U.S. patent application number 13/047447 was filed with the patent office on 2011-08-11 for novel antifungal agent containing heterocyclic compound.
Invention is credited to Shinya Abe, Toru Haneda, Katsura Hata, Satoshi Inoue, Masayuki Matsukura, Kazutaka NAKAMOTO, Keigo Tanaka, Itaru Tsukada, Norihiro Ueda, Naoaki Watanabe.
Application Number | 20110195999 13/047447 |
Document ID | / |
Family ID | 34425323 |
Filed Date | 2011-08-11 |
United States Patent
Application |
20110195999 |
Kind Code |
A1 |
NAKAMOTO; Kazutaka ; et
al. |
August 11, 2011 |
NOVEL ANTIFUNGAL AGENT CONTAINING HETEROCYCLIC COMPOUND
Abstract
The present invention provides an antifungal agent represented
by the formula: ##STR00001## wherein A.sup.1 represents a 3-pyridyl
group which may have a substituent, a quinolyl group which may have
a substituent, or the like; X.sup.1 represents a group represented
by the formula --NH--C(.dbd.O)--, a group represented by the
formula --C(.dbd.O)--NH--, or the like; E represents a furyl group,
a thienyl group, a pyrrolyl group, a phenyl group, a pyridyl group,
a tetrazolyl group, a thiazolyl group or a pyrazolyl group; with
the proviso that A.sup.1 may have 1 to 3 substituents, and E has
one or two substituents.
Inventors: |
NAKAMOTO; Kazutaka;
(Tsukuba-Shi, JP) ; Tsukada; Itaru; (Tsukuba-Shi,
JP) ; Tanaka; Keigo; (Tsukuba-Shi, JP) ;
Matsukura; Masayuki; (Tsukuba-Shi, JP) ; Haneda;
Toru; (Kamisu-shi, JP) ; Inoue; Satoshi;
(Tsukuba-Shi, JP) ; Ueda; Norihiro; (Tsukuba-Shi,
JP) ; Abe; Shinya; (Tsukuba-Shi, JP) ; Hata;
Katsura; (Tsukuba-Shi, JP) ; Watanabe; Naoaki;
(Tsukuba-Shi, JP) |
Family ID: |
34425323 |
Appl. No.: |
13/047447 |
Filed: |
March 14, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10573890 |
Mar 29, 2006 |
7932272 |
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PCT/JP2004/014063 |
Sep 27, 2004 |
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13047447 |
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Current U.S.
Class: |
514/338 ;
514/336; 514/342; 514/352; 546/122; 546/262; 546/269.7; 546/276.4;
546/280.4; 546/284.7; 546/310 |
Current CPC
Class: |
A61K 31/435 20130101;
A61K 31/443 20130101; A61K 31/433 20130101; A61K 31/428 20130101;
A61P 33/06 20180101; A61K 31/44 20130101; A61K 31/47 20130101; A61K
31/505 20130101; A61K 31/455 20130101; A61P 31/10 20180101; A61K
31/498 20130101; A61K 31/472 20130101; A61K 31/4365 20130101; A61K
31/517 20130101; C07D 213/82 20130101; A61K 31/423 20130101; A61K
31/4355 20130101; A61K 31/4965 20130101; A61K 31/404 20130101; C07D
409/12 20130101 |
Class at
Publication: |
514/338 ;
546/284.7; 546/262; 546/310; 546/276.4; 546/269.7; 546/280.4;
546/122; 514/336; 514/342; 514/352 |
International
Class: |
A61K 31/4375 20060101
A61K031/4375; C07D 405/12 20060101 C07D405/12; C07D 213/46 20060101
C07D213/46; C07D 213/78 20060101 C07D213/78; C07D 401/12 20060101
C07D401/12; C07D 417/12 20060101 C07D417/12; C07D 409/12 20060101
C07D409/12; C07D 471/04 20060101 C07D471/04; A61K 31/443 20060101
A61K031/443; A61K 31/4436 20060101 A61K031/4436; A61K 31/4439
20060101 A61K031/4439; A61K 31/444 20060101 A61K031/444; A61K
31/4427 20060101 A61K031/4427; A61K 31/44 20060101 A61K031/44; A61P
31/10 20060101 A61P031/10 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 30, 2003 |
JP |
2003-342273 |
Mar 10, 2004 |
JP |
2004-068186 |
Claims
1. A compound represented by the formula (I-a), or a salt or a
hydrate thereof: ##STR00716## wherein A.sup.1 represents a
3-pyridyl group; X.sup.1 represents a group represented by the
formula --NH--C(.dbd.Y.sup.1)-- or a group represented by the
formula --C(.dbd.Y.sup.1)--NH--, wherein Y.sup.1 represents an
oxygen atom, a sulfur atom or NR.sup.Y1, wherein R.sup.Y1
represents a C.sub.1-6 alkoxy group or a cyano group; and E
represents a furyl group, a pyrrolyl group, a pyridyl group, a
tetrazolyl group, a thiazolyl group, a pyrazolyl group or a phenyl
group; with the proviso that A.sup.1 optionally has 1 to 3
substituents selected from the following substituent groups a-1 and
a-2, and E has 1 or 2 substituents selected from the following
substituent groups a-1 and a-2; substituent group a-1: a halogen
atom, a hydroxyl group, a mercapto group, a cyano group, a carboxyl
group, an amino group, a carbamoyl group, a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-10 aryl group, a 5- to 10-membered
heterocyclic group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkylidene C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, a 5- to 10-membered heterocyclic C.sub.1-6
alkyl group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy
group, a C.sub.2-6 alkynyloxy group, a C.sub.3-8 cycloalkoxy group,
a C.sub.6-10 aryloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy
group, a C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to
10-membered heterocyclic C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkylthio
group, a C.sub.6-10 aryl C.sub.1-6 alkylthio group, a 5- to
10-membered heterocyclic C.sub.1-6 alkylthio group, a
mono-C.sub.1-6 alkylamino group, a mono-C.sub.2-6 alkenylamino
group, a mono-C.sub.2-6 alkynylamino group, a mono-C.sub.3-8
cycloalkylamino group, a mono-C.sub.6-10 arylamino group, a
mono-C.sub.3-8 cycloalkyl C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group, a mono-5- to
10-membered heterocyclic C.sub.1-6 alkylamino group, a di-C.sub.1-6
alkylamino group, a N--C.sub.2-6 alkenyl-N--C.sub.1-6 alkylamino
group, a N--C.sub.2-6 alkynyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.3-8 cycloalkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.3-8
cycloalkyl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N-5- to 10-membered heterocyclic C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group, a C.sub.1-6 alkylcarbonyl group, a C.sub.1-6
alkoxycarbonyl group, a C.sub.1-6 alkylsulfonyl group, a group
represented by the formula --C(.dbd.N--R.sup.a1)R.sup.a2 (wherein
R.sup.a1 represents a hydroxyl group or a C.sub.1-6 alkoxy group;
and R.sup.a2 represents a C.sub.1-6 alkyl group), a C.sub.6-10
aryloxy C.sub.1-6 alkyl group and a 5- to 10-membered heterocycle
oxy C.sub.1-6 alkyl group; substituent group a-2: a C.sub.1-6 alkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl group, a 5- to
10-membered heterocyclic group, a C.sub.3-8 cycloalkyl C.sub.1-6
alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, a 5- to
10-membered heterocyclic C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy
group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6 alkynyloxy group,
a C.sub.3-8 cycloalkoxy group, a C.sub.6-10 aryloxy group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a C.sub.6-10 aryl
C.sub.1-6 alkoxy group, a 5- to 10-membered heterocyclic C.sub.1-6
alkoxy group, a C.sub.1-6 alkylthio group, a C.sub.2-6 alkenylthio
group, a C.sub.2-6 alkynylthio group, a C.sub.3-8 cycloalkylthio
group, a C.sub.6-10 arylthio group, a C.sub.3-8 cycloalkyl
C.sub.1-6 alkylthio group, a C.sub.6-10 aryl C.sub.1-6 alkylthio
group, a 5- to 10-membered heterocyclic C.sub.1-6 alkylthio group,
a mono-C.sub.1-6 alkylamino group, a mono-C.sub.2-6 alkenylamino
group, a mono-C.sub.2-6 alkynylamino group, a mono-C.sub.3-8
cycloalkylamino group, a mono-C.sub.6-10 arylamino group, a
mono-C.sub.3-8 cycloalkyl C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group, a mono-5- to
10-membered heterocyclic C.sub.1-6 alkylamino group, a di-C.sub.1-6
alkylamino group, a N--C.sub.2-6 alkenyl-N--C.sub.1-6 alkylamino
group, a N--C.sub.2-6 alkynyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.3-8 cycloalkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.3-8
cycloalkyl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N-5- to 10-membered heterocyclic C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group, a C.sub.6-10 aryloxy-C.sub.1-6 alkyl group and a
5- to 10-membered heterocycle oxy C.sub.1-6 alkyl group; with the
proviso that each group described in the substituent group a-2 has
1 to 3 substituents selected from the following substituent group
b; substituent group b: a halogen atom, a hydroxyl group, a
mercapto group, a cyano group, a carboxyl group, an amino group, a
carbamoyl group, a nitro group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl group, a 5- to
10-membered heterocyclic group, a C.sub.1-6 alkoxy group, a
C.sub.6-10 aryloxy group, a 5- to 10-membered heterocycle oxy
group, a C.sub.1-6 alkylcarbonyl group, a C.sub.1-6 alkoxycarbonyl
group, a C.sub.1-6 alkylsulfonyl group, a trifluoromethyl group, a
trifluoromethoxy group, a mono-C.sub.1-6 alkylamino group, a
di-C.sub.1-6 alkylamino group, a mono-C.sub.6-10 arylamino group
optionally having one amino group or aminosulfonyl group and a
N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group
optionally having one amino group; with the proviso that the
following (1)-(5) are excluded: (1) a compound in which E
represents a group represented by the formula: ##STR00717## wherein
R.sup.A1 represents a phenyl group having a halogen atom, a methoxy
group, an ethoxy group, a C.sub.1-6 alkoxycarbonyl group or a
carboxyl group, (2) a compound in which E represents a group
represented by the formula: ##STR00718## wherein R.sup.A2
represents a halogen atom or a methoxy group; R.sup.A3 represents a
C.sub.1-6 alkyl group having a carboxyl group, a C.sub.3-8
cycloalkyl group having a carboxyl group or a phenyl group having a
carboxyl group, (3) a compound in which A.sup.1 represents a group
represented by the formula: ##STR00719## wherein R.sup.A4
represents a hydrogen atom or a halogen atom; Ar represents a
phenyl group optionally having a substituent; and X.sup.1
represents a group represented by the formula --C(.dbd.O)--NH--,
(4) a compound in which A.sup.1 represents a group represented by
the formula: ##STR00720## wherein R.sup.A5 represents a hydrogen
atom, a C.sub.1-6 alkyl group or a trifluoromethyl group; R.sup.A6
represents a hydrogen atom or a trifluoromethyl group; Ar.sup.2
represents a phenyl group optionally having a substituent; and
X.sup.1 represents a group represented by the formula
--C(.dbd.O)--NH--, and (5) a compound in which A.sup.1 represents a
group represented by the formula: ##STR00721## wherein R.sup.A7
represents a hydrogen atom, a halogen atom or a C.sub.1-6 alkyl
group; Ar.sup.3 represents a phenyl group optionally having a
substituent; and X.sup.1 represents a group represented by the
formula --C(.dbd.O)--NH-- or a group represented by the formula
--NH--C(.dbd.O)--.
