methyl-3-(4-phenylbenzyl)benzo[b]furan (0.30 g),
N,N'-carbonyldiimidazole (0.28 g), DBU (0.26 ml) and
1-n-pentane-sulfonamide (0.27 g).
[1702] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.79(3H, t, J=7.3
Hz), 1.21-1.26(2H, m), 1.34(2H, quint., J=7.5 Hz), 1.67(2H, quint.,
J=7.7 Hz), 2.51(3H, s), 3.49(2H, t, J=7.7 Hz), 4.07(2H, s),
7.32(1H, t, J=7.3 Hz), 7.36 (2H, d, J=8.1 Hz), 7.42(2H, t, J=7.6
Hz), 7.57-7.62(5H, m), 7.82(1H, dd, J=8.6 and 1.6 Hz), 8.15(1H, s),
11.99(1H, br s). IR(Nujol): 1687cm.sup.-1 mp: 130.5-132.degree.
C.
Example 32-2
[1703] In the same manner as in Example 1,
5-(1-benzenesulfonylcarbamoyl)--
2-methyl-3-(4-phenylbenzyl)benzo[b]furan (0.31 g) was obtained as
white crystals from
5-carboxy-2-methyl-3-(4-phenylbenzyl)benzo[b]furan (0.30 g),
N,N'-carbonyldiimidazole (0.28 g), DBU (0.26 ml) and
benzenesulfonamide (0.28 g).
[1704] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.49(3H, s),
4.04(2H, s), 7.30-7.35(3H, m), 7.42(2H, t, J=7.7 Hz), 7.54-7.63(7H,
m), 7.69(1H, t, J=7.4 Hz), 7.74(1H, dd, J=8.6 and 1.8 Hz),
7.97-7.99(2H, m), 8.07(1H, d, J=1.7 Hz), 12.5(1H, br s). IR(Nujol):
1686cm.sup.-1 mp: 188-190.degree. C.
Example 33-1
[1705] In the same manner as in Example 1,
5-(1-n-butanesulfonyl-carbamoyl-
)-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (0.26 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]fura- n (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-butanesulfonamide (0.275 g).
[1706] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.85(3H, t, J=7.4
Hz), 1.34-1.42(2H, m), 1.61-1.68(2H, m), 2.42(3H, s), 3.49(2H, t,
J=8.3 Hz), 4.09(2H, s), 7.19(1H, d, J=8.4 Hz), 7.33 (1H, dd, J=8.3
and 2.2 Hz), 7.61(1H, d, J=8.6 Hz), 7.64(1H, d, J=2.3 Hz), 7.83
(1H, dd, J=8.7 and 1.9 Hz), 7.99(1H, d, J=1.7 Hz), 11.95(1H, brs).
IR(Nujol): 1698cm.sup.-1 mp: 145.5-146.degree. C.
Example 33-2
[1707] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-5-(1-n-h-
exanesulfonylcarbamoyl)-2-methylbenzo[b]furan (0.22 g) was obtained
as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]fura- n (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-hexanesulfonamide (0.33 g).
[1708] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.1
Hz), 1.18-1.23(4H, m), 1.33-1.40(2H, m), 1.62-1.68(2H, m), 2.42(3H,
s), 3.48(2H, t, J=7.7 Hz), 4.09(2H, s), 7.14(1H, d, J=8.4 Hz), 7.33
(1H, dd, J=8.3 and 2.2 Hz), 7.61(1H, d, J=8.6 Hz), 7.64(1H, d,
J=2.2 Hz), 7.82(1H, dd, J=8.7 and 1.8 Hz), 7.99(1H, d, J=1.7 Hz),
11.94(1H, brs). IR(Nujol): 1688 cm.sup.-1 mp: 139-139.5.degree.
C.
Example 33-3
[1709] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(2-thiophenesulfonylcarbamoyl)benzo[b]furan (0.33 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]fura- n (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
2-thiophene-sulfonamide (0.33 g).
[1710] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.39(3H, s),
4.07(2H, s), 7.15-7.21(2H, m), 7.32(1H, dd, J=8.3 and 2.3 Hz),
7.58(1H, d, J=8.6 Hz), 7.63(1H, d, J=2.2 Hz), 7.78(1H, dd, J=8.6
and 1.8 Hz), 7.83(1H, dd, J=3.7 and 1.1 Hz), 7.95(1H, d, J=1.6 Hz),
8.02(1H, dd, J=4.9 and 0.9 Hz), 12.57(1H, brs). IR(Nujol): 1703
cm.sup.-1 mp: 198-199.degree. C.
Example 34-1
[1711] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-ethyl--
5-(1-n-pentanesulfonylcarbamoyl)benzo[b]furan (0.15 g) was obtained
as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]furan (0.30 g),
N,N'-carbonyldiimidazole (0.26 g), DBU (0.26 ml) and
1-n-pentanesulfonamide (0.26 g).
[1712] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.3
Hz), 1.18(3H, t, J=7.5 Hz), 1.22-1.38(4H, m), 1.65-1.71(2H, m),
2.77(2H, quartet, J=7.5 Hz), 3.48(2H, t, J=7.8 Hz), 4.10(2H, s),
7.14(1H, d, J=8.4 Hz), 7.33(1H, dd, J=8.4 and 2.1 Hz),
7.63-7.66(2H, m), 7.83(1H, dd, J=8.8 and 1.9 Hz), 8.01(1H, s),
11.95(1H, brs). IR(Nujol): 1689 cm.sup.-1 mp: 131-132.degree.
C.
Example 34-2
[1713] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2,4-dichlorobenzyl)-2-ethylbenzo[b]furan (0.26 g) was obtained as
white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]furan (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.33 g).
[1714] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.16(3H, t, J=7.6
Hz), 2.75(2H, quartet, J=7.6 Hz), 4.08(2H, s), 7.12(1H, d, J=8.4
Hz), 7.32(1H, d, J=8.4 Hz), 7.58-7.65(4H, m), 7.70(1H, t, J=7.0
Hz), 7.76(1H, d, J=8.8 Hz), 7.96-7.99(3H, m), 12.46(1H, brs).
IR(Nujol): 1704 cm.sup.-1 mp: 196-197.degree. C.
Example :34-3
[1715] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-ethyl--
5-(8-quinolinesulfonylcarbamoyl)benzo[b]furan (0.39 g) was obtained
as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]furan (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
8-quinolinesulfonamide (0.33 g).
[1716] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.15(3H, t, J=7.5
Hz), 2.74(2H, quartet, J=7.5 Hz), 4.08(2H, s), 7.03(1H, d, J=8.4
Hz), 7.29(1H, dd, J=8.3 and 2.1 Hz), 7.54(1H, d, J=8.7 Hz),
7.59(1H, dd, J=8.3 and 4.3 Hz), 7.68(1H, d, J=2.1 Hz), 7.71(1H, dd,
J=8.7 and 1.6 Hz), 7.82(1H, t, J=7.8 Hz), 7.99(1H, s), 8.34(1H, d,
J=8.0 Hz), 8.51(2H, d, J=7.8 Hz), 8.80 (1H, dd, J=4.2 and 1.6 Hz).
IR(Nujol): 1687 cm.sup.-1 m p: 232-233.degree. C.
Example 34-4
[1717] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-ethyl--
5-((2-methylbenzene)sulfonylcarbamoyl)benzo[b]furan (0.24 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]fu- ran (0.36 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
2-methylbenzene-sulfonamide (0.31 g).
[1718] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.17(3H, t, J=7.6
Hz), 2.57(3H, s), 2.77(2H, quartet, J=7.5 Hz), 4.08(2H, s),
7.15(1H, d, J=8.4 Hz), 7.32(1H, dd, J=8.3 and 2.2 Hz), 7.38(1H, d,
J=7.6 Hz), 7.44(1H, t, J=7.4 Hz), 7.57(1H, t, J=7.5 Hz), 7.60(1H,
d, J=8.7 Hz), 7.63(1H, d, J=2.2 Hz), 7.77(1H, d, J=8.8 Hz),
7.97(1H, s), 8.02(1H, d, J=8.1 Hz), 12.56(1H, brs). IR(Nujol): 1694
cm.sup.-1 mp: 182-183.degree. C. Example 35-1
[1719] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-5-(1-n-p-
entanesulfonylcarbamoyl)-2-propylbenzo[b]furan (0.36 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-propylbenzo[b]fura- n (0.36 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-pentanesulfonamide (0.30 g).
[1720] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.89(3H, t, J=7.3 Hz),
0.95(3H, t, J=7.4 Hz), 1.30-1.47(4H, m), 1.70-1.79(2H, m),
1.83-1.90(2H, m), 2.77(2H, t, J=7.5 Hz), 3.57(2H, t, J=8.0 Hz),
4.05(2H, s), 6.88(1H, d, J=8.4 Hz), 7.10 (1H, dd, J=8.3 and 2.2
Hz), 7.45(1H, d, J=2.1 Hz), 7.50(1H, d, J=8.6 Hz), 7.71(1H, dd,
J=8.6 and 1.9 Hz), 7.76(1H, d, J=1.6 Hz), 8.36(1H, brs). IR(Nujol):
1693 cm.sup.-1 mp: 114-115.degree. C.
Example 35-2
[1721] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2,4-dichlorobenzyl)-2-propylbenzo[b]furan (0.24 g) was obtained as
white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-propylbenzo[b]furan (0.36 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.31 g).
[1722] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.83(3H, t, J=7.4
Hz), 1.56-1.63(2H, m), 2.70(2H, t, J=7.4 Hz), 4.08(2H, s), 7.10(1H,
d, J=8.4 Hz), 7.32(1H, dd, J=8.3 and 2.2Hz), 7.58-7.65(4H, m),
7.70(1H, t, J=7.4 Hz), 7.76(1H, dd, J=8.7 and 1.8 Hz),
7.96-7.99(3H, m), 12.45(1H, brs) IR(Nujol): 1708 cm.sup.-1 mp:
197-197.5.degree. C.
Example 35-3
[1723] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-5-(2-nit-
robenzenesulfonylcarbamoyl)-2-propylbenzo[b]furan (0.18 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-propylbenzo[b]fura- n (0.36 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
2-nitrobenzenesulfonamide (0.40 g).
[1724] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.84(3H, t, J=7.3
Hz), 1.58-1.64(2H, m), 2.72(2H, t, J=7.4 Hz), 4.09(2H, s), 7.13(1H,
d, J=8.3 Hz), 7.32(1H, dd, J=8.4 and 2.2 Hz), 7.61(1H, d, J=8.7
Hz), 7.63(1H, d, J=2.0 Hz), 7.82(1H, dd, J=8.8 and 1.3 Hz),
7.85-8.00(3H, m), 8.03(1H, s), 8.22-8.25(1H, m) IR(Nujol): 1692
cm.sup.-1 mp: 219-220.degree. C.
Example 36
[1725] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-5-(1-n-p-
entanesulfonylcarbamoyl)benzo[b]furan (0.24 g) was obtained as a
yellow oil from 5-carboxy-3-(2,4-dichlorobenzyl)benzo[b]furan (0.26
g), N,N'-carbonyldiimidazole (0.26 g), DBU (0.24 ml) and
n-pentanesulfonamide (0.24 g).
[1726] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.82(3H, t, J=7.2
Hz), 1.23-1.40(4H, m), 1.65-1.73(2H, m), 3.51(2H, t, J=7.7 Hz),
4.14(2H, s), 7.37(2H, s), 7.64(1H, s), 7.70(1H, d, J=8.8 Hz),
7.87(1H, s), 7.91(1H, dd, J=8.7 and 1.6 Hz), 8.269(1H, s),
12.01(1H, brs) IR(Nujol): 1682 cm.sup.-1
Example 37
[1727] In the same manner as in Example 1,
5-carboxy-3-(2,4-dichlorobenzyl- )-2-methylbenzo[b]thiophene (440
mg, 1.25 mmol) was suspended in dimethylformamide and
carbonyldiimidazole (305 mg, 1.88 mmol) was added, which was
followed by stirring at room temperature for 1 hr. Then,
1-n-pentanesulfonamide (284 mg, 1.88 mmol) and DBU (286 mg, 1.88
mmol) were added and the mixture was refluxed under heating at
100.degree. C. for 15 hr. The reaction mixture was concentrated
under reduced pressure and water and 3N hydrochloric acid were
added to acidify the mixture. The mixture was extracted with ethyl
acetate, and the organic layer was washed with saturated brine and
dried over anhydrous magnesium sulfate. The desiccant was filtered
off and the filtrate was concentrated under reduced pressure. The
residual oil was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate=3/2) and recrystallized from
2-propanol-n-hexane to give
3-(2,4-dichlorobenzyl)-2-methyl-5-(1-n-pentan-
esulfonylcarbamoyl)benzo[b]thiophene (410 mg, 68%) as colorless
crystals.
[1728] mp: 158.5-159.3.degree. C. .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 12.01(1H, brs), 8.15(1H, d, J=1.4 Hz), 8.06(1H, d, J=8.4 Hz),
7.82(1H, dd, J=1.6 and 8.4 Hz), 7.66(1H, d, J=2.1 Hz), 7.25(1H, dd,
J=2.1 and 8.4 Hz), 6.72(1H, d, J=8.4 Hz), 4.25(2H, s), 3.48(2H, m),
2.44 (3H, s), 1.66(2H, quint., J=7.5 Hz), 1.34(2H, quint., J=7.7
Hz), 1.24(2H, sextet, J=7.6 Hz), 0.80(3H, t, J=7.3 Hz) IR(Nujol):
1661 cm.sup.-1 Mass(FD): m/e 483(M)
Example 38-1
[1729] In the same manner as in Example 1,
2-(2,4-dichlorobenzyl)-3-ethyl--
7-(1-n-pentanesulfonylcarbamoyl)benzo[b]thiophene (0.17 g) was
obtained as white crystals from
7-carboxy-2-(2,4-dichlorobenzyl)-3-ethylbenzo[b]thiop- hene (0.25
g), N,N'-carbonyldiimidazole (0.22 g), DBU (0.20 ml) and
1-n-pentanesulfonamide (0.21 g).
[1730] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.89(3H, t, J=7.4 Hz),
1.20 (3H, t, J=7.7 Hz), 1.30-1.38(2H, m), 1.41-1.48(2H, m),
1.85-1.93(2H, m), 2.89(2H, quartet, J=7.6 Hz), 3.62(2H, t, J=8.3
Hz), 4.31(2H, s), 7.13(1H, d, J=8.3 Hz), 7.16(1H, dd, J=8.4 and 2.0
Hz), 7.41(1H, d, J=2.2 Hz), 7.49(1H, t, J=7.8 Hz), 7.62(1H, d,
J=7.5 Hz), 7.96(1H, d, J=7.9 Hz), 8.4(1H, brs) IR(Nujol): 1667
cm.sup.-1 Mass(FD): m/e 497(M) mp: 176-178.degree. C.
Example 38-2
[1731] In the same manner as in Example 1,
7-(benzenesulfonylcarbamoyl)-2--
(2,4-dichlorobenzyl)-3-ethylbenzo[b]thiophene (0.15 g) was obtained
as white crystals from
7-carboxy-2-(2,4-dichlorobenzyl)-3-ethylbenzo[b]thiop- hene (0.25
g), N,N'-carbonyldiimidazole (0.22 g), DBU (0.20 ml) and
benzenesulfonamide (0.22 g).
[1732] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 1.14(3H, t, J=7.6 Hz),
2.84(2H, quartet, J=7.5 Hz), 4.24(2H, s), 7.04(1H, d, J=8.3 Hz),
7.12(1H, dd, J=8.3 and 2.0 Hz), 7.38(2H, d, J=2.0 Hz), 7.54(2H, t,
J=7.7 Hz), 7.62(1H, t, J=7.4 Hz), 7.70(1H, d, J=7.5 Hz), 7.87(1H,
d, J=7.9 Hz), 8.18(2H, d, J=7.9 Hz) IR(Nujol): 1704 cm.sup.-1
Mass(FD): m/e 503(M) mp: 181-183.degree. C.
Example 39
[1733] In the same manner as in Example 1, N,N'-carbonyldiimidazole
(0.290 g) was added to a mixture of
6-carboxy-1-(2,4-dichlorobenzyl)-3-methyl-2-- benzimidazolone
(0.314 g) and N,N-dimethylformamide (9 ml), and the mixture was
stirred at room temperature for 1 hr. 1-n-Butanesulfonamide (0.246
g) and DBU (0.273 g) were added and the mixture was stirred at
100.degree. C. for 16 hr. The solvent was evaporated and the
resulting mixture was extracted with chloroform and water. The
organic layer was concentrated and the residue was purified by
preparative thin layer chromatography to give
6-(1-n-butanesulfonylcarbamoyl)-1-(2,4-dichloroben-
zyl)-3-methyl-2-benzimidazolone (0.123 g).
[1734] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.2
Hz), 1.29(2H, m), 1.51(2H, m), 3.00(2H, m), 3.39(3H, s), 5.11(2H,
s), 6.93(1H, d, J=8.3 Hz), 7.13(1H, d, J=8.2 Hz), 7.34(1H, d),
7.50(1H, s), 7.68(1H, s), 7.78(1H, d, J=8.1 Hz) IR(Nujol): 1666
cm.sup.-1 mp: 358-360.degree. C. Mass(FD): m/e 469(M)
Example 40
[1735] In the same manner as in Example 1,
6-(1-n-butanesulfonyl-carbamoyl-
)-1-(2,4-dichlorobenzyl)benzotriazole (0.13 g) was obtained from
6-carboxy-1-(2,4-dichlorobenzyl)-benzotriazole (0.12 g),
N,N'-carbonyl-diimidazole (0.12 g), DBU (0.11 ml) and
1-n-butanesulfonamide (0.10 g).
[1736] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.90(3H, t, J=7.4 Hz),
1.40-1.48(2H, m), 1.76-1.82(2H, m), 3.57 (2H, t, J=8.4 Hz),
5.93(2H, s), 6.89(1H, d, J=8.4 Hz), 7.13(1H, dd, J=8.4 and 2.1 Hz),
7.38 (1H, d, J=2.0 Hz), 7.92(1H, d, J=8.9 Hz), 8.13(1H, d, J=8.7
Hz), 8.26(1H, s), 10.0(1H, brs) IR(Nujol): 1688 cm.sup.-1 Mass(FD):
m/e 440 (M) mp: 158-160.degree. C.
Example 41-1
[1737] In the same manner as in Example 1,
6-carboxy-1-(2,4-dichlorobenzyl- )-3-methyl-1H-indazole (0.44 g,
1.31 mmol) was dissolved in dimethylformamide (16 ml) and
N,N'-carbonyldiimidazole (319 mg, 2.0 mmol) was added, which was
followed by stirring at room temperature for 1 hr. Then,
1-n-butanesulfonamide (270 mg, 2.0 mmol) and DBU (300 mg, 2.0 mmol)
were added and the mixture was refluxed under heating at
100.degree. C. for 14 hr. Dimethylformamide was evaporated and the
residue was adjusted to pH 3 with 1N hydrochloric acid. The
precipitated oil was extracted with ethyl acetate. The organic
layer was washed with saturated brine, and dried over anhydrous
sodium sulfate. The desiccant was filtered off and the filtrate was
concentrated under reduced pressure. The residual oil was purified
by silica gel column chromatography (eluent: hexane/ethyl
acetate=1/1) to give 6-(1-n-butanesulfonylcarbamoyl)-1-(2,4--
dichlorobenzyl)-1H-3-methylindazole as a crystalline oil (0.53 g).
This was recrystallized from ethyl acetate-hexane to give colorless
crystals (0.36 g, 60%).
[1738] mp: 133.6-135.0.degree. C. .sup.1H-NMR(CDCl.sub.3, .delta.
ppm): 8.82(1H, brs), 7.94(1H, s), 7.78(1H, d, J=8.4 Hz), 7.56(1H,
d, J=8.4 Hz), 7.42(1H, d, J=1.7 Hz), 7.09(1H, dd, J=1.9 and 8.4
Hz), 6.63(1H, d, J=8.4 Hz), 5.64(2H, s), 3.58(2H, m), 2.62(3H, s),
1.83(2H, quint, J=7.4 Hz), 1.47(2H, sextet, J=7.4 Hz), 0.94(3H, t,
J=7.4 Hz) IR(Nujol): 1681 cm.sup.-1 Mass(FD): m/e 453(M)
Example 41-2
[1739] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-3-methyl-
-6-(1-pentanesulfonylcarbamoyl)-1H-indazole (0.39 g) was obtained
as pale-yellow amorphous from
6-carboxy-1-(2,4-dichlorobenzyl)-3-methyl-1H-i- ndazole (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-pentanesulfonamide (0.30 g). .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 0.82(3H, t, J=7.2 Hz), 1.22-1.40(4H, m), 1.66-1.74(2H, m),
2.51(3H, s), 3.52(2H, t, J=7.7 Hz), 5.69(2H, s), 6.78(1H, d, J=8.4
Hz), 7.34(1H, dd, J=8.4 and 2.0 Hz), 7.64(1H, d, J=8.5 Hz),
7.67(1H, d, J=2.0 Hz), 7.87(1H, d, J=8.5 Hz), 8.33(1H, s),
12.07(1H, brs) IR(Nujol): 1690 cm.sup.-1
Example 41-3
[1740] In the same manner as in Example 1,
6-(benzenesulfonylcarbamoyl)-1--
(2,4-dichlorobenzyl)-3-methyl-1H-indazole (0.36 g) was obtained as
white crystals from
6-carboxy-1-(2,4-dichlorobenzyl)-3-methyl-1H-indazole (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.31 g).
[1741] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.50(3H, s),
5.68(2H, s), 6.75(1H, d, J=8.5 Hz),7.33(1H; dd, J=8.4 and 2.0 Hz),
7.56(1H, d, J=8.7 Hz), 7.64(2H, t, J=7.7 Hz), 7.67(1H, d, J=2.0
Hz), 7.72(1H, t, J=7.5 Hz), 7.83(1H, d, J=8.5 Hz), 8.02(2H, d,
J=7.9 Hz), 8.31(1H, s), 12.60(1H, brs) IR(Nujol): 1699 cm.sup.-1
mp: 227.5-229.degree. C.
Example 41-4
[1742] In the same manner as in Example 1,
(E)-1-(2,4-dichlorobenzyl)-3-me-
thyl-6-((2-phenylethenyl)sulfonylcarbamoyl)-1H-indazole (0.17 g)
was obtained as white crystals from
6-carboxy-1-(2,4-dichlorobenzyl)-3-methyl- -1H-indazole (0.335 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.37 g).
[1743] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.50(3H, s),
5.68(2H, s), 6.76(1H, d, J=8.4 Hz), 7.33(1H, dd, J=8.4 and 2.2 Hz),
7.43-7.47(3H, m), 7.53(1H, d, J=15.4 Hz), 7.64(1H, d, J=8.5 Hz),
7.67(1H, d, J=15.5 Hz), 7.76-7.79(2H, m), 7.85(1H, d, J=8.4 Hz),
8.34(1H, s), 12.35(1H, brs) IR(Nujol): 1694 cm.sup.-1 mp:
209.5-210.5.degree. C.
Example 42
[1744] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-1-(2,4-dichlorobenzyl)-3-ethyl-2,4(1H,3H)-quinazolinedione (0.58
g) was obtained as white crystals from
7-carboxy-1-(2,4-dichlorobenzyl)-3-ethyl--
2,4(1H,3H)-quinazolinedione (0.79 g), N,N'-carbonyldiimidazole
(0.44 g), DBU (0.41 g) and 1-n-butanesulfonamide (0.37 g).
[1745] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.4
Hz), 1.18(3H, t, J=7.2 Hz), 1.32-1.40(2H, m), 1.61(2H, quint.,
J=8.0 Hz), 3.46(2H, t, J=7.1 Hz), 4.01(2H, quartet, J=7.2 Hz),
5.39(2H, s), 7.11(1H, d, J=8.5 Hz), 7.29(1H, d, J=8.4 Hz), 7.51(1H,
s), 7.74(1H, d, J=2.0 Hz), 7.77(1H, d, J=8.1 Hz), 8.21(1H, d, J=8.7
Hz), 8.23(1H, s), 12.3(1H, brs) IR(Nujol): 1712, 1693, 1658
cm.sup.-1 Mass(FD): m/e 511(M) mp: 212-214.degree. C.
Example 43
[1746] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-3-(2,4-dichlorobenzyl)-1-methyl-2,4(1H,3H)-quinazolinedione (0.65
g) was obtained as white crystals from
7-carboxy-3-(2,4-dichlorobenzyl)-1-methyl-
-2,4(1H,3H)-quinazolinedione (0.57 g), N,N'-carbonyldiimidazole
(0.36 g), DBU (0.34 ml) and 1-n-butanesulfonamide (0.31 g).
[1747] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.88(3H, t, J=7.4
Hz), 1.39-1.46(2H, m), 1.70(2H, quint., J=7.7 Hz), 3.56(2H, t,
J=7.9 Hz), 3.60(3H, s), 5.14(2H, s), 7.18(1H, d, J=8.4 Hz),
7.30(1H, dd, J=8.4 and 2.1 Hz), 7.65(1H, d, J=2.1 Hz), 7.80 (1H, d,
J=8.2 Hz), 7.98(1H, s), 8.16(1H, d, J=8.2 Hz), 12.5(1H, brs)
IR(Nujol): 1712, 1693, 1658 cm.sup.-1 Mass(FD): m/e 497(M) mp:
212-214.degree. C.
Example 44
[1748] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-3-(2,4-dichlorobenzyl)-4(3H)-quinazolinone (0.38 g) was obtained
as white crystals from
7-carboxy-3-(2,4-dichlorobenzyl)-4(3H)-quinazolinone (0.35 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-butanesulfonamide (0.27 g).
[1749] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.87(3H, t, J=7.6
Hz), 1.38-1.46(2H, m), 1.66-1.73(2H, m), 3.54(2H, t, J=7.8 Hz),
5.25(2H, s), 7.21(1H, d, J=8.4 Hz), 7.38(1H, dd, J=8.4 and 2.1 Hz),
7.69 (1H, d, J=2.1 Hz), 7.99(1H, dd, J=8.3 and 1.7 Hz), 8.23(1H, d,
J=8.3 Hz), 8.25(1H, d, J=1.7 Hz), 8.58(1H, s), 12.40(1H, brs)
IR(Nujol): 1694 cm.sup.-1 Mass(FD): m/e 468 (M+1) mp:
245-247.degree. C.
Example 45
[1750] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-2-(2,4-dichlorobenzyl)-3-methyl-4(3H)-quinazolinone (0.09 g) was
obtained as white crystals from
7-carboxy-2-(2,4-dichlorobenzyl)-3-methyl- -4(3H)-quinazolinone
(0.19 g), N,N'-carbonyldiimidazole (0.21 g), DBU (0.20 ml) and
1-n-butanesulfonamide (0.20 g).
[1751] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 0.96(3H, t, J=7.4 Hz),
1.48-1.53(2H, m), 1.84-1.91(2H, m), 3.58-3.62(5H, m), 4.29(2H, s),
7.14(1H, d, J=8.3 Hz), 7.23-7.26(1H, m), 7.50 (1H, d, J=2.1 Hz),
7.89(1H, d, J=8.3 Hz), 7.97(1H, s), 8.36(1H, brs), 8.39(1H, d,
J=8.3 Hz) IR(Nujol): 1690, 1661 cm.sup.-1 Mass(FD): m/e 482 (M+1)
mp: 244-246.degree. C.
Example 46
[1752] In the same manner as in Example 1, except that pH was
adjusted to 1 with 3N hydrochloric acid in a post-treatment step,
6-(1-n-butanesulfonylcarbamoyl)-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-meth-
ylquinazoline hydrochloride (0.16 g) was obtained as pale-yellow
crystals from
6-carboxy-3-(2,4-dichlorobenzyl)-3,4-dihydro-2-methylquinazoline
hydrochloride (0.27 g), N,N'-carbonyldiimidazole (0.34 g), DBU
(0.31 ml) and 1-n-butanesulfonamide (0.29 g).
[1753] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.82 (3H, t, J=7.4
Hz), 1.27-1.33(2H, m), 1.48-1.56(2H, m), 2.43(3H, s), 3.04(2H, t,
J=7.7 Hz), 4.72(2H, s), 4.86(2H, s), 7.01(1H, d, J=8.3 Hz),
7.49(1H, dd, J=8.4 and 2.1 Hz), 7.59 (1H, d, J=8.4 Hz), 7.66(1H,
s), 7.75(1H, d, J=2.1 Hz), 7.85(1H, d, J=8.4 Hz), 12.0(1H, brs)
IR(Nujol): 1642 cm.sup.-1 Mass(FD): m/e 467 (M) mp: 258.degree. C.
(decomposition)
Example 47-1
[1754] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-2-methyl-
-7-(1-n-pentanesulfonylcarbamoyl)-4(1H)-quinazolinone (0.47 g) was
obtained as white crystals from
7-carboxy-1-(2,4-dichlorobenzyl)-2-methyl- -4(1H)-quinazolinone
(0.36 g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-pentanesulfonamide (0.30 g).
[1755] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.80(3H, t, J=7.3
Hz), 1.18-1.26(2H, m), 1.29-1.35(2H, m), 1.60-1.67(2H, m), 2.67(3H,
s), 3.48(2H, t, J=8.3 Hz), 5.70(2H, s), 7.14(1H, d, J=8.6 Hz),
7.33-7.36(1H, m), 7.83-7.86(2H, m), 8.07(1H, d, J=8.4 Hz), 8.33(1H,
d, J=8.3 Hz) IR(Nujol): 1738, 1694 cm.sup.-1 Mass(FD): m/e 496(M+1)
mp: 168-170.degree. C.