2. The compound according to claim 1, or the salt or the hydrate
thereof, wherein A.sup.1 represents the 3-pyridyl group having the
1 to 3 substituents selected from the substituent groups a-1 and
a-2.
3. The compound according to claim 1, or the salt or the hydrate
thereof, wherein A.sup.1 represents the 3-pyridyl group having 1 to
3 substituents selected from the following substituent groups c-1
and c-2; substituent group c-1: a halogen atom, an amino group, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl
group, a 5- to 10-membered heterocyclic group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl
group, a 5- to 10-membered heterocyclic C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6
alkynyloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a
C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkoxy group, a mono-C.sub.1-6 alkylamino
group, a mono-C.sub.2-6 alkenylamino group, a mono-C.sub.2-6
alkynylamino group, a mono-C.sub.3-8 cycloalkylamino group, a
mono-C.sub.6-10 arylamino group, a mono-C.sub.3-8 cycloalkyl
C.sub.1-6 alkylamino group, a mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group, a mono-5- to 10-membered heterocyclic C.sub.1-6
alkylamino group, a C.sub.1-6 alkylcarbonyl group and a group
represented by the formula --C(.dbd.N--OH)R.sup.a2, wherein
R.sup.a2 has the same meaning as defined above; substituent group
c-2: a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10
aryl group, a 5- to 10-membered heterocyclic group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl
group, a 5- to 10-membered heterocyclic C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6
alkynyloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group,
C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkoxy group, a mono-C.sub.1-6 alkylamino
group, a mono-C.sub.2-6 alkenylamino group, a mono-C.sub.2-6
alkynylamino group, a mono-C.sub.3-8 cycloalkylamino group, a
mono-C.sub.6-10 arylamino group, a mono-C.sub.3-8 cycloalkyl
C.sub.1-6 alkylamino group, a mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group and a mono-5- to 10-membered heterocyclic
C.sub.1-6 alkylamino group; with the proviso that each group
described in substituent group c-2 has 1 to 3 substituents selected
from the following substituent group d; substituent group d: a
halogen atom, a hydroxyl group, a carboxyl group, an amino group, a
carbamoyl group, a C.sub.1-6 alkoxy group, a mono-C.sub.1-6
alkylamino group, a di-C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 arylamino group optionally having one amino group
or aminosulfonyl group, a N--C.sub.6-10 aryl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group optionally having one amino
group, a cyano group, a C.sub.6-10 aryl group, a 5- to 10-membered
heterocyclic group and a C.sub.1-6 alkoxycarbonyl group.
4. The compound according to claim 3, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00722## wherein R.sup.1, R.sup.2 and R.sup.3 may be
the same as or different from each other and represent a
substituent selected from the substituent groups c-1 and c-2.
5. The compound according to claim 4, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00723## wherein R.sup.1 and R.sup.2 have the same
meanings as defined above, respectively; and R.sup.6 and R.sup.7
may be the same or different from each other and represent a
hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl
group or a group represented by the formula
--CHR.sup.8--(CH.sub.2).sub.n1--R.sup.9; wherein R.sup.8 represents
a hydrogen atom, a carboxyl group or a C.sub.1-6 alkoxycarbonyl
group; R.sup.9 represents a hydroxyl group, a carboxyl group, a
carbamoyl group, a C.sub.3-8 cycloalkyl group, a furyl group, a
thienyl group, a pyrrolyl group, a pyridyl group, a triazolyl
group, a tetrahydrofuryl group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkoxycarbonyl group, a mono-C.sub.1-6 alkylamino group,
a di-C.sub.1-6 alkylamino group, a phenyl group optionally having 1
to 3 substituents selected from the substituent group d defined
above, a mono-C.sub.6-10 arylamino group optionally having one
amino group or an N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group optionally having one amino group; and n1
represents an integer from 0 to 3.
6. The compound according to claim 3, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00724## wherein R.sup.11 represents a hydrogen atom
or a group represented by the formula
--CHR.sup.12--(CH.sub.2).sub.n2--R.sup.13; wherein R.sup.12
represents a hydrogen atom or a carboxyl group; R.sup.13 represents
a carboxyl group or a phenyl group optionally having 1 to 3
substituents selected from the substituent group d; and n2
represents an integer from 0 to 3.
7. The compound according to claim 1, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00725## wherein R.sup.14 represents a C.sub.1-6 alkyl
group having one C.sub.1-6 alkoxy group.
8. The compound according to claim 1, or the salt or the hydrate
thereof, wherein A.sup.1 represents the 3-pyridyl group having 1 to
3 substituents selected from the following substituent groups c'-1
and c'-2; substituent group c'-1: an amino group, a C.sub.1-6 alkyl
group and a mono-C.sub.1-6 alkylamino group; and substituent group
c'-2: a C.sub.1-6 alkyl group and a mono-C.sub.1-6 alkylamino
group; with the proviso that each group described in substituent
group c'-2 has 1 to 3 substituents selected from the following
substituent group d'; substituent group d': a halogen atom, a
hydroxyl group, a cyano group, a carboxyl group and a C.sub.1-6
alkoxy group.
9. The compound according to claim 1, or the salt or the hydrate
thereof, wherein X.sup.1 represents a group represented by the
formula --C(.dbd.O)--NH-- or a group represented by the formula
--NH--C(.dbd.O)--.
10. The compound according to claim 1, or the salt or the hydrate
thereof, wherein X.sup.1 represents a group represented by the
formula --C(.dbd.O)--NH--.
11. The compound according to claim 1, or the salt or the hydrate
thereof, wherein E represents a furyl group, a pyrrolyl group,
pyridyl group or a phenyl group; with the proviso that E has 1 or 2
substituents selected from the substituent groups a-1 and a-2.
12. The compound according to claim 1, or the salt or the hydrate
thereof, wherein E represents a furyl group, a pyrrolyl group,
pyridyl group or a phenyl group; with the proviso that E has 1 or 2
substituents selected from the following substituent groups e-1 and
e-2; substituent group e-1: a halogen atom, a hydroxyl group, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.6-10 aryl group, a C.sub.3-8 cycloalkyl
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkylidene C.sub.1-6 alkyl
group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, 5- to 10-membered
heterocyclic C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a
C.sub.2-6 alkenyloxy group, a C.sub.2-6 alkynyloxy group, a
C.sub.6-10 aryloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy
group, a C.sub.6-10 aryl C.sub.1-6 alkoxy C.sub.1-6 alkylthio
group, a mono-C.sub.6-10 arylamino group, a mono-C.sub.6-10 aryl
C.sub.1-6 alkylamino group, a N--C.sub.6-10 aryl-N--C.sub.1-6
alkylamino group, a N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group, a C.sub.6-10 aryloxy C.sub.1-6 alkyl group and a
5- to 10-membered heterocycle oxy C.sub.1-6 alkyl group;
substituent group e-2: a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, a 5- to 10-membered heterocyclic C.sub.1-6
alkyl group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy
group, a C.sub.2-6 alkynyloxy group, a C.sub.6-10 aryloxy group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a C.sub.6-10 aryl
C.sub.1-6 alkoxy group, 5- to 10-membered heterocycle-C.sub.1-6
alkoxy group, a C.sub.6-10 arylthio group, a C.sub.6-10 aryl
C.sub.1-6 alkylthio group, a mono-C.sub.6-10 arylamino group, a
mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group, a N--C.sub.6-10
aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.6-10 aryl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group, a C.sub.6-10 aryloxy C.sub.1-6
alkyl group and a 5- to 10-membered heterocycle oxy C.sub.1-6 alkyl
group; with the proviso that each group described in substituent
group e-2 has 1 to 3 substituents selected from the following
substituent group f; substituent group f: a halogen atom, a
hydroxyl group, a cyano group, an amino group, a nitro group, a
C.sub.3-8 cycloalkyl group, a C.sub.1-6 alkoxy group, a C.sub.6-10
aryloxy group, a 5- to 10-membered heterocycle oxy group, a
C.sub.1-6 alkylcarbonyl group, a C.sub.1-6 alkoxycarbonyl group, a
C.sub.1-6 alkylsulfonyl group, a mono-C.sub.6-10 arylamino group, a
trifluoromethyl group, a trifluoromethoxy group and a C.sub.1-6
alkyl group.
13. The compound according to claim 1, or the salt of the hydrate
thereof, wherein E represents a furyl group, a pyrrolyl group,
pyridyl group or a phenyl group; with the proviso that E has one
substituent selected from the following substituent groups g-1 and
g-2; substituent group g-1: a C.sub.3-8 cycloalkyl C.sub.1-6 alkyl
group, a phenyl C.sub.1-6 alkyl group, a furyl C.sub.1-6 alkyl
group, a thienyl C.sub.1-6 alkyl group, a benzofuryl C.sub.1-6
alkyl group, a benzothienyl C.sub.1-6 alkyl group, a C.sub.1-6
alkoxy group, a phenoxy group, a C.sub.3-8 cycloalkyl C.sub.1-6
alkoxy group, a phenyl C.sub.1-6 alkoxy group, a furyl C.sub.1-6
alkoxy group, a thienyl C.sub.1-6 alkoxy group, a pyridyl C.sub.1-6
alkoxy group, a phenoxy C.sub.1-6 alkyl group and a pyridyloxy
C.sub.1-6 alkyl group; substituent group g-2: a C.sub.3-8
cycloalkyl C.sub.1-6 alkyl group, a phenyl C.sub.1-6 alkyl group, a
furyl C.sub.1-6 alkyl group, a thienyl C.sub.1-6 alkyl group, a
benzofuryl C.sub.1-6 alkyl group, a benzothienyl C.sub.1-6 alkyl
group, a C.sub.1-6 alkoxy group, a phenoxy group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkoxy group, a phenyl C.sub.1-6 alkoxy group,
a furyl C.sub.1-6 alkoxy group, a thienyl C.sub.1-6 alkoxy group, a
pyridyl C.sub.1-6 alkoxy group, a phenoxy C.sub.1-6 alkyl group and
a pyridyloxy C.sub.1-6 alkyl group; with the proviso that each
group described in substituent group g-2 has 1 to 3 substituents
selected from the following substituent group h; substituent group
h: a halogen atom, a hydroxyl group, a cyano group and a C.sub.1-6
alkyl group.
14. The compound according to claim 13, or the salt or the hydrate
thereof, wherein E represents a 2-furyl group, a 3-pyrrolyl group,
a 2-pyridyl group, a 3-pyridyl group or a phenyl group; with the
proviso that E has one substituent selected from the substituent
groups g-1 and g-2.
15. The compound according to claim 4, or the salt or the hydrate
thereof, wherein X.sup.1 represents a group represented by the
formula --C(.dbd.O)--NH--, A.sup.1 represents a group represented
by the formula: ##STR00726## wherein R.sup.1, R.sup.2 and R.sup.3
are the same as or different from each other and represent a
substituent selected from the substituent groups c-1 and c-2; and E
represents a 2-furyl group, a 3-pyrrolyl group, a 2-pyridyl group,
a 3-pyridyl group or a phenyl group; with the proviso that E has
one substituent selected from the following substituent groups g-1
and g-2; substituent group g-1: a C.sub.3-8 cycloalkyl C.sub.1-6
alkyl group, a phenyl C.sub.1-6 alkyl group, a furyl C.sub.1-6
alkyl group, a thienyl C.sub.1-6 alkyl group, a benzofuryl
C.sub.1-6 alkyl group, a benzothienyl C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a phenoxy group, a C.sub.3-8 cycloalkyl
C.sub.1-6 alkoxy group, a phenyl C.sub.1-6 alkoxy group, a furyl
C.sub.1-6 alkoxy group, a thienyl C.sub.1-6 alkoxy group, a pyridyl
C.sub.1-6 alkoxy group, a phenoxy C.sub.1-6 alkyl group and a
pyridyloxy C.sub.1-6 alkyl group; substituent group g-2: a
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a phenyl C.sub.1-6
alkyl group, a furyl C.sub.1-6 alkyl group, a thienyl C.sub.1-6
alkyl group, a benzofuryl C.sub.1-6 alkyl group, a benzothienyl
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a phenoxy group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a phenyl C.sub.1-6
alkoxy group, a furyl C.sub.1-6 alkoxy group, a thienyl C.sub.1-6
alkoxy group, a pyridyl C.sub.1-6 alkoxy group, a phenoxy C.sub.1-6
alkyl group and a pyridyloxy C.sub.1-6 alkyl group; with the
proviso that each group described in substituent group g-2 has 1 to
3 substituents selected from the following substituent group h;
substituent group h: a halogen atom, a hydroxyl group, a cyano
group and a C.sub.1-6 alkyl group.
16. The compound according to claim 15, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00727## wherein R.sup.1 and R.sup.2 have the same
meanings as defined above, respectively; and R.sup.6 and R.sup.7
are the same or different from each other and represent a hydrogen
atom, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group or a
group represented by the formula
--CHR.sup.8--(CH.sub.2).sub.n1--R.sup.9; wherein R.sup.8 represents
a hydrogen atom, a carboxyl group or a C.sub.1-6 alkoxycarbonyl
group; R.sup.9 represents a hydroxyl group, a carboxyl group, a
carbamoyl group, a C.sub.3-8 cycloalkyl group, a furyl group, a
thienyl group, a pyrrolyl group, a pyridyl group, a triazolyl
group, a tetrahydrofuryl group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkoxycarbonyl group, a mono-C.sub.1-6 alkylamino group,
a di-C.sub.1-6 alkylamino group, a phenyl group optionally having 1
to 3 substituents selected from the substituent group d defined
above, a mono-C.sub.6-10 arylamino group optionally having one
amino group or an N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group optionally having one amino group; and n1
represents an integer from 0 to 3.
17. The compound according to claim 15, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00728## wherein R.sup.11 represents a hydrogen atom
or a group represented by the formula
--CHR.sup.12--(CH.sub.2).sub.n2--R.sup.13; wherein R.sup.12
represents a hydrogen atom or a carboxyl group; R.sup.13 represents
a carboxyl group or a phenyl group optionally having 1 to 3
substituents selected from the substituent group d defined above;
and n2 represents an integer from 0 to 3.
18. The compound according to claim 15, or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula: ##STR00729## wherein R.sup.14 represents a C.sub.1-6 alkyl
group having one C.sub.1-6 alkoxy group.
19. A pharmaceutical composition comprising: the compound according
to claim 1, or the salt or the hydrate thereof; and a
pharmaceutically acceptable carrier.
20. An antifungal composition comprising: the compound according to
claim 1, or the salt or the hydrate thereof as an active
ingredient; and a pharmaceutically acceptable carrier.
21. A method for the treatment of fungal infection comprising
administering a pharmacologically effective amount of the compound
according to claim 1, or the salt or the hydrate thereof to a
patient in need thereof.
22. A method for the treatment of fungal infection comprising
administering the pharmaceutical composition according to claim 19,
or the salt or the hydrate thereof to a patient in need
thereof.
23. A method for the treatment of fungal infection comprising
administering a pharmacologically effective amount of the
antifungal composition according to claim 20 to a patient in need
thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a 37 CFR .sctn.1.53(b) divisional
of U.S. application Ser. No. 10/573,890 filed Mar. 29, 2006, which
claims priority on PCT International Application No.
PCT/JP2004/014063, which in turn claims priority on Japanese Patent
Application Nos. 2003-342273 filed Sep. 30, 2003, and 2004-068186
filed Mar. 10, 2004. The entire contents of each of these
applications is hereby incorporated by reference.
TECHNICAL FIELD
[0002] The present invention relates to a novel antifungal agent
containing a heterocyclic compound.
BACKGROUND ART
[0003] In recent years, managements of opportunistic infections
have become more and more significant more than ever because of an
increase in the number of elderly people and immunocompromised
patients as a result of advanced chemotherapies or the like. As
demonstrated by the fact that opportunistic infections are
occurring one after another by different weakly avirulent bacteria,
it is shown that the problem of infectious disease will not ends as
long as there are underlying diseases that diminish the immune
functions of patients. Consequently, new strategies for infectious
diseases control, including the problem of resistant bacteria, will
be one of the important issues in the soon-to-come aged
society.
[0004] In the field of antifungal agents, heretofore, for instance,
amphotericine B which is based on a polyene skeleton, fluconazole,
itraconazole and voriconazole which are based on an azole skeleton,
or the like, have been developed for the treatment of deep seated
mycoses. Among pre-existing drugs already available commercially
are many agents having similar mechanism of action, and currently,
the appearance of azole-resistant fungi or the like has been
problems.
[0005] In recent years, as a 1,3-.beta.-glucan synthetase inhibitor
with a novel mechanism, naturally occurring compound-derived cyclic
hexapeptides caspofungin and micafungin or the like, have been
developed; however, from the fact that these agents only exist in
injectable form, they are not yet sufficient practically as
antifungal agents.
[0006] Since there have been the situations that the pre-existing
antifungal agents are insufficient for treatment of the deep seated
mycoses, there is a demand and need for development of agents which
are based on a novel mechanism and are of high safety.
[0007] As the prior art related to antifungal agents based on such
a novel mechanism, Patent Document 1 describes heterocyclic
compounds which demonstrates effects against the onset, progress,
and persistence of infections by inhibiting the expression of cell
wall proteins, inhibiting the cell wall assembly and also adhesion
onto cells, and preventing pathogens from showing pathogenicity,
with the process which transports GPI
(Glycosylphosphatidylinositol)-anchored proteins to the cell wall
being inhibited. However, groups of the compounds disclosed in
Patent Document 1 have 2-benzyl pyridine moieties as the common
structure, clearly differing structurally from compounds according
to the present invention. In addition, the groups of the compounds
disclosed in Patent Document 1 bear the problem that, although
these compounds demonstrate activities in vitro, they are easily
metabolized inside the body, or the like.
[0008] Meanwhile, there are Patent Documents 2 through 8 as the
prior art that disclose structurally most similar compounds to the
heterocyclic compound (1) according to the present invention.
Patent Document 2 discloses N-(4-pyridyl)carboxamide derivatives
having the effects as pesticides, in particular as insecticides,
acaricides and nematicides. Patent Documents 3 through 6 disclose
2-aryloxy nicotinamide derivatives having phosphodiesterase 4
(PDE4) inhibitory action. Patent Document 7 discloses
6-(arylamino)nicotinamide derivatives having cannabinoid receptor
modulation action and Patent Document 8 discloses
6-(aryloxy)nicotinamide derivatives having Na.sup.+/Ca.sup.2+
exchanger inhibitory action. However, Patent Documents 2 through 8
do not disclose the compounds according to the present invention.
In addition, Patent Documents 2 through 8 do not describe that the
compounds disclosed in these documents exhibit antifungal and
antimalarial actions for Candida, Aspergillus, Cryptococcus or the
like which are general fungal strains in human mycosis at all.
[0009] [Patent Document 1] International Publication No. WO
02/04626 pamphlet; [0010] [Patent Document 2] U.S. Pat. No.
5,852,042 Specification; [0011] [Patent Document 3] European Patent
Application No. 1229034 specification; [0012] [Patent Document 4]
International Publication No. WO 02/060875 pamphlet; [0013] [Patent
Document 5] International Publication No. WO 02/060896 pamphlet;
[0014] [Patent Document 6] International Publication No. WO
03/068232 pamphlet; [0015] [Patent Document 7] International
Publication No. WO 2004/029027 pamphlet; and [Patent Document 8]
International Publication No. WO 2004/000813 pamphlet.
DISCLOSURE OF THE INVENTION
[0016] It is an object of the present invention to 1) provide an
antifungal agent which has excellent antifungal action not found in
the antifungal agents in the prior art, and which is also excellent
in terms of property, safety and metabolic stability, and 2)
provide an excellent antimalarial agent.