Example 47-2
[1756] In the same manner as in Example 1,
7-(benzenesulfonylcarbamoyl)-1--
(2,4-dichlorobenzyl)-2-methyl-4(1H)-quinazolinone (0.50 g) was
obtained as white crystals from
7-carboxy-1-(2,4-dichlorobenzyl)-2-methyl-4(1H)-quina- zolinone
(0.36 g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.31 g).
[1757] .sup.1H-NMR(CDCl.sub.3, .delta. ppm): 2.66(3H, s), 5.68(2H,
s), 7.11(1H, d, J=8.5 Hz), 7.31(1H, dd, J=8.4 and 2.1 Hz), 7.61(2H,
t, J=7.9 Hz), 7.71(1H, t, J=7.5 Hz), 7.80(1H, s), 7.84(1H, d, J=2.1
Hz), 7.94(2H, d, J=7.9 Hz), 8.03(1H, d, J=8.2 Hz), 8.29(1H, d,
J=8.3 Hz) IR(Nujol) :1735, 1698 cm.sup.-1 Mass(FD): m/e 502(M+1)
mp: 214-216.degree. C.
Example 48
[1758] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-1,4-dihy-
dro-2-methyl-7-(1-n-pentanesulfonylcarbamoyl)quinazoline
hydrochloride (0.075 g) was obtained as white crystals from
7-carboxy-1-(2,4-dichlorobe- nzyl)-1,4-dihydro-2-methylquinazoline
1/2 sulfate (0.100 g), N,N'-carbonyldiimidazole (0.122 g), DBU
(0.11 ml) and benzenesulfonamide (0.113 g).
[1759] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.79(3H, t, J=7.3
Hz), 1.18-1.34(4H, m), 1.55-1.65(2H, m), 2.43(3H, s), 3.40-3.50(2H,
m), 4.86(2H, s), 5.30(2H, s), 7.27(1H, s), 7.37 (1H, s), 7.38(1H,
d, J=2.0 Hz), 7.41(1H, d, J=8.2 Hz), 7.79(1H, d, J=1.9 Hz),
7.81(1H, d, J=7.9 Hz), 11.4(1H, brs), 12.1(1H, brs) IR(Nujol): 1685
cm.sup.-1 Mass(FD): m/e 482(M+1) mp: 184-186.degree. C.
Example 49
[1760] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-1-(2,4-dichlorobenzyl)-3-methyl-2(1H)-quinoxalinone (0.17 g) was
obtained from
7-carboxy-1-(2,4-dichlorobenzyl)-3-methyl-2(1H)-quinoxalino- ne
(0.28 g), N,N'-carbonyldiimidazole (0.23 g), DBU (0.21 ml) and
1-n-butanesulfonamide (0.19 g).
[1761] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.4
Hz), 1.3 2-1.40(2H, m), 1.62(2H, quint., J=7.5 Hz), 2.51(3H, s),
3.47(2H, t, J=7.5 Hz), 5.48(2H, s), 6.88(1H, d, J=8.6 Hz), 7.25(1H,
dd, J=8.5 and 2.3 Hz), 7.69 (1H, s), 7.75(1H, d, J=2.3Hz), 7.86(1H,
d, J=8.4 Hz), 7.90(1H, d, J=8.3 Hz), 12.2(1H, brs) IR(Nujol) :1708,
1692 cm.sup.-1 Mass(FD): m/e 481 (M) mp: 223-225.degree. C.
Example 50
[1762] In the same manner as in Example 1,
7-(1-n-butanesulfonyl-carbamoyl-
)-1-(2,4-dichlorobenzyl)-4-methyl-2,3-(1H,4H)-quinoxalinedione
(0.32 g) was obtained from
7-carboxy-1-(2,4-dichlorobenzyl)-4-methyl-2,3-(1H,4H)-q-
uinoxalinedione (0.28 g), N,N'-carbonyldiimidazole (0.22 g), DBU
(0.20 ml) and 1-n-butanesulfonamide (0.18 g).
[1763] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.80(3H, t, J=7.3
Hz), 1.30-1.38(2H, m), 1.60(2H, quint., J=7.7 Hz), 3.46(2H, t,
J=7.2 Hz), 3.59(3H, s), 5.37(2H, s), 7.17(1H, d, J=8.5 Hz),
7.28(1H, dd, J=8.5 and 2.2 Hz), 7.45 (1H, d, J=1.8 Hz), 7.58(1H, d
J=8.8 Hz), 7.75(1H, d, J=2.1 Hz), 7.86(1H, dd, J=7.2 and 1.8 Hz),
12.1(1H, brs) IR(Nujol): 1682 cm.sup.-1 Mass(FD): m/e 497 (M) mp:
243-246.degree. C.
Example 51
[1764] In the same manner as in Example 1,
4-(2,4-dichlorobenzyl)-5-ethyl--
3-(1-n-pentanesulfonylcarbamoyl)imidazo[1,2-b]pyrazole (0.140 g)
was obtained from
3-carboxy-4-(2,4-dichlorobenzyl)-5-ethylimidazo[1,2-b]pyraz- ole
(0.546 g), N,N'-carbonyldiimidazole (0.524 g),
1-n-pentanesulfonamide (0.488 g) and DBU (0.491 g).
[1765] .sup.1H-NMR(CD.sub.3OD, .delta. ppm): 0.77(3H, t, J=7.1 Hz),
1.11-1.27(7H, m), 1.58(2H, m), 2.45(2H, m), 3.26(2H, m), 5.78(2H,
s), 6.43(1H, d, J=8.4 Hz), 7.12(1H, dd, J=8.4 and 2.1 Hz), 7.36(1H,
s), 7.43(1H, d, J=2.1 Hz), 8.01 (1H, s) IR(Nujol): 1661 cm.sup.-1
Mass(FD): m/e 470(M) mp: 165-166.5.degree. C.
Example 52
[1766] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-6-(1-n-pentanesulfonylcarbamoyl)imidazo[1,2-a]pyridine (0.07 g)
was obtained from a crude purification product of
6-carboxy-3-(2,4-dichlorobe- nzyl)-2-methylimidazol[2-a]pyridine
(0.40 g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-pentanesulfonamide (0.31 g).
[1767] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.8(3H, t, J=7.2
Hz), 1.21-1.37(4H, m), 1.61-1.68(2H, m), 2.26(3H, s), 3.33(2H, m),
4.44(2H, s), 6.86(1H, d, J=8.1 Hz), 7.30(1H, dd, J=8.3 and 2.2 Hz),
7.62(1H, d, J=9.3 Hz), 7.69(1H, d, J=2.1 Hz), 7.77 (1H, brs),
8.84(1H, s) IR(Nujol): 1659 cm.sup.-1 mp: 264-267.degree. C.
Example 53-1
[1768] In the same manner as in Example 1,
6-(n-pentanesulfonylcarbamoyl)-- 4-(4-phenylphenyloxy)quinoline (91
mg) was obtained as a brown powder from
4-(4-phenylphenyloxy)-6-quinolinecarboxylic acid (227 mg).
[1769] .sup.1H-NMR(DMSO-d.sub.6): 0.83 (3H, t, J=7 Hz), 1.19-1.39
(4H, br), 1.57-1.70 (2H, br), 3.20 (2H, br), 6.72 (1H, d, J=4 Hz),
7.38-7.53 (5H, m), 7.73 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 8.00
(1H, d, J=8 Hz), 8.32 (1H, d, J=8 Hz), 8.73 (1H, d, J=4 Hz), 8.98
(1H, s)
Example 53-2
[1770] In the same manner as in Example 1,
6-(n-pentanesulfonylcarbamoyl)-- 4-(4-phenylbenzyloxy)quinoline
(814 mg) was obtained as a white powder from
4-(4-phenylbenzyloxy)-6-quinolinecarboxylic acid (600 mg).
[1771] .sup.1H-NMR (DMSO-d.sub.6): 0.80 (3H, t, J=7 Hz), 1.20-1.33
(4H, br), 1.52-1.64 (2H, br), 3.03-3.09 (2H, m), 5.49 (2H, s), 7.15
(1H, d, J=7 Hz), 7.38 (1H, m), 7.48 (2H, m), 7.64-7.75 (6H, m),
7.87 (1H, d, J=8 Hz), 8.26 (1H, d, J=8 Hz), 8.70 (1H, d, J=7 Hz),
8.80 (1H, s)
Example 54
[1772] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-ethyl--
5-(((E)-pentene-1-sulfonyl)carbamoyl)benzo[b]furan (0.24 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-ethylbenzo[b]fu- ran (0.30 g),
N,N'-carbonyldiimidazole (0.28 g), DBU (0.26 ml) and
1-pentene-1-sulfonamide (0.30 g). .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 0.86(3H, t, J=7.4 Hz), 1.18(3H, t, J=7.5 Hz), 1.40-1.48(2H,
m), 2.23(2H, quartet, J=7.0 Hz), 2.77(2H, quartet, J=7.5 Hz),
4.09(2H, s), 6.76(1H, d, J=15.2 Hz), 6.83-6.90(1H, m), 7.13(1H, d,
J=8.4 Hz), 7.33 (1H, dd, J=8.4 and 2.2 Hz), 7.62(1H, d, J=8.7 Hz),
7.64(1H, d, J=2.1 Hz), 7.81(1H, dd, J=8.8 and 1.8 Hz), 7.99(1H, d,
J=1.6 Hz), 12.05(1H, brs) IR(Nujol): 1657 cm.sup.-1 mp:
191-192.degree. C.
Example 55-1
[1773] In the same manner as in Example 1,
1-(2,4-dichlorobenzyl)-3-ethyl--
6-(1-n-pentanesulfonylcarbamoyl)-1H-indazole (0.47 g) was obtained
from 6-carboxy-1-(2,4-dichlorobenzyl)-3-ethyl-1H-indazole (0.35 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
1-n-pentanesulfonamide (0.30 g).
[1774] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.82(3H, t, J=7.2
Hz), 1.23-1.40(7H, m), 1.65-1.73(2H, m), 2.95(2H, quartet, J=7.6
Hz), 3.52(2H, t, J=7.8 Hz), 5.70(2H, s), 6.71(1H, d, J=8.4 Hz),
7.34(1H, dd, J=8.4 and 2.1 Hz), 7.64(1H, dd, J=8.5 and 1.3 Hz),
7.68(1H, d, J=2.1 Hz), 7.91(1H, d, J=8.5 Hz), 8.32(1H, s),
12.07(1H, brs) IR(Nujol): 1690 cm.sup.-1
Example 55-2
[1775] In the same manner as in Example 1,
6-(benzenesulfonylcarbamoyl)-1--
(2,4-dichlorobenzyl)-3-ethyl-1H-indazole (0.38 g) was obtained as
pale-yellow crystals from
6-carboxy-1-(2,4-dichlorobenzyl)-3-ethyl-1H-ind- azole (0.35 g),
N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.31 g).
[1776] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 1.27(3H, t, J=7.5
Hz), 2.93(2H, quartet, J=7.6 Hz), 5.69(2H, s), 6.67(1H, d, J=8.4
Hz), 7.33(1H, dd, J=8.4 and 2.2 Hz), 7.55(1H, dd, J=8.5 and 1.3
Hz), 7.64(2H, t, J=7.4 Hz), 7.68(1H, d, J=2.1 Hz), 7.72(1H, t,
J=7.4 Hz), 7.87(1H, d, J=8.5 Hz), 8.01(2H, d, J=7.8 Hz), 8.28(1H,
s), 12.55(1H, brs) IR(Nujol): 1697 cm.sup.-1 mp: 208-209.degree.
C.
Example 56
[1777] In the same manner as in Example 1,
6-(benzenesulfonylcarbamoyl)-3--
(2,4-dichlorobenzyl)-2-methylimidazo[1,2-a]pyridine (0.07 g) was
obtained as a brown solid from a crude purification product of
6-carboxy-3-(2,4-dichlorobenzyl)-2-methylimidazo[1,2-a]pyridine
(0.20 g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.30 ml) and
benzenesulfonamide (0.31 g).
[1778] mp: 308-310.degree. C. .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 2.33(3H, s), 4.51(2H, s), 7.05(1H, d, J=8.3 Hz), 7.30(1H, dd,
J=8.4 and 2.1 Hz), 7.56(2H, t, J=7.6 Hz), 7.60-7.63 (1H, m),
7.71(1H, d, J=2.2 Hz), 7.87(1H, d, J=8.4 Hz), 7.94(2H, d, J=7.2
Hz), 8.09-8.14(1H, m), 8.98(1H, brs) IR(Nujol): 1664 cm.sup.-1
Mass(FD): m/e 473(M)
Example 57-1
[1779] In the same manner as in Example 1,
3-((2,3-dichlorobenzyl)-2-methy-
l-5-(n-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (32 mg)
was obtained as white crystals from
3-(2,3-dichlorobenzyl)-2-methyl-3H-imidaz-
o[4,5-b]pyridine-5-carboxylic acid (45 mg).
[1780] .sup.1H-NMR(DMSO-d.sub.6): 0.79(3H, t, J=8 Hz),
1.19-1.40(4H, m), 1.65-1.75(2H, m), 2.51(3H, s), 3.52(2H, t, J=8
Hz), 5.86(2H, s), 6.60(1H, d, J=8 Hz), 7.27(1H, t, J=8 Hz),
7.62(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz), 8.22(1H, dd, J=8 Hz)
Mass(ESI): 467(M-H).sup.31
Example 57-2
[1781] In the same manner as in Example 1,
3-((3-chlorobenzo[b]thiophene-2-
-yl)methyl)-2-methyl-5-n-pentanesulfonylcarbamoyl-3H-imidazo[4,5-b]pyridin-
e (47 mg) was obtained as pale-yellow crystals from
3-((3-chlorobenzo[b]thiophen-2-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine-5-carboxylic acid (78 mg).
[1782] .sup.1H-NMR(DMSO-d.sub.6): 0.79(3H, t, J=8 Hz),
1.22-1.41(4H, m), 1.68-1.78(2H, m), 2.63(3H, s), 3.57(2H, t, J=8
Hz), 6.13(2H, s), 7.43-7.58(2H, m), 7.80(1H, d, J=8 Hz), 7.92(1H,
d, J=8 Hz), 8.03(1H, d, J=8 Hz), 8.20(1H, dd, J=2.8 Hz) Mass(ESI):
489(M-H).sup.-
Example 58
[1783] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(n-pentanesulfonylcarbamoyl)benzo[b]thiophene (125 mg) was
obtained as white crystals from
3-(2-chloro-4-phenylbenzyl)-2-methylbenzo-
[b]thiophene-5-carboxylic acid (130 mg).
[1784] .sup.1H-NMR(DMSO-d.sub.6): 0.78(3H, t, J=7 Hz),
1.17-1.38(4H, m), 1.60-1.72(2H, m), 2.47(3H, s), 3.49(2H, t, J=8
Hz), 6.81(1H, d, J=8 Hz), 7.32-7.48(4H, m), 7.65(2H, d, J=8 Hz),
7.80-7.86(2H, m), 8.08(1H, d, J=8 Hz), 8.23(1H, s) Mass(ESI):
524(M-H).sup.-
Example 59
[1785] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(((E)-1-pentene-1-sulfonyl)carbamoyl)-3H-imidazo[4,5-b]pyridine
(47 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-phenylben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (78
mg).
[1786] .sup.1H-NMR(DMSO-d.sub.6): 0.86(3H, t, J=7 Hz),
1.40-1.49(2H, m), 2.20-2.28(2H, m), 2.52(3H, s), 5.87(2H, s),
6.72-6.80(2H, m), 6.87-6.97(1H, m), 7.35-7.48(3H, m), 7.53(1H, d,
J=8 Hz), 7.67(1H, d, J=8 Hz), 7.85(1H, s), 7.98(1H, dd, J=2.8 Hz),
8.19(1H, d, J=8 Hz) Mass(ESI): 507(M-H).sup.-
Example 60-1
[1787] In the same manner as in. Example 1,
1-(2-chloro-4-phenylbenzyl)-3--
methyl-6-(1-pentanesulfonylcarbamoyl)-1H-indazole (0.16 g) was
obtained as pale-yellow crystals from
6-carboxy-1-(2-chloro-4-phenylbenzyl)-3-methyl-- 1H-indazole (0.28
g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.31 ml) and
1-pentanesulfonamide (0.30 g).
[1788] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.3
Hz), 1.22-1.30(2H, m), 1.32-1.39(2H, m), 1.66-1.73(2H, m), 2.53(3H,
s), 3.52(2H, t, J=7.7 Hz), 5.75(2H, s), 6.84(1H, d, J=8.2 Hz),
7.36-7.40(1H, m), 7.45(2H, t, J=7.6 Hz), 7.54(1H, dd, J=8.0 and 1.9
Hz), 7.64-7.67(3H, m), 7.78(1H, d, J=1.9 Hz), 7.88(1H, d, J=8.3
Hz), 8.38(1H, s), 12.09(1H, brs) IR(Nujol): 1684 cm.sup.-1 mp:
172-173.degree. C.
Example 60-2
[1789] In the same manner as in Example 1,
6-(benzenesulfonylcarbamoyl)-1--
(2-chloro-4-phenylbenzyl)-3-methyl-1H-indazole (0.17 g) was
obtained as pale-yellow crystals from
6-carboxy-1-(2-chloro-4-phenylbenzyl)-3-methyl-- 1H-indazole (0.25
g), N,N'-carbonyldiimidazole (0.30 g), DBU (0.30 ml) and
benzenesulfonamide (0.29 g). .sup.1H-NMR(DMSO-d.sub.6, .delta.
ppm): 2.51(3H, s), 5.73(2H, s), 6.80(1H, d, J=8.1 Hz),
7.36-7.40(1H, m), 7.45(2H, t, J=7.7 Hz), 7.53(1H, dd, J=8.2 and 1.9
Hz), 7.56(1H, dd, J=8.6 and 1.2 Hz), 7.60-7.68(3H, m),
7.69-7.74(1H, m), 7.78(1H, d, J=1.8 Hz), 7.84(1H, d, J=8.9 Hz),
7.99-8.02(2H, m), 8.34(1H, s), 12.57(1H, brs) IR(Nujol): 1702
cm.sup.-1 mp: 211-212.degree. C.
Example 60-3
[1790] In the same manner as in Example 1,
(E)-1-(2-chloro-4-phenylbenzyl)-
-3-methyl-6-((2-phenylethenyl)sulfonylcarbamoyl)-1H-indazole (0.25
g) was obtained as pale-yellow crystals from
6-carboxy-1-(2-chloro-4-phenylbenzy- l)-3-methyl-1H-indazole (0.27
g), N,N'-carbonyldiimidazole (0.32 g), DBU (0.31 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.37 g).
[1791] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.52(3H, s),
5.74(2H, s), 6.81(1H, d, J=8.2 Hz), 7.35-7.83(15H, m), 7.87(1H, d,
J=9.0 Hz), 8.39(1H, s), 12.35(1H, brs). IR(Nujol): 1687 cm.sup.-1
mp: 241-242.degree. C.
Example 60-4
[1792] In the same manner as in Example 1,
1-(2-chloro-4-phenylbenzyl)-3-m- ethyl-6-(((E)
-1-pentene-1-sulfonyl)carbamoyl)-1H-indazole (0.10 g) was obtained
as pale-yellow crystals from 6-carboxy-1-(2-chloro-4-phenylbenzy-
l)-3-methyl-1H-indazole (0.22 g), N,N'-carbonyldiimidazole (0.16
g), DBU (0.15 ml) and 1-pentene-1-sulfonamide (0.15 g).
[1793] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.86(3H, t, J=7.4
Hz), 1.42-1.48(2H, m), 2.21-2.27(2H, m), 2.53(3H, s), 5.74(2H, s),
6.77-6.83(2H, m), 6.87-6.92(1H, m), 7.38(1H, t, J=7.3 Hz), 7.45(2H,
t, J=7.6 Hz), 7.54(1H, dd, J=7.8 and 2.1 Hz), 7.61-7.67(3H, m),
7.79(1H, d, J=1.8 Hz), 7.87(1H, d, J=8.5 Hz), 8.35(1H, s),
12.20(1H, brs) IR(Nujol): 1682 cm.sup.-1 mp: 201-202.degree. C.
Example 60-5
[1794] In the same manner as in Example 1,
1-(2-chloro-4-phenylbenzyl)-3-m-
ethyl-6-((4-vinylbenzene)sulfonylcarbamoyl)-1H-indazole (0.10 g)
was obtained as a pale-yellow powder from
6-carboxy-1-(2-chloro-4-phenylbenzy- l)-3-methyl-1H-indazole (0.25
g), N,N'-carbonyldiimidazole (0.18 g), DBU (0.18 ml) and
(4-vinylbenzene)sulfonamide (0.22 g).
[1795] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.51(3H, s),
5.46(1H, d, J=11.0 Hz), 5.74(2H, s), 6.02(1H, d, J=17.7 Hz),
6.75-6.84(2H, m), 7.34-7.85(11H, m), 7.97(2H, d, J=8.5 Hz),
8.33(1H, s), 12.51(1H, brs) IR(Nujol): 1694 cm.sup.-1
Example 60-6
[1796] In the same manner as in Example 1,
1-(2-chloro-4-phenylbenzyl)-3-m-
ethyl-6-((4-methylbenzene)sulfonylcarbamoyl)-1H-indazole (0.10 g)
was obtained as white crystals from
6-carboxy-1-(2-chloro-4-phenylbenzyl)-3-m- ethyl-1H-indazole (0.25
g), N,N'-carbonyldiimidazole (0.18 g), DBU (0.18 ml) and
(4-methylbenzene)sulfonamide (0.20 g).
[1797] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.36(3H, s),
2.50(3H, s), 5.72(2H, s), 6.02(1H, d, J=17.7 Hz), 6.79(1H, d, J=8.1
Hz), 7.37-7.48(5H, m), 7.52(1H, d, J=8.1 Hz), 7.58(1H, d, J=7.8
Hz), 7.80(1H, d, J=8.4 Hz), 7.86(2H, d, J=8.2 Hz), 8.27(1H, s),
12.50(1H, brs) IR(Nujol): 1706 cm.sup.-1 mp: 188-190.degree. C.
Example 61-1
[1798] In the same manner as in Example 1,
1-(4-bromo-2-chlorobenzyl)-3-me-
thyl-6-(1-pentanesulfonylcarbamoyl)-1H-indazole (0.25 g) was
obtained as pale-yellow amorphous from
1-(4-bromo-2-chlorobenzyl)-6-carboxy-3-methyl-- 1H-indazole (0.25
g), N,N'-carbonyldiimidazole (0.21 g), DBU (0.20 ml) and
1-pentanesulfonamide (0.20 g).
[1799] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.82(3H, t, J=7.2
Hz), 1.24-1.40(4H, m), 1.67-1.73(2H, m), 2.51(3H, s), 3.52(2H, t,
J=7.7 Hz), 5.67(2H, s), 6.71(1H, d, J=8.3 Hz), 7.46(1H, dd, J=8.3
and 1.9 Hz), 7.64(1H, d, J=8.4 Hz), 7.79(1H, d, J=2.0 Hz), 7.87(1H,
d J=8.4 Hz), 8.34(1H, s), 12.06(1H, brs) IR(Nujol): 1694
cm.sup.-1
Example 61-2
[1800] In the same manner as in Example 1,
6-(benzenesulfonylcarbamoyl)-1--
(4-bromo-2-chlorobenzyl)-3-methyl-1H-indazole (0.19 g) was obtained
as white crystals from
1-(4-bromo-2-chlorobenzyl)-6-carboxy-3-methyl-1H-inda- zole (0.25
g), N,N'-carbonyldiimidazole (0.21 g), DBU (0.20 ml) and
benzenesulfonamide (0.21 g).
[1801] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.50(3H, s),
5.66(2H, s), 6.67(1H, d, J=8.3 Hz), 7.46(1H, dd, J=8.3 and 1.9 Hz),
7.56(1H, d, J=8.4 Hz), 7.64(2H, brt, J=6.6 Hz), 7.71(1H, brd, J=7.1
Hz), 7.78(1H, d, J=7.1 Hz), 7.80-7.84(1H, m), 8.01(2H, d, J=7.5
Hz), 8.29(1H, s), 12.58(1H, brs) IR(Nujol): 1702 cm.sup.-1 mp:
213-215.degree. C.
Example 61-3
[1802] In the same manner as in Example 1,
(E)-1-(4-bromo-2-chlorobenzyl)--
3-methyl-6-((2-phenylethenyl)sulfonylcarbamoyl)-1H-indazole (0.18
g) was obtained as white crystals from
1-(4-bromo-2-chlorobenzyl)-6-carboxy-3-me- thyl-1H-indazole (0.25
g), N,N'-carbonyldiimidazole (0.21 g), DBU (0.20 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.24 g).
[1803] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.50(3H, s),
5.66(2H, s), 6.68(1H, d, J=8.4 Hz), 7.43-7.48(4H, m), 7.53(1H, d,
J=15.6 Hz), 7.63(1H, dd, J=8.5 and 1.3 Hz), 7.67(1H, d, J=15.5 Hz),
7.77(1H, d, J=1.9 Hz), 7.78(2H, d, J=2.0 Hz), 7.85(1H, d, J=8.5
Hz), 8.34(1H, s), 12.35(1H, brs) IR(Nujol): 1691 cm.sup.-1 mp:
211.5-212.5.degree. C.
Example 62-1
[1804] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(((E)-1-pentene-1-sulfonyl)carbamoyl)benzo[b]furan (0.095 g) was
obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methyl- benzo[b]furan (0.27 g),
N,N'-carbonyldiimidazole (0.26 g), DBU (0.26 ml) and
1-pentene-1-sulfonamide (0.26 g).
[1805] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.86(3H, t, J=7.4
Hz), 1.39-1.48(2H, m), 2.23(2H, quartet, J=7.3 Hz), 2.41(3H, s),
4.08(2H, s), 6.76(1H, d, J=15.1 Hz), 6.83-6.90(1H, m), 7.17(1H, d,
J=8.4 Hz), 7.33(1H, dd, J=8.3 and 2.2 Hz), 7.60(1H, d, J=8.6Hz),
7.64(1H, d, J=2.7 Hz), 7.80(1H, dd, J=8.6 and 1.8 Hz), 7.96(1H, d,
J=1.7Hz), 12.07(1H, brs) IR(Nujol): 1659 cm.sup.-1 mp:
158-159.degree. C.
Example 62-2
[1806] In the same manner as in Example 1,
(E)-3-(2,4-dichlorobenzyl)-2-me-
thyl-5-((2-phenylethenyl)sulfonylcarbamoyl)benzo[b]furan (0.14 g)
was obtained as pale-yellow crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-- methylbenzo[b]furan (0.27 g),
N,N'-carbonyldiimidazole (0.26 g), DBU (0.26 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.31 g).
[1807] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.39(3H, s),
4.07(2H, s), 7.15(1H, d, J=8.4 Hz), 7.31(1H, dd, J=8.4 and 2.1 Hz),
7.40-7.57(6H, m), 7.62(1H, d, J=2.2 Hz), 7.69-7.72(2H, m), 7.83(1H,
dd, J=8.6 and 1.8 Hz), 7.97(1H, d, J=1.7 Hz) IR(Nujol): 1685
cm.sup.-1 mp: 184-185.degree. C.
Example 62-3
[1808] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-((4-vinylbenzene)sulfonylcarbamoyl)benzo[b]furan (0.23 g) was
obtained as a pale-yellow powder from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylben- zo-[b]furan (0.27 g),
N,N'-carbonyldiimidazole (0.26 g), DBU (0.26 ml) and
4-vinylbenzenesulfonamide (0.31 g).
[1809] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.39(3H, s),
4.07(2H, s), 5.46(1H, d, J=11.1 Hz), 6.01(1H, d, J=17.6 Hz),
6.82(1H, dd, J=17.7 and 11.1 Hz), 7.16(1H, d, J=8.4 Hz), 7.32(1H,
dd, J=8.3 and 2.2 Hz), 7.57(1H, d, J=8.7 Hz), 7.62(1H, d, J=2.1
Hz), 7.70(2H, d, J=8.4 Hz), 7.75(1H, dd, J=8.6 and 1.8 Hz),
7.91-7.94(3H, m), 12.40(1H, brs) IR(Nujol): 1684 cm.sup.-1 mp:
210-211.degree. C.
Example 63-1
[1810] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(1-pentanesulfonylcarbamoyl)benzo[b]furan (0.20 g) was
obtained as white crystals from
5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylbenzo[b- ]furan (0.25
g), N,N'-carbonyldiimidazole (0.23 g), DBU (0.22 ml) and
1-pentane-sulfonamide (0.22 g).
[1811] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.77(3H, t, J=7.3
Hz), 1.19-1.35(4H, m), 1.61-1.67(2H, m), 2.45(3H, s), 3.45-3.55(2H,
m), 4.14(2H, s), 7.25(1H, d, J=8.1 Hz), 7.36(1H, t, J=7.3 Hz),
7.44(2H, t, J=7.6 Hz), 7.54(1H, dd, J=8.0 and 1.8 Hz), 7.61(1H, d,
J=8.7 Hz), 7.65(2H, d, J=7.3 Hz), 7.76(1H, d, J=1.8 Hz), 7.83(1H,
dd, J=8.7 and 1.8 Hz), 8.05(1H, s), 12.01(1H, brs) IR(Nujol): 1685
cm.sup.-1 mp: 150-151.degree. C.