[0017] In view of the aforementioned circumstances, the present
inventors have intensively studied to attain the above object. As a
result, the present inventions have succeeded in synthesizing novel
heterocycle-containing compounds represented by the following
formula (I):
##STR00002##
which has the chemical structural characteristics of a heterocyclic
group A and a heterocyclic group or a phenyl group E being bonded
through a linker X, and have discovered that these compounds have
excellent antifungal action, so as to arrive at the present
invention.
[0018] That is to say, the present invention provides:
[1]: an antifungal agent comprising a compound represented by the
formula (I), or a salt or a hydrate thereof:
##STR00003##
[0019] [wherein A represents a 5- to 10-membered heterocyclic group
containing at least one nitrogen atom;
[0020] X represents a group represented by the formula
--NH--C(.dbd.Y)--(CH.sub.2).sub.n--, a group represented by the
formula --C(.dbd.Y)--NH--(CH.sub.2).sub.n--, a group represented by
the formula --C(.dbd.Z)--(CH.sub.2).sub.n--, a group represented by
the formula --CH.sub.2--NH--(CH.sub.2).sub.n--, a group represented
by the formula --NH--CH.sub.2--(CH.sub.2).sub.n-- or a group
represented by the formula --Z--CH.sub.2--(CH.sub.2).sub.n--;
[0021] Y represents an oxygen atom, a sulfur atom or NR.sup.Y
(wherein R.sup.Y represents a C.sub.1-6 alkoxy group or a cyano
group);
[0022] Z represents an oxygen atom or a sulfur atom;
[0023] n represents an integer from 0 to 3;
[0024] E represents a furyl group, a thienyl group, a pyrrolyl
group, a pyridyl group, a tetrazolyl group, a thiazolyl group, a
pyrazolyl group or a phenyl group;
[0025] with the proviso that A may contain 1 to 3 substituents
selected from the following substituent groups a-1 and a-2, and
that E has one or two substituents selected from the following
substituent groups a-1 and a-2;
[0026] <Substituent Group a-1>
Substituent group a-1 represents the group consisting of: a halogen
atom, a hydroxyl group, a mercapto group, a cyano group, a carboxyl
group, an amino group, a carbamoyl group, a C.sub.1-6 alkyl group,
a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.3-8
cycloalkyl group, a C.sub.6-10 aryl group, a 5- to 10-membered
heterocyclic group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkylidene C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, a 5- to 10-membered heterocyclic C.sub.1-6
alkyl group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy
group, a C.sub.2-6 alkynyloxy group, a C.sub.3-8 cycloalkoxy group,
a C.sub.6-10 aryloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy
group, a C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to
10-membered heterocyclic C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a C.sub.2-6 alkenylthio group, a C.sub.2-6
alkynylthio group, a C.sub.3-8 cycloalkylthio group, a C.sub.6-10
arylthio group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkylthio group, a
C.sub.6-10 aryl C.sub.1-6 alkylthio group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkylthio group, a mono-C.sub.1-6 alkylamino
group, a mono-C.sub.2-6 alkenylamino group, a mono-C.sub.2-6
alkynylamino group, a mono-C.sub.3-8 cycloalkylamino group, a
mono-C.sub.6-10 arylamino group, a mono-C.sub.3-8 cycloalkyl
C.sub.1-6 alkylamino group, a mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group, a mono-5- to 10-membered heterocyclic C.sub.1-6
alkylamino group, a di-C.sub.1-6 alkylamino group, a N--C.sub.2-6
alkenyl-N--C.sub.1-6 alkylamino group, a N--C.sub.2-6
alkynyl-N--C.sub.1-6 alkylamino group, a N--C.sub.3-8
cycloalkyl-N--C.sub.1-6 alkylamino group, a N--C.sub.6-10
aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.3-8 cycloalkyl
C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a N--C.sub.6-10 aryl
C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a N-5- to
10-membered heterocyclic C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino
group, a C.sub.1-6 alkylcarbonyl group, a C.sub.1-6 alkoxycarbonyl
group, a C.sub.1-6 alkylsulfonyl group, a group represented by the
formula --C(.dbd.N--R.sup.a1)R.sup.a2 (wherein R.sup.a1 represents
a hydroxyl group or a C.sub.1-6 alkoxy group; Rae represents a
C.sub.1-6 alkyl group), a C.sub.6-10 aryloxy C.sub.1-6 alkyl group
and a 5- to 10-membered heterocycle oxy C.sub.1-6 alkyl group;
[0027] <Substituent Group a-2>
Substituent Group a-2 represents the group consisting of: a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl
group, a 5- to 10-membered heterocyclic group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl
group, a 5- to 10-membered heterocyclic C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6
alkynyloxy group, a C.sub.3-8 cycloalkoxy group, a C.sub.6-10
aryloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a
C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkoxy group, a C.sub.1-6 alkylthio group, a
C.sub.2-6 alkenylthio group, a C.sub.2-6 alkynylthio group, a
C.sub.3-8 cycloalkylthio group, a C.sub.6-10 arylthio group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkylthio group, a C.sub.6-10 aryl
C.sub.1-6 alkylthio group, a 5- to 10-membered heterocyclic
C.sub.1-6 alkylthio group, a mono-C.sub.1-6 alkylamino group, a
mono-C.sub.2-6 alkenylamino group, a mono-C.sub.2-6 alkynylamino
group, a mono-C.sub.3-8 cycloalkylamino group, a mono-C.sub.6-10
arylamino group, a mono-C.sub.3-8 cycloalkyl C.sub.1-6 alkylamino
group, a mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group, a mono-5-
to 10-membered heterocyclic C.sub.1-6 alkylamino group, a
di-C.sub.1-6 alkylamino group, a N--C.sub.2-6 alkenyl-N--C.sub.1-6
alkylamino group, a N--C.sub.2-6 alkynyl-N--C.sub.1-6 alkylamino
group, a N--C.sub.3-8 cycloalkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.3-8
cycloalkyl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a
N-5- to 10-membered heterocyclic C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group, a C.sub.6-10 aryloxy-C.sub.1-6 alkyl group and a
5- to 10-membered heterocycle oxy C.sub.1-6 alkyl group;
[0028] with the proviso that each group described in the
substituent group a-2 has 1 to 3 substituents selected from the
following substituent group b;
[0029] <Substituent Group b>
Substituent group b represents the group consisting of: a halogen
atom, a hydroxyl group, a mercapto group, a cyano group, a carboxyl
group, an amino group, a carbamoyl group, a nitro group, a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10
aryl group, a 5- to 10-membered heterocyclic group, a C.sub.1-6
alkoxy group, a C.sub.6-10 aryloxy group, a 5- to 10-membered
heterocycle oxy group, a C.sub.1-6 alkylcarbonyl group, a C.sub.1-6
alkoxycarbonyl group, a C.sub.1-6 alkylsulfonyl group, a
trifluoromethyl group, a trifluoromethoxy group, a mono-C.sub.1-6
alkylamino group, a di-C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 arylamino group which may have one amino group or
aminosulfonyl group and a N--C.sub.6-10 aryl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group which may have one amino
group]; [2]: the antifungal agent according to item [1], wherein X
represents a group represented by the formula
--NH--C(.dbd.Y)--CH.sub.2--, a group represented by the formula
--C(.dbd.Y)--NH--CH.sub.2--, a group represented by the formula
--CH.sub.2--NH-- or a group represented by the formula
--NH--CH.sub.2-- (wherein Y has the same meaning as defined above);
[3]: a compound represented by the formula (I-a), or a salt or a
hydrate thereof:
##STR00004##
[0030] [wherein A.sup.1 represents a 3-pyridyl group, a pyrazinyl
group, a pyrimidinyl group, a pyrazolyl group, a quinolyl group, an
isoquinolyl group, a naphthyldinyl group, a quinoxalinyl group, a
cinnolinyl group, a quinazolinyl group, an imidazopyridyl group, a
benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group,
an indolyl group, a pyrrolopyridyl group, a thienopyridyl group, a
furopyridyl group, a 2,3-dihydro-1H-pyrrolo[2,3-b]-pyridin-5-yl
group or a benzothiadiazolyl group;
[0031] X.sup.1 represents a group represented by the formula
--NH--C(.dbd.Y.sup.1)-- or a group represented by the formula
--C(.dbd.Y.sup.1)--NH--;
[0032] Y.sup.1 represents an oxygen atom, a sulfur atom or
NR.sup.Y1 (wherein R.sup.Y1 represents a C.sub.1-6 alkoxy group or
a cyano group);
[0033] E represents a furyl group, a thienyl group, a pyrrolyl
group, a pyridyl group, a tetrazolyl group, a thiazolyl group, a
pyrazolyl group or a phenyl group;
[0034] with the proviso that A.sup.1 may contain 1 to 3
substituents selected from the substituent groups a-1 and a-2 as
defined above, and that E has 1 or 2 substituents selected from the
substituent groups a-1 and a-2 defined above]
[with the proviso that (1) a compound in which E represents a group
represented by the formula:
##STR00005##
[0035] (wherein R.sup.A1 represents a phenyl group having a halogen
atom, a methoxy group, an ethoxy group, a C.sub.1-6 alkoxycarbonyl
group or a carboxyl group),
[0036] (2) a compound in which E represents a group represented by
the formula:
##STR00006##
(wherein R.sup.A2 represents a halogen atom or a methoxy group;
R.sup.A3 represents a C.sub.1-6 alkyl group having a carboxyl
group, a C.sub.3-8 cycloalkyl group having a carboxyl group or a
phenyl group having a carboxyl group),
[0037] (3) a compound in which A.sup.1 represents a group
represented by the formula:
##STR00007##
(wherein R.sup.A4 represents a hydrogen atom or a halogen atom; Ar
represents a phenyl group which may have a substituent) and X.sup.1
represents a group represented by the formula
--C(.dbd.O)--NH--,
[0038] (4) a compound in which A.sup.1 represents a group
represented by the formula:
##STR00008##
(wherein R.sup.A5 represents a hydrogen atom, a C.sub.1-6 alkyl
group or a trifluoromethyl group; R.sup.A6 represents a hydrogen
atom or a trifluoromethyl group; Ar.sup.2 represents a phenyl group
that may have a substituent) and X.sup.1 represents a group
represented by the formula --C(.dbd.O)--NH-- and
[0039] (5) a compound in which A.sup.1 represents a group
represented by the formula:
##STR00009##
(wherein R.sup.A7 represents a hydrogen atom, a halogen atom or a
C.sub.1-6 alkyl group; Ar.sup.3 represents a phenyl group which may
have a substituent) and X.sup.1 represents a group represented by
the formula --C(.dbd.O)--NH-- or a group represented by the formula
--NH--C(.dbd.O)--are excluded]; [4]: the compound according to item
[3], or the salt or the hydrate thereof, wherein A.sup.1 represents
a 3-pyridyl group, a quinolyl group, a naphthyldinyl group, a
quinoxalinyl group, an imidazopyridyl group, a benzothiazolyl
group, a pyrrolopyridyl group, a thienopyridyl group or a
furopyridyl group (with the proviso that A.sup.1 may have 1 to 3
substituents selected from the substituent groups a-1 and a-2
defined above); [5]: the compound according to item [3], or the
salt or the hydrate thereof, wherein A.sup.1 represents a 3-pyridyl
group (with the proviso that A.sup.1 may have 1 to 3 substituents
selected from the following substituent groups c-1 and c-2);
[0040] <Substituent Group c-1>
Substituent group c-1 represents the group consisting of: a halogen
atom, an amino group, a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-10 aryl group, a 5- to 10-membered heterocyclic group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, a 5- to 10-membered heterocyclic C.sub.1-6
alkyl group, a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy
group, a C.sub.2-6 alkynyloxy group, a C.sub.3-8 cycloalkyl
C.sub.1-6 alkoxy group, a C.sub.6-10 aryl C.sub.1-6 alkoxy group, a
5- to 10-membered heterocyclic C.sub.1-6 alkoxy group, a
mono-C.sub.1-6 alkylamino group, a mono-C.sub.2-6 alkenylamino
group, a mono-C.sub.2-6 alkynylamino group, a mono-C.sub.3-8
cycloalkylamino group, a mono-C.sub.6-10 arylamino group, a
mono-C.sub.3-8 cycloalkyl C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group, a mono-5- to
10-membered heterocyclic C.sub.1-6 alkylamino group, a C.sub.1-6
alkylcarbonyl group and a group represented by the formula
--C(.dbd.N--OH)R.sup.a2 (wherein R.sup.a2 has the same meaning as
defined above);
[0041] <Substituent Group c-2>
Substituent group c-2 represents the group consisting of: a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl
group, a 5- to 10-membered heterocyclic group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl
group, a 5- to 10-membered heterocyclic C.sub.1-6 alkyl group, a
C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6
alkynyloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group,
C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkoxy group, a mono-C.sub.1-6 alkylamino
group, a mono-C.sub.2-6 alkenylamino group, a mono-C.sub.2-6
alkynylamino group, a mono-C.sub.3-8 cycloalkylamino group, a
mono-C.sub.6-10 arylamino group, a mono-C.sub.3-8 cycloalkyl
C.sub.1-6 alkylamino group, a mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group and a mono-5- to 10-membered heterocyclic
C.sub.1-6 alkylamino group;
[0042] with the proviso that each group described in substituent
group c-2 has 1 to 3 substituents selected from the following
substituent group d;
[0043] <Substituent Group d>
Substituent group d represents the group consisting of: a halogen
atom, a hydroxyl group, a carboxyl group, an amino group, a
carbamoyl group, a C.sub.1-6 alkoxy group, a mono-C.sub.1-6
alkylamino group, a di-C.sub.1-6 alkylamino group, a
mono-C.sub.6-10 arylamino group that may have one amino group or
aminosulfonyl group, a N--C.sub.6-10 aryl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group which may have one amino group,
a cyano group, a C.sub.6-10 aryl group, a 5- to 10-membered
heterocyclic group and a C.sub.1-6 alkoxycarbonyl group. [6]: the
compound according to item [3], or the salt or the hydrate thereof,
wherein A.sup.1 represents a group represented by the formula:
##STR00010##
[wherein R.sup.1, R.sup.2 and R.sup.3 may be the same as or
different from each other and represent a substituent selected from
the substituent groups c-1 and c-2 defined above]; [7]: the
compound according to item [3], or the salt or the hydrate thereof,
wherein A.sup.1 represents a group represented by the formula:
##STR00011##
[wherein R.sup.1 and R.sup.2 have the same meanings as defined
above, respectively; R.sup.6 and R.sup.7 may be the same or
different from each other and represent a hydrogen atom, a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group or a group
represented by the formula --CHR.sup.8--(CH.sub.2).sub.n1--R.sup.9
(wherein R.sup.8 represents a hydrogen atom, a carboxyl group or a
C.sub.1-6 alkoxycarbonyl group; R.sup.9 represents a hydroxyl
group, a carboxyl group, a carbamoyl group, a C.sub.3-8 cycloalkyl
group, a furyl group, a thienyl group, a pyrrolyl group, a pyridyl
group, a triazolyl group, a tetrahydrofuryl group, a C.sub.1-6
alkoxy group, a C.sub.1-6 alkoxycarbonyl group, a mono-C.sub.1-6
alkylamino group, a di-C.sub.1-6 alkylamino group, a phenyl group
which may have 1 to 3 substituents selected from the substituent
group d defined above, a mono-C.sub.6-10 arylamino group which may
have one amino group or an N--C.sub.6-10 aryl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group which may have one amino group;
n1 represents an integer from 0 to 3)]; [8]: the compound according
to item [3], or the salt or the hydrate thereof, wherein A.sup.1
represents a group represented by the formula:
##STR00012##
(wherein R.sup.11 represents a hydrogen atom or a group represented
by the formula --CHR.sup.12--(CH.sub.2).sub.n2--R.sup.13 (wherein
R.sup.12 represents a hydrogen atom or a carboxyl group; R.sup.13
represents a carboxyl group or a phenyl group which may have 1 to 3
substituents selected from the substituent group d defined above;
n2 represents an integer from 0 to 3)); [9]: the compound according
to item [3], or the salt or the hydrate thereof, wherein A.sup.1
represents a group represented by the formula:
##STR00013##
(wherein R.sup.14 represents a C.sub.1-6 alkyl group having one
C.sub.1-6 alkoxy group); [10]: the compound according to item [3],
or the salt or the hydrate thereof, wherein A.sup.1 represents a
6-quinolyl group, a [1,5]naphthylidin-2-yl group, a 6-quinoxalinyl
group, an imidazo[1,2-a]pyridin-6-yl group, a benzothiazol-6-yl
group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a
pyrrolo[3,2-b]pyridin-1-yl group, a thieno[2,3-b]pyridin-5-yl
group, a thieno[3,2-b]pyridin-6-yl group or a
furo[3,2-b]pyridin-6-yl group (with the proviso that A.sup.1 may
have 1 to 3 substituents selected from the substituent groups c-1
and c-2 defined above); [11]: the compound according to item [3],
or the salt or the hydrate thereof, wherein A.sup.1 represents a
6-quinolyl group, a [1,5]naphthylidin-2-yl group, a 6-quinoxalinyl
group, an imidazo[1,2-a]pyridin-6-yl group, a benzothiazol-6-yl
group, a pyrrolo[3,2-b]pyridin-1-yl group, a
1H-pyrrolo[2,3-b]pyridin-5-yl group which may have one amino group,
a thieno[2,3-b]pyridin-5-yl group which may have one amino group, a
thieno[3,2-b]pyridin-6-yl group which may have one amino group or
furo[3,2-b]pyridin-6-yl group which may have one amino group. [12]:
the compound according to item [3], or the salt or the hydrate
thereof, wherein A.sup.1 represents a 6-quinolyl group; [13]: the
compound according to item [3], or the salt or the hydrate thereof,
wherein A.sup.1 represents a [1,5]naphthylidin-2-yl group; [14]:
the compound according to item [3], or the salt or the hydrate
thereof, wherein A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl
group; [15]: the compound according to item [3], or the salt or the
hydrate thereof, wherein A.sup.1 represents a benzothiazol-6-yl
group; [16]: the compound according to item [3], or the salt or the
hydrate thereof, wherein A.sup.1 represents a 3-pyridyl group, a
pyrazinyl group, a pyrimidinyl group, a quinolyl group, an
isoquinolyl group, a naphthyldinyl group, a quinoxalinyl group, a
cinnolinyl group, a quinazolinyl group, an imidazopyridyl group, a
benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group,
an indolyl group, a pyrrolopyridyl group, a thienopyridyl group, a
furopyridyl group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl
group or a benzothiadiazolyl group (with the proviso that A.sup.1
may have 1 to 3 substituents selected from the substituent groups
a-1 and a-2 defined above); [17]: the compound according to item
[3], or the salt or the hydrate thereof, wherein A.sup.1 represents
a 3-pyridyl group, a pyrazinyl group, a pyrimidinyl group, a
quinolyl group, an isoquinolyl group, a naphthyldinyl group, a
quinoxalinyl group, a cinnolinyl group, a quinazolinyl group, an
imidazopyridyl group, a benzothiazolyl group, a benzoxazolyl group,
a benzimidazolyl group, an indolyl group, a pyrrolopyridyl group, a
thienopyridyl group, a furopyridyl group, a
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group or a
benzothiadiazolyl group (with the proviso that A.sup.1 may have 1
to 3 substituents selected from the substituent groups c-1 and c-2
defined above); [18]: the compound according to item [3], or the
salt or the hydrate thereof, wherein A.sup.1 represents a 3-pyridyl
group, a pyrazinyl group, a pyrimidinyl group, a quinolyl group, an
isoquinolyl group, a naphthyldinyl group, a quinoxalinyl group, a
cinnolinyl group, a quinazolinyl group, an imidazopyridyl group, a
benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group,
an indolyl group, a pyrrolopyridyl group, a thienopyridyl group, a
furopyridyl group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl
group or a benzothiadiazolyl group (with the proviso that A.sup.1
may have 1 to 3 substituents selected from the following
substituent groups c'-1 and c'-2);
[0044] <Substituent Group c'-1>
Substituent group c'-1 represents the group consisting of: an amino
group, a C.sub.1-6 alkyl group and a mono-C.sub.1-6 alkylamino
group; and
[0045] <Substituent Group c'-2>
Substituent group c'-2 represents the group consisting of: a
C.sub.1-6 alkyl group and a mono-C.sub.1-6 alkylamino group;
[0046] with the proviso that each group described in substituent
group c'-2 has 1 to 3 substituents selected from the following
substituent group d';
[0047] <Substituent Group d'>
Substituent group d' represents the group consisting of: a halogen
atom, a hydroxyl group, a cyano group, a carboxyl group and a