Example 63-2
[1812] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-phenylbenzyl)-2-methylbenzo[b]furan (0.18 g) was
obtained as white crystals from
5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-methylbenzo-[- b]furan
(0.25 g), N,N'-carbonyldiimidazole (0.23 g), DBU (0.22 ml) and
benzenesulfonamide (0.23 g).
[1813] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.43(3H, s),
4.12(2H, s), 7.22(1H, d, J=8.1 Hz), 7.37(1H, t, J=7.4 Hz), 7.45(2H,
t, J=7.6 Hz), 7.53(1H, d, J=8.1 Hz), 7.57-7.62(3H, m),
7.63-7.69(3H, m), 7.74-7.77(2H, m), 7.95-8.00(3H, m), 12.45(1H,
brs) IR(Nujol): 1703 cm.sup.-1 mp: 185-186.degree. C.
Example 63-3
[1814] In the same manner as in Example 1,
(E)-3-(2-chloro-4-phenylbenzyl)-
-2-methyl-5-((2-phenylethenyl)sulfonylcarbamoyl)benzo[b]furan (0.28
g) was obtained as white crystals from
5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-m- ethylbenzo[b]furan (0.25
g), N,N'-carbonyldiimidazole (0.23 g), DBU (0.22 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.27 g).
[1815] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.43(3H, s),
4.12(2H, s), 7.20(1H, d, J=7.8 Hz), 7.34-7.58(10H, m), 7.64(2H, d,
J=7.4 Hz), 7.69(2H, brs), 7.75(1H, s), 8.04(1H, s) IR(Nujol): 1698
cm.sup.-1 mp: 218-219.degree. C.
Example 63-4
[1816] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(4-vinylbenzenesulfonylcarbamoyl)benzo[b]furan (0.28 g) was
obtained as a white powder from
5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-m- ethylbenzo[b]furan (0.25
g), N,N'-carbonyldiimidazole (0.23 g), DBU (0.22 ml) and
4-vinylbenzenesulfonamide (0.27 g).
[1817] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.43(3H, s),
4.12(2H, s), 5.44(1H, d, J=11.0 Hz), 5.99(1H, d, J=17.7 Hz),
6.78(1H, dd, J=17.7 and 11.0 Hz), 7.22(1H, d, J=8.2Hz), 7.37(1H, t,
J=7.2 Hz), 7.44(2H, t, J=7.7 Hz), 7.54(1H, dd, J=8.1 and 1.8 Hz),
7.59(1H, d, J=8.7 Hz), 7.64-7.69(4H, m), 7.74-7.77(2H, m), 7.93(2H,
d, J=8.4 Hz), 8.00(1H, d, J=1.7 Hz), 12.46(1H, brs) IR(Nujol): 1706
cm.sup.-1 mp: 176-178.degree. C.
Example 63-5
[1818] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(((E)-1-pentene-1-sulfonyl)carbamoyl)benzo[b]furan (0.28 g)
was obtained as a white powder from
5-carboxy-3-(2-chloro-4-phenylbenzyl)-2-m- ethylbenzo[b]furan (0.22
g), N,N'-carbonyldiimidazole (0.16 g), DBU (0.15 ml) and
1-pentene-1-sulfonamide (0.27 g).
[1819] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.84(3H, t, J=7.4
Hz), 1.37-1.45(2H, m), 2.18-2.24(2H, m), 2.45(3H, s), 4.14(2H, s),
6.75(1H, d, J=15.2 Hz), 6.82-6.89(1H, m), 7.23(1H, d, J=8.0 Hz),
7.37(1H, t, J=7.4 Hz), 7.44(2H, t, J=7.6 Hz), 7.77(1H, d, J=1.9
Hz), 7.81(1H, d, J=8.6 Hz), 8.04(1H, s), 12.07(1H, brs) IR(Nujol):
1688 cm.sup.-1 mp: 166-167.degree. C.
Example 64-1
[1820] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2-me-
thyl-5-(1-pentanesulfonylcarbamoyl)benzo[b]furan (0.07 g) was
obtained as white crystals from
3-(4-bromo-2-chlorobenzyl)-5-carboxy-2-methylbenzo-[b- ]furan (0.21
g), N,N'-carbonyldiimidazole (0.19 g), DBU (0.18 ml) and
1-pentanesulfonamide (0.18 g).
[1821] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 0.81(3H, t, J=7.3
Hz), 1.23-1.29(2H, m), 1.31-1.38(2H, m), 1.63-1.70(2H, m), 2.42(3H,
s), 3.49(2H, t, J=7.8 Hz), 4.07(2H, s), 7.12(1H, d, J=8.4 Hz),
7.45(1H, dd, J=8.3 and 2.1 Hz), 7.61(1H, d, J=8.6 Hz), 7.75(1H, d,
J=2.1 Hz), 7.82(1H, dd, J=8.6 and 1.9 Hz), 7.99(1H, d, J=1.7 Hz),
11.95(1H, brs) IR(Nujol): 1688 cm.sup.-1 mp: 133-134.5.degree.
C.
Example 64-2
[1822] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-bromo-2-chlorobenzyl)-2-methylbenzo[b]furan (0.21 g) was
obtained as white crystals from
3-(4-bromo-2-chlorobenzyl)-5-carboxy-2-methylbenzo-[b- ]furan (0.21
g), N,N'-carbonyldiimidazole (0.19 g), DBU (0.18 ml) and
benzenesulfonamide (0.18 g).
[1823] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.39(3H, s),
4.05(2H, s), 7.09(1H, d, J=8.3 Hz), 7.45(1H, dd, J=8.3 and 2.0 Hz),
7.58(1H, d, J=8.7 Hz), 7.62(2H, t, J=7.7 Hz), 7.68-7.72(1H, m),
7.74(1H, d, J=2.1 Hz), 7.75(1H, dd, J=8.7 and 1.8 Hz), 7.93(1H, d,
J=1.7 Hz), 7.96-7.99(2H, m), 12.45(1H, brs) IR(Nujol): 1703
cm.sup.-1 mp: 176-177.degree. C.
Example 64-3
[1824] In the same manner as in Example 1,
(E)-3-(4-bromo-2-chlorobenzyl)--
2-methyl-5-((2-phenylethenyl)sulfonylcarbamoyl)benzo[b]furan (0.13
g) was obtained as white crystals from
3-(4-bromo-2-chlorobenzyl)-5-carboxy-2-me- thylbenzo[b]furan (0.21
g), N,N'-carbonyldiimidazole (0.19 g), DBU (0.18 ml) and
(E)-(2-phenylethenyl)sulfonamide (0.21 g).
[1825] .sup.1H-NMR(DMSO-d.sub.6, .delta. ppm): 2.40(3H, s),
4.05(2H, s), 7.09(1H, d, J=8.3Hz), 7.42-7.47(5H, m), 7.49(1H, d,
J=15.4 Hz), 7.59(1H, d, J=8.7 Hz), 7.64(1H, d, J=15.5 Hz), 7.73(1H,
d, J=2.1 Hz), 7.74-7.77(1H, m), 7.82(1H, dd, J=8.7 and 1.9 Hz),
7.99(1H, d, J=1.8 Hz), 12.20(1H, brs) IR(Nujol): 1687 cm.sup.-1 mp:
214-215.degree. C.
Example 65-1
[1826] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(84 mg) was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(4-methylbenzene)-sulfonamide (76 mg).
[1827] .sup.1H-NMR(CDCl.sub.3): 2.42(3H, s), 2.62(3H, s), 5.55(2H,
s), 6.70(1H, d, J=8 Hz), 7.21(1H, dd, J=8 and 1 Hz), 7.35(2H, d,
J=8 Hz), 7.52(1H, d, J=1 Hz), 8.01-8.12(3H, m) Mass(ESI): m/z 487
(M-1) mp: 127-128.degree. C.
Example 65-2
[1828] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(96 mg) was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(4-vinylbenzene)-sulfonamide (82 mg).
[1829] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 5.42(1H, d, J=10 Hz),
5.54(2H, s), 5.89(1H, d, J=16 Hz), 6.65-6.80(2H, m), 7.21(1H, dd,
J=8 and 1 Hz), 7.50-7.59(3H, m), 8.04-8.14(4H, m) Mass(ESI): m/z
499 (M-1) mp: 194-195.degree. C.
Example 65-3
[1830] In the same manner as in Example 1,
(E)-3-(2,4-dichlorobenzyl)-2-me-
thyl-5-[(2-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(96 mg) was obtained as colorless crystals from
3-(2,4-dichlorobenzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(E)-(2-phenylethenyl)-sulfonamide (82 mg).
[1831] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.56(2H, s), 6.62(1H,
d, J=8 Hz), 7.10-7.21(2H, m), 7.37-7.46(2H, m), 7.50-7.58(2H, m),
7.82(1H, d, J=15 Hz), 8.11(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz),
10.0(1H, s) Mass(ESI): m/z 499 (M-1) mp: 192-194.degree. C.
Example 65-4
[1832] In the same manner as in Example 1,
5-((5-chlorothiophene-2-yl)sulf-
onylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(150 mg) was obtained as a white powder from
3-(2,4-dichlorobenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (165 mg) and
5-chlorothiophene-2-sulfonamide (140 mg).
[1833] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.55(2H, s), 6.68(1H,
d, J=8 Hz), 6.95(1H, d, J=4 Hz), 7.20(1H, dd, J=8 and 2 Hz),
7.52(1H, d, J=2 Hz), 7.76(1H, d, J=4 Hz), 8.11(1H, d, J=8 Hz),
8.15(1H, d, J=8 Hz), 10.05(1H, brs) Mass(ESI): m/e 513 (M-H).sup.-
mp: 206-207.degree. C.
Example 65-5
[1834] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(152 mg) was obtained as a white powder from
3-(2,4-dichlorobenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (166 mg) and
5-bromothiophene-2-sulfonamide (176 mg).
[1835] .sup.1H-NMR(CDCl.sub.3): 2.64(3H, s), 5.56(2H, s), 6.68(1H,
d, J=8 Hz), 7.10(1H, d, J=4 Hz), 7.22(1H, d, J=8 Hz), 7.53(1H, s),
7.74(1H, d, J=4 Hz), 8.11(1H, d, J=8 Hz), 8.16(1H, d, J=8 Hz),
10.05(1H, brs) Mass(ESI): m/e 557, 559 (M-H).sup.- mp:
168-169.degree. C.
Example 66-1
[1836] In the same manner as in Example 1,
(E)-3-(4-bromo-2-chlorobenzyl)--
2-methyl-5-[(2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(77 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl-
)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(E)-(2-phenylethenyl)sulfonamide (72 mg).
[1837] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.56(2H, s), 6.62(1H,
d, J=8 Hz), 7.15(1H, d, J=15 Hz), 7.33(1H, dd, J=8 and 1 Hz),
7.38-7.46(3H, m), 7.50-7.58(2H, m), 7.68(1H, brs), 7.81(1H, d, J=15
Hz), 8.11(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz), 10.0(1H, brs)
Mass(ESI): m/z 545 (M-1) mp: 204-205.degree. C.
Example 66-2
[1838] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2-me-
thyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(96 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(4-vinylbenzene)-sulfonamide (72 mg).
[1839] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 5.44(1H, d, J=10 Hz),
5.52(2H, s), 5.89(1H, d, J=16 Hz), 6.61(1H, d, J=8 Hz), 6.75(1H,
dd, J=16 and 10 Hz), 7.38(1H, d, J=8 Hz), 7.54(2H, d, J=8 Hz),
7.69(1H, brs), 8.03-8.15(4H, m) Mass(ESI) m/z 545 (M-1) mp:
208-210.degree. C.
Example 67-1
[1840] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(70 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
(4-vinylbenzene)sulfonamide (73 mg).
[1841] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 5.42(1H, d, J=10 Hz),
5.61(2H, s), 5.85(1H, d, J=16 Hz), 6.70(1H, dd, J=16 and 10 Hz),
6.89(1H, d, J=8 Hz), 7.38-7.52(6H, m), 7.59(2H, d, J=8 Hz),
7.73(1H, brs), 8.01-8.12(4H, m) Mass(ESI): m/z 541 (M-1) mp:
178-179.degree. C.
Example 67-2
[1842] In the same manner as in Example 1,
(E)-3-(2-chloro-4-phenylbenzyl)-
-2-methyl-5-[(2-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(78 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzy-
l)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg)
and (E)-(2-phenylethenyl)sulfonamide (73 mg).
[1843] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.61(2H, s), 6.80(1H,
d, J=8 Hz), 7.12(1H, d, J=15 Hz), 7.34-7.60(11H, m), 7.71(1H, d,
J=2 Hz), 7.79(1H, d, J=15 Hz), 8.11(1H, d, J=8 Hz), 8.19(1H, d, J=8
Hz), 10.6(1H, brs) Mass(ESI): m/z 541 (M-1) mp: 216-218.degree.
C.
Example 67-3
[1844] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-5-[-
(5-chlorothiophene-2-yl)sulfonylcarbamoyl]-2-methyl-3H-imidazo[4,5-b]pyrid-
ine (78 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxyl-
ic acid (100 mg) and 5-chlorothiophene-2-sulfonamide (79 mg).
[1845] .sup.1H-NMR(CDCl.sub.3): 2.69(3H, s), 5.60(2H, s),
6.84-6.91(2H, m), 7.34-7.50(4H, m), 7.52-7.60(2H, m), 7.67-7.74(2H,
m), 8.09(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz) Mass(ESI): m/z 555
(M-1) mp: 210-212.degree. C.
Example 67-4
[1846] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(221 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenz-
yl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg)
and (4-methylbenzene)sulfonamide (136 mg).
[1847] .sup.1H-NMR(CDCl.sub.3): 2.39(3H, s), 2.67(3H, s), 5.62(2H,
s), 6.87(1H, d, J=8 Hz), 7.27(2H, d, J=8 Hz), 7.36-7.50(4H, m),
7.58(2H, d, J=8 Hz), 7.72(1H, d, J=2 Hz), 7.99(2H, d, J=8 Hz),
8.05(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz) Mass(ESI): m/z 529 (M-1)
mp: 171-173.degree. C.
Example 67-5
[1848] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e (198 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg)
and 5-bromothiophene-2-sulfonamide (192 mg).
[1849] .sup.1H-NMR(CDCl.sub.3): 2.68(3H, s), 5.61(2H, s), 6.87(1H,
d, J=8 Hz), 7.03(1H, d, J=5 Hz), 7.36-7.50(4H, m), 7.57(2H, d, J=8
Hz), 7.65(1H, d, J=5 Hz), 7.72(1H, s), 8.09(1H, d, J=8 Hz),
8.15(1H, d, J=8 Hz). Mass(ESI): m/z 601 (M-1) mp: 205-207.degree.
C. Example 67-6
[1850] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-5-[-
(4-ethylbenzene)sulfonylcarbamoyl]-2-methyl-3H-imidazo[4,5-b]pyridine
(213 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylbenzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg) and
(4-ethylbenzene)sulfonamide (147 mg).
[1851] .sup.1H-NMR(CDC.sub.3): 1.22(3H, t, J=8 Hz), 2.63-2.75(5H,
m), 5.62(2H, s), 6.88(1H, d J=8 Hz), 7.29(2H, d, J=8 Hz),
7.36-7.50(4H, m), 7.60(2H, d, J=8 Hz), 7.73(1H, d, J=2 Hz),
8.01(2H, d, J=8 Hz), 8.07(1H, d, J=8 Hz), 8.11(1H, d, J=8 Hz).
Mass(ESI): m/z 529 (M-1) mp: 205-206.degree. C.
Example 68
[1852] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
[2-chloro-4-(thiophen-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine
(53 mg) was obtained as colorless crystals from
3-[2-chloro-4-(thiophene-2-yl-
)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (58
mg) and benzenesulfonamide (36 mg).
[1853] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.59(2H, s), 6.85(1H,
d, J=8 Hz), 7.10(1H, t, J=4 Hz), 7.32-7.39(2H, m), 7.44-7.52(3H,
m), 7.59(2H, d, J=8 Hz), 7.72(1H, brs), 8.05-8.14(4H, m).
Mass(ESI): m/z 521 (M-1) mp: 225-226.degree. C.
Example 69
[1854] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
[2-chloro-4-(5-chlorothiophene-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]pyri-
dine (27 mg) was obtained as colorless crystals from
3-[2-chloro-4-(5-chlorothiophene-2-yl)benzyl]-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylic acid (30 mg) and benzenesulfonamide (17
mg).
[1855] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.59(2H, s), 6.82(1H,
d, J=8 Hz), 6.91(1H, d, J=4 Hz), 7.12(1H, d, J=4 Hz), 7.38(1H, d,
J=8 Hz), 7.46-7.54(2H, m), 7.59-7.65(2H, m), 8.04-8.19(4H, m).
Mass(ESI): m/z 555 (M-1) mp: 215-217.degree. C.
Example 70-1
[1856] In the same manner as in Example 1,
3-(2-chloro-4-ethylbenzyl)-2-me-
thyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (42
mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-ethylbenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg) and
1-pentanesulfonamide (29 mg).
[1857] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=8 Hz), 1.22(3H, d,
J=8 Hz), 1.28-1.50(4H, m), 1.81-1.95(2H, m), 2.58-2.68(5H, m),
3.51-3.59(2H, m), 5.55(2H, s), 6.65(1H, d, J=8 Hz), 7.02(1H, brd,
J=8 Hz), 7.31(1H, brs), 8.12(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz),
9.81(1H, brs). Mass(ESI): m/z 461 (M-1) mp: 138-139.degree. C.
Example 70-2
[1858] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-ethylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (30 mg)
was obtained as pale-yellow crystals from
3-(2-chloro-4-ethylbenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg) and
benzenesulfonamide (30 mg).
[1859] .sup.1H-NMR(CDCl.sub.3): 1.24(3H, t, J=8 Hz), 2.59-2.70(5H,
m), 5.56(2H, s), 6.68(1H, d J=8 Hz), 7.04(1H, brd, J=8 Hz),
7.33(1H, brs), 7.51-7.68(3H, m), 8.05(1H, d, J=8 Hz), 8.10(1H, d,
J=8 Hz), 8.19(2H, d, J=8 Hz). Mass(ESI): m/z 467 (M-1) mp:
167-168.degree. C.
Example 70-3
[1860] In the same manner as in Example 1,
3-(2-chloro-4-ethylbenzyl)-2-me-
thyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(33 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-ethylbenzyl)--
2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg) and
(4-methylbenzene)sulfonamide (33 mg).
[1861] .sup.1H-NMR(CDCl.sub.3): 1.24(3H, t, J=8 Hz), 2.41(3H, s),
2.60-2.70(5H, m), 5.56(2H, s), 6.65(1H, d, J=8 Hz), 7.04(1H, brd,
J=8 Hz), 7.30-7.37(3H, m), 8.01-8.10(4H, m). Mass(ESI): m/z 481
(M-1) mp: 190-191.degree. C.
Example 70-4
[1862] In the same manner as in Example 1,
(E)-3-(2-chloro-4-ethylbenzyl)--
2-methyl-5-[(2-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(33 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-ethylbenz-
yl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (42 mg)
and (E)-(2-phenylethenyl)sulfonamide (35 mg).
[1863] .sup.1H-NMR(CDCl.sub.3): 1.23(3H, t, J=8 Hz), 2.57-2.68(5H,
m), 5.55(2H, s), 6.61(1H, d, J=8 Hz), 7.02(1H, brd, J=8 Hz),
7.15(1H, d, J=15 Hz), 7.31(1H, brs), 7.36-7.46(3H, m), 7.55(2H, d,
J=8 Hz), 7.81(1H, d, J=15 Hz), 8.09(1H, d, J=8 Hz), 8.18(1H, d, J=8
Hz). Mass(ESI): m/z 493 (M-1) mp: 184-185.degree. C.
Example 71
[1864] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-vinylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (46 mg)
was obtained as pale-yellow crystals from
3-(2-chloro-4-vinylbenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (125 mg) and
benzenesulfonamide (69 mg).
[1865] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.37(1H, d, J=10 Hz),
5.57(2H, s), 5.80(1H, d, J=16 Hz), 6.68(1H, dd, J=16 and 10 Hz),
6.86(1H, d, J=8 Hz), 7.23-7.30((1H, overlapped with H.sub.2O),
7.49-7.69(4H, m), 8.05(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz),
8.17(2H, d, J=8 Hz). Mass(ESI): m/z 465 (M-1) mp: 174-175.degree.
C.
Example 72
[1866] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-methylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (50
mg) was obtained as a white powder from
3-(2-chloro-4-methylbenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine-5-carboxylic acid (60 mg) and
benzenesulfonamide (49 mg).
[1867] .sup.1H-NMR(CDCl.sub.3): 2.35(3H, s), 2.61(3H, s), 5.54(2H,
s), 6.66(1H, d, J=8 Hz), 7.02(1H, d), 7.31(1H, s), 7.48-7.69(3H,
m), 8.00-8.10(2H, m), 8.12-8.21(2H, m), 10.05(1H, brs). Mass(ESI):
m/e 453 (M-H).sup.- mp: 213-215.degree. C.
Example 73
[1868] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(n-pentyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(81 mg) was obtained as a white powder from
3-(2-chloro-4-(n-pentyl)benzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (110 mg) and
benzene-sulfonamide (70 mg).
[1869] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.24-1.38(4H,
m), 1.50-1.68(2H, m) 2.52-2.64(2H, m), 2.62(3H, s), 5.56(2H, s),
6.64(1H, d, J=8 Hz), 7.02(1H, d, J=8 Hz), 7.31(1H, s),
7.48-7.68(3H, m), 8.01-8.12(2H, m), 8.14-8.22(2H, m), 10.05(1H,
brs). Mass(ESI): m/e 509 (M-H).sup.- mp: 174-175.degree. C.
Example 74
[1870] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-isobutylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (99
mg) was obtained as a white powder from
3-(2-chloro-4-isobutylbenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine-5-carboxylic acid (102 mg) and
benzenesulfonamide (70 mg).
[1871] .sup.1H-NMR(CDCl.sub.3): 0.90(6H, d, J=7 Hz), 1.76-1.95(1H,
m),2.46(2H, d, J=7 Hz), 2.61(3H, s), 5.56(2H, s), 6.63(1H, d, J=8
Hz), 6.98(1H, d, J=8 Hz), 7.29(1H, s), 7.49-7.68(3H, m),
8.01-8.12(2H, m), 8.14-8.22(2H, m), 10.05(1H, brs). Mass(ESI): m/e
495 (M-H).sup.- mp: 183-184.degree. C.
Example 75
[1872] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(cyclohexylmethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(120 mg) was obtained as a white powder from
3-(2-chloro-4-(cyclohexyl-me-
thyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(141 mg) and benzenesulfonamide (88 mg).
[1873] .sup.1H-NMR(CDCl.sub.3): 0.82-1.76(11H, m), 2.46(2H, d, J=7
Hz), 2.61(3H, s), 5.56(2H, s), 6.61(1H, d, J=8 Hz), 6.97(1H, d, J=8
Hz), 7.28(1H, s), 7.49-7.69(3H, m), 8.01-8.12(2H, m), 8.14-8.21(2H,
m), 10.05(1H, brs). Mass(ESI): m/e 535 (M-H).sup.- mp:
170-171.degree. C.
Example 76
[1874] In the same manner as in Example 1,
(E)-5-(benzenesulfonylcarbamoyl-
)-3-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e (128 mg) was obtained as a white powder from
(E)-3-(2-chloro-4-(2-phenyl-
ethenyl)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (140 mg) and benzenesulfonamide (85 mg).
[1875] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.58(2H, s), 6.83(1H,
d, J=8 Hz), 7.03(1H, d, J=16 Hz), 7.16(1H, d, J=16 Hz),
7.27-7.66(10H, m), 8.01-8.11(2H, m), 8.11-8.30(2H, m), 10.05(1H,
brs). Mass(ESI): m/e 541 (M-H).sup.- mp: 262-263.degree. C.
Example 77
[1876] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-benzyloxy-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (8
mg) was obtained as a white powder from
3-(4-benzyloxy-2-chlorobenzyl)-2-methyl-3-
H-imidazo[4,5-b]pyridine-5-carboxylic acid (98 mg) and
benzenesulfonamide (57 mg).
[1877] .sup.1H-NMR(CDCl.sub.3) 2.63(3H, s), 5.08(2H, s), 5.52(2H,
s), 6.79(1H, d, J=8 Hz), 6.88(1H, dd, J=8 and 2 Hz), 7.12(1H, d,
J=2 Hz), 7.30-7.45(5H, m), 7.48-7.66(3H, m), 8.00-8.10(2H, m),
8.12-8.22(2H, m), 10.05(1H, brs). Mass(ESI): m/e 545 (M-H).sup.-
mp: 190-191.degree. C.
Example 78
[1878] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-methoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (51
mg) was obtained as a white powder from
3-(2-chloro-4-methoxybenzyl)-2-methyl-3H--
imidazo[4,5-b]pyridine-5-carboxylic acid (65 mg) and
benzenesulfonamide (50 mg).
[1879] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 3.81(3H, s), 5.51(2H,
s), 6.80(2H, s), 7.02(1H, s), 7.49-7.68(3H, m), 7.99-8.10(2H, m),
8.12-8.22(2H, m), 10.50(1H, brs). Mass(ESI): m/e 469 (M-H).sup.-
mp: 151-152.degree. C.
Example 79
[1880] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-isopropoxybenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(53 mg) was obtained as a white powder from
3-(2-chloro-4-isopropoxybenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (61 mg) and
benzenesulfonamide (45 mg).
[1881] .sup.1H-NMR(CDCl.sub.3): 1.33(6H, d, J=7 Hz), 2.63(3H, s),
4.53(1H, sept, J=7 Hz), 5.50(2H, s), 6.75(2H, s), 7.00(1H, s),
7.48-7.70(3H, m), 8.03(1H, d, J=8 Hz), 8.07(1H, d, J=8 Hz),
8.16(2H, d, J=8 Hz), 10.20(1H, brs). Mass(ESI): m/e 497 (M-H).sup.-
mp: 177-179.degree. C.
Example 80
[1882] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-(n-butoxy)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(88 mg) was obtained as a white powder from
3-(4-(n-butoxy)-2-chlorobenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (75 mg) and
benzenesulfonamide (51 mg).
[1883] .sup.1H-NMR(CDCl.sub.3): 0.98(3H, t, J=7 Hz), 1.39-1.57(2H,
m), 1.69-1.82(2H, m), 2.63(3H, s), 3.97(2H, t, J=7 Hz), 5.51(2H,
s), 6.78(2H, s), 7.02(1H, s), 7.49-7.68(3H, m), 7.99-8.10(2H, m),
8.13-8.20(2H, m), 10.05(1H, brs). Mass(ESI): m/e 511 (M-H).sup.-
mp: 181-182.degree. C.
Example 81
[1884] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyrid-
ine (46 mg) was obtained as a white powder from
3-(2-chloro-4-((cyclohexyl-
methyl)-oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (45 mg) and benzenesulfonamide (30 mg).
[1885] .sup.1H-NMR(CDCl.sub.3): 0.95-1.90(11H, m), 2.62(3H, s),
3.74(2H, d, J=7 Hz), 5.51(2H, s), 6.78(2H, s), 7.01(1H, s),
7.48-7.68(3H, m), 7.99-8.09(2H, m), 8.12-8.21(2H, m), 10.05(1H,
brs). Mass(ESI): m/e 551 (M-H).sup.- mp: 122-125.degree. C.
Example 82
[1886] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine (54 mg) was obtained as a white powder
from
3-(2-chloro-4-((2-(N-methyl-N-(2-pyridinyl)amino)ethyl)oxy)benzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (103 mg) and
benzenesulfonamide (56 mg).
[1887] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 3.12(3H, s), 3.98(2H,
t, J=5 Hz), 4.19(2H, t, J=5 Hz), 5.51(2H, s), 6.51(1H, d, J=8 Hz),
6.57(1H, dd, J=8 and 5 Hz), 6.78(2H, s), 7.10(1h, s), 7.38-7.67(4H,
m), 7.99-8.10(2H, m), 8.12-8.21(3H, m), 10.05(1H, brs). Mass(ESI):
m/e 591 (M+H).sup.+ mp: 104-105.degree. C.
Example 83
[1888] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(53 mg) was obtained as a white powder from
3-(2-chloro-4-(methylthio)benzyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (131 mg) and
benzenesulfonamide (92 mg).
[1889] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 2.62(3H, s), 5.52(2H,
s), 6.74(1H, d, J=8 Hz), 7.10(1H, d, J=8 Hz), 7.33(1H, s),
7.48-7.68(3H, m), 8.00-8.10(2H, m), 8.12-8.20(2H, m), 10.05(1H,
brs). Mass(ESI): m/e 485 (M-H).sup.- mp: 165-166.degree. C.
Example 84
[1890] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(methylsulfinyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(90 mg) was obtained as a pale-yellow powder from
3-(2-chloro-4-(methyl-sulfi-
nyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(99 mg) and benzenesulfonamide (64 mg).
[1891] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 2.78(3H, s), 5.63(2H,
s), 6.82(1H, d, J=8 Hz), 7.43(1H, d, J=8 Hz), 7.50-7.71(3H, m),
7.88(1H, s), 8.05-8.15(2H, m), 8.15-8.22(2H, m), 10.05(1H, brs).
Mass(ESI): m/e 501 (M-H).sup.- mp: 230-231.degree. C.
Example 85
[1892] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(methanesulfonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(118 mg) was obtained as white crystals from
3-(2-chloro-4-(methane-sulfo-
nyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(100 mg) and benzenesulfonamide (62 mg).
[1893] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 3.29(3H, s),
5.93(2H, s), 6.93(1H, d, J=8 Hz), 7.63(2H, t, J=8 Hz),
7.70-7.80(2H, m), 7.90(1H, d, J=8 Hz), 8.03(2H, d, J=8 Hz),
8.13-8.18(2H, m).
[1894] Mass(ESI): m/z 517 (M-H).sup.-
Example 86
[1895] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-(benzylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(55 mg) was obtained as pale-yellow crystals from
3-(4-(benzylamino)-2-chloro-
benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (70
mg) and benzenesulfonamide (41 mg).
[1896] .sup.1H-NMR(DMSO-d.sub.6): 2.45(3H, s), 4.23(2H, d, J=6 Hz),
5.62(2H, s), 6.49(1H, dd, J=2 and 8 Hz), 6.61-6.68(3H, m),
7.20-7.32(5H, m), 7.65(2H, t, J=8 Hz), 7.72(1H, t, J=7 Hz),
7.87(1H, dd, J=1 and 8 Hz), 8.03(2H, d, J=8 Hz), 8.07(1H, d, J=8
Hz). Mass(ESI): m/z 544 (M-H).sup.-
Example 87
[1897] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(4-(n-butylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(50 mg) was obtained as pale-yellow crystals from
3-(4-(n-butylamino)-2-chlor-
obenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (45
mg) and benzenesulfonamide (29 mg).
[1898] .sup.1H-NMR(DMSO-d.sub.4): 0.89(3H, t, J=8 Hz),
1.30-1.421(2H, m), 1.43-1.55(2H, m), 2.47(3H, s), 2.93(2H, q, J=7
Hz), 5.63(2H, s), 5.97(1H, t, J=7 Hz), 6.45(1H, d, J=8 Hz),
6.63(1H, d, J=7 Hz), 6.67(1H, d, J=8 Hz), 7.65(2H, t, J=7 Hz),
7.73(1H, t, J=7 Hz), 7.87(1H, dd, J=1 and 8 Hz), 8.02(2H, d, J=8
Hz), 8.08(1H, d, J=8 Hz). Mass(ESI): m/z 510 (M-H).sup.-
Example 88
[1899] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(N,N-dimethylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(60 mg) was obtained as white crystals from
3-(2-chloro-4-(N,N-dimethyl-a-
mino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(55 mg) and benzenesulfonamide (38 mg).
[1900] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 2.89(6H, s),
5.68(2H, s), 6.60(1H, dd, J=2 and 8 Hz), 6.74(1H, d, J=8 Hz),
6.77(1H, d, J=2 Hz), 7.64(2H, t, J=8 Hz), 7.73(1H, t, J=8 Hz),
7.86(1H, d, J=8 Hz), 8.03(2H, d, J=8 Hz), 8.08(1H, d, J=8 Hz).
Mass(ESI): m/z 482 (M-H).sup.-
Example 89
[1901] In the same manner as in Example 1,
3-(4-(acetamido)-2-chlorobenzyl-
)-5-(benzenesulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(92 mg) was obtained as white crystals from
3-(4-(acetylamino)-2-chlorobenzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (98 mg) and
benzenesulfonamide (64 mg).
[1902] .sup.1H-NMR(DMSO-d.sub.6): 2.02(3H, s), 2.44(3H, s),
5.73(2H, s), 6.73(1H, d, J=8 Hz), 7.27(1H, d, J=8 Hz), 7.60(2H, t,
J=7 Hz), 7.70(1H, t, J=7 Hz), 7.86(1H, d, J=8 Hz), 7.97-8.00(3H,
m), 8.10(1H, d, J=8 Hz). Mass(ESI): m/z 496 (M-H).sup.-
Example 90
[1903] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(methanesulfonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne (61 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-(methanesulfonylamino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid (69 mg) and benzenesulfonamide (41 mg).
[1904] .sup.1H-NMR(DMSO-d.sub.6): 2.47(3H, s), 3.04(3H, s),
5.77(2H, s), 6.78(1H, d, J=8 Hz), 7.10(1H, d, J=8 Hz), 7.36(1H, s),
7.62(2H, t, J=7 Hz), 7.71(1H, t, J=7 Hz), 7.87(1H, d, J=8 Hz),
8.02(2H, d, J=8 Hz), 8.11(1H, d, J=8 Hz). Mass(ESI): m/z 532
(M-H).sup.-
Example 91
[1905] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-nitrobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (284mg)
was obtained as pale-brown crystals from
3-(2-chloro-4-nitrobenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (240 mg) and
benzenesulfonamide (163 mg).
[1906] .sup.1H-NMR(DMSO-d.sub.6): 2.47(3H, s), 5.93(2H, s),
6.93(1H, d, J=8 Hz), 7.63(2H, t, J=7 Hz), 7.72(1H, t, J=7 Hz),
7.90(1H, d, J=8 Hz), 8.08(1H, dd, J=2 and 8 Hz), 8.15(1H, d, J=8
Hz), 8.43(1H, s). Mass(ESI): m/z 484 (M-H).sup.-
Example 92
[1907] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-formylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (115
mg) was obtained as colorless crystals from
3-(2-chloro-4-formylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (199 mg) and
benzenesulfonamide (142 mg).
[1908] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 5.92(2H, s),
6.91(1H, d, J=8 Hz), 7.60-7.69(2H, m), 7.71(1H, d, J=8 Hz),
7.79(1H, d, J=8 Hz), 7.90(1H, d, J=8 Hz), 8.02(2H, d, J=8 Hz),
8.10-8.19(2H, m), 9.99(1H, s), 12.25(1H, brs) Mass(ESI): m/z 467
(M-1) mp: 253-255.degree. C.
Example 93
[1909] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
[2-chloro-4-1(2,4-dioxo-1,3-thiazolidine-5-ylidene)methyl]benzyl]-2-methyl-
-3H-imidazo[4,5-b]pyridine (46 mg) was obtained as pale-yellow
crystals from
3-[2-chloro-4-[(thiazolidine-2,4-dione-5-ylidene)methyl]benzyl]-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (59 mg) and
benzenesulfonamide (32 mg).
[1910] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 5.89(2H, s),
6.85(1H, d, J=8 Hz), 7.45(1H, brd, J=8 Hz), 7.60-7.75(3H, m),
7.79(1H, s), 7.86(1H, s), 7.90(1H, d, J=8 Hz), 8.00-8.05(2H, m),
8.15(1H, d, J=8 Hz). Mass(ESI): m/z 566 (M-1) mp: 271-274.degree.
C.
Example 94
[1911] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-fluorobenzyl)-2-methyl-3H-imidazo14,5-b]pyridine (67
mg) was obtained as white crystals from
3-(2-chloro-4-fluorobenzyl)-2-methyl-3H-i-
midazo[4,5-b]pyridine-5-carboxylic acid (65 mg) and
benzenesulfonamide (48 mg).
[1912] .sup.1H-NMR(DMSO-d.sub.6): 2.47(3H, s), 5.81(2H, s),
6.85(1H, dt, J=1 and 8 Hz), 7.15(1H, dt, J=2 and 8 Hz),
7.58-7.67(3H, m), 7.73(1H, t, J=8 Hz), 7.89(1H, d, J=8 Hz),
8.03(2H, d, J=8 Hz), 8.13(1H, d, J=8 Hz). Mass(ESI): m/z 457
(M-H).sup.-
Example 95
[1913] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-2--
methyl-3-(2,4,6-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine (82 mg)
was obtained as white crystals from
2-methyl-3-(2,4,6-trichlorobenzyl)-3H-imi-
dazo[4,5-b]pyridine-5-carboxylic acid (70 mg) and
benzenesulfonamide (45 mg).
[1914] .sup.1H-NMR(DMSO-d.sub.6): 2.68(3H, s), 5.85(2H, s),
7.67(2H, t, J=8 Hz), 7.73-7.81(3H, m), 7.84(1H, d, J=8 Hz),
8.04(2H, d, J=8 Hz), 8.10(1H, d, J=8 Hz). Mass(ESI): m/z 507
(M-H).sup.-
Example 96
[1915] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-2--
methyl-3-(2,3,4-trichlorobenzyl)-3H-imidazo[4,5-b]pyridine (141 mg)
was obtained as white crystals from
2-methyl-3-(2,3,4-trichlorobenzyl)-3H-imi-
dazo[4,5-b]pyridine-5-carboxylic acid (140 mg) and
benzenesulfonamide (89 mg).
[1916] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s),5.82(2H, s), 6.62(1H,
d, J=8 Hz), 7.53(1H, d, J=8 Hz), 7.61(1H, t, J=8 Hz), 7.70(1H, t,
J=8 Hz), 7.88(1H, d, J=8 Hz), 8.01(2H, d, J=8 Hz), 8.13(1H, d, J=8
Hz). Mass(ESI): m/z 507 (M-H).sup.-
Example 97
[1917] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2,4-dichloro-5-fluorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(108 mg) was obtained as white crystals from
3-(2,4-dichloro-5-fluorobenzyl)-2-met-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (100 mg) and
benzene-sulfonamide (67 mg).
[1918] .sup.1H-NMR(DMSO-d.sub.4): 2.50(3H, s), 5.80(2H, s),
6.97(1H, d, J=9 Hz), 7.65(2H, t, J=8 Hz), 7.73(1H, t, J=8 Hz),
7.88(1H, d, J=8 Hz), 7.98(1H, d, J=8 Hz), 8.03(2H, d, J=8 Hz),
8.13(1H, d, J=8 Hz). Mass(ESI): m/z 491 (M-H).sup.-
Example 98
[1919] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-iodobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (58 mg)
was obtained as white crystals from
3-(2-chloro-4-iodobenzyl)-2-methyl-3H-imi-
dazo[4,5-b]pyridine-5-carboxylic acid (70 mg) and
benzenesulfonamide (39 mg).
[1920] .sup.1H-NMR(DMSO-d.sub.6): 2.47(3H, s), 5.78(2H, s),
6.50(1H, d, J=8 Hz), 7.60-7.67(3H, m), 7.72(1H, t, J=7 Hz),
7.88(1H, d, J=8 Hz), 7.98(1H, s), 8.03(2H, d, J=8 Hz), 8.13(2H, d,
J=8 Hz). Mass(ESI): m/z 565 (M-H).sup.-
Example 99
[1921] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
((2,5-dichlorothiophen-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(57 mg) was obtained as white crystals from
3-((2,5-dichlorothiophene-3-yl)me-
thyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (55 mg)
and benzenesulfonamide (38 mg).
[1922] .sup.1H-NMR(DMSO-d.sub.6): 2.57(3H, s), 5.63(2H, s),
6.95(1H, s), 7.65(2H, t, J=7 Hz), 7.73(1H, t, J=7 Hz), 7.88(1H, d,
J=8 Hz), 8.05(2H, d, J=8 Hz), 8.10(1H, d, J=8 Hz). Mass(ESI): m/z
479 (M-H).sup.-
Example 100
[1923] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4,5-(methylenedioxy)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(43 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4,5-(methyl-
enedioxy)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (80 mg) and benzenesulfonamide (55 mg).
[1924] .sup.1H-NMR(DMSO-d.sub.6): 2.49(3H, s), 5.72(2H, s),
6.03(2H, s), 6.42(1H, s), 7.20(1H, s), 7.63(2H, t, J=7 Hz),
7.72(1H, t, J=7 Hz), 7.87(1H, d, J=8 Hz), 8.03(2H, d, J=8 Hz),
8.10(1H, d, J=8 Hz). Mass(ESI): m/z 483 (M-H).sup.-
Example 101
[1925] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
((2-chloroquinolin-3-yl)methyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(20 mg) was obtained as white crystals from
3-((2-chloroquinolin-3-yl)methyl)-2-m-
ethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (80 mg) and
benzenesulfonamide (54 mg).
[1926] .sup.1H-NMR(DMSO-d.sub.6): 2.53(3H, s), 5.92(2H, s),
7.56-7.72(4H, m), 7.78-8.00(8H, m), 8.15(1H, d, J=8 Hz). Mass(ESI):
m/z 490 (M-H).sup.-
Example 102-1
[1927] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(90 mg) was obtained as white crystals from
3-(2-chloro-4-(trifluoromethy-
l)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (90
mg) and benzenesulfonamide (57 mg).
[1928] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 5.92(2H, s),
6.90(1H, d, J=8 Hz), 7.61-7.67(3H, m), 7.90(1H, d, J=8 Hz),
8.01-8.03(3H, m), 8.17(1H, d, J=8 Hz). Mass(ESI): m/z 507
(M-H).sup.-
Example 102-2
[1929] In the same manner as in Example 1,
3-[2-chloro-4-(trifluoromethyl)-
-benzyl]-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(143 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoro-
-methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (160 mg) and 1-pentanesulfonamide (98 mg).
[1930] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=8 Hz), 1.27-1.52(4H,
m), 1.81-1.95(2H, m), 2.62(3H, s), 3.51-3.59(2H, m), 5.63(2H, s),
6.75(1H, d, J=8 Hz), 7.45(1H, brd, J=8 Hz), 7.79(1H, brs), 8.16(1H,
d, J=8 Hz), 8.24(1H, d, J=8 Hz), 9.75(1H, brs). Mass(ESI): m/z 501
(M-1) mp: 154-155.degree. C.
Example 102-3
[1931] In the same manner as in Example 1,
3-[2-chloro-4-(trifluoromethyl)-
-benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]-
pyridine (176 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (160 mg) and 4-(methylbenzene)sulfonamide (111
mg).
[1932] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 2.61(3H, s), 5.62(2H,
s), 6.77(1H, d, J=8 Hz), 7.32(2H, d, J=8 Hz), 7.47(1H, brd, J=8
Hz), 7.80(1H, brs), 8.02(2H, d, J=8 Hz, 8.09(1H, d, J=8 Hz),
8.12(1H, d, J=8 Hz). Mass(ESI): m/z 521 (M-1) mp: 174-175.degree.
C.
Example 103
[1933] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(1-bromonaphthalen-2-ylmethyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(67 mg) was obtained as white crystals from
3-(1-bromonaphthalen-2-ylmethyl)-2-me-
thyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (65 mg) and
benzenesulfonamide (42 mg).
[1934] .sup.1H-NMR(DMSO-d.sub.6): 2.45(3H, s), 6.06(2H, s),
6.80(1H, d, J=8 Hz), 7.60-7.80(5H, m), 7.89-7.94(2H, m),
7.99-8.03(3H, m), 8.17(1H, d, J=8 Hz), 8.33(1H, d, J=8 Hz).
Mass(ESI): m/z 533 (M-H).sup.-
Example 104-1
[1935] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-ylmethyl-
)-2,7-dimethyl-5-(pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(184 mg) was obtained as a white powder from
3-(1-bromo-naphthalen-2-ylmethyl)-
-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (328 mg)
and pentanesulfonamide (183 mg).
[1936] .sup.1H-NMR(CDCl.sub.3): 0.84(3H, t, J=7 Hz), 1.20-1.43(4H,
m), 1.73-1.88(2H, m), 2.63(3H, s), 2.74(3H, s), 3.43-3.55(2H, m),
5.79(2H, s), 6.78(1H, d, J=8 Hz), 7.52-7.86(4H, m), 8.02(1H, s),
8.38(1H, d, J=8 Hz), 9.85(1H, brs). Mass(ESI): m/e 541, 543
(M-H).sup.- mp: 210-211.degree. C.
Example 104-2
[1937] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazol4,5-b]pyridine
(278 mg) was obtained as a white powder from
3-(1-bromonaphthalen-2-ylmethyl)--
2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (328 mg)
and benzenesulfonamide (191 mg).
[1938] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 2.67(3H, s), 5.80(2H,
s), 6.79(1H, d, J=8 Hz), 7.41-7.88(7H, m), 7.90(1H, s),
8.02-8.12(2H, m), 8.41(1H, d, J=8 Hz), 10.05(1H, brs). Mass(ESI):
m/e 547, 549 (M-H).sup.- mp: 229-230.degree. C.
Example 104-3
[1939] In the same manner as in Example 1,
(E)-3-(1-bromonaphthalen-2-ylme-
thyl)-2,7-dimethyl-5-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-b-
]pyridine (268 mg) was obtained as a white powder from
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazol4,5-b]pyridine-5-
-carboxylic acid (337 mg) and (E)-(2-phenylethenyl)sulfonamide (228
mg).
[1940] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 2.73(3H, s), 5.80(2H,
s), 6.73(1H, d, J=8 Hz), 7.09(1H, d, J=16 Hz), 7.32-7.72(8H, m),
7.77(1H, d, J=16 Hz), 7.80-7.87(1H, m), 7.99(1H, s), 8.39(1H, d,
J=8 Hz), 10.07(1H, brs). Mass(ESI): m/e 573, 575 (M-H).sup.- mp:
262-263.degree. C.
Example 104-4
[1941] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-ylmethyl-
)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyr-
idine (190 mg) was obtained as a white powder from
3-(1-bromonaphthalen-2--
ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(248 mg) and (4-methylbenzene)sulfonamide (156 mg).
[1942] .sup.1H-NMR(CDCl.sub.3): 2.38(3H, s), 2.62(3H, s), 2.68(3H,
s), 5.81(2H, s), 6.79(1H, d, J=8 Hz), 7.26(2H, d, J=8 Hz),
7.53-7.88(4H, m), 7.90(1H, s), 7.96(2H, d, J=8 Hz), 8.32(1H, d, J=8
Hz), 10.05(1H, brs). Mass(ESI): m/e 561, 563 (M-H).sup.- mp:
227-228.degree. C.
Example 104-5
[1943] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-ylmethyl-
)-2,7-dimethyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyri-
dine (186 mg) was obtained as a white powder from
3-(1-bromonaphthalen-2-y-
lmethyl)-2,7-dimethyl-3H-imidazol4,5-b]pyridine-5-carboxylic acid
(250 mg) and (4-vinylbenzene)sulfonamide (165 mg).
[1944] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 2.68(3H, s), 5.42(1H,
d, J=10 Hz), 5.80(2H, s), 5.85(1H, d, J=17 Hz), 6.71(1H, dd, J=17
and 10 Hz), 6.78(1H, d, J=8 Hz), 7.46(2H, d, J=8 Hz), 7.53-7.88(4H,
m), 7.90(1H, s), 8.02(2H, d, J=8 Hz), 8.41(1H, d, J=8 Hz),
10.05(1H, brs). Mass(ESI): m/e 573, 575 (M-H).sup.- mp:
234-236.degree. C.
Example 104-6
[1945] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-ylmethyl-
)-2,7-dimethyl-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-3H-imidazo[4,5-
-b]pyridine (207 mg) was obtained as a white powder from
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (249 mg) and 5-chlorothiophene-2-sulfonamide (180
mg).
[1946] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 2.70(3H, s), 5.80(2H,
s), 6.79(1H, d, J=8 Hz), 6.89(1H, d, J=4 Hz), 7.53-7.88(5H, m),
7.95(1H, s), 8.40(1H, d, J=8 Hz), 10.05(1H, brs). Mass(ESI): m/e
587, 589 (M-H).sup.31 mp: 213-214.degree. C.
Example 105
[1947] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2,7--
dimethyl-5-(pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(159 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-di-
methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160 mg) and
pentanesulfonamide (92 mg).
[1948] .sup.1H-NMR(CDCl.sub.3): 0.89(3H, t, J=8 Hz), 1.28-1.50(4H,
m), 1.80-1.93(2H, m), 2.60(3H, s), 2.73(3H, s), 3.50-3.59(2H, m),
5.50(2H, s), 6.53(1H, d, J=8 Hz), 7.31(1H, brd, J=8 Hz), 7.66(1H,
brs), 8.02(1H, s), 9.80(1H, brs). Mass(ESI): m/z 527 (M-1) mp:
148-149.degree. C.
Example 106-1
[1949] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2,7--
dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(161 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzy-
l)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160
mg) and (4-methylbenzene)sulfonamide (104 mg).
[1950] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 2.59(3H, s), 2.68(3H,
s), 5.50(2H, s), 6.59(1H, d, J=8 Hz), 7.30-7.38(3H, m), 7.68(1H, d,
J=2 Hz), 7.90(1H, brs), 8.04(2H, d, J=8 Hz). Mass(ESI): m/z 547
(M-1) mp: 206-208.degree. C.
Example 106-2
[1951] In the same manner as in Example 1,
(E)-3-(4-bromo-2-chlorobenzyl)-- 2,7-dimethyl-5-[(2-phenylethenyl)
sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyri- dine (162 mg) was
obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid (160 mg) and (E)-(2-phenylethene)sulfonamide (111
mg).
[1952] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 2.72(3H, s), 5.50(2H,
s), 6.51(1H, d, J=8 Hz), 7.15(1H, d, J=15 Hz), 7.31(1H, brd, J=8
Hz), 7.39-7.47(3H, m), 7.50-7.59(2H, m), 7.67(1H, brs), 7.81(1H, d,
J=15 Hz), 8.00(1H, s), 10.01(1H, brs). Mass(ESI): m/z 559 (M-1) mp:
225-227.degree. C.
Example 106-3
[1953] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-5-[(- 5-chlorothiophen-2-yl)
sulfonylcarbamoyl]-2,7-dimethyl-3H-imidazo[4,5-b]py- ridine (191
mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid (200 mg) and 5-chlorothiophene-2-sulfonamide (150
mg).
[1954] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 2.70(3H, s), 5.50(2H,
s), 6.56(1H, d, J=8 Hz), 6.95(1H, d, J=4 Hz), 7.32(1H, dd, J=8 and
1 Hz), 7.67(1H, brs), 7.76(1H, d, J=4 Hz), 7.96(1H, s). Mass(ESI):
m/z 573 (M-1) mp: 214-215.degree. C.
Example 106-4
[1955] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-2,7--
dimethyl-5-1(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
was obtained as colorless crystals (208 mg) from
3-(4-bromo-2-chlorobenzy-
l)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200
mg) and (4-vinylbenzene)sulfonamide (139 mg).
[1956] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 2.68(3H, s), 5.43(1H,
d, J=10 Hz), 5.50(2H, s), 5.88(1H, d, J=16 Hz), 6.57(1H, d, J=8
Hz), 6.73(1H, dd, J=16 and 10 Hz), 7.34(1H, dd, J=8 and 2 Hz),
7.55(2H, d, J=8 Hz), 7.68(1H, d, J=2 Hz), 7.90(1H, s), 8.10(2H, d,
J=8 Hz). Mass(ESI): m/z 559 (M-1) mp: 204-205.degree. C.
Example 106-5
[1957] In the same manner as in Example 1,
3-(4-bromo-2-chlorobenzyl)-5-[(-
5-bromothiophen-2-yl)sulfonylcarbamoyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyri-
dine (238 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid (200 mg) and 5-bromothiophene-2-sulfonamide (184
mg).
[1958] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 2.62(3H, s),
5.74(2H, s), 6.60(1H, d, J=8 Hz), 7.39(1H, d, J=5 Hz), 7.46(1H, dd,
J=8 and 2 Hz), 7.70(1H, d, J=5 Hz), 7.83(1H, s), 7.87(1H, d, J=2
Hz). mp: 210-211.degree. C.
Example 107-1
[1959] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-nitrobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine (81
mg) was obtaiend as a pale-brown powder from
3-(2-chloro-4-nitrobenzyl)-2,7-d-
imethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (135 mg) and
benzenesulfonamide (88 mg).
[1960] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 2.58(3H, s),
5.89(2H, s), 6.88(1H, d, J=8 Hz), 7.55-7.76(4H, m), 7.98(1H, d, J=8
Hz), 8.07(1H, d, J=8 Hz), 8.23(1H, s), 8.43(1H, s). Mass(ESI): m/e
498 (M-H).sup.-
Example 107-2
[1961] In the same manner as in Example 1,
3-(2-chloro-4-nitrobenzyl)-2,7--
dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(151 mg) was obtained as a yellow powder from
3-(2-chloro-4-nitrobenzyl)--
2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (180 mg)
and (4-methylbenzene)sulfonamide (88 mg).
[1962] .sup.1H-NMR(DMSO-d.sub.6): 2.37(3H, s), 2.46(3H, s),
2.58(3H, s), 5.89(2H, s), 6.88(1H, d, J=8 Hz), 7.40(2H, d, J=8 Hz),
7.73(1H, s), 7.88(2H, d, J=8 Hz), 8.08(1H, dd, J=8 and 2 Hz),
8.43(1H, d, J=2 Hz). Mass(ESI): m/e 512 (M-H).sup.-
Example 107-3
[1963] In the same manner as in Example 1,
(E)-3-(2-chloro-4-nitrobenzyl)--
2,7-dimethyl-5-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyrid-
ine (183 mg) was obtained as a yellow powder from
3-(2-chloro-4-nitrobenzy-
l)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (180
mg) and (E)-(2-phenylethene)sulfonamide (137 mg).
[1964] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 2.62(3H, s),
5.90(2H, s), 6.84(1H, d, J=8 Hz), 7.38-7.47(3H, m), 7.49(1H, d,
J=15 Hz), 7.65(1H, d, J=15 Hz), 7.70-7.80(2H, m), 7.84(1H, s),
8.07(1H, d, J=8 Hz), 8.42(1H, s). Mass(ESI): m/e 524
(M-H).sup.-
Example 107-4
[1965] In the same manner as in Example 1,
3-(2-chloro-4-nitrobenzyl)-2,7--
dimethyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(85 mg) was obtained as a yellow powder from
3-(2-chloro-4-nitrobenzyl)-2-
,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (180 mg)
and (4-vinylbenzene)sulfonamide (137 mg).
[1966] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 2.60(3H, s),
5.48(1H, d, J=12 Hz), 5.91(2H, s), 6.02(1H, d, J=18 Hz), 6.82(1H,
dd, J=18 and 12 Hz), 6.92(1H, d, J=8 Hz), 7.67-7.78(3H, m),
7.97(2H, d, J=8 Hz), 8.09(1H, d, J=8 Hz), 8.44(1H, s). Mass(ESI):
m/e 524 (M-H).sup.-
Example 108
[1967] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-cyanobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (24 mg)
was obtained as a pale-yellow powder from
3-(2-chloro-4-cyanobenzyl)-2-methyl-
-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (32 mg) and
benzenesulfonamide (25 mg).
[1968] .sup.1H-NMR(CDCl.sub.3): 2.59(3H, s), 5.63(2H, s), 6.75(1H,
d, J=8 Hz), 7.45-7.70(4H, m), 7.81(1H, s), 8.06-8.20(4H, m),
10.05(1H, brs). Mass(ESI): m/e 464 (M-H).sup.- mp: 242-243.degree.
C.
Example 109-1
[1969] In the same manner as in Example 1,
(E)-3-(2-chloro-4-(trifluoro-me-
thyl)benzyl)-2-methyl-5-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,-
5-b]pyridine (152 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (160 mg) and (E)-(2-phenylethene)sulfonamide
(119 mg).
[1970] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.64(2H, s), 6.73(1H,
d, J=8 Hz), 7.14(1H, d, J=15 Hz), 7.38-7.48(4H, m), 7.50-7.58(2H,
m), 7.78-7.85(2H, m), 8.14(1H, d, J=8 Hz), 8.21(1H, d, J=8 Hz),
9.97(1H, brs). Mass(ESI): m/z 533 (M-1) mp: 140-142.degree. C.
Example 109-2
[1971] In the same manner as in Example 1,
3-(2-chloro-4-(trifluoromethyl)-
-benzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]p-
yridine (41 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (160 mg) and (4-vinylbenzene)sulfonamide (119
mg).
[1972] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.44(1H, d, J=10 Hz),
5.63(2H, s), 5.88(1H, d, J=16 Hz), 6.68-6.80(2H, m), 7.47(1H, brd,
J=8 Hz), 7.54(2H, d, J=8 Hz), 7.80(1H, s), 8.08-8.16(4H, m).
Mass(ESI): m/z 533 (M-1) mp: 157-158.degree. C.
Example 109-3
[1973] In the same manner as in Example 1,
3-(2-chloro-4-(trifluoromethyl)-
-benzyl)-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine (189 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (160 mg) and 5-chlorothiophene-2-sulfonamide
(128 mg).
[1974] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.63(2H, s), 6.77(1H,
d, J=8 Hz), 6.95(1H, d, J=4 Hz), 7.46(1H, brd, J=8 Hz), 7.75(1H, d,
J=4 Hz), 7.80(1H, brs), 8.14(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz).
Mass(ESI): m/z 547 (M-1) mp: 170-171.degree. C.
Example 109-4
[1975] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)
sulfonylcarbamoyl)-3-(2-chloro-4-(trifluoromethyl)benzyl)
-2-methyl-3H-imidazo[4,5-b]pyridine was obtained as colorless
crystals (203 mg) from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine-5-carboxylic acid (160 mg) and
5-bromothiophene-2-sulfonami- de (157 mg).
[1976] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.63(2H, s), 6.76(1H,
d, J=8 Hz), 7.09(1H, d, J=4 Hz), 7.46(1H, brd, J=8 Hz), 7.71(1H, d,
J=4 Hz), 7.79(1H, brs), 8.14(1H, d, J=8 Hz), 8.19(1H, d, J=8 Hz).
Mass(ESI): m/z 593 (M-1) mp: 172-173.degree. C.