C.sub.1-6 alkoxy group. [19]: the compound according to any one of
items [3] to [18], or the salt or the hydrate thereof, wherein
X.sup.1 represents a group represented by the formula
--C(.dbd.O)--NH-- or a group represented by the formula
--NH--C(.dbd.O)--; [20]: the compound according to any one of items
[3] to [18], or the salt or the hydrate thereof, wherein X.sup.1
represents a group represented by the formula --C(.dbd.O)--NH--;
[21]: the compound according to any one of items [3] to [20], or
the salt or the hydrate thereof, wherein E represents a furyl
group, a thienyl group, a pyrrolyl group, a phenyl group or pyridyl
group (with the proviso that E has 1 or 2 substituents selected
from the substituent groups a-1 and a-2 defined above); [22]: the
compound according to any one of items [3] to [20], or the salt or
the hydrate thereof, wherein E represents a furyl group, a thienyl
group, a pyrrolyl group, a phenyl group or pyridyl group (with the
proviso that E has 1 or 2 substituents selected from the following
substituent groups e-1 and e-2);
[0048] <Substituent Group e-1>
Substituent group e-1 represents the group consisting of: a halogen
atom, a hydroxyl group, a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group,
a C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkylidene C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6
alkyl group, 5- to 10-membered heterocyclic C.sub.1-6 alkyl group,
a C.sub.1-6 alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6
alkynyloxy group, a C.sub.6-10 aryloxy group, a C.sub.3-8
cycloalkyl C.sub.1-6 alkoxy group, a C.sub.6-10 arylthio group, a
C.sub.6-10 aryl C.sub.1-6 alkoxy group, a 5- to 10-membered
heterocyclic C.sub.1-6 alkoxy group, a C.sub.6-10 arylthio group, a
C.sub.6-10 aryl C.sub.1-6 alkylthio group, a mono-C.sub.6-10
arylamino group, a mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group,
a N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino group, a N--C.sub.6-10
aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group, a N--C.sub.6-10
aryl N--C.sub.1-6 alkyl group and a 5- to 10-membered heterocycle
oxy C.sub.1-6 alkyl group;
[0049] <Substituent Group e-2>
Substituent group e-2 represents the group consisting of: a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.6-10 aryl group, a C.sub.3-8 cycloalkyl
C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, a
5- to 10-membered heterocyclic C.sub.1-6 alkyl group, a C.sub.1-6
alkoxy group, a C.sub.2-6 alkenyloxy group, a C.sub.2-6 alkynyloxy
group, a C.sub.6-10 aryloxy group, a C.sub.3-8 cycloalkyl C.sub.1-6
alkoxy group, a C.sub.6-10 aryl C.sub.1-6 alkoxy group, 5- to
10-membered heterocycle-C.sub.1-6 alkoxy group, a C.sub.6-10
arylthio group, a C.sub.6-10 aryl C.sub.1-6 alkylthio group, a
mono-C.sub.6-10 arylamino group, a mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group, a N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino
group, a N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino
group, a C.sub.6-10 aryloxy C.sub.1-6 alkyl group and a 5- to
10-membered heterocycle oxy C.sub.1-6 alkyl group;
[0050] with the proviso that each group described in substituent
group e-2 has 1 to 3 substituents selected from the following
substituent group f;
[0051] <Substituent Group f>
Substituent group f represents the group consisting of: a halogen
atom, a hydroxyl group, a cyano group, an amino group, a nitro
group, a C.sub.3-8 cycloalkyl group, a C.sub.1-6 alkoxy group, a
C.sub.6-10 aryloxy group, a 5- to 10-membered heterocycle oxy
group, a C.sub.1-6 alkylcarbonyl group, a C.sub.1-6 alkoxycarbonyl
group, a C.sub.1-6 alkylsulfonyl group, a mono-C.sub.6-10 arylamino
group, a trifluoromethyl group, a trifluoromethoxy group and a
C.sub.1-6 alkyl group; [23]: the compound according to any one of
items [3] to [20], or the salt or the hydrate thereof, wherein E
represents a furyl group, a thienyl group, a pyrrolyl group, a
phenyl group or a pyridyl group (with the proviso that E has one
substituent selected from the following substituent groups g-1 and
g-2);
[0052] <Substituent Group g-1>
Substituent group g-1 represents the group consisting of: a
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a phenyl C.sub.1-6
alkyl group, a furyl C.sub.1-6 alkyl group, a thienyl C.sub.1-6
alkyl group, a benzofuryl C.sub.1-6 alkyl group, a benzothienyl
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a phenoxy group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a phenyl C.sub.1-6
alkoxy group, a furyl C.sub.1-6 alkoxy group, a thienyl C.sub.1-6
alkoxy group, a pyridyl C.sub.1-6 alkoxy group, a phenoxy C.sub.1-6
alkyl group and a pyridyloxy C.sub.1-6 alkyl group; <Substituent
Group g-2> Substituent group g-2 represents the group consisting
of: a C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a phenyl
C.sub.1-6 alkyl group, a furyl C.sub.1-6 alkyl group, a thienyl
C.sub.1-6 alkyl group, a benzofuryl C.sub.1-6 alkyl group, a
benzothienyl C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a
phenoxy group, a C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group, a
phenyl C.sub.1-6 alkoxy group, a furyl C.sub.1-6 alkoxy group, a
thienyl C.sub.1-6 alkoxy group, a pyridyl C.sub.1-6 alkoxy group, a
phenoxy C.sub.1-6 alkyl group and a pyridyloxy C.sub.1-6 alkyl
group;
[0053] with the proviso that each group described in substituent
group g-2 has 1 to 3 substituents selected from the following
substituent group h;
[0054] <Substituent Group h>
Substituent group h represents the group consisting of: a halogen
atom, a hydroxyl group, a cyano group and a C.sub.1-6 alkyl group;
[24]: the compound according to any one of items [3] to [20], or
the salt or the hydrate thereof, wherein E represents a 2-furyl
group, a 2-thienyl group, a 3-pyrrolyl group, a phenyl group, a
2-pyridyl group or 3-pyridyl group (with the proviso that E has one
substituent selected from the substituent groups g-1 and g-2
defined above); [25]: the compound according to item [3], or the
salt or the hydrate thereof, wherein X.sup.1 represents a group
represented by the formula --C(.dbd.O)--NH--, and A.sup.1
represents a group represented by the formula:
##STR00014##
(wherein R.sup.1, R.sup.2 and R.sup.3 have the same meanings as
defined above, respectively), and E represents a 2-furyl group, a
2-thienyl group, a 3-pyrrolyl group, a phenyl group, a 2-pyridyl
group or a 3-pyridyl group (with the proviso that E has one
substituent selected from the substituent group g-1 or g-2 defined
above). [26]: the compound according to item [25], or the salt or
the hydrate thereof, wherein A.sup.1 represents a group represented
by the formula:
##STR00015##
(wherein R.sup.1, R.sup.2, R.sup.6 and R.sup.7 have the same
meanings as defined above, respectively); [27]: the compound
according to item [25], or the salt or the hydrate thereof, wherein
A.sup.1 represents a group represented by the formula:
##STR00016##
(wherein R.sup.11 has the same meaning as defined above); [28]: the
compound according to item [25], or the salt or the hydrate
thereof, wherein A.sup.1 represents a group represented by the
formula:
##STR00017##
(wherein R.sup.14 has the same meaning as defined above); [29]: the
compound according to item [3], or the salt or the hydrate thereof,
wherein X.sup.1 represents a group represented by the formula
--C(.dbd.O)--NH--, A.sup.1 represents a 6-quinolyl group, a
[1,5]naphthylidin-2-yl group, a 6-quinoxalinyl group, an
imidazo[1,2-a]pyridin-6-yl group, a benzothiazol-6-yl group, a
pyrrolo[3,2-b]pyridin-1-yl group, a1H-pyrrolo[2,3-b]pyridin-5-yl
group which may have one amino group, a thieno[2,3-b]pyridin-5-yl
group which may have one amino group, a thieno[3,2-b]pyridin-6-yl
group which may have one amino group or a furo[3,2-b]pyridin-6-yl
group which may have one amino group, and E represents a 2-furyl
group, a 2-thienyl group, a 3-pyrrolyl group, a phenyl group or a
2-pyridyl group (with the proviso that E has a substituent selected
from the substituent group g-1 or g-2 defined above); [30]: the
compound according to item [29], or the salt or the hydrate
thereof, wherein A.sup.1 represents a 6-quinolyl group; [31]: the
compound according to item [29], or the salt or the hydrate
thereof, wherein A.sup.1 represents a [1,5]naphthylidin-2-yl group;
[32]: the compound according to item [29], or the salt or the
hydrate thereof, wherein A.sup.1 represents an
imidazo[1,2-a]pyridin-6-yl group; [33]: the compound according to
item [29], or the salt or the hydrate thereof, wherein A.sup.1
represents a benzothiazol-6-yl group; [34]: A compound represented
by the formula (I-b), or a salt or a hydrate thereof:
##STR00018##
[wherein A.sup.2 represents a 6-quinolyl group, a 4-quinazolinyl
group or a pyrido[2,3-d]pyrimidin-4-yl group which may have an
amino group;
[0055] X.sup.2 represents a group represented by the formula
--O--CH.sub.2--, a group represented by the formula
--S--CH.sub.2--, a group represented by the formula
--C(.dbd.O)--CH.sub.2--, a group represented by the formula
--NH--CH.sub.2-- or a group represented by the formula
--CH.sub.2--NH--;
[0056] R.sup.10 represents a C.sub.1-6 alkyl group, a C.sub.6-10
aryloxy group or a C.sub.6-10 aryl C.sub.1-6 alkoxy group];
[35]: the compound according to item [34], or the salt or the
hydrate thereof, wherein X.sup.2 represents a group represented by
the formula --NH--CH.sub.2-- or a group represented by the formula
--CH.sub.2--NH--; [36]: a pharmaceutical composition comprising the
compound according to item [3] or [34], or the salt or the hydrate
thereof; [37]: an antifungal agent comprising, as an active
ingredient, the compound according to item [3] or [34], or the salt
or the hydrate thereof; [38]: a method for prevention or treatment
of fungal infection comprising administering a pharmacologically
effective amount of the compound according to item [3] or [34], or
the salt or the hydrate thereof; [39]: a use of the compound
according to item [3] or [34], or the salt or the hydrate thereof,
for manufacture of an antifungal agent; [40]: a method for
prevention or treatment of fungal infection comprising
administering a pharmacologically effective amount of the
antifungal agent according to item [1].