Example 110
[1977] In the same manner as in Example 1,
5-(benzenesulfonylcarbamoyl)-3--
(2-chloro-4-phenylbenzyl)-2-methylbenzo[b]thiophene (65 mg) was
obtained as white crystals from
3-(2-chloro-4-phenylbenzyl)-2-methylbenzo[b]-thiop-
hene-5-carboxylic acid (90 mg) and benzenesulfonamide (54 mg).
[1978] .sup.1H-NMR(DMSO-d.sub.6): 2.46(3H, s), 4.30(2H, s),
6.78(1H, d, J=8 Hz), 7.35-7.45(4H, m), 7.58-7.70(5H, m),
7.76-7.80(2H, m), 7.97(2H, d, J=8 Hz), 8.03(1H, d, J=8 Hz),
8.18(1H, s).
[1979] Mass(ESI): m/z 530 (M-H).sup.-
Example 111-1
[1980] In the same manner as in Example 1,
1-(2-chloro-4-phenylbenzyl)-6-(-
(5-chlorothiophen-2-yl)sulfonylcarbamoyl)-3-methyl-1H-indazole (39
mg) was obtained as white crystals from
6-carboxy-1-(2-chloro-4-phenylbenzyl)-3-m- ethyl-1H-indazole (200
mg) and 5-chlorothiophene-2-sulfonamide (157 mg).
[1981] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s) 5.70(2H, s), 6.77(1H,
d, J=8 Hz), 6.98(1H, d, J=3 Hz), 7.32(1H, d, J=3 Hz), 7.34-7.47(3H,
m), 7.52(1H, d, J=8 Hz), 7.64-7.68(3H, m), 7.74-7.77(2H, m),
8.11(1H, s). Mass(ESI): m/z 554 (M-H).sup.-
Example 111-2
[1982] In the same manner as in Example 1,
6-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-1-(2-chloro-4-phenylbenzyl)-3-methyl-1H-indazole (197
mg) was obtained as white crystals from
6-carboxy-1-(2-chloro-4-phenylbenzyl)-3-m- ethyl-1H-indazole (200
mg) and 5-bromothiophene-2-sulfonamide (193 mg).
[1983] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.70(2H, s),
6.77(1H, d, J=8 Hz), 7.07(1H, d, J=3 Hz), 7.28(1H, d, J=4 Hz),
7.35-7.48(3H, m), 7.52(1H, d, J=8 Hz), 7.63-7.67(3H, m),
7.73-7.77(2H, m), 8.10(1H, s). Mass(ESI): m/z 600 (M-H).sup.-
Example 112
[1984] In the same manner as in Example 1,
3-(1-bromonaphthalen-2-ylmethyl- )-5-((5-bromothiophene-2-yl)
sulfonylcarbamoyl)-2,7-dimethyl-3H-imidazo[4,- 5-b]pyridine (216
mg) was obtained as a white powder from
3-(1-bromonaphthalen-2-ylmethyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (209 mg) and 5-bromothiophene-2-sulfonamide (166
mg).
[1985] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 2.70(3H, s), 5.80(2H,
s), 6.78(1H, d, J=8 Hz), 7.03(1H, d, J=4 Hz), 7.53-7.88(5H, m),
7.95(1H, s), 8.40(1H, d, J=8 Hz), 10.05(1H, brs). Mass(ESI): m/e
631, 633, 635 (1:2:1, M-H).sup.- mp: 247-248.degree. C.
Example 113
[1986]
(E)-5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethenyl)-be-
nzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (42 mg) was suspended in a
mixed solvent of chloroform (4 ml), 1,4-dioxane (2 ml) and methanol
(2 ml), and platinum oxide (2 mg) was added. The mixture was
stirred at room temperature for 6.5 hr under a hydrogen atmosphere
at 1 atm. The reaction mixture was filtrated and the solvent was
evaporated. The resultant mixture was purified by silica gel column
chromatography (chloroform/methanol=20/1) and crystallized from
ethyl acetate/hexane to give
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine (18 mg) as a white powder.
[1987] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 2.90(4H, s), 5.56(2H,
s), 6.63(1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.10-7.32(6H, m),
7.49-7.67(3H, m), 8.02-8.12(2H, m), 8.14-8.21(2H, m), 10.05(1H,
brs). Mass(ESI): m/e 543 (M-H).sup.- mp: 180-181.degree. C.
Example 114
[1988]
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-nitrobenzyl)-2-methyl-3H-
-imidazo[4,5-b]pyridine (245 mg) was suspended in ethanol (3 ml)
and reduced iron (141 mg) and acetic acid (0.289 ml) were added,
and the mixture was refluxed under heating overnight. The reaction
mixture was filtered through Celite, and the filtrate was washed
with a mixed solvent of methanol/chloroform (1/4) and the filtrate
was concentrated under reduced pressure. To the concentrated
residue were added a saturated aqueous sodium hydrogen carbonate
solution, water and a mixed solvent of methanol/chloroform (1/4)
and the aqueous phase was made alkaline. The precipitated insoluble
matter was filtered through Celite and the filtrate was washed with
a mixed solvent of methanol/chloroform ({fraction (1/9)}). The
filtrate was partitioned and the organic layer was dried over
anhydrous magnesium sulfate and filtrated. The filtrate was
concentrated under reduced pressure to give a crude product as a
pale-brown powder. The crude product (100 mg) was recrystallized
from N,N-dimethylformamide-water to give
3-(4-amino-2-chlorobenzyl)-5-(benzene-
sulfonylcarbamoyl)-2-methyl-3H-i-imidazol4,5-b]pyridine (75 mg) as
brown crystals.
[1989] .sup.1H-NMR(DMSO-d.sub.6): 2.50(3H, s), 5.62(2H, s),
6.45(1H, d, J=8 Hz), 6.62(1H, d, J=8 Hz), 6.67(1H, s), 7.63(2H, t,
J=7 Hz), 7.72(1H, t, J=7 Hz), 7.87(1H, d, J=8 Hz), 8.04(2H, d, J=8
Hz), 8.08(1H, d, J=8 Hz). Mass(ESI): m/z 454(M-H).sup.-
Example 115
[1990]
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-(hydroxymethyl)benzyl)-2-
-methyl-3H-imidazo[4,5-b]pyridine was obtained as colorless
crystals (80 mg) from
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-formylbenzyl)-2-methy-
l-3H-imidazo[4,5-b]pyridine (170 mg).
[1991] .sup.1H-NMR(CDCl.sub.3--CD.sub.3OD): 2.64(3H, s), 4.68(2H,
s), 5.59(2H, s), 6.80(1H, d, J=8 Hz), 7.22(1H, brd, J=8 Hz),
8.05(1H, d, J=8 Hz), 8.09(1H, d, J=8 Hz), 8.13-8.19(2H, m).
Mass(ESI): m/z469 (M-1) mp: 198-199.degree. C.
Example 116
[1992] To a suspension of
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-formy-
lbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (95 mg, 0.20 mmol) in
tert-butyl alcohol (2 ml) and water (0.5 ml) were added
2-methyl-2-butene (63 mg, 0.90 mmol) and sodium dihydrogenphosphate
(32 mg, 0.20 mmol) at room temperature. To the suspension was added
sodium chlorite (63 mg, 0.56 mmol) and the mixture was stirred at
room temperature. One hour later, 2-methyl-2-butene (63 mg, 0.90
mmol) and sodium dihydrogenphosphate (32 mg, 0.20 mmol) were added.
Two hours later, 1,4-dioxane (2 ml) was added and the mixture was
heated to 60.degree. C. When the solution became transparent, it
was stirred at room temperature for 1 hr. Water was added to the
reaction mixture and the mixture was adjusted to pH 4 with 1N
hydrochloric acid. The mixture was stirred for 30 min under
ice-cooling and filtrated to give a colorless powder (97 mg). The
powder was suspended in acetone and the suspension was heated and
stirred at room temperature for 30 min to give
5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chlorobenzyl)-2-methyl-3H-imi-
dazo[4,5-b]pyridine (70 mg) as colorless crystals.
[1993] .sup.1H-NMR(DMSO-d.sub.6): 2.48(3H, s), 5.90(2H, s),
6.82(1H, d, J=8 Hz), 7.60-7.68(2H, m), 7.71(1H, d, J=8 Hz),
7.80(1H, d, J=8 Hz), 8.00-8.08(3H, m), 8.17(1H, d, J=8 Hz).
Mass(ESI): m/z 483 (M-1) mp: 155-160.degree. C.
Example 117
[1994] In the same manner as in Preparation Example
14--1,5-(benzene-sulfonylcarbamoyl)-3-(2-chloro-4-((methanesulfonyloxy)me-
thyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine was obtained from
5-(benzene-sulfonylcarbamoyl)-3-[2-chloro-4-(hydroxymethyl)benzyl]-2-meth-
yl-3H-imidazo[4,5-b]pyridine (58 mg). This compound was used in the
next reaction without purification.
Example 118
[1995] To a solution of phenol (12 mg, 0.13 mmol) in
N,N-dimethylformamide (0.5 ml) was added sodium hydride (60% in
mineral oil, 5.2 mg) under ice-cooling. Thirty minutes later, a
solution of 5-(benzenesulfonylcarbam-
oyl)-3-(2-chloro-4-((methanesulfonyloxy)methyl)benzyl)-2-methyl-3H-imidazo-
[4,5-b]pyridine (68 mg, 0.12 mmol) in N,N-dimethylformamide (1 ml)
was dropwise added, which was followed by stirring at room
temperature for 3 hr. The reaction mixture was cooled with ice and
water was added. Its pH was adjusted to 4 by dropwise addition of
1N hydrochloric acid. The resulting product was extracted with
ethyl acetate, washed three times with water, dried over anhydrous
magnesium sulfate, and concentrated. The residue was subjected to
silica gel thin layer chromatography (eluent:
chloroform/methanol=20/1) and crystallized from ethyl acetate to
give
5-(benzenesulfonylcarbamoyl)-3-(2-chloro-4-((phenyloxy)methyl)-benzyl)-2--
methyl-3H-imidazo[4,5-b]pyridine (30 mg) as colorless crystals.
[1996] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 5.05(2H, s), 5.59(2H,
s), 6.74(1H, d, J=8 Hz), 6.91-7.01(3H, m), 7.23-7.33(3H, m),
7.49-7.67(4H, m), 8.06(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz),
8.15-8.21(2H, m). Mass(ESI): m/z 545 (M-1) mp: 203-205.degree.
C.
Example 119
[1997] To a solution of
5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chloro-
benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine (25 mg, 0.052 mmol) in
N,N-dimethylformamide (0.3 ml) were added ethanol (4 mg, 0.088
mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride
(12 mg, 0.062 mmol) and 1-hydroxybenzotriazole (10 mg, 0.075 mmol)
at room temperature. Three hours later, ethyl acetate and water
were added to the reaction mixture and the mixture was adjusted to
pH 4 with 1N hydrochloric acid. The organic layer was washed with
water four times, dried over anhydrous magnesium sulfate and
concentrated. The residue was subjected to silica gel thin layer
chromatography (eluent: chloroform/methanol=10/1) and crystallized
from ethyl acetate to give 5-(benzenesulfonylcarbamoyl)-3-(2-
-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(18 mg) as colorless crystals.
[1998] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=8 Hz), 2.60(3H, s),
4.40(2H, q, J=8 Hz), 5.63(2H, s), 6.72(1H, d, J=8 Hz),
7.50-7.59(2H, m), 7.62(1H, d, J=8 Hz), 7.86(1H, d, J=8 Hz),
8.09(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz), 8.15-8.20(3H, m).
Mass(ESI): m/z 511 (M-1) mp: 196-197.degree. C.
Example 120
[1999]
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-(methylcarbamoyl)benzyl)-
-2-methyl-3H-imidazo[4,5-b]pyridine was obtained as colorless
crystals (18 mg) from
5-(benzenesulfonylcarbamoyl)-3-(4-carboxy-2-chlorobenzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine (29 mg) and
methylamine/tetrahydrofuran solution (2M, 0.05 ml).
[2000] .sup.1H-NMR(CDCl.sub.3--CD.sub.3OD): 2.67(3H, s), 3.99(3H,
s), 5.60(2H, s), 6.99(1H, d, J=8 Hz), 7.50-7.69(4H, m), 7.96(1H,
brs), 8.05-8.15(4H, m). Mass(ESI): m/z 496 (M-1) mp:
257-260.degree. C.
Example 121
5-(Benzenesulfonylcarbamoyl)-3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-im-
idazo[4,5-b]pyridine
[2001] In the same manner as in Preparation Example 4-7, the
objective compound (139 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carbo-
xylic acid (160 mg) and benzenesulfonamide (96 mg).
[2002] .sup.1H-NMR(CDCl.sub.3): 2.60(3H, s), 2.68(3H, s), 5.51(2H,
s), 6.59(1H, d, J=8 Hz), 7.35(1H, dd, J=8, 2 Hz), 7.51-7.69(4H, m),
7.91(1H, br s), 8.17 (2H, d, J=8 Hz). Mass(ESI): m/z 533 (M-1) mp
231-232.degree. C.
Example 122
[2003] In the same manner as in Example 1,
3-(2-chloro-4-(E)-(2-phenyl-eth-
enyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,-
5-b]pyridine (221 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide
(126 mg).
[2004] .sup.1H-NMR(CDCl.sub.3): 2.36(3H, s), 2.64(3H, s), 5.58(2H,
s), 6.92(1H, d, J=8 Hz), 7.03(1H, d, J=16 Hz), 7.15(1H, d, J=19
Hz), 7.25-7.38(6H, m), 7.50(2H, d, J=8 Hz), 7.63(1H, s),
8.00-8.09(4H, m) Mass(ESI): m/z 555(M-H).sup.-
Example 123
[2005] In the same manner as in Example 1,
3-(2-chloro-4-(E)-(2-phenyl-eth-
enyl)benzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-
-b]pyridine (229 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (200 mg) and (4-vinylbenzene)sulfonamide
(135 mg).
[2006] .sup.1H-NMR(CDCl.sub.3): 2.65(3H, s), 5.37(1H, d, J=9 Hz),
5.57(2H, s), 5.79(1H, d, J=16 Hz), 6.68(1H, dd, J=9, 17 Hz),
6.84(1H, d, J=8 Hz), 7.02-7.53(8H, m), 7.63(1H, s), 8.05-8.08(4H,
m) Mass(ESI): m/z 567(M-H).sup.-
Example 124
[2007] In the same manner as in Example 1,
3-(2-chloro-4-(E)-(2-phenyl-eth-
enyl)benzyl)-2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidaz-
o[4,5-b]pyridine (227 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (200 mg) and (E)-(2-phenylethene)sulfonamide
(135 mg).
[2008] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.58(2H, s), 6.77(1H,
d, J=8 Hz), 6.98-7.17(3H, m), 7.29-7.53(11H, m), 7.63(1H, s),
7.77(1H, d, J=16 Hz), 8.10(1H, d, J=8 Hz), 8.15(1H, d, J=8 Hz)
Mass(ESI): m/z 567(M-H).sup.-
Example 125
[2009] In the same manner as in Example 1,
3-(2-chloro-4-(E)-(2-phenyl-eth-
enyl)benzyl)-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine (227 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (200 mg) and 5-chlorothiophene-2-sulfonamide
(145 mg).
[2010] .sup.1H-NMR(CDCl.sub.3): 2.66(3H, s), 5.57(2H, s), 6.82(1H,
d, J=8 Hz), 6.99(1H, d, J=3 Hz), 7.02(1H, d, J=16 Hz), 7.13(1H, d,
J=16 Hz), 7.29-7.39(4H, m), 7.50(1H, d, J=7 Hz), 7.63(1H, s),
7.75(1H, d, J=3 Hz), 8.09(1H, d, J=8 Hz), 8.13(1H, d, J=8 Hz),
Mass(ESI): m/z 581(M-H).sup.-
Example 126
[2011] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-3-(E)-(2-chloro-4-(2-phenylethenyl)benzyl)-2-methyl-3H-imidaz-
o[4,5-b]pyridine (226 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phenylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (200 mg) and 5-bromothiophene-2-sulfonamide
(178 mg).
[2012] .sup.1H-NMR(CDCl.sub.3): 2.68(3H, s), 5.57(2H, s), 6.82(1H,
d, J=8 Hz), 7.00-7.16(3H, m), 7.28-7.38(4H, m), 7.51(2H, d, J=8
Hz), 7.63(1H, s), 7.70(1H, d, J=3 Hz), 8.08(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz) Mass(ESI): m/z 627(M-H).sup.-
Example 127
[2013] In the same manner as in Example 1,
3-(2-chloro-4-(E)-(2-phenyl-eth-
enyl)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyri-
dine (202 mg) was obtained as white crystals from
3-(2-chloro-4-(E)-(2-phe-
nylethenyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (200 mg) and 1-pentanesulfonamide(111 mg).
[2014] .sup.1H-NMR(CDCl.sub.3): 8.03(3H, t, J=7 Hz), 1.22-1.43(4H,
m), 1.80-1.92(2H, m), 2.67 (3H, s), 3.53(2H, t, J=8 Hz), 5.58(2H,
s), 6.77(1H, d, J=8 Hz), 6.99(1H, d, J=16 Hz), 7.13(1H, d, J=17
Hz), 7.29-7.36(4H, m), 7.49(2H, d, J=8 Hz), 7.63(1H, s), 8.13(1H,
d, J=8 Hz), 8.20(1H, d, J=8 Hz) Mass(ESI): m/z 537(M+H).sup.+
Example 128
[2015] In the same manner as in Example 1,
3-(2-chloro-4-(2-phenylethyl)-b-
enzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]py-
ridine (193 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide (127
mg).
[2016] .sup.1H-NMR(CDCl.sub.3): 2.42(3H, s), 2.02(3H, s), 2.86(4H,
s), 5.56(2H, s), 6.62(1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz),
7.13-7.33(8H, m), 8.02-8.09(4H, m) Mass(ESI): m/z
557(M-H).sup.-
Example 129
[2017] In the same manner as in Example 1,
3-(2-chloro-4-(2-phenylethyl)-b-
enzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyr-
idine (174 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenyl-
ethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(200 mg) and (4-vinylbenzene)sulfonamide (226 mg).
[2018] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 2.91(4H, s), 5.43(1H,
d, J=10 Hz), 5.88(1H, d, J=16 Hz), 6.64(1H, d, J=8 Hz), 6.74(1H,
dd, J=9, 16 Hz), 7.00(1H, d, J=8 Hz), 7.16-7.33(6H, m), 7.64(2H, d,
J=8 Hz), 8.04-8.14(4H, m) Mass(ESI): m/z 569(M-H).sup.-
Example 130
[2019] In the same manner as in Example 1,
3-(2-chloro-4-(2-phenylethyl)-b-
enzyl)-2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5--
b]pyridine (242 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (200 mg) and (E)-(2-phenylethene)sulfonamide (226
mg).
[2020] .sup.1H-NMR(CDCl.sub.3): 2.61(3H, s), 2.91(4H, s), 5.57(2H,
s), 6.62(1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.14-7.32(7H, m),
7.42-7.45(3H, m), 7.53(2H, d, J=8 Hz), 7.83(1H, d, J=15 Hz),
8.08(1H, d, J=8 Hz), 8.17(1H, d, J=8 Hz) Mass(ESI): m/z
569(M-H).sup.-
Example 131
[2021] In the same manner as in Example 1,
3-(2-chloro-4-(2-phenylethyl)-b-
enzyl)-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[4,-
5-b]pyridine (199 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (200 mg) and 5-chlorothiophene-2-sulfonamide (243
mg).
[2022] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 2.92(3H, s), 5.56(2H,
s), 6.64(1H, d, J=8 Hz), 6.96(1H, d, J=3 Hz), 7.01(1H, d, J=8 Hz),
7.16-7.32(6H, m), 7.78(1H, d, J=3 Hz), 8.08(1H, d, J=8 Hz),
8.14(1H, d, J=8 Hz) Mass(ESI): m/z 583(M-H).sup.-
Example 132
[2023] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine (263 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenylethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (200 mg) and 5-bromothiophene-2-sulfonamide (298
mg).
[2024] .sup.1H-NMR(CDCl.sub.3): 2.62(3H, s), 2.90(4H, s), 5.56(2H,
s), 6.65(1H, d, J=8 Hz), 7.01(1H, d, J=8 Hz), 7.08(1H, d, J=3 Hz),
7.12-7.30(6H, m), 7.74(1H, d, J=4 Hz), 8.07(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz) Mass(ESI): m/z 629(M-H).sup.-
Example 133
[2025] In the same manner as in Example 1,
3-(2-chloro-4-(2-phenylethyl)-b-
enzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(166 mg) was obtained as white crystals from
3-(2-chloro-4-(2-phenylethyl-
)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200
mg) and 1-pentanesulfonamide (186 mg).
[2026] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.28-1.47(4H,
m), 1.83-1.94(2H, m), 2.62(3H, s), 2.90(4H, s), 3.56(2H, t, J=8
Hz), 5.56(2H, s), 6.63(1H, d, J=8 Hz), 6.97(1H, d, J=8 Hz),
7.13-7.80(6H, m), 8.13(1H, d, J=8 Hz), 8.20(1H, d, J=8 Hz)
Mass(ESI): m/z 537(M-H).sup.-
Example 134
[2027] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)--
2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(259 mg) was obtained as white crystals from
3-(4-benzyloxy-2-chlorobenzy-
l)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (230 mg)
and (4-methylbenzene)sulfonamide (145 mg).
[2028] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 2.64(3H, s), 5.06(2H,
s), 5.52(2H, s), 6.78-6.88(2H, m), 7.12(1H, s), 7.29-7.43(7H, m),
8.03-8.07(4H, m) Mass(ESI): m/z 559(M-H).sup.-
Example 135
[2029] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)--
2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(214 mg) was obtained as white crystals from
3-(4-benzyloxy-2-chlorobenzy-
l)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg)
and (4-vinylbenzene)sulfonamide (135 mg).
[2030] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 5.07(2H, s), 5.42(1H,
d, J=9 Hz), 5.51(2H, s), 5.86(1H, d, J=17 Hz), 6.67-6.90(3H, m),
7.12(1H, d, J=2 Hz), 7.32-7.43(5H, m), 7.52(2H, d, J=8 Hz),
8.02-8.13(4H, m) Mass(ESI): m/z 571(M-H).sup.-
Example 136
[2031] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)--
2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyrid-
ine (212 mg) was obtained as white crystals from
3-(4-benzyloxy-2-chlorobe-
nzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg)
and (E)-(2-phenylethene)sulfonamide (135 mg).
[2032] .sup.1H-NMR(CDCl.sub.3): 2.13(3H, s), 5.06(2H, s), 5.53(2H,
s), 6.73(1H, d, J=8 Hz), 6.84(1H, dd, J=2, 8 Hz), 7.10-7.18(2H, m),
7.32-7.43(8H, m), 7.50-7.53(2H, m), 7.82(1H, d, J=15 Hz), 8.07(1H,
d, J=8 Hz), 8.15(1H, d, J=8 Hz) Mass(ESI): m/z 571(M-H).sup.-
Example 137
[2033] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)--
5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine (178 mg) was obtained as white crystals from
3-(4-benzyloxy-2-chloro-
benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200
mg) and 5-chlorothiophene-2-sulfonamide (145 mg).
[2034] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 5.06(2H, s), 5.51(2H,
s), 6.78(1H, d, J=8 Hz), 6.85(1H, dd, J=2, 8 Hz), 6.92(1H, d, J=3
Hz), 7.12(1H, d, J=2 Hz), 7.32-7.42(5H, m), 7.78(1H, d, J=7 Hz),
8.06(1H, d, J=8 Hz), 8.10(1H, d, J=8 Hz) Mass(ESI): m/z
585(M-H).sup.-
Example 138
[2035] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)-- 5-((5-bromothiophen-2-yl)
sulfonylcarbamoyl)-2-methyl-3H-imidazo[4,5-b]pyr- idine (227 mg)
was obtained as white crystals from 3-(4-benzyloxy-2-chloro-
benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200
mg) and 5-bromothiophene-2-sulfonamide (178 mg).
[2036] .sup.1H-NMR(CDCl.sub.3): 2.63(3H, s), 5.05(2H, s), 5.52(2H,
s), 6.80(1H, d, J=5 Hz), 6.84(1H, dd, J=2, 8 Hz), 7.07(1H, d, J=7
Hz), 7.10(1H, d, J=3 Hz), 7.32-7.42(5H, m), 7.72(1H, d, J=3 Hz),
8.07(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz) Mass(ESI): m/z
630(M-H).sup.-
Example 139
[2037] In the same manner as in Example 1,
3-(4-benzyloxy-2-chlorobenzyl)--
2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(184 mg) was obtained as white crystals from
3-(4-benzyloxy-2-chlorobenzyl)-2-meth-
yl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200 mg) and
1-pentane-sulfonamide (111 mg).
[2038] .sup.1H-NMR(CDCl.sub.3): 0.87(3H, t, J=8 Hz), 1.30-1.48(4H,
m), 1.83-1.93(2H, m), 2.64(3H, s), 3.53(2H, t, J=8 Hz), 5.04(2H,
s), 5.51(2H, s), 6.74(1H, d, J=8 Hz), 6.82(1H, dd, J=2, 8 Hz),
7.10(1H, d, J=8 Hz), 7.30-7.40(5H, m), 8.10(1H, d, J=8 Hz),
8.17(1H, d, J=8 Hz) Mass(ESI): m/z 539(M-H).sup.-
Example 140
[2039] In the same manner as in Example 1,
3-(2-chloro-4-((cyclohexylmethy-
l)-oxy)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo--
[4,5-b]pyridine (211 mg) was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide
(124 mg).
[2040] .sup.1H-NMR(CDCl.sub.3): 0.97-1.36(5H, m), 1.67-1.87(6H, m),
2.41(3H, s), 2.63(3H, s), 3.74(2H, d, J=7 Hz), 5.51(2H, s),
6.77(2H, s), 7.01(1H, s), 7.32(2H, d, J=8 Hz), 8.02-8.07(4H, m)
Mass(ESI): m/z 565(M-H).sup.-
Example 141
[2041] In the same manner as in Example 1,
3-(2-chloro-4-((cyclohexylmethy-
l)-oxy)benzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4-
,5-b]pyridine (203 mg) was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazol4,5-b]py-
ridine-5-carboxylic acid (200 mg) and (4-vinylbenzene)sulfonamide
(133 mg).
[2042] .sup.1H-NMR(CDCl.sub.3): 0.98-1.38(5H, m), 1.68-1.88(6H, m),
2.64(3H, s), 3.75(2H, d, J=7 Hz), 5.43(1H, d, J=11 Hz), 5.50(2H,
s), 5.87(1H, d, J=16 Hz), 6.69-6.78(3H, m), 7.00(1H, s), 7.53(2H,
d, J=8 Hz), 8.00-8.12(4H, m) Mass(ESI): m/z 577(M-H).sup.-
Example 142
[2043] In the same manner as in Example 1,
3-(2-chloro-4-((cyclohexylmethy-
l)-oxy)benzyl)-2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imid-
azo[4,5-b]pyridine (193 mg) was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (200 mg) and
(E)-(2-phenylethene)sulfonamide (133 mg).
[2044] .sup.1H-NMR(CDCl.sub.3): 0.96-1.36(5H, m), 1.68-1.84(6H, m),
2.64(3H, s), 3.72(2H, d, J=7 Hz), 5.51(2H, s), 6.69-6.74(2H, m),
7.00(1H, d, J=2 Hz), 7.14(1H, d, J=15 Hz), 7.36-7.46(3H, m),
7.52-7.56(2H, m), 7.81(1H, d, J=16 Hz), 8.08(1H, d, J=8 Hz),
8.13(1H, d, J=8 Hz) Mass(ESI): m/z 577(M-H).sup.-
Example 143
[2045] In the same manner as in Example 1,
3-(2-chloro-4-((cyclohexylmethy-
l)-oxy)benzyl)-5-((5-chlorothiophen-2-yl)
sulfonylcarbamoyl)-2-methyl-3H-i- midazo[4,5-b]pyridine (155 mg)
was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (200 mg) and
5-chlorothiophene-2-sulfonamide (143 mg).
[2046] .sup.1H-NMR(CDCl.sub.3): 0.97-1.36(5H, m), 1.37-1.87(6H, m),
2.65(3H, s), 3.73(2H, d, J=7 Hz), 5.50(2H, s), 6.73-6.82(2H, m),
6.94(1H, d, J=2 Hz), 7.00(1H, s), 7.76(1H, d, J=3 Hz), 8.06(1H, d,
J=8 Hz), 8.10(1H, d, J=8 Hz) Mass(ESI): m/z 591(M-H).sup.-
Example 144
[2047] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine (178 mg) was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (200 mg) and
5-bromothiophene-2-sulfonamide (175 mg).
[2048] .sup.1H-NMR(CDCl.sub.3): 0.97-1.36(5H, m), 1.68-1.87(6H, m),
2.64(3H, s), 3.73(2H, d, J=7 Hz), 5.50(2H, s), 6.72-6.80(2H, m),
7.00(1H, s), 7.08(1H, d, J=3 Hz), 7.72(1H, d, J=3 Hz), 8.05(1H, d,
J=8 Hz), 8.11(1H, d, J=8 Hz) Mass(ESI): m/z 537(M-H).sup.-Example
145
[2049] In the same manner as in Example 1,
3-(2-chloro-4-((cyclohexylmethy-
l)-oxy)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]py-
ridine (178 mg) was obtained as white crystals from
3-(2-chloro-4-((cyclohexylmethyl)oxy)benzyl)-2
-methyl-3H-imidazo[4,5-b]p- yridine-5-carboxylic acid (200 mg) and
1-pentanesulfonamide (110 mg).
[2050] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=8 Hz), 0.96-1.48(9H,
m), 1.68-1.92(8H, m), 2.64(3H, s), 3.53(2H, t, J=8 Hz), 3.72(2H, d,
J=7 Hz), 5.46(2H, s), 6.70-6.76(2H, m), 6.78 (1H, s), 8.09(1H, d,
J=8 Hz), 8.16(1H, d, J=8 Hz) Mass(ESI):m/z 545(M-H).sup.-
Example 146
[2051] In the same manner as in Example 1,
3-(2-chloro-4-(methylthio)benzy-
l)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridi-
ne (181 mg) was obtained as colorless crystals from
3-(2-chloro-4-(methylthio)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylic acid (160 mg).
[2052] .sup.1H-NMR(CDCl.sub.3): 2.41(3H, s), 2.50(3H, s), 2.63(3H,
s), 5.52(2H, s), 6.73(1H, d, J=8 Hz), 7.09(1H, d, J=8 Hz),
7.30-7.37(3H, m), 8.00-8.07(4H, m). Mass(ESI) : m/z 499(M-1) mp
180-181.degree. C.
Example 147
[2053] In the same manner as in Example 1,
3-(2-chloro-4-(methylthio)benzy-
l)-2-methyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridin-
e (174 mg) was obtained as colorless crystals from
3-(2-chloro-4-(methylth-
io)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(160 mg).
[2054] .sup.1H-NMR(CDCl.sub.3): 2.50(3H, s), 2.64(3H, s), 5.44(1H,
d, J=11 Hz), 5.53(2H, s), 5.88(1H, d, J=18 Hz), 6.57(1H, d, J=8
Hz), 6.71(2H, dd, J=18,11 Hz), 7.08(1H, dd, J=8.2 Hz), 7.32(1H, d,
J=2 Hz), 7.54(2H, d, J=8 Hz), 8.00-8.14(4H, m). Mass(ESI): m/z
513(M+1) mp 197-198.degree. C.
Example 148
[2055] In the same manner as in Example 1,
3-(2-chloro-4-(methylthio)benzy-
l)-2-methyl-5-(E)-[(2-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[4,5-b]py-
ridine (174 mg) was obtained as colorless crystals from
3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-ca-
rboxylic acid (160 mg).
[2056] .sup.1H-NMR(CDCl.sub.3): 2.48(3H, s), 2.63(3H, s), 5.53(2H,
s), 6.67(1H, d, J=8 Hz), 7.06(1H, dd, J=8.1 Hz), 7.14(1H, d, J=15
Hz), 7.23-7.33(1H, overlapped with H.sub.2O), 7.36-7.47(3H, m),
7.50-7.59(2H, m), 7.81(1H, d, J=15 Hz), 8.09(1H, d, J=8 Hz),
8.17(1H, d, J=8 Hz), 10.01(1H, br s). Mass(ESI):m/z 513(M+1). mp
175-176.degree. C.
Example 149
[2057] In the same manner as in Example 1,
3-(2-chloro-4-(methylthio)benzy- l)-5-[(5-chlorothiophen-2-yl)
sulfonylcarbamoyl]-2 -methyl-3H-imidazo[4,5-- b]pyridine (186 mg)
was obtained as colorless crystals from
3-(2-chloro-4-(methylthio)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylic acid (160 mg).
[2058] .sup.1H-NMR(CDCl.sub.3): 2.40(3H, s), 2.65(3H, s), 5.53(2H,
s), 6.73(1H, d, J=8 Hz), 6.95(1H, d, J=5 Hz), 7.08(1H, dd, J=8.2
Hz), 7.31(1H, d, J=2 Hz), 7.77(1H, d, J=5 Hz), 7.70(1H, d, J=8 Hz),
8.12(1H, d, J=8 Hz). Mass(ESI):m/z 528(M+1) mp 170-171.degree.
C.
Example 150
[2059] In the same manner as in Example 1,
3-[2-chloro-4-(methylthio)benzy-
l]-5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-2-methyl-3H-imidazo[4,5-b]p-
yridine (211 mg) was obtained as colorless crystals from
3-(2-chloro-4-(methylthio)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-c-
arboxylic acid (160 mg).
[2060] .sup.1H-NMR(CDCl.sub.3): 2.49(3H, s), 2.65(3H, s), 5.52(2H,
s), 6.73(1H, d, J=8 Hz), 7.02-7.13(2H, m), 7.31(1H, br s), 7.72(1H,
d, J=5 Hz), 8.08(1H, d, J=8 Hz), 8.12(1H, d, J=8 Hz). Mass(ESI):m/z
572(M+1) mp 169-170.degree. C.
Example 151
[2061] In the same manner as in Example 1,
3-(2-chloro-4-(methylthio)benzy-
l)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(169 mg) was obtained as colorless crystals from
3-(2-chloro-4-(methylthio)ben-
zyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160
mg).
[2062] .sup.1H-NMR(CDCl.sub.3): 0.90(3H, t, J=8 Hz), 1.26-1.49(4H,
m), 1.81-1.95(2H, m), 2H, m), 2.47(3H, s), 2.64(3H, s),
3.50-3.60(2H, m), 5.52(2H, s), 6.70(1H, d, J=8 Hz), 7.05(1H, dd,
J=8.1 Hz), 7.30(1H, d, J=1 Hz), 8.12(1H, d, J=8 Hz), 8.19(1H, d,
J=8 Hz), 9.81(1H, br s). Mass(ESI):m/z 481(M+1) mp 184-185.degree.
C.
Example 152
[2063] In the same manner as in Example 1,
3-(2-chloro-4-(ethoxycarbonyl)--
benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]p-
yridine (173 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (150 mg) and (4-methylbenzene)sulfonamide (103
mg).
[2064] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=7 Hz), 2.42(3H, s),
2.59(3H, s), 4.39(2H, q, J=7 Hz), 5.63(2H, s), 6.70(1H, d, J=8 Hz),
7.27-7.33(2H, m), 7.83(1H, d, J=8 Hz), 8,00-8.07(5H, m)
Mass(ESI):m/z 525(M-H).sup.-
Example 153
[2065] In the same manner as in Example 1,
3-(2-chloro-4-(ethoxycarbonyl)--
benzyl)-2-methyl-5-((4-vinylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]py-
ridine (212 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (200 mg) and (4-vinylbenzene)sulfonamide (147
mg).
[2066] .sup.1H-NMR(CDCl.sub.3): 1.40(3H, t, J=7 Hz), 2.59(3H, s),
4.40(2H, q, J=7 Hz), 5.43(1H, d, J=9 Hz), 5.64(2H, s), 5.88(1H, d,
J=16 Hz), 6.68-6.77(2H, m), 7.52(1H, d, J=8 Hz), 7.83(1H, dd, J=2.8
Hz), 8.05-8.16(5H, m) Mass(ESI):m/z 537(M-H).sup.-
Example 154
[2067] In the same manner as in Example 1,
3-(2-chloro-4-(ethoxycarbonyl)--
benzyl)-2-methyl-5-(E)-((2-phenylethenyl)sulfonylcarbamoyl)-3H-imidazo[4,5-
-b]pyridine (237 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (200 mg) and (E)-(2-phenylethene)sulfonamide (147
mg).
[2068] .sup.1H-NMR(CDCl.sub.3): 11.38(3H, t, J=7 Hz), 2.60(3H, s),
4.37(2H, q, J=7 Hz), 5.65(2H, s), 6.65(1H, d, J=8 Hz), 7.14(1H, d,
J=15 Hz), 7.36-7.53(5H, m), 7.77- 7.85(2H, m), 8.12-8.20(3H, m)
Mass(ESI):m/z 537(M-H).sup.-
Example 155
[2069] In the same manner as in Example 1,
3-(2-chloro-4-(ethoxycarbonyl)--
benzyl)-5-((5-chlorothiophen-2-yl)sulfonylcarbamoyl)-2-methyl-3H-imidazo[4-
,5-b]pyridine (210 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (200 mg) and 5-chlorothiophene-2-sulfonamide (159
mg).
[2070] .sup.1H-NMR(CDCl.sub.3): 1.39(3H, t, J=7 Hz), 2.60(3H, s),
4.38(2H, q, J=7 Hz), 5.62(2H, s), 6.70(1H, d, J=8 Hz), 6.93(1H, d,
J=3 Hz), 7.26(1H, s), 7.73(1H, d, J=4 Hz), 7.83(1H, dd, J=2,8 Hz),
8.11-8.17(3H, m) Mass(ESI): m/z 551(M-H).sup.-
Example 156
[2071] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl-3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine (229 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (200 mg) and 5-bromothiophene-2-sulfonamide (194
mg).
[2072] .sup.1H-NMR(CDCl.sub.3): 1.19(3H, t, J=7 Hz), 2.62(3H, s),
4.38(2H, q, J=8 Hz), 5.63(2H, s), 6.71(1H, d, J=8 Hz), 7.07(1H, d,
J=4 Hz), 7.71(1H, d, J=3 Hz), 7.83(1H, dd, J=2.8 Hz), 8.09-8.15(3H,
m) Mass(ESI):m/z 597(M-H).sup.-
Example 157
[2073] In the same manner as in Example 1,
3-(2-chloro-4-(ethoxycarbonyl)--
benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(197 mg) was obtained as white crystals from
3-(2-chloro-4-(ethoxycarbony-
l)-benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(200 mg) and 1-pentanesulfonamide (121 mg).
[2074] .sup.1H-NMR(CDCl.sub.3): 0.88(3H, t, J=7 Hz), 1.27-1.47(7H,
m), 1.82-1.92(2H, m), 2.60(3H, s), 3.53(2H, t, J=8 Hz), 4.38(2H, q,
J=7 Hz), 5.62(2H, s), 6.67(1H, d, J=8 Hz), 7.83(1H, dd, J=2.8 Hz),
8.14-8.24(3H, m) Mass(ESI):m/z 505(M-H).sup.-
Example 158
[2075] In the same manner as in Example 1,
3-(2-chloro-4-((phenyloxy)methy-
l)-benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5--
b]pyridine (182 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide (127
mg).
[2076] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.38(s, 3H),
2.48(s, 3H), 5.12(s, 2H), 5.83(s, 3H), 6.76(d, J=8 Hz, 1H),
6.90-7.04(m, 3H), 7.24-7.38(m, 3H), 7.42(d, J=8 Hz, 2H), 7.66(s,
1H), 7.83-7.95(m, 3H), 8.14(d, J=8 Hz, 1H) MS(ESI):m/e 559(M-H)
Example 159
[2077] In the same manner as in Example 1,
3-(2-chloro-4-((phenyloxy)methy-
l)-benzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b-
]pyridine (135 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and (4-vinylbenzene)sulfonamide (135
mg).
[2078] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.46(s, 3H),
5.11(s, 2H), 5.46(d, J=11 Hz, 1H), 5.83(s, 2H), 6.01(d, J=18 Hz,
1H), 6.74(d, J=8 Hz, 1H), 6.81(dd, J=11.18 Hz, 1H), 6.90-7.03(m,
3H), 7.24-7.36(m, 3H), 7.64-7.75(m, 3H), 7.90(d, J=8 Hz, 1H),
7.98(d, J=8 Hz, 2H), 8.13(d, J=8 Hz, 1H) MS(ESI):m/e 571(M-H)
Example 160
[2079] In the same manner as in Example 1,
3-(2-chloro-4-((phenyloxy)methy-
l)-benzyl)-2-methyl-5-[(E)-(2-phenylethenyl)sulfonylcarbamoyl]-3H-imidazo[-
4,5-b]pyridine (152 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and (E)-(2-phenylethene)sulfonamide
(135 mg).
[2080] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.46(s, 3H),
5.60(s, 2H), 5.84(s, 2H), 6.68(d, J=8 Hz, 1H), 6.90-7.02(m, 3H),
7.24-7.36(m, 3H), 7.40-7.59(m, 4H), 7.66(s-like, 2H), 7.73-7.82(m,
2H), 7.98(d, J=8 Hz, 1H), 8.18(d, J=8 Hz, 1H) MS(ESI):m/e
571(M-H)
Example 161
[2081] In the same manner as in Example 1,
3-(2-chloro-4-((phenyloxy)methy- l)
benzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-2-methyl-3H-imidaz-
o-[4,5-b]pyridine (120 mg) was obtained as pale-yellow crystals
from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and 5-chlorothiophene-2-sulfonamide
(178 mg).
[2082] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.45(s, 3H),
5.61(s, 2H), 5.83(s, 2H), 6.70(d, J=8 Hz, 1H), 6.90-7.02(m, 3H),
7.24-7.35(m, 4H), 7.65(s,. 1H), 7.76(d, J=4 Hz, 1H), 7.97(d, J=8
Hz, 1H), 8.18(d, J=8 Hz, 1H) MS(ESI):m/e 585,587
Example 162
[2083] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[-
4,5-b]pyridine (153 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and 5-bromothiophene-2-sulfonamide
(178 mg).
[2084] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.45(s, 3H),
5.10(s, 2H), 5.81(s, 2H), 6.69(d, J=8 Hz, 1H), 6.90-7.02(m, 3H),
7.24-7.35(m, 3H), 7.39(d, J=4 Hz, 1H), 7.65(s, 1H), 7.70(d, J=4 Hz,
1H), 7.97(d, J=8 Hz, 1H), 8.17(d, J=8 Hz, 1H) MS(ESI):m/e
629,630,633
Example 163
[2085] In the same manner as in Example 1,
3-(2-chloro-4-((phenyloxy)methy- l)-benzyl)-2-methyl-5-(1
-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyrid- ine (180 mg) was
obtained as pale-yellow crystals from
3-(2-chloro-4-((phenyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and 1-pentanesulfonamide (111
mg).
[2086] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:0.80(t, J=7.5 Hz,
3H), 1. 17-1.43(m, 4H), 1.63-1.77(m, 2H), 2.48(s, 3H), 3.53(t,
J=7.5 Hz, 2H), 5.51(s, 2H), 5.83(s, 2H), 6.74(d, J=8 Hz, 1H),
6.90-7.04(m, 3H), 7.23-7.48(m, 3H), 7.65(s, 1H), 8.02(d, J=8 Hz,
1H), 8.20(d, J=8 Hz, 1H) MS(ESI):m/e 539(M-1)
Example 164
[2087] In the same manner as in Example 1,
3-[2-chloro-4-(dimethylamino-me-
thyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,-
5-b]pyridine (80 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-(dimethylaminomethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (115 mg) and (4-methylbenzene)sulfonamide
(83 mg).
[2088] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.34(s, 3H),
2.40(s, 6H), 2.46(s, 3H), 3.78(s, 2H), 5.70(s, 2H), 6.60(d, J=8 Hz,
1H), 7.23(d, J=8 Hz, 1H), 7.30(d, J=8 Hz, 2H), 7.60(s, 1H), 7.80(d,
J=8 Hz, 1H), 7.93(d, J=8 Hz, 1H), 8.03(d, J=8 Hz, 1H) MS(ESI):m/e
512(M+H)
Example 165
[2089] In the same manner as in Example 1,
3-[2-chloro-4-((imidazol-1-yl)m-
ethyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4-
,5-b]pyridine (180 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((imidazol-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (184 mg) and (4-methylbenzene)sulfonamide
(125 mg).
[2090] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.39(s, 3H),
2.45(s, 3H), 5.22(s, 2H), 5.77(s, 2H), 6.67(d, J=8 Hz, 1H), 6.98(s,
1H), 7.14(d, J=8 Hz, 1H), 7.25(s, 1H), 7.40(d, J=8 Hz, 2H), 7.48(s,
1H), 7.84-7.93(m, 4H), 8. 10(d, J=8 Hz, 1H) MS(ESI):m/e
533(M-H)
Example 166
[2091] In the same manner as in Example 1,
3-[2-chloro-4-((piperidin-1-yl)-
methyl)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[-
4,5-b]pyridine (57 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((piperidin-1-yl)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]p-
yridine-5-carboxylic acid (148 mg) and (4-methylbenzene)sulfonamide
(96 mg).
[2092] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:1.43(br peak, 2H),
1.55(br peak, 4H), 2.34(s, 3H), 2.46(s, 3H), 2.66(br peak, 4H),
3.79(br peak, 2H), 5.69(s, 2H), 6.56(d, J=8 Hz, 1H), 7.23(d, J=8
Hz, 1H), 7.29(d, J=8 Hz, 2H), 7.58(s, 1H), 7.80(d, J=8 Hz, 2H),
7.90(d, J=8 Hz, 1H), 8.03(d, J=8 Hz, 1H) MS(ESI): m/e
552.2(M+H)
Example 167
[2093] In the same manner as in Example 1,
3-[2-chloro-4-(phenylthiomethyl-
)-benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b-
]pyridine (119 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-(phenylthiomethyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridin-
e-5-carboxylic acid (175 mg) and (4-methylbenzene)sulfonamide (107
mg).
[2094] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.38(s, 3H),
2.41(s, 3H), 4.24(s, 2H), 5.79(s, 2H), 6.68(d, J=8 Hz, 1H),
7.12-7.35(m, 6H), 7.43(d, J=8 Hz, 1H), 7.54(s, 1H), 7.85-7.98(m,
3H), 8.13(d, J=8 Hz, 1H) Mass (ESI) m/e 575.0 (M-H)
Example 168
[2095] In the same manner as in Example 1,
3-(4-((benzyloxy)methyl)-2-chlo-
robenzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b-
]pyridine was obtained as pale-yellow crystals (195 mg) from
3-(4-((benzyloxy)methyl)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide (123
mg).
[2096] .sup.1H-NMR (300 MHz, DMSO-d.sub.6).delta.:2.38(s, 3H),
2.46(s, 3H), 4.53(s, 4H), 5.82(s, 2H), 6.73(d, J=8 Hz, 1H),
7.20-7.38(m, 6H), 7.42(d, J=8 Hz, 2H), 7.56(s, 1H), 7.85-7.94(m,
3H), 8.13(d, J=8 Hz, 1H) Mass (ESI) m/e 573 (M-H)
Example 169
[2097] In the same manner as in Example 1,
3-[4-(benzimidazol-2-yl)-2-chlo-
robenzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b-
]pyridine was obtained as pale-yellow crystals (140 mg) from
3-14-(benzimidazol-2-yl)-2-chlorobenzyl]-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (200 mg) and (4-methylbenzene)sulfonamide (124
mg).
[2098] .sup.1H-NMR(300 MHz, DMSO-d,).delta.:2.34(s, 3H), 2.50(s,
3H), 5.90(s, 2H), 6.98(d, J=8 Hz, 1H), 7.20-7.30(m, 2H), 7.38(d,
J=8 Hz, 2H), 7.57-7.69(m, 2H), 7.86-7.94(m, 3H), 8.06(d, J=8 Hz,
1H), 8.16(d, J=8 Hz, 1H), 8.37(s, 1H) Mass (ESI) m/e 569 (M-H)
Example 170
[2099] In the same manner as in Example 1,
2-methyl-5-[(4-methylbenzene)-s-
ulfonylcarbamoyl]-3-[4-(1-methylbenzimidazol-2-yl)-2-chlorobenzyl]-3H-imid-
azo[4,5-b]pyridine was obtained as pale-yellow crystals (81 mg)
from
2-methyl-3-[4-(1-methylbenzimidazol-2-yl)-2-chlorobenzyl]-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (200 mg) and
(4-methylbenzene)sulfonamide (120 mg).
[2100] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.37(s, 3H),
2.53(s, 3H), 3.89(s, 3H), 5.94(s, 2H), 6.90(d, J=8 Hz, 1H),
7.21-7.37(m, 3H), 7.42(d, J=8 Hz, 2H), 7.65(d, J=8 Hz, 1H), 7.70(d,
J=8 Hz, 1H), 7.78(d, J=8 Hz, 1H), 7.90(d, J=8 Hz, 2H), 8.09(s, 1H),
8,17(d, J=8 Hz, 1H) Mass (ESI) m/e 585 (M+H)
Example 171
[2101] In the same manner as in Example 1,
3-[(1-ethylbenzimidazol-2-yl)me-
thyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyr-
idine was obtained as pale-yellow crystals (167 mg) from
3-[(1-ethylbenzimidazol-2-yl)methyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and (4-methylbenzene)sulfonamide (139
mg).
[2102] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:1.20(t, J=7.5 Hz,
3H), 2.37(s, 3H), 2.65(s, 3H), 4.53(q, J=7.5 Hz, 2H), 6.10(s, 2H),
7.17(t, J=8 Hz, 1H), 7.26(t, J=8 Hz, 1H), 7.42(d, J=8 Hz, 2H),
7.53(d, J=8 Hz, 1H), 7.60(d, J=8 Hz, 1H), 7.87(d, J=8 Hz, 1H),
7.90(d, J=8 Hz, 1H), 8.12(d, J=8 Hz, 1H) Mass (ESI) m/e 487.2
(M-H)
Example 172
[2103] In the same manner as in Example 1,
3-(2-chloro-4-(thiophen-2-yl)be-
nzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
was obtained as pale-yellow crystals (174 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and 1-pentanesulfonamide (106 mg).
[2104] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:0.79(t, J=7.5 Hz,
3H), 1.10-1.45(m, 4H), 1.56-1.81(m, 2H), 2.50(s, 3H), 3.43-3.63(m,
2H), 5.83(s, 2H), 6.80(d, J=8 Hz, 1H), 7.13(t, J=5 Hz, 1H), 7.50(d,
J=8 Hz, 1H), 7.55-7.70(m, 2H), 7.86(s-like, 1H), 8.03(d, J=8 Hz,
1H), 8.21(d, J=8 Hz, 1H) Mass (ESI) m/e 515.2 (M-H)
Example 173
[2105] In the same manner as in Example 1,
3-(2-chloro-4-(thiophen-2-yl)be-
nzyl)-2-methyl-5-[(4-methylbenzene)
sulfonylcarbamoyl]-3H-imidazo[4,5-b]py- ridine was obtained as
pale-yellow crystals (199 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and (4-methylbenzene)sulfonamide (120
mg).
[2106] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.37(s, 3H),
2.50(s, 3H), 5.84(s, 2H), 6.80(d, J=8 Hz, 1H), 7.16(t, J=5 Hz, 1H),
7.40(d, J=8 Hz, 2H), 7.53(dd, J=8, 2 Hz, 1H), 7.58-7.65(m, 2H),
7.82-7.94(m, 4H), 8.13(d, J=8 Hz, 1H) Mass (ESI) m/e 535.1
(M-H)
Example 174
[2107] In the same manner as in Example 1,
3-(2-chloro-4-(thiophen-2-yl)be-
nzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-2-methyl-3H-imidazo[4,5-
-b]pyridine was obtained as pale-yellow crystals (194 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and 5-chlorothiophene-2-sulfonamide (139
mg).
[2108] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.50(s, 3H),
5.83(s, 2H), 6.75(d, J=8 Hz, 1H), 7.15(t, J=5 Hz, 1H), 7.28(d, J=4
Hz, 1H), 7.51(dd, J=8.2 Hz, 1H), 7.56-7.65(m, 2H), 7.74(d, J=4 Hz,
1H), 7.88(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H), 8.17(d, J=8 Hz, 1H)
Mass (ESI) m/e 561.0
Example 175
[2109] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine was obtained as pale-yellow crystals (228 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and 5-bromothiophene-2-sulfonamide (170
mg).
[2110] .sup.1H-NMR(300 MHz, DMSO-d,).delta.:2.50(s, 3H), 5.83(s,
2H), 6.75(d, J=8 Hz, 1H), 7.14(t, J=5 Hz, 1H), 7.37(d, J=4 Hz, 1H),
7.52(dd, J=8.2 Hz, 1H), 7.57-7.64(m, 2H), 7.70(d, J=4 Hz, 1H),
7.87(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H), 8.17(d, J=8 Hz, 1H) Mass
(ESI) m/e 606.7
Example 176
[2111] In the same manner as in Example 1,
3-(2-chloro-4-(thiophen-2-yl)be-
nzyl)-2-methyl-5-[(E)-(2-phenylethene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]-
pyridine was obtained as pale-yellow crystals (199 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and ((E)-(2-phenylethene)sulfonamide (129
mg).
[2112] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.50(s, 3H),
5.85(s, 2H), 6.71(d, J=8 Hz, 1H), 7.15(t, J=5 Hz, 1H), 7.36-7.82(m,
10H), 7.88(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H), 8.18(d, J=8 Hz, 1H)
Mass (ESI) m/e 547.1 (M-H)
Example 177
[2113] In the same manner as in Example 1,
3-(2-chloro-4-(thiophen-2-yl)be-
nzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyri-
dine was obtained as pale-yellow crystals (194 mg) from
3-(2-chloro-4-(thiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (180 mg) and (4-vinylbenzene)sulfonamide (129
mg).
[2114] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.58(s, 3H),
5.45(d, J=11Hz, 1H), 5.83(s, 2H), 6.01(d, J=19 Hz, 1H),
6.72-6.90(m, 2H), 7.16(t, J=5 Hz, 3H), 7.55(dd, J=8.2 Hz, 1H),
7.58-7.65(m, 2H), 7.69(d, J=8 Hz, 1H), 7.84-7.92(m, 2H), 7.97(d,
J=8 Hz, 2H), 8.14(d, J=8 Hz, 1H) Mass (ESI) m/e 547.1 (M-H)
Example 178
[2115] In the same manner as in Example 1,
3-(2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl)-2-methyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyr-
idine was obtained as pale-yellow crystals (177 mg) from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and 1-pentanesulfonamide (98
mg).
[2116] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:0.79(t, J=7.5 Hz,
3H), 1.14-1.41(m, 4H), 1.60-1.75(m, 2H), 2.51(s, 3H), 3.51(t, J=7.5
Hz, 2H), 5.83(s, 2H), 6.78(d, J=8 Hz, 1H), 7.18(d, J=4 Hz, 1H),
7.41(dd, J=8.2 Hz, 1H), 7.50(d, J=4 Hz, 1H), 7.85(d, J=2 Hz, 1H),
8.01(d, J=8 Hz, 1H), 8.19(d, J=8 Hz, 1H) Mass (ESI) m/e 549.0
Example 179
[2117] In the same manner as in Example 1,
3-(2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4-
,5-b]pyridine was obtained as pale-yellow crystals (179 mg) from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and (4-methylbenzene)sulfonamide
(111 mg).
[2118] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.37(s, 3H),
2.50(s, 3H), 5.83(s, 2H), 6.78(d, J=8 Hz, 1H), 7.20(d, J=4 Hz, 1H),
7.40(d, J=8 Hz, 2H), 7.48(dd, J=8.2 Hz, 1H), 7.52(d, J=4 Hz, 1H),
7.83-7.95(m, 4H), 8.15(d, J=8 Hz, 1H) Mass (ESI) m/e 569.2
Example 180
[2119] In the same manner as in Example 1,
3-(2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl)-5-[(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-2-methyl-3H-imi-
dazo[4,5-b]pyridine was obtained as pale-yellow crystals (182 mg)
from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and
5-chlorothiophene-2-sulfonamide (128 mg).
[2120] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.50(s, 3H),
5.82(s, 2H), 6.73(d, J=8 Hz, 1H), 7.18(d, J=4 Hz, 1H), 7.29(d, J=8
Hz, 1H), 7.45(dd, J=8.2 Hz, 1H), 7.51(d, J=4 Hz, 1H), 7.76(d, J=4
Hz, 1H), 7.86(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H), 8.17(d, J=8 Hz,
1H) Mass (ESI) m/e 595.1, 597.0, 599.0
Example 181
[2121] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imid-
azo[4,5-b]pyridine was obtained as pale-yellow crystals (207 mg)
from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and
5-bromothiophene-2-sulfonamide (156 mg).
[2122] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.50(s, 3H),
5.82(s, 2H), 6.74(d, J=8 Hz, 1H), 7.19(d, J=4 Hz, 1H), 7.38(d, J=4
Hz, 1H), 7.47(dd,J=8.2 Hz, 1H), 7.51(d, J=4 Hz, 1H), 7.70(d, J=4
Hz, 1H), 7.87(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H), 8.18(d, J=8 Hz,
1H) Mass (ESI) m/e 639.1, 641.3, 643.5
Example 182
[2123] In the same manner as in Example 1,
3-(2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl)-2-methyl-5-[(E)-(2-phenylethene)sulfonylcarbamoyl]-3H-imidaz-
o[4,5-b]pyridine was obtained as pale-yellow crystals (182 mg) from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and
(E)-(2-phenylethene)sulfonamide (118 mg).
[2124] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.50(s, 3H),
5.84(s, 2H), 6.72(d, J=8 Hz, 1H), 7.18(d, J=4 Hz, 1H), 7.35-7.60(m,
6H), 7.60-7.84(m, 3H), 7.86(d, J=2 Hz, 1H), 7.98(d, J=8 Hz, 1H),
8.17(d, J=8 Hz, 1H) Mass (ESI) m/e 581.0, 583.2
Example 183
[2125] In the same manner as in Example 1,
3-(2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl)-2-methyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,-
5-b]pyridine was obtained as pale-yellow crystals (180 mg) from
3-(2-chloro-4-(5-chlorothiophen-2-yl)benzyl)-2-methyl-3H-imidazo[4,5-b]py-
ridine-5-carboxylic acid (180 mg) and (4-vinylbenzene)sulfonamide
(118 mg).