BEST MODE FOR CARRYING OUT THE INVENTION
[0057] The present invention is explained below in more detail by
reference to the symbols and the terms used herein being defined
and the following examples.
[0058] Herein, a structural formula of a compound sometimes
represents a certain isomer for convenience of description.
However, compounds according to the present invention may include
all possible isomers, such as structurally possible geometric
isomers, optical isomers generated due to the presence of
asymmetric carbons, stereoisomers, tautomers, and mixtures of
isomers, and are not limited to formulae being used for the
convenience of description, and may be either of two isomers of a
mixture of both isomers. Thus, the compounds according to the
present invention may be either optically active compounds having
an asymmetric carbon atom in their molecules or their racemates,
and are not restricted to either of them but include both.
Furthermore, the compounds according to the present invention may
exhibit crystalline polymorphism, but likewise are not restricted
to any one of these, but may be in any one of these crystal forms
or exist as a mixture of two or more crystal forms. The compounds
according to the present invention also include both anhydrous and
hydrated forms.
[0059] In addition, compounds resulting from compounds according to
the present invention that undergo in vivo metabolism such as
oxidation, reduction, hydrolysis and conjugation (so-called
metabolites), and compounds that undergo in vivo metabolism such as
oxidation, reduction, hydrolysis and conjugation and generates
compounds according to the present invention (so-called prodrugs)
are also encompassed by the scope of the present invention.
[0060] The term "C.sub.1-6 alkyl group" used in the present
specification means a linear or branched chain alkyl group
containing 1 to 6 carbon atoms, which is a monovalent group derived
by removal of any one of the hydrogen atoms from an aliphatic
hydrocarbon containing 1 to 6 carbons. Specifically, examples of
"C.sub.1-6 alkyl group" include a methyl group, an ethyl group, a
n-propyl group, an iso-propyl group, a n-butyl group, an iso-butyl
group, a sec-butyl group, a tert-butyl group, a n-pentyl group, an
iso-pentyl group, a sec-pentyl group, a neopentyl group, a
1-methylbutyl group, a 2-methylbutyl group, a 1,1-dimethylpropyl
group, a 1,2-dimethylpropyl group, a n-hexyl group, an iso-hexyl
group, a 1-methylpentyl group, a 2-methylpentyl group, a
3-methylpentyl group, a 1,1-dimethylbutyl group, a
1,2-dimethylbutyl group, a 2,2-dimethylbutyl group, a
1,3-dimethylbutyl group, a 2,3-dimethylbutyl group, a
3,3-dimethylbutyl group, a 1-ethylbutyl group, a 2-ethylbutyl
group, a 1,1,2-trimethylpropyl group, a 1,2,2-trimethylpropyl
group, a 1-ethyl-1-methylpropyl group, a 1-ethyl-2-methylpropyl
group or the like, and preferably, a methyl group, an ethyl group,
a n-propyl group, an iso-propyl group, a n-butyl group, an
iso-butyl group, a sec-butyl group, a tert-butyl group or the
like.
[0061] The term "C.sub.2-6 alkenyl group" used in the present
specification means a linear or branched chain alkenyl group
containing 2 to 6 carbon atoms, which may contain 1 to 2
double-bonds. Specifically, examples of "C.sub.2-6 alkenyl group"
include an ethenyl group, a 1-propenyl group, a 2-propenyl group, a
1-butenyl group, a 2-butenyl group, a 3-butenyl group, a
2-methyl-1-propenyl group, a pentenyl group, a 3-methyl-2-butenyl
group, a hexenyl group, a hexane dienyl group or the like, and
preferably an ethenyl group, a 1-propenyl group, a 2-propenyl
group, a 1-butenyl group, a 2-butenyl group, a 3-butenyl group, a
2-methyl-1-propenyl group, a 3-methyl-2-butenyl group or the
like.
[0062] The term "C.sub.2-6 alkynyl group" used in the present
specification means a linear or branched chain alkynyl group
containing 2 to 6 carbon atoms, which may contain 1 to 2
triple-bonds. Specifically, examples of "C.sub.2-6 alkynyl group"
include an ethynyl group, a 1-propynyl group, a 2-propynyl group, a
1-butynyl group, a 2-butynyl group, a 3-butynyl group, a pentynyl
group, a hexynyl group, a hexane diynyl group or the like, and
preferably, an ethynyl group, a 1-propynyl group, a 2-propynyl
group, a 1-butynyl group, a 2-butynyl group, a 3-butynyl group or
the like.
[0063] The term "C.sub.3-8 cycloalkyl group" used in the present
specification means a cyclic aliphatic hydrocarbon group containing
3 to 8 carbon atoms. Specifically, examples of "C.sub.3-8
cycloalkyl group" include a cyclopropyl group, a cyclobutyl group,
a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a
cyclooctyl group or the like, and preferably, a cyclopropyl group,
a cyclobutyl group, a cyclopentyl group, a cyclohexyl group or the
like.
[0064] The term "C.sub.1-6 alkoxy group" used in the present
specification means a group in which an oxygen atom is bonded to
terminus of the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "C.sub.1-6 alkoxy group" include a
methoxy group, an ethoxy group, a n-propoxy group, an iso-propoxy
group, a n-butoxy group, an iso-butoxy group, a sec-butoxy group, a
tert-butoxy group, a n-pentyloxy group, an iso-pentyloxy group, a
sec-pentyloxy group, a neopentyloxy group, a 1-methylbutoxy group,
a 2-methylbutoxy group, a 1,1-dimethylpropoxy group, a
1,2-dimethylpropoxy group, a n-hexyloxy group, an iso-hexyloxy
group, a 1-methylpentyloxy group, a 2-methylpentyloxy group, a
3-methylpentyloxy group, a 1,1-dimethylbutoxy group, a
1,2-dimethylbutoxy group, a 2,2-dimethylbutoxy group, a
1,3-dimethylbutoxy group, a 2,3-dimethylbutoxy group, a
3,3-dimethylbutoxy group, a 1-ethylbutoxy group, a 2-ethylbutoxy
group, a 1,1,2-trimethylpropoxy group, a 1,2,2-trimethylpropoxy
group, a 1-ethyl-1-methylpropoxy group, a 1-ethyl-2-methylpropoxy
group or the like and preferably, a methoxy group, an ethoxy group,
a n-propoxy group, an iso-propoxy group, a n-butoxy group, an
iso-butoxy group, a sec-butoxy group, a tert-butoxy group and the
like.
[0065] The term "C.sub.1-6 alkylthio group" used in the present
specification means a group in which a sulfur atom is bonded to
terminus of the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "C.sub.1-6 alkylthio group" include a
methylthio group, an ethylthio group, a n-propylthio group, an
iso-propylthio group, a n-butylthio group, an iso-butylthio group,
a sec-butylthio group, a tert-butylthio group, a n-pentylthio
group, an iso-pentylthio group, a sec-pentylthio group, a
neopentylthio group, a 1-methylbutylthio group, a 2-methylbutylthio
group, a 1,1-dimethylpropylthio group, a 1,2-dimethylpropylthio
group, a n-hexylthio group, an iso-hexylthio group, a
1-methylpentylthio group, a 2-methylpentylthio group, a
3-methylpentylthio group, a 1,1-dimethylbutylthio group, a
1,2-dimethylbutylthio group, a 2,2-dimethylbutylthio group, a
1,3-dimethylbutylthio group, a 2,3-dimethylbutylthio group, a
3,3-dimethylbutylthio group, a 1-ethylbutylthio group, a
2-ethylbutylthio group, a 1,1,2-trimethylpropylthio group, a
1,2,2-trimethylpropylthio group, a 1-ethyl-1-methylpropylthio
group, a 1-ethyl-2-methylpropylthio group or the like, and
preferably, a methylthio group, an ethylthio group, a n-propylthio
group, an iso-propylthio group, a n-butylthio group, an
iso-butylthio group, a sec-butylthio group, a tert-butylthio group
or the like.
[0066] The term "C.sub.1-6 alkylcarbonyl group" used in the present
specification means a group in which a carbonyl group is bonded to
terminus of the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "C.sub.1-6 alkylcarbonyl group" include a
methylcarbonyl group, an ethylcarbonyl group, a n-propylcarbonyl
group, an iso-propylcarbonyl group or the like.
[0067] The term "C.sub.1-6 alkoxycarbonyl group" used in the
present specification means a group in which a carbonyl group is
bonded to terminus of the "C.sub.1-6 alkoxy group" defined above.
Specifically, examples of "C.sub.1-6 alkoxycarbonyl group" include
a methoxycarbonyl group, an ethoxycarbonyl group, a
n-propoxycarbonyl group, an iso-propoxycarbonyl group or the
like.
[0068] The term "C.sub.1-6 alkylsulfonyl group" used in the present
specification means a group in which a sulfonyl group is bonded to
terminus of the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "C.sub.1-6 alkylsulfonyl group" include a
methylsulfonyl group, an ethylsulfonyl group, a n-propylsulfonyl
group, an iso-propylsulfonyl group or the like.
[0069] The term "C.sub.2-6 alkenyloxy group" used in the present
specification means a group in which an oxygen atom is bonded to
terminus of the "C.sub.2-6 alkenyl group" defined above.
Specifically, examples of "C.sub.2-6 alkenyloxy group" include an
ethenyloxy group, a 1-propenyloxy group, a 2-propenyloxy group, a
1-butenyloxy group, a 2-butenyloxy group, a 3-butenyloxy group, a
2-methyl-1-propenyloxy group, a pentenyloxy group, a
3-methyl-2-butenyloxy group, a hexenyloxy group, a hexane dienyloxy
group or the like, and preferably, an ethenyloxy group, a
1-propenyloxy group, a 2-propenyloxy group, a 1-butenyloxy group, a
2-butenyloxy group, a 3-butenyloxy group, a 2-methyl-1-propenyloxy
group, a 3-methyl-2-butenyloxy group or the like.
[0070] The term "C.sub.2-6 alkenylthio group" used in the present
specification means a group in which a sulfur atom is bonded to
terminus of the "C.sub.2-6 alkenyl group" defined above.
Specifically, examples of "C.sub.2-6 alkenylthio group" include an
ethenylthio group, a 1-propenylthio group, a 2-propenylthio group,
a 1-butenylthio group, a 2-butenylthio group, a 3-butenylthio
group, a 2-methyl-1-propenylthio group, a pentenylthio group, a
3-methyl-2-butenylthio group, a hexenylthio group, a hexane
dienylthio group or the like, and preferably, an ethenylthio group,
a 1-propenylthio group, a 2-propenylthio group, a 1-butenylthio
group, a 2-butenylthio group, a 3-butenylthio group, a
2-methyl-1-propenylthio group, a 3-methyl-2-butenylthio group or
the like.