[2126] .sup.1H-NMR(300 MHz, DMSO-d.sub.6).delta.:2.49(s, 3H),
5.46(d, J=1 Hz, 1H), 5.83(s, 2H), 6.01(d, J=18 Hz, 1H),
6.70-6.98(m,2H),7.20(d, J=4 Hz, 1H),7.46(dd, J=8.2 Hz, 1H), 7.52(d,
J=4 Hz, 1H), 7.70(d, J=8 Hz, 2H), 7.83-7.92(m, 2H), 7.96(d, J=8 Hz,
2H), 8.14(d, J=8 Hz, 1H) Mass (ESI) m/e 581.2
Example 184
[2127] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2,7-
-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
was obtained as colorless crystals (165 mg) from
3-(2-chloro-4-phenylbenzyl)--
2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160 mg).
mp 227-228.degree. C.
[2128] .sup.1H-NMR(CDCl.sub.3):0.85(3H, t, J=8 Hz), 1.21-1.44(4H,
m), 1.78-1.90(2H, m), 2.67(3H, s), 2.75(3H, s), 3.49-3.56(2H, m),
5.60(2H, s), 6.76(1H, d, J=8 Hz), 7.33-7.47(3H, m), 7.52-7.57(2H,
m), 7.70(1H, d, J=1 Hz), 8.01(1H, s), 9.87(1H, br s) Mass (ESI) m/z
523 (M-1)
Example 185
[2129] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-5-1-
(5-chlorothiophen-2-yl)sulfonylcarbamoyl]-2,7-dimethyl-3H-imidazo[4,5-b]py-
ridine was obtained as colorless crystals (177 mg) from
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylic acid (160 mg). mp 241-242.degree. C.
[2130] .sup.1H-NMR(CDCl.sub.3):2.67(3H, s), 2.72(3H, s), 5.59(2H,
s), 6.81(1H, d, J=8 Hz), 6.90(1H, d, J=5 Hz), 7.35-7.49(4H, m),
7.54-7.58(2H, m), 7.67-7.72(2H, m), 7.96(1H, s) Mass (ESI) m/z 571
(M+1)
Example 186
[2131] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyr-
idine was obtained as colorless crystals (175 mg) from
3-(2-chloro-4-phenylbenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carb-
oxylic acid (160 mg). mp 243-244.degree. C.
[2132] .sup.1H-NMR(CDCl.sub.3): 2.67(3H, s), 2.71(3H, s), 5.59(2H,
s), 6.81(1H, d, J=8 Hz), 7.03(1H, d, J=5 Hz), 7.35-7.49(4H,
m),7.56(2H, d, J=8 Hz),7.65(1H, d, J=5 Hz), 7.71(1H, J=1 Hz),
7.95(1H, s) Mass (ESI) m/z 615 (M-1)
Example 187
[2133] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2,7-
-dimethyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
was obtained as colorless crystals (180 mg) from
3-(2-chloro-4-phenylbenz-
yl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (160
mg). mp 220-22 1.degree. C.
[2134] .sup.1H-NMR(CDCl.sub.3):2.66(3H, s), 2.68(3H, s), 5.41(1H,
d, J=10 Hz), 5.60(2H, s), 5.83(1H, d, J=18 Hz), 6.65(2H, dd, J=18,
10 Hz), 6.81(1H, d, J=8 Hz), 7.35-7.50(6H, m), 7.57(2H, d, J=8 Hz),
7.72(1H, d, J=1 Hz), 7.90(1H, s), 8.04(2H, d, J=8 Hz) Mass (ESI)
m/z 555 (M-1)
Example 188
[2135] In the same manner as in Example 1,
3-[2-chloro-4-(thiophen-2-yl)be-
nzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridin-
e was obtained as colorless crystals (165 mg) from
3-12-chloro-4-(thiophen-
-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (160 mg). mp 220-224.degree. C.
[2136] .sup.1H-NMR(CDCl.sub.3):0.85(3H, t, J=8 Hz), 1.20-1.44(4H,
m), 1.75-1.90(2H, m), 2.65(3H, s), 2.74(3H, s), 3.47-3.56(2H, m),
5.56(2H, s), 6.73(1H, d, J=8 Hz), 7.08(1H, t, J=4 Hz),
7.28-7.34(2H, m), 7.40(1H, br d, J=8 Hz), 7.70(1H, s), 8.01(1H, s),
9.85(1H, br s) Mass (ESI) m/z 529 (M-1)
Example 189
[2137] In the same manner as in Example 1,
3-[2-chloro-4-(thiophen-2-yl)be-
nzyl]-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b-
]pyridine was obtained as colorless crystals (187 mg) from
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (180 mg). mp 224-226.degree. C.
[2138] .sup.1H-NMR(CDCl.sub.3):2.39(3H, s), 2.69(3H, s), 2.68(3H,
s), 5.56(2H, s), 6.79(1H, d, J=8 Hz), 7.10(1H, t, J=4 Hz),
7.20-7.38(3H, m), 7.45(1H, br d, J=8 Hz), 7.72(1H, d, J=1 Hz),
7.89(1H, s), 7.95-8.02(2H, m), 10.10(1H, br s) Mass (ESI) m/z 549
(M-1)
Example 190
[2139] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[-
4,5-b]pyridine was obtained as colorless crystals (199 mg) from
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (180 mg). mp 246-248.degree. C.
[2140] .sup.1H-NMR(CDCl.sub.3):2.66(3H, s), 2.70(3H, s), 5.55(2H,
s), 6.79(1H, d, J=8 Hz), 7.03(1H, d, J=4 Hz), 7.10(1H, t, J=4 Hz),
7.33-7.36(2H, m), 7.45(1H, dd, J=8, 1 Hz), 7.65(1H, d, J=4 Hz),
7.71(1H, s), 7.94(1H, s), 10.19(1H, br s) Mass (ESI) m/z 620
(M-1)
Example 191
[2141] In the same manner as in Example 1,
3-[2-chloro-4-(thiophen-2-yl)be-
nzyl]-2,7-dimethyl-5-[(E)-(2-phenylethenyl)
sulfonylcarbamoyl]-3H-imidazo[- 4,5-b]pyridine was obtained as
colorless crystals (196 mg) from
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (180 mg). mp 216-217.degree. C
[2142] .sup.1H-NMR(CDCl.sub.3):2.64(3H, s), 2.72(3H, s), 5.57(2H,
s), 6.72(1H, d, J=8 Hz), 7.08-7.11(2H, m), 7.30-7.52(8H, m),
7.71(1H, d, J=1 Hz), 7.77(1H, d, J=15 Hz), 7.98(1H, s), 10.06(1H,
br s) Mass (ESI) m/z 561 (M+1)
Example 192
[2143] In the same manner as in Example 1,
3-[2-chloro-4-(thiophen-2-yl)be-
nzyl]-2,7-dimethyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]-
pyridine was obtained as colorless crystals (187 mg) from
3-[2-chloro-4-(thiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (180 mg). mp 220-222.degree. C.
[2144] .sup.1H-NMR(CDCl.sub.3):2.65(3H, s), 2.68(3H, s), 5.41(1H,
d, J=11 Hz), 5.56(2H, s), 5.84(1H, d, J=18 Hz), 6.70(2H, dd, J=18,
11 Hz), 6.79(1H, d, J=8 Hz), 7.11(1H, t, J=4 Hz), 7.32-7.37(2H, m),
7.42-7.48(3H, m), 7.72(1H, d, J=1 Hz), 7.89(1H, s), 8.04(2H, d, J=8
Hz), 10.13(1H, s)
Example 193
[2145] In the same manner as in Example 1,
3-[2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl]-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b-
]pyridine was obtained as colorless crystals (187 mg) from
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (180 mg). mp 215-217.degree. C.
[2146] .sup.1H-NMR(CDCl.sub.3):0.86(3H, t, J=8 Hz), 1.23-1.45(4H,
m), 1.77-1.90(2H, m), 2.65(3H, s), 2.74(3H, s), 3.47-3.56(2H, m),
5.55(2H, s), 6.74(1H, d, J=8 Hz), 6.89(1H, t, J=4 Hz), 7.09(1H, d,
J=4 Hz), 7.31(1H, dd, J=8, 1 Hz), 7.59(1H, d, J=1 Hz), 8.01(1H, s),
9.82(1H, br s) Mass (ESI) m/z 563 (M-1)
Example 194
[2147] In the same manner as in Example 1,
3-12-chloro-4-(5-chlorothiophen-
-2-yl)benzyl]-2,7-dimethyl-5-1(4-methylbenzene)sulfonylcarbamoyl]-3H-imida-
zo[4,5-b]pyridine was obtained as colorless crystals (178 mg) from
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (180 mg). mp 240-241.degree. C.
[2148] .sup.1H-NMR(CDCl.sub.3):2.40(3H, s), 2.64(3H, s), 2.68(3H,
s), 5.55(2H, s), 6.76(1H, d, J=8 Hz), 6.91(1H, d, J=4 Hz), 7.12(1H,
d, J=4 Hz), 7.23-7.37(3H, m), 7.61(1H, d, J=1 Hz), 7.89(1H, s),
7.99(2H, d, J=8 Hz), 10.08(1H, br s) Mass (ESI) m/z 583 (M-1)
Example 195
[2149] In the same manner as in Example 1,
5-[(5-bromothiophen-2-yl)sulfon-
ylcarbamoyl]-3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H--
imidazo[4,5-b]pyridine was obtained as colorless crystals (175 mg)
from
3-12-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (180 mg). mp 252-253.degree. C.
[2150] .sup.1H-NMR(CDCl.sub.3):2.66(3H, s), 2.70(3H, s), 5.54(2H,
s), 6.78(1 H, d, J=8 Hz), 6.91(1H, d, J=4 Hz), 7.04(1H, d, J=4 Hz),
7.11(1H, d, J=4 Hz), 7.33(1H, dd, J=8, 1 Hz), 7.60(1H, br s),
7.67(1H, d, J=4 Hz), 7.94(1H, s), 10.18(1H, br s) Mass (ESI) m/z
654 (M-1)
Example 196
[2151] In the same manner as in Example 1,
3-[2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl]-2,7-dimethyl-5-[(E)-(2-phenylethenyl)sulfonylcarbamoyl]-3H-i-
midazo[4,5-b]pyridine was obtained as colorless crystals (208 mg)
from
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (180 mg). mp 224-225.degree. C.
[2152] .sup.1H-NMR(CDCl.sub.3):2.64(3H, s), 2.72(3H, s), 5.55(2H,
s), 6.72(1H, d, J=8 Hz), 6.90(1H, d, J=4 Hz), 7.09(1H, d, J=4 Hz),
7.12(1H, d, J=8 Hz), 7.32(1H, dd, J=8, 1 Hz), 7.35-7.44(3H, m),
7.47-7.52(2H, m), 7.6 0(1H, d, J=1 Hz), 7.77(1H, d, J=15 Hz),
7.98(1H, s), 10.03(1H, br s) Mass (ESI) m/z 595 (M-1)
Example 197
[2153] In the same manner as in Example 1,
3-[2-chloro-4-(5-chlorothiophen-
-2-yl)benzyl]-2,7-dimethyl-5-[(4-vinylbenzene)sulfonylcarbamoyl]-3H-imidaz-
o[4,5-b]pyridine was obtained as colorless crystals (184 mg) from
3-[2-chloro-4-(5-chlorothiophen-2-yl)benzyl]-2,7-dimethyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (180 mg). mp 217-218.degree. C.
[2154] .sup.1H-NMR(CDCl.sub.3):2.65(3H, s), 2.68(3H, s), 5.42(1H,
d, J=11 Hz), 5.55(2H, s), 5.86(1H, d, J=18 Hz), 6.65-6.80(2H, m),
6.92(2H, d, J=4 Hz), 7.12(1H, d, J=4 Hz), 7.33(1H, dd, J=8, 1 Hz),
7.28(2H, d, J=8 Hz), 7.62(1H, d, J=1 Hz), 7.89(1H, s), 8.05(2H, d,
J=8 Hz), 10.10(1H, s) Mass (ESI) m/z 595 (M-1)
Example 198
[2155] In the same manner as in Example 1,
3-[2-chloro-4-(n-pentanethio)-b-
enzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]py-
ridine (186 mg) was obtained as colorless crystals from
3-[2-chloro-4-(n-pentanethio)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-
-carboxylic acid (170 mg). mp 153-155.degree. C.
[2156] .sup.1H-NMR (CDCl.sub.3):0.91(3H, t, J=7.5 Hz),
1.25-1.48(4H, m), 1.55-1.73(2H, m), 2.42(3H, s), 2.63(3H, s),
2.94(2H, t, J=7.5 Hz), 5.53(2H, s), 6.68(1H, d, J=8 Hz), 7.12(1H,
dd, J=8, 1 Hz), 7.27-7.40(3H, m), 8.00-8.10(4H, m) Mass (ESI) m/z
557 (M+1)
Example 199
[2157] In the same manner as in Example 1,
3-[4-(benzylthio)-2-chlorobenzy-
l-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridin-
e (156 mg) was obtained as colorless crystals from
3-[4-(benzylthio)-2-chl-
oro]benzyl-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(180 mg). mp 165-166.degree. C.
[2158] .sup.1H-NMR (CDCl.sub.3): 2.42(3H, s), 2.60(3H, s), 4.15(2H,
s), 5.52(2H, s), 6.65(1H, d, J=8 Hz), 7.12(1H, dd, J=8, 1 Hz),
7.21-7.36(7H, m), 7.39(1H, d, J=1 Hz), 8.01-8.10(4H, m) Mass (ESI)
m/z 577 (M+1)
Example 200
[2159] In the same manner as in Example 1,
3-(2-chloro-4-((3-pyridyloxy)-m-
ethyl)benzyl)-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4-
,5-b]pyridine (159 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-((3-pyridyloxy)methyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyr-
idine-5-carboxylic acid (160 mg) and (4-methylbenzene)sulfonamide
(101 mg).
[2160] .sup.1H-NMR (300 MHz, DMSO-d.sub.6).delta.:2.38(s, 3H),
2.46(s, 3H), 5.19(s, 2H), 5.84(s, 2H), 6.75(d, J=8 Hz, 1H),
7.23-7.38(m, 2H), 7.38-7.49(m, 3H), 7.70(s, 1H), 7.85-7.94(m, 3H),
8.13(d, J=8 Hz, 1H), 8.18(dd, J=5, 2 Hz, 1H), 8.35(d, J=2 Hz, 1H)
Mass (ESI) m/e 562.1 (M+H)
Example 201
[2161] In the same manner as in Example 1,
3-(2-chloro-4-ethylthiobenzyl)--
2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(156 mg) was obtained as colorless crystals from
3-(2-chloro-4-ethylthio--
benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (180
mg). mp 162-163.degree. C.
[2162] .sup.1H-NMR (CDCl.sub.3):1.35(3H, t, J=7.5 Hz), 2.42(3H, s),
2.63(3H, s), 2.97(2H, q, J=7.5 Hz), 5.53(2H, s), 6.69(1H, d, J=8
Hz), 7.13(1H, dd, J=8, 1 Hz), 7.33(2H, d, J=8 Hz), 7.39(1H, d, J=1
Hz), 8.01-8.10(4H, m) Mass (ESI) m/z 360 (M-1)
Example 202
[2163] In the same manner as in Example 1,
3-(4-(N-butyrylamino)-2-chlorob-
enzyl)-2-methyl-5-((4-methylbenzene)
sulfonylcarbamoyl)-3H-imidazo[4,5-b]p- yridine (225 mg) was
obtained as colorless crystals from
3-(4-(N-butyrylamino)-2-chlorobenzyl)
-2-methyl-3H-imidazo[4,5-b]pyridine- -5-carboxylic acid (210 mg)
and (4-methylbenzene)sulfonamide (232 mg).
[2164] .sup.1H-NMR (CDCl.sub.3):1.00(3H, t, J=7 Hz), 1.69-1.81(2H,
m), 2.35(2H, t, J=7 Hz), 2.42(3H, s), 2.64(3H, s), 5.51(2H, s),
6.84(1H, d, J=8 Hz), 7.25(1H, d, J=7 Hz), 7.33(1H, d, J=7 Hz),
7.40(1H, s), 7.97-8.03(5H, m) Mass (ESI) m/z 538 (M-H).sup.1 mp
242-246.degree. C
Example 203
[2165] In the same manner as in Example 1,
3-(4-(N-benzoylamino)-2-chlorob-
enzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]py-
ridine (139 mg) was obtained as colorless crystals from
3-(4-(N-benzoylamino)-2-chlorobenzyl)
-2-methyl-3H-imidazo[4,5-b]pyridine- -5-carboxylic acid (150 mg)
and (4-methylbenzene)sulfonamide (153 mg).
[2166] .sup.1H-NMR (CDCl.sub.3):2.40(3H, s), 2.69(3H, s), 5.57(2H,
s), 6.97(1H, d, J=8 Hz), 7.31(2H, d, J=7 Hz), 7.46-7.58(4H, m),
7.90(2H, d, J=8 Hz), 7.98-8.11(4H, m) Mass (ESI) m/z 572
(M-H).sup.- mp 270-274.degree. C.
Example 204
[2167] In the same manner as in Example 1,
3-(4-(N-benzoyl-N-methylamino)--
2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)
sulfonylcarbamoyl)-3H-imidaz- o[4,5-b]pyridine (227 mg) was
obtained as a pale-yellow powder from
3-(4-(N-benzoyl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid (225 mg) and
(4-methylbenzene)sulfonamide (221 mg).
[2168] .sup.1H-NMR (CDCl.sub.3):2.43(3H, s), 2.53(3H, s), 3.49(3H,
s), 5.52(2H, s), 6.54(1H, d, J=8 Hz), 6.85(1H, d, J=8 Hz),
7.18-7.37(8H, m), 8.03-8.10(4H, m) Mass (ESI) m/z 586
(M-H).sup.-
Example 205
5-(Benzenesulfonylcarbamoyl)-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imida-
zo[4,5-b]pyridine Sodium Salt
[2169] N,N-Dimethylformamide (33 ml) was added to
5-(benzenesulfonyl-carba-
moyl)-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
(1.0 g) and the mixture was heated to 80.degree. C. The undissolved
crystals were filtered off, washed with N,N-dimethylformamide (3
ml) and stirred at room temperature. A 1N aqueous solution (12 ml)
of sodium hydroxide was added at room temperature and the mixture
was stirred for 30 min. The precipitated crystals were collected by
filtration, washed with N,N-dimethylformamide/water=3/1 and water
and dried under reduced pressure at 60.degree. C. for 8 hr to give
the objective compound (600 mg) as colorless crystals.
[2170] .sup.1H-NMR (DMSO-d.sub.6):2.49(3H, s), 5.59(2H, s),
6.49(1H, d, J=8 Hz), 7.32-7.51(7H, m), 7.65(2H, d, J=8 Hz),
7.80-7.86(3H, m), 7.94(1H, d, J=8 Hz), 8.01(1H, d, J=8 Hz) Mass
(ESI) m/z 515
Example 206
[2171] In the same manner as in Example 205,
5-[(4-vinylbenzene)sulfonyl-c-
arbamoyl]-3-(2-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b]pyridine
sodium (532 mg) was obtained as colorless crystals from
5-[(4-vinylbenzene)-sulfonylcarbamoyl]-3-(2
-chloro-4-phenylbenzyl)-2-met- hyl-3H-imidazo[4,5-b]pyridine (1
g).
[2172] .sup.1H-NMR (DMSO-d):2.49(3H, s), 5.30(1H, d, J=10 Hz),
5.59(2H, s), 5.86(1H, d, J=17 Hz), 6.50(1H, d, J=8 Hz), 6.74(1H,
dd, J=17, 10 Hz), 7.34-7.52(6H, m), 7.64(2H, d, J=8 Hz),
7.75-7.85(3H, m), 7.93(1H, d, J=8 Hz), 8.00(1H, d, J=8 Hz) Mass
(ESI) m/z 541 (M-1) mp>300.degree. C.
Example 207
[2173] In the same manner as in Example 205,
5-[(5-bromothiophen-2-yl) sulfonylcarbamoyl]-3-(2
-chloro-4-phenylbenzyl)-2-methyl-3H-imidazo[4,5-b- ]pyridine sodium
(1.02 g) was obtained as colorless crystals from
5-[(5-bromothiophen-2-yl)sulfonylcarbamoyl]-3
-(2-chloro-4-phenylbenzyl)-- 2-methyl-3H-imidazo[4,5-b]pyridine
(1.2 g).
[2174] .sup.1H-NMR (DMSO-d.sub.6):2.49(3H, s), 5.62(2H, s),
6.51(1H, d, J=8 Hz), 7.08(1H, J=5 Hz), 7.29(1H, d, J=3 Hz),
7.34-7.53(4H, m), 7.67(2H, d, J=8 Hz), 7.85(1H, s), 7.96(1H, d, J=8
Hz), 8.01(1H, d, J=8 Hz) mp>250.degree. C.
Example 208
[2175] In the same manner as in Example 205,
3-(4-bromo-2-chlorobenzyl)-2,- 7-dimethyl-5
-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridi- ne
sodium (972 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-[(4-methylbenzene)-sulfonyl-car-
bamoyl]-3H-imidazo[4,5-b]pyridine (1 g).
[2176] .sup.1H-NMR (DMSO-d.sub.6):2.30(3H, s), 2.43(3H, s),
2.56(3H, s), 5.48(2H, s), 6.35(1H, d, J=8 Hz), 7.17(2H, d, J=8 Hz),
7.40(1H, d, J=8 Hz), 7.71(2H, d, J=8 Hz), 7.83(2H, s)
mp>250.degree. C.
Example 209
[2177] In the same manner as in Example 1,
3-(4-(N-butyryl-N-methylamino)--
2-chlorobenzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo-
[4,5-b]pyridine (58 mg) was obtained as a pale-yellow powder from
3-(4-(N-butyryl-N-methylamino)-2-chlorobenzyl)-2-methyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid (90 mg) and (4-methylbenzene)sulfonamide
(96 mg).
[2178] .sup.1H-NMR (CDCl.sub.3):0.87(3H, t, J=7 Hz), 1.56-1.69(2H,
m), 2.12(2H, br), 2.43(3H, s), 2.63(3H, s), 3.27(3H, s), 5.61(2H,
s), 6.68(1H, d, J=8 Hz), 7.03(1H, dd, J=8, 2 Hz), 7.30-7.39(3H, m),
8.04-8.13(4H, m), 10.09(1H, s) Mass(ESI):m/z 552(M-H).sup.-
Example 210
[2179] In the same manner as in Example 1,
3-(2-chloro-4-(N-(n-pentyl)-ami-
no)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5--
b]pyridine (189 mg) was obtained as colorless crystals from
3-(2-chloro-4-(N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridi-
ne-5-carboxylic acid (170 mg) and (4-methylbenzene)sulfonamide (188
mg).
[2180] .sup.1H-NMR (CDCl.sub.3):0.91(3H, t, J=7 Hz), 1.34-1.42(4H,
m), 1.57-1.62(2H, m), 2.42(3H, s), 2.66(3H, s), 3.05-3.13(2H, m),
3.83(1H, br), 5.45(2H, s), 6.48(1H, dd, J=8, 2 Hz), 6.65(1H, d, J=2
Hz), 6.79(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 7.97-8.05(4H, m),
10.14(1H, s) Mass(ESI): m/z 538(M-H).sup.- mp 222-223.degree.
C.
Example 211
[2181] In the same manner as in Example 1,
3-(2-chloro-4-(N-methyl-N-(n-pe-
ntyl)amino)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imid-
azo[4,5-b]pyridine (12 mg) was obtained as colorless crystals from
3-(2-chloro-4-(N-methyl-N-(n-pentyl)amino)benzyl)-2-methyl-3H-imidazo[4,5-
-b]pyridine-5-carboxylic acid (45 mg) and
(4-methylbenzene)sulfonamide (48 mg).
[2182] .sup.1H-NMR (CDCl.sub.3):0.90(3H, t, J=7 Hz), 1.15-1.45(4H,
m), 1.55-1.65(2H, m), 2.42(3H, s), 2.67(3H, s), 2.94(3H, s),
5.47(2H, s), 6.53(1H, d, J=8 Hz), 6.70(1H, s), 6.81(1H, d, J=8 Hz),
7.27-7.35(2H, m), 7.98-8.04(4H, m), 10.18(1H, s) Mass(ESI) : m/z
552(M-H).sup.- mp 175-177.degree. C.
Example 212
[2183] In the same manner as in Example 1,
3-(4-(N-benzenesulfonylamino)-2-
-chlorobenzyl)-2-methyl-5-((4-methylbenzene)
sulfonylcarbamoyl)-3H-imidazo- [4,5-b]pyridine (157 mg) was
obtained as colorless crystals from 3-(4-(N-benzenesulfonylamino)-2
-chlorobenzyl)-2 -methyl-3H-imidazo[4,5-b- ]pyridine-5-carboxylic
acid (165 mg) and (4-methylbenzene)sulfonamide (155 mg).
[2184] .sup.1H-NMR (DMSO-d.sub.6):2.37(3H, s), 2.39(3H, s),
5.70(2H, s), 6.72(1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.24(1H, s),
7.42(2H, d, J=8 Hz), 7.55-7.65(3H, m), 7.77(2H, d, J=8 Hz),
7.83-7.92(3H, m), 8.09(1H, d, J=8 Hz) Mass(ESI):m/z 608(M-H).sup.-
mp 234-236.degree. C.
Example 213
[2185] In the same manner as in Example 1,
3-(2-chloro-4-(isopropoxyl-carb-
onyl)benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,-
5-b]pyridine (133 mg) was obtained as colorless crystals from
3-(2-chloro-4-(isopropoxylcarbonyl)benzyl)-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (250 mg) and (4-methylbenzene)sulfonamide
(331 mg).
[2186] .sup.1H-NMR (CDCl.sub.3):1.36(3H, s), 1.38(3H, s), 2.42(3H,
s), 2.59(3H, s), 5.20-5.32(1H, m), 5.64(2H, s), 6.71(1H, d, J=8
Hz), 7.33(2H, d, J=8 Hz), 7.85(1H, dd, J=8, 2 Hz), 8.02-8.16(5H,
m), 10.07(1H, s) Mass(ESI) : m/z 539(M-H).sup.- mp 199-201.degree.
C.
Example 214
[2187] In the same manner as in Example 1,
3-(2-chloro-4-(cyclohexyl-oxyca-
rbonyl)benzyl)-2-methyl-5-((4-methylbenzene) sulfonylcarbamoyl)
-3H-imidazo[4,5-b]pyridine (312 mg) was obtained as colorless
crystals from
3-(2-chloro-4-(cycohexyloxycarbonyl)benzyl)-2-methyl-3H-imidazo[4,5--
b]pyridine-5-carboxylic acid (289 mg) and
(4-methylbenzene)sulfonamide (231 mg).
[2188] .sup.1H-NMR (CDCl.sub.3):1.32-1.65(6H, m), 1.78(2H, br s),
1.92(2H, br s), 2.42(3H, s), 2.59(3H, s), 4.99-5.06(1H, m),
5.64(2H, s), 6.71(1H, d, J=8 Hz), 7.73(2H, d, J=8 Hz), 7.86(1H, d,
J=8 Hz), 8.02-8.16(5H, m), 10.09(1H, s) Mass(ESI):m/z
579(M-H).sup.-
Example 215
[2189] In the same manner as in Example 1,
3-(2-chloro-4-(3-phenylureido)--
benzyl)-2-methyl-5-((4-methylbenzene)sulfonylcarbanoyl)-3H-imidazo[4,5-b]p-
yridine (60 mg) was obtained as colorless crystals from
3-(2-chloro-4-(3-phenylureido)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine--
5-carboxylic acid (207 mg) and (4-methylbenzene)sulfonamide (244
mg).
[2190] .sup.1H-NMR (CDCl.sub.3):2.38(3H, s), 2.68(3H, s), 5.52(2H,
s), 6.93(1H, d, J=8 Hz), 7.05(1H, t, J=7 Hz), 7.22(1H, dd, J=8, 2
Hz), 7.27-7.33(4H, m), 7.42(2H, d, J=8 Hz), 7.87(1H, d, J=2 Hz),
7.98-8.02(5H, m), 8.28(1H, s) Mass(ESI):m/z 587(M-H).sup.-
Example 216
[2191] In the same manner as in Example 1,
3-[2-chloro-4-propoxybenzyl]-2--
methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(213 mg) was obtained as colorless crystals from
3-[2-chloro-4-propoxy-be-
nzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (200
mg).
[2192] .sup.1H-NMR (CDCl.sub.3):1.04(3H, t, J=7 Hz), 1.74-1.88(2H,
m), 2.42(3H, s), 2.63(3H, s), 3.93(2H, t, J=7 Hz), 5.51(2H, s),
6.78(2H, s), 7.02(1H, s), 7.32(1H, s), 7.35(1H, s), 8.00-8.10(4H,
m), 10.12(1H, br s) Mass(ESI):m/z 511(M-1) mp 144-146.degree.
C.
Example 217
[2193] In the same manner as in Example 1,
3-[2-chloro-4-(n-pentoxy)benzyl-
]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridin-
e (231 mg) was obtained as colorless crystals from
3-12-chloro-4-(n-pentox-
y)-benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid
(200 mg).
[2194] .sup.1H-NMR (CDCl.sub.3):0.93(3H, t, J=7 Hz), 1.30-1.50(6H,
m), 1.73-1.85(2H, m), 2.42(3H, s), 2.64(3H, s), 3.95(2H, t, J=7
Hz), 5.51(2H, s), 6.78(2H, s), 7.02(1H, s), 7.32(1H, s), 7.35(1H,
s), 8.00-8.10(4H, m), 10.12(1H, br s) Mass(ESI):m/z 539(M-1) mp
162-163.degree. C.
Example 218
[2195] In the same manner as in Example 1,
3-(2-chloro-4-ethoxy)benzyl-2-m-
ethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(3.18 mg) was obtained as colorless crystals from
3-(2-chloro-4-ethoxy)-b-
enzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (280
mg).
[2196] .sup.1H-NMR (CDCl.sub.3):1.42(3H, t, J=7.5 Hz), 2.43(3H, s),
2.64(3H, s), 4.04(2H, q, J=7 Hz), 5.51(2H, s), 6.78(1H, s),
6.79(1H, s), 7.02(1H, br s), 7.34(1H, d, J=8 Hz), 8.00-8.09(4H, m),
10.11(1H, br s) Mass(ESI):m/z 497(M-1) mp 190-191.degree. C.
Example 219
[2197] In the same manner as in Example 1,
3-[2-chloro-4-(2-methoxyethoxy)-
-benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]-
pyridine (203 mg) was obtained as colorless crystals from
3-[2-chloro-4-(2-methoxyethoxy)benzyl]-2-methyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (189 mg).
[2198] .sup.1H-NMR (CDCl.sub.3): 2.43(3H, s), 2.64(3H, s), 3.46(3H,
s), 3.70-3.80(2H, m), 4.08-4.18(2H, m), 5.52(2H, s), 6.74-6.87(2H,
m), 7.07(1H, br s), 7.35(2H, d, J=8 Hz), 7.99-8.10(4H, m)
Mass(ESI): m/z 527(M-1) mp 156-158.degree. C.
Example. 220
[2199] In the same manner as in Example 1,
3-[2-chloro-4-[(thiophen-2-yl)m-
ethyloxy]benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidaz-
o[4,5-b]pyridine (215 mg) was obtained as colorless crystals from
3-12-chloro-4-[(thiophen-2-yl)methyloxylbenzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylic acid (180 mg).
[2200] .sup.1H-NMR (CDCl.sub.3):2.42(3H, s), 2.64(3H, s), 5.23(2H,
s), 5.52(2H, s), 6.81(1H, d, J=8 Hz), 6.88(1H, dd, J=8, 2 Hz),
7.02(1H, dd, J=5, 3 Hz), 7.10-7.14(2H, m), 7.30-7.36(3H, m),
8.00-8.10(4H, m), 10.09(1H, br s) Mass(ESI): m/z 565(M-1) mp
184-185.degree. C.
Example 221
[2201] In the same manner as in Example 1,
3-[2-chloro-4-1(thiophen-3-yl)m-
ethyloxylbenzyl]-2-methyl-5-[(4-methylbenzene)
sulfonylcarbamoyl]-3H-imida- zo[4,5-b]pyridine (126 mg) was
obtained as colorless crystals from
3-[2-chloro-4-[(thiophen-3-yl)methyloxy]benzyl]-2-methyl-3H-imidazo[4,5-b-
]pyridine-5-carboxylic acid (115 mg).
[2202] .sup.1H-NMR (CDCl.sub.3):2.42(3H, s), 2.64(3H, s), 5.08(2H,
s), 5.52(2H, s), 6.81(1H, d, J=8 Hz), 6.87(1H, dd, J=8, 2 Hz),
7.11(1H, d, J=2 Hz), 7.14(1H, br d, J=5 Hz), 7.28-7.39(4H, m),
8.00-8.09(4H, d, J=8 Hz) Mass(ESI):m/z 565(M-1) mp 198-200.degree.
C.
Example 222
[2203] In the same manner as in Example 1,
3-(2-chloro-4-phenylethynyl)-be-
nzyl-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]-
pyridine (123 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylethynyl)benzyl-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-
-5-carboxylic acid (125 mg).
[2204] .sup.1H-NMR (CDCl.sub.3):2.39(3H, s), 2.62(3H, s), 2.69(3H,
s), 5.58(2H, s), 6.70(1H, br d, J=8 Hz), 7.12(1H, dd, J=8, 1 Hz),
7.23-7.43(6H, m), 7.48-7.58(2H, m), 7.65(1H, br s), 7.91(1H, br s),
8.00-8.01(2H, m), 10.10(1H, br s) Mass(ESI) : m/z 567(M-1) mp
221-222.degree. C.
Example 223
[2205] In the same manner as in Example 1,
3-[2-chloro-4-(cyclopentyl-meth-
yloxy)benzyl]-2-methyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4-
,5-b]pyridine (66 mg) was obtained as colorless crystals from
3-[2-chloro-4-(cyclopentylmethyloxy)benzyl-2-methyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (69 mg).
[2206] .sup.1H-NMR (CDCl.sub.3):1.36-1.44(2H, m), 1.50-1.71(3H, m),
1.75-1.91(2H, m), 2.35(1H, m), 2.42(3H, s), 2.64(3H, s), 3.83(2H,
d, J=5 Hz), 5.51(2H, s), 6.78(2H, s), 6.02(1H, br s), 7.33(2H, d,
J=8 Hz), 7.98-8.10(4H, m) Mass(ESI) : m/z 551(M-1) mp
177-178.degree. C.
Example 224
[2207] In the same manner as in Example 1,
3-(2-chloro-4-phenylethynyl)-be-
nzyl-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(204 mg) was obtained as colorless crystals from
3-(2-chloro-4-phenylethy-
nyl)-benzyl-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic
acid (200 mg).
[2208] .sup.1H-NMR (CDCl.sub.3):0.86(3H, t, J=8 Hz), 1.25-1.48(4H,
m), 1.81-1.96(2H, m), 2.62(3H, s), 2.75(3H, s), 3.49-3.61(2H, m),
5.57(2H, s), 6.65(1H, d, J=8 Hz), 7.29-7.41(4H, m), 7.48-7.56(2H,
m), 7.65(1H, br s), 8.03(1H, s), 9.85(1H, br s) Mass(ESI):m/z
547(M-1) mp 201-203.degree. C.
Example 225
[2209] In the same manner as in Example 1,
3-(2-chloro-4-(1-hexynyl)benzyl-
-2-methyl-5-(N-(4-methylphenylsulfonyl)carbamoyl-3H-imidazo[4,5-b]pyridine
(448 mg) was obtained as colorless crystals from
3-(2-chloro-4-(1-hexynyl-
)-benzyl-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (400
mg).
[2210] .sup.1H-NMR (CDCl.sub.3):0.95(3H, t, J=6 Hz), 1.40-1.65(4H),
2.35-2.48(5H), 2.60(3H, s), 5.57(2H, s), 6.65(1H, d, J=8 Hz),
7.22(1H, d, J=8 Hz), 7.34(2H, d, J=8 Hz), 7.52(1H, s),
8.02-8.12(4H) mp 175-176.degree. C.
Example 226
[2211] In the same manner as in Example 1,
3-(2-chloro-4-(cyclohexyl-methy-
loxy)benzyl)-2,7-dimethyl-5-((1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b-
]pyridine (240 mg) was obtained as colorless crystals from
3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid (254 mg) and 1-pentanesulfonamide (135
mg).
[2212] .sup.1H-NMR (CDCl.sub.3):0.89(3H, t, J=7 Hz), 0.96-1.93(17H,
m), 2.64(3H, s), 2.73(3H, s), 3.55(2H, m), 3.72(2H, d, J=7 Hz),
5.48(2H, s), 6.71(2H, br s), 6.98(1H, d, J=1 Hz), 7.99(1H, s)
Mass(ESI):m/z 559(M-1)
Example 227
[2213] In the same manner as in Example 1,
3-(2-chloro-4-(cyclohexyl-methy-
loxy)benzyl)-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidaz-
o[4,5-b]pyridine (252 mg) was obtained as colorless crystals from
3-(2-chloro-4-(cyclohexylmethyloxy)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]-
pyridine-5-carboxylic acid (247 mg) and
(4-methylbenzene)sulfonamide (148 mg).
[2214] .sup.1H-NMR (CDCl.sub.3): 0.98-1.87(11H, m), 2.42(3H, s),
2.62(3H, s), 2.66(3H, s), 3.74(2H, d, J=7 Hz), 5.49 (2H, s),
6.71(2H, br s), 7.00(1H, d, J=1 Hz), 7.33(2H, d, J=8 Hz), 7.88(1H,
s), 8.03(2H, d, J=8 Hz) Mass (ESI) m/z 579(M-1)
Example 228
[2215] In the same manner as in Example 1,
3-(2-chloro-4-ethylbenzyl)-2,7--
dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
(178 mg) was obtained as colorless crystals from
3-(2-chloro-4-ethylbenzyl)-2,7-di-
methyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (190 mg) and
1-pentanesulfonamide (125 mg).
[2216] .sup.1H-NMR (CDCl.sub.3):0.88(3H, t, J=7 Hz), 1.22(3H, t,
J=7 Hz), 1.28-1.48(4H, m), 1.88-1.93(2H, m), 2.62(3H, s), 2.62(2H,
q, J=7 Hz), 2.74(3H, s), 3.52-3.57(2H, m), 5.52 (2H, s), 6.60(1H,
d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.31(1H, s), 8.01(1H, s)
Example 229
[2217] In the same manner as in Example 1,
3-(2-chloro-4-ethylbenzyl)-2,7--
dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridine
(173 mg) was obtained as colorless crystals from
3-(2-chloro-4-ethylbenzy-
l)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (190
mg) and (4-methylbenzene)sulfonamide (142 mg).
[2218] .sup.1H-NMR (CDCl.sub.3):1.24(3H, t, J=7 Hz), 2.42(3H, s),
2.61(3H, s), 2.64(2H, q, J=7 Hz), 2.68(3H, s), 5.53 (2H, s),
6.61(1H, d, J=8 Hz), 7.01(1H, d, J=8 Hz), 7.30-7.34(3H, m),
7.90(1H, s), 8.04(2H, d, J=8 Hz)
Example 230
[2219] In the same manner as in Example 1,
3-(2-chloro-4-(trifluoromethyl)-
-benzyl)-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyri-
dine (210 mg) was obtained as pale-yellow crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (248 mg) and 1-pentanesulfonamide (135
mg).
[2220] .sup.1H-NMR (CDCl.sub.3):0.88(3H, t, J=8 Hz), 1.25-1.48(4H,
m), 1.80-1.94(2H, m), 2.61(3H, s), 2.76(3H, s), 3.50-3.58(2H, m),
5.60 (2H, s), 6.72(1H, d, J=8 Hz), 7.44(1H, br d, J=8 Hz), 7.77(1H,
br s), 8.05(1H, s), 9.78(1H, br s)
Example 231
[2221] In the same manner as in Example 1,
3-(2-chloro-4-(trifluoromethyl)-
-benzyl)-2,7-dimethyl-5-1(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,-
5-b]pyridine (178 mg) was obtained as colorless crystals from
3-(2-chloro-4-(trifluoromethyl)benzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyri-
dine-5-carboxylic acid (238 mg) and (4-methylbenzene)sulfonamide
(159 mg).
[2222] .sup.1H-NMR (CDCl.sub.3):2.42(3H, s), 2.60(3H, s), 2.69(3H,
s), 5.61(2H, s), 6.73(1H, d, J=8 Hz), 7.33(2H, d, J=8 Hz), 7.44(1H,
br d, J=8 Hz), 7.78(1H, br s), 7.93(1H, s), 8.02(1H, s), 10.05(1H,
br s)
Example 232
[2223] In the same manner as in Example 1,
3-(2-chloro-4-ethoxybenzyl)-2,7-
-dimethyl-5-(1-pentanesulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine
was obtained as colorless crystals from
3-(2-chloro-4-ethoxybenzyl)-2,7-dimet-
hyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (260 mg) and
1-pentanesulfonamide (164 mg).
[2224] .sup.1H-NMR (CDCl.sub.3):0.89(3H, t, J=7 Hz), 1.26-1.51(7H,
m), 1.80-1.94(2H, m), 2.64(3H, s), 2.73(3H, s), 3.52-3.57(2H, m),
4.01(2H, q, J=7 Hz), 5.49(2H, s), 6.72(2H, s), 6.99(1H, s),
7.99(1H, s), 9.89(1H, br s)
Example 233
[2225] In the same manner as in Example 1,
3-(2-chloro-4-ethoxybenzyl)-2,7- -dimethyl-5-[(4-methylbenzene)
sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyridin- e was obtained as
colorless crystals from 3-(2-chloro-4-ethoxybenzyl)-2,7--
dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (250 mg) and
(4-methylbenzene)-sulfonamide (178 mg).
[2226] .sup.1H-NMR (CDCl.sub.3):1.42(3H, t, J=7 Hz), 2.42(3H, s),
2.62(3H, s), 2.66(3H, s), 4.03(2H, q, J=7 Hz), 5.49(2H, s),
6.72(1H, d, J=8 Hz), 6.77(1H, d, J=8 Hz), 7.01(1H, d, J=1 Hz),
7.33(2H, d, J=8 Hz), 7.88(11H, s), 8.03(2H, d, J=8 Hz), 10.14(11H,
br s)
Example 234
[2227] In the same manner as in Example 1,
3-(2,4-dichlorobenzyl)-2-methyl-
-5-(p-toluenesulfonylcarbamoyl)benzo[b]furan (90 mg) was obtained
as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (300 mg),
N,N'-carbonyldiimidazole (218 mg), DBU (0.20 ml) and
(4-methyl-benzene)sulfonamide (230 mg).
[2228] .sup.1H-NMR (DMSO-d.sub.6, (5ppm):2.37(3H, s), 4.06(2H, s),
7.16(1H, d, J=8.4 Hz), 7.32(1H, dd, J=8.2 and 2.0 Hz), 7.38(2H, d,
J=8.0 Hz), 7.54(1H, d, J=8.7 Hz), 7.62(1H, d, J=1.9 Hz), 7.75(1H,
d, J=8.9 Hz), 7.83(2H, d, J=8.2 Hz), 7.90(1H, s), 12.35(1H, br s)
IR(Nujol):1700 cm.sup.-1 mp: 120-121.degree. C.
Example 235
[2229] In the same manner as in Example 1,
5-((5-bromothiophen-2-yl)sulfon-
ylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (350 mg)
was obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methyl- benzo[b]furan (280 mg),
N,N'-carbonyldimidazole (190 mg), DBU (0.18 ml) and
(5-bromothiophen-2-yl)sulfonamide (280 mg).
[2230] .sup.1H-NMR (DMSO-d.sub.6, .delta.ppm):2.40(3H, s), 4.08(2H,
s), 7.17(1H, d, J=8.4 Hz), 7.33(1H, dd, J=8.4 and 2.2 Hz), 7.35(1H,
d, J=4.1 Hz), 7.58(1H, d, J=8.7 Hz) 7.63(1H, d, J=2.1 Hz),7.64(1H,
d, J=4.0 Hz), 7.79(1H, d, J=8.7 Hz), 7.96(1H, s) IR(Nujol):1699
cm.sup.-1 mp: 165-167.degree. C.
Example 236
[2231] In the same manner as in Example 1,
5-((5-chlorothiophen-2-yl)sulfo-
nylcarbamoyl)-3-(2,4-dichlorobenzyl)-2-methylbenzo[b]furan (210 mg)
was obtained as white crystals from
5-carboxy-3-(2,4-dichlorobenzyl)-2-methyl- benzo-[b]furan (230 mg),
N,N'-carbonyldiimidazole (170 mg), DBU (0.16 ml) and
(5-chlorothiophen-2-yl)sulfonamide (210 mg).
[2232] .sup.1H-NMR (DMSO-d.sub.6, .delta.ppm):2.40(3H, s), 4.07(2H,
s), 7.16(1H, d, J=8.4 Hz), 7.20(1H, d, J=4.0),7.32(1H, dd, J=8.3
and 2.3 Hz), 7.55(1H, d, J=8.6 Hz), 7.60-7.64(2H, m), 7.81(1H, dd,
J=8.7 and 1.8 Hz), 7.94(1H, d, J=1.5 Hz) IR(Nujol): 1700 cm.sup.-1
mp: 181-183.degree. C.
Example 237
[2233] In the same manner as in Example 1,
3-(2-chloro-4-phenylbenzyl)-2-m-
ethyl-5-(4-pentene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (91
mg) was obtained as white crystals from
3-(2-chloro-4-phenylbenzyl)-2-methyl--
3H-imidazo[4,5-b]pyridine-5-carboxylic acid (150 mg),
N,N'-carbonyldiimidazole (84 mg), DBU (79 mg) and
4-pentene-1-sulfonamide (77 mg).
[2234] .sup.1H-NMR (DMSO-d.sub.4, .delta.ppm):1.75-1.83(2H, m),
2.10-2.16(2H, m), 2.49(3H, s), 3.52(2H, t, J=7.7 Hz), 4.94(1H, d,
J=11.3 Hz), 4.98(1H, dd, J=17.1 and 2.6 Hz), 5.70-5.76(1H, m),
5.86(2H, s), 6.89(1H, d, J=8.1 Hz), 7.38(1H, t, J=7.3 Hz), 7.45(2H,
t, J=7.3 Hz), 7.54(1H, dd, J=8.1 and 1.7 Hz), 7.66(2H, d, J=7.4
Hz), 7.84(1H, d, J=1.8 Hz), 8.01(1H, d, J=8.3 Hz), 8.20(1H, d,
J=8.2 Hz), 11.76(1H, br s) mp: 152-155.degree. C.
Example 238
[2235] In the same manner as in Example 1,
2-(2-chloro-4-phenylbenzyl)-3-m-
ethyl-6-(p-toluenesulfonylcarbamoyl)-2H-indazole (1.00 g) was
obtained as white crystals from
6-carboxy-2-(2-chloro-4-phenylbenzyl)-3-methyl-2H-ind- azole (1.131
g), N,N'-carbonyldiimidazole (0.63 g), DBU (0.58 ml) and
p-toluenesulfonamide (0.67 g).
[2236] .sup.1H-NMR (DMSO-d.sub.6, .delta.ppm):2.39(3H, s), 2.65(3H,
s), 5.77(2H, s), 6.80(1H, d, J=8.1 Hz), 7.34-7.47(6H, m), 7.56(1H,
d, J=8.2 Hz), 7.66(2H, d, J=7.8 Hz), 7.78-7.81(2H, m), 7.89(2H, d,
J=8.2 Hz), 8.22(1H, s), 12.42(1H, br s) mp: 236-237.degree. C.
Example 239
[2237]
3-(2-Chloro-4-(1-hexynyl)benzyl)-2-methyl-5-(N-(4-methylphenyl-sulf-
onyl)carbamoyl-3H-imidazo[4,5-b]pyridine (240 mg) was reduced in
dioxane using platinum oxide as a catalyst to give
3-(2-chloro-4-hexylbenzyl)-2-m-
ethyl-5-(N-(4-methylphenylsulfonyl)carbamoyl-3H-imidazo[4,5-b]pyridine
(181 mg) as colorless crystals.
[2238] .sup.1H-NMR (CDCl.sub.3):0.88(3H, t, J=6 Hz), 1.22-1.66(8H),
2.43(3H, s), 2.59(2H, t, J=6 Hz), 2.62(3H, s), 5.55(2H, s),
6.65(1H, d, J=8 Hz), 7.02(1H, d, J=8 Hz), 7.28-7.37(3H),
8.01-8.11(4H) mp: 162-163.degree. C.
Example 240
[2239] To a solution (5 ml) of
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-(-
(4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (500
mg) in toluene were successively added sodium tert-butoxide (123
mg), piperidine (109 mg), (R)-(+)-BINAP (8 mg) and
tris(dibenzylideneacetone)dipalladium(- 0) (4 mg) under a nitrogen
atmosphere, and the mixture was stirred at 90.degree. C. for 30 hr.
The reaction mixture was concentrated under reduced pressure and
water was added. 1N Hydrochloric acid was added to adjust to pH 7,
and the mixture was extracted with a mixed solvent of chloroform
and methanol (chloroform:methanol=4:1) The organic layer was washed
with saturated brine, dried over anhydrous magnesium sulfate and
concentrated under reduced pressure. Ethanol was added to the
residue and the mixture was heated and allowed to cool. The
precipitated crystals were collected by filtration. The crystals
were dissolved in N,N-dimethylformamide (12 ml) and hot water (8.5
ml) was gradually added on an oil bath at 80.degree. C. The mixture
was allowed to cool with stirring and the precipitated crystals
were collected by filtration. The crystals were washed with water,
and dried under reduced pressure with heating to give
3-(2-chloro-4-piperidinobenzyl)-2,7-dimethyl-5-((4-methyl-
benzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (391 mg) as
pale-pink crystals.
[2240] .sup.1H-NMR (CDCl.sub.3):1.65-1.70(6H, m), 2.42(3H, s),
2.64(3H, s), 2.65(3H, s), 3.19(4H, t, J=7 Hz), 5.45(2H, s),
6.75(2H, s), 6.95(1H, s), 7.32(2H, d, J=8 Hz), 7.86(1H, s),
8.04(2H, d, J=8 Hz), 10.18(1H, s) Mass(ESI) : m/z 550(M-H).sup.-
mp: 190-192.degree. C.
Example 241
[2241] In the same manner as in Example 240,
3-(2-chloro-4-morpholino-benz-
yl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo[4,5-b]p-
yridine (78 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzyl)sulfonylcarbam-
oyl)-3H-imidazo[4,5-b]pyridine (500 mg) and morpholine (191
mg).
[2242] .sup.1H-NMR (CDCl.sub.3):2.42(3H, s), 2.65(3H, s), 2.66(3H,
s), 3.18(4H, t, J=7 Hz), 3.85(4H, t, J=7 Hz), 5.46(2H, s),
6.73-6.82(2H, m), 6.95(1H, d, J=2 Hz), 7.33(2H, d, J=8 Hz),
7.86(1H, s), 8.05(2H, d, J=8 Hz), 10.14(1H, s) Mass(ESI) : m/z
552(M-H).sup.- mp: 235-237.degree. C.
Example 242
[2243] In the same manner as in Example 240,
3-(2-chloro-4-(hexamethylene--
imino)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imida-
zo[4,5-b]pyridine (142 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)-sulfonyl-car-
bamoyl)-3H-imidazo[4,5-b]pyridine (600 mg) and hexamethylene-imine
(206 mg).
[2244] .sup.1H-NMR (CDCl.sub.3):1.50-1.60(4H, m), 1.80(4H, br),
2.42(3H, s), 2.65(3H, s), 2.66(3H, s), 3.43(4H, t, J=7 Hz),
5.44(2H, s), 6.53(1H, dd, J=8, 2 Hz), 6.70(1H, d, J=2 Hz), 6.76(1H,
d, J=8 Hz), 7.32(2H, d, J=8 Hz), 7.85(1H, s), 8.04(2H, d, J=8 Hz)
Mass(ESI) : m/z 564(M-H).sup.- mp: 210-212.degree. C.
Example 243
[2245] In the same manner as in Example 240,
3-(2-chloro-4-(1-pyrrolidinyl-
)-benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-imidazo-[-
4,5-b]pyridine (195 mg) was obtained as colorless crystals from
3-(4-bromo-2-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)
sulfonylcarbamoyl)-3H-imidazo[4,5-b]pyridine (600 mg) and
pyrrolidine (148 mg).
[2246] .sup.1H-NMR (CDCl.sub.3):1.98-2.04(4H, m), 2.42(3H, s),
2.65(3H, s), 2.66(3H, s), 3.27(4H, t, J=7 Hz), 5.45(2H, s),
6.43(1H, dd, J=8, 2 Hz), 6.59(1H, d, J=2 Hz), 6.83(1H, d, J=8 Hz),
7.32(2H, d, J=8 Hz), 7.84(1H, s), 8.03(2H, d, J=8 Hz), 10.21(1H, s)
Mass(ESI) : m/z 536(M-H).sup.- mp: 212-214.degree. C.
Example 244
[2247] In the same manner as in Example 240,
3-(2-chloro-4-(4-methyl-piper-
azin-1-yl)benzyl)-2,7-dimethyl-5-((4-methylbenzene)sulfonylcarbamoyl)-3H-i-
midazo[4,5-b]pyridine (411 mg) was obtained as colorless crystals
from 3-(4-bromo-2
-chlorobenzyl)-2,7-dimethyl-5-((4-methylbenzene)-sulfonylcar-
bamoyl)-3H-imidazo[4,5-b]pyridine (600 mg) and
1-methyl-piperazine(154 mg).
[2248] .sup.1H-NMR (CDCl.sub.3):2.35(3H, s), 2.42(3H, s), 2.55(4H,
t, J=7 Hz), 2.64(3H, s), 2.65(3H, s), 3.24(4H, t, J=7 Hz), 5.46(2H,
s), 6.77(2H, s), 6.96(1H, s), 7.33(2H, d, J=8 Hz), 7.86(1H,
s),8.03(2H, d, J=8 Hz) Mass(ESI) : m/z 568(M+H).sup.+ mp:
149-151.degree. C.
Example 245
[2249] In the same manner as in Example 1,
3-(2-chloro-4-methylthiobenzyl)-
-2,7-dimethyl-5-[(4-methylbenzene)sulfonylcarbamoyl]-3H-imidazo[4,5-b]pyri-
dine (234 mg) was obtained as colorless crystals from
3-(2-chloro-4-methylthiobenzyl)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5--
carboxylic acid (250 mg) and (4-methylbenzene)sulfonamide (356
mg).
[2250] .sup.1H-NMR (CDCl.sub.3):2.42(3H, s), 2.50(3H, s), 2.62(3H,
s), 2.67(3H, s), 5.51(2H, s), 6.69(1H, d, J=8 Hz), 7.08(1H, dd,
J=1, 8 Hz), 7.32-7.35(3H, m), 7.88(1H, s), 8.04(2H, d, J=8 Hz)
Example 246
[2251] In the same manner as in Example 1,
3-(2-chloro-4-methylthiobenzyl)-
-2,7-dimethyl-5-(1-pentanesulfonylcarbamoyl-3H-imidazo[4,5-b]pyridine
(188 mg) was obtained as colorless crystals from
3-(2-chloro-4-methylthiobenzy-
l)-2,7-dimethyl-3H-imidazo[4,5-b]pyridine-5-carboxylic acid (260
mg) and 1-pentanesulfonamide (326 mg).
[2252] .sup.1H-NMR (CDCl.sub.3):0.88(3H, t, J=7 Hz), 1.28-1.48(4H,
m), 1.83-1.93(2H, m), 2.48(3H, s), 2.63(3H, s), 2.74(3H, s),
3.55(2H, m), 5.51(2H, s), 6.66(1H, d, J=8 Hz), 7.03(1H, dd, J=1, 8
Hz), 7.31(1H, d, J=1 Hz), 8.00(1H, s)
[2253] The above-mentioned sulfonamide compounds and
pharmaceutically acceptable salts thereof of the present invention
are useful as pharmaceutical preparations that can be used for the
prophylaxis and treatment of impaired glucose tolerance disorder,
diabetes (e.g., type II diabetes), diabetic complications (e.g.,
diabetic gangrene, diabetic arthropathy, diabetic bone resorption,
diabetic glomerulosclerosis, diabetic nephropathy, diabetic
dermatopathy, diabetic neuropathy, diabetic cataract, diabetic
retinopathy and the like), insulin resistant syndrome (e.g.,
insulin receptor disorders, Rabson-Mendenhall syndrome,
leprechaunism, Kobberling-Dunnigan syndrome, Seip syndrome,
Lawrence syndrome, Cushing syndrome, acromegaly and the like),
polycystic ovary syndrome, hyperlipidemia, atherosclerosis,
cardiovascular disorders (e.g., stenocardia, cardiac failure and
the like), hyperglycemia (e.g., those characterized by abnormal
saccharometabolism such as feeding disorders), hypertension and the
like, based on their blood sugar level-depressing activity, as well
as angina pectoris, hypertension, pulmonary hypertension,
congestive heart failure, glomerulopathy (e.g., diabetic
glomerulosclerosis), tubulointerstitial disorders (e.g., kidney
diseases induced by FK506, cyclosporin and the like), renal
failure, atherosclerosis, angiostenosis (e.g., after percutaneous
arterioplasty), distal angiopathy, cerebral apoplexy, chronic
reversible obstructions (e.g., bronchitis, asthma inclusive of
chronic asthma and allergic asthma), autoimmune diseases, allergic
rhinitis, urticaria, glaucoma, diseases characterized by
enteromotility (e.g., hypersensitive enteropathy), impotence (e.g.,
organic impotence, psychic impotence and the like), nephritis,
cancer cachexia or restenosis after PTCA, pancreatitis, cachexia
(e.g., progressive weight loss due to lipolysis, myolysis, anemia,
edema, anorexia and the like in chronic diseases such as cancer,
tuberculosis, endocrine diseases and AIDS, and the like, based on
their cGMP-PDE (especially PDE-V)-inhibiting activity, smooth
muscle relaxing activity, bronchodilating activity, vasodilating
activity, smooth muscle cell suppressing activity and antiallergic
activity.
[2254] This application is based on application Nos. 208295/1997
and 114718/1998 filed in Japan, the contents of which are
incorporated hereinto by reference.
* * * * *