[0071] The term "C.sub.2-6 alkynyloxy group" used in the present
specification means a group in which an oxygen atom is bonded to
terminus of the "C.sub.2-6 alkynyl group" defined above.
Specifically, examples of "C.sub.2-6 alkynyloxy group" include an
ethynyloxy group, a 1-propynyloxy group, a 2-propynyloxy group, a
1-butynyloxy group, a 2-butynyloxy group, a 3-butynyloxy group, a
pentynyloxy group, a hexynyloxy group, a hexane diynyloxy group or
the like, and preferably, an ethynyloxy group, a 1-propynyloxy
group, a 2-propynyloxy group, a 1-butynyloxy group, a 2-butynyloxy
group, a 3-butynyloxy group or the like.
[0072] The term "C.sub.2-6 alkynylthio group" used in the present
specification means a group in which a sulfur atom is bonded to
terminus of the "C.sub.2-6 alkynyl group" defined above.
Specifically, examples of "C.sub.2-6 alkynylthio group" include an
ethynylthio group, a 1-propynylthio group, a 2-propynylthio group,
a 1-butynylthio group, a 2-butynylthio group, a 3-butynylthio
group, a pentynylthio group, a hexynylthio group, a hexane
diynylthio group or the like, and preferably, an ethynylthio group,
a 1-propynylthio group, a 2-propynylthio group, a 1-butynylthio
group, a 2-butynylthio group, a 3-butynylthio group or the
like.
[0073] The term "C.sub.3-8 cycloalkoxy group" used in the present
specification means a group in which an oxygen atom is bonded to
terminus of the "C.sub.3-8 cycloalkyl group" defined above.
Specifically, examples of "C.sub.3-8 cycloalkoxy group" include a
cyclopropoxy group, a cyclobutoxy group, a cyclopentyloxy group, a
cyclohexyloxy group, a cycloheptyloxy group, a cyclooctyloxy group
or the like, and preferably, a cyclopropoxy group, a cyclobutoxy
group, a cyclopentyloxy group, a cyclohexyloxy group or the
like.
[0074] The term "C.sub.3-8 cycloalkylthio group" used in the
present specification means a group in which a sulfur atom is
bonded to terminus of the "C.sub.3-8 cycloalkyl group" defined
above. Specifically, examples of "C.sub.3-8 cycloalkylthio group"
include a cyclopropylthio group, a cyclobutylthio group, a
cyclopentylthio group, a cyclohexylthio group, a cycloheptylthio
group, a cyclooctylthio group or the like, and preferably, a
cyclopropylthio group, a cyclobutylthio group, a cyclopentylthio
group, a cyclohexylthio group or the like.
[0075] The term "C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group" used
in the present specification means a group in which any hydrogen
atom within the "C.sub.1-6 alkyl group" defined above is
substituted by the "C.sub.3-8 cycloalkyl group" defined above.
Specifically, examples of "C.sub.3-8 cycloalkyl C.sub.1-6 alkyl
group" include a cyclopropylmethyl group, a cyclobutylmethyl group,
a cyclopentylmethyl group, a cyclohexylmethyl group, a
cyclopropylethyl group, a cyclobutylethyl group, a cyclopentylethyl
group, a cyclohexylethyl group or the like.
[0076] The term "C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy group" used
in the present specification means a group in which any hydrogen
atom within the "C.sub.1-6 alkoxy group" defined above is
substituted by the "C.sub.3-8 cycloalkyl group" defined above.
Specifically, examples of "C.sub.3-8 cycloalkyl C.sub.1-6 alkoxy
group" include a cyclopropylmethoxy group, a cyclobutylmethoxy
group, a cyclopentylmethoxy group, a cyclohexylmethoxy group, a
cyclopropylethoxy group, a cyclobutylethoxy group, a
cyclopentylethoxy group, a cyclohexylethoxy group or the like.
[0077] The term "C.sub.3-8 cycloalkyl C.sub.1-6 alkylthio group"
used in the present specification means a group in which any
hydrogen atom within the "C.sub.1-6 alkylthio group" defined above
is substituted by the "C.sub.3-8 cycloalkyl group" defined above.
Specifically, examples of "C.sub.3-8 cycloalkyl C.sub.1-6 alkylthio
group" include a cyclopropylmethylthio group, a
cyclobutylmethylthio group, a cyclopentylmethylthio group, a
cyclohexylmethylthio group, a cyclopropylethylthio group, a
cyclobutylethylthio group, a cyclopentylethylthio group, a
cyclohexylethylthio group or the like.
[0078] The term "C.sub.3-8 cycloalkylidene C.sub.1-6 alkyl group"
used in the present specification means a group in which any carbon
atom of a saturated cyclic aliphatic hydrocarbon containing 3 to 8
carbon atoms and the "C.sub.1-6 alkyl group" defined above are
bonded through a double-bond. Specifically, examples of "C.sub.3-8
cycloalkylidene C.sub.1-6 alkyl group" include a cyclopropylidene
methyl group, a cyclobutylidene methyl group, a cyclopentilydene
methyl group, a cyclohexylidene methyl group, a cyclopropylidene
ethyl group, a cyclobutylidene ethyl group, a cyclopentylidene
ethyl group, a cyclohexylidene ethyl group or the like.
[0079] The term "C.sub.6-10 aryl group" used in the present
specification means an aromatic cyclic hydrocarbon group containing
6 to 10 carbon atoms. Specifically, examples of "C.sub.6-10 aryl
group" include a phenyl group, a 1-naphthyl group, a 2-naphthyl
group, an indenyl group, an azulenyl group, a heptalenyl group or
the like, and preferably, a phenyl group, a 1-naphthyl group, a
2-naphthyl group or the like.
[0080] The term "C.sub.6-10 aryloxy group" used in the present
specification means a group in which an oxygen atom is bonded to
terminus of the "C.sub.6-10 aryl group" defined above.
Specifically, examples of "C.sub.6-10 aryloxy group" include a
phenoxy group, a 1-naphthyloxy group, a 2-naphthyloxy group, an
indenyloxy group, an azulenyloxy group, a heptalenyloxy group or
the like, and preferably, a phenoxy group, a 1-naphthyloxy group, a
2-naphthyloxy group or the like.
[0081] The term "C.sub.6-10 arylthio group" used in the present
specification means a group in which a sulphur atom is bonded to
terminus of the "C.sub.6-10 aryl group" defined above.
Specifically, examples of "C.sub.6-10 arylthio group" include a
phenylthio group, a 1-naphthylthio group, a 2-naphthylthio group,
an indenylthio group, an azulenylthio group, a heptalenylthio group
or the like, and preferably, a phenylthio group, a 1-naphthylthio
group, a 2-naphthylthio group or the like.
[0082] The term "C.sub.6-10 aryl C.sub.1-6 alkyl group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkyl group" defined above is substituted by
the "C.sub.6-10 aryl group" defined above. Specifically, examples
of "C.sub.6-10 aryl C.sub.1-6 alkyl group" include a benzyl group,
a 1-naphthylmethyl group, a 2-naphthylmethyl group, a phenethyl
group, a 1-naphthylethyl group, a 2-naphthylethyl group, a
3-phenyl-1-propyl group or the like.
[0083] The term "phenyl C.sub.1-6 alkyl group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkyl group" defined above is substituted by a phenyl
group. Specifically, examples of "phenyl C.sub.1-6 alkyl group"
include a benzyl group, a phenethyl group, a 3-phenyl-1-propyl
group or the like.
[0084] The term "C.sub.6-10 aryl C.sub.1-6 alkoxy group" used in
the present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkoxy group" defined above is substituted by
the "C.sub.6-10 aryl group" defined above. Specifically, examples
of "C.sub.6-10 aryl C.sub.1-6 alkoxy group" include a benzyloxy
group, a 1-naphthylmethoxy group, a 2-naphthylmethoxy group, a
phenethyloxy group, a 1-naphthylethoxy group, a 2-naphthylethoxy
group, a 3-phenyl-1-propoxy group or the like.
[0085] The term "phenyl C.sub.1-6 alkoxy group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkoxy group" defined above is substituted by a phenyl
group. Specifically, examples of "phenyl C.sub.1-6 alkoxy group"
include a benzyloxy group, a phenethyloxy group, a
3-phenyl-1-propoxy group or the like.
[0086] The term "C.sub.6-10 aryl C.sub.1-6 alkylthio group" used in
the present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkylthio group" defined above is substituted
by the "C.sub.6-10 aryl group" defined above. Specifically,
examples of "C.sub.6-10 aryl C.sub.1-6 alkylthio group" include a
benzylthio group, a phenethylthio group, a 3-phenyl-1-propylthio
group or the like.
[0087] The term "mono-C.sub.1-6 alkylamino group" used in the
present specification means a group in which one hydrogen atom
within an amino group is substituted by the "C.sub.1-6 alkyl group"
defined above. Specifically, examples of "mono-C.sub.1-6 alkylamino
group" include a methylamino group, an ethylamino group, a
n-propylamino group, an iso-propylamino group, a n-butylamino
group, an iso-butylamino group, a sec-butylamino group, a
tert-butylamino group, a n-pentylamino group, an iso-pentylamino
group, a sec-pentylamino group, a neopentylamino group, a
1-methylbutylamino group, a 2-methylbutylamino group, a
1,1-dimethylpropylamino group, a 1,2-dimethylpropylamino group, a
n-hexylamino group, an iso-hexylamino group, a 1-methylpentylamino
group, a 2-methylpentylamino group, a 3-methylpentylamino group, a
1,1-dimethylbutylamino group, a 1,2-dimethylbutylamino group, a
2,2-dimethylbutylamino group, a 1,3-dimethylbutylamino group, a
2,3-dimethylbutylamino group, a 3,3-dimethylbutylamino group, a
1-ethylbutylamino group, a 2-ethylbutylamino group, a
1,1,2-trimethylpropyl amino group, a 1,2,2-trimethylpropylamino
group, a 1-ethyl-1-methylpropylamino group, a
1-ethyl-2-methylpropylamino group or the like, and preferably, a
methylamino group, an ethylamino group, a n-propylamino group, an
iso-propylamino group, a n-butylamino group, an iso-butylamino
group, a sec-butylamino group, a tert-butylamino group or the
like.
[0088] The term "mono-C.sub.2-6 alkenylamino group" used in the
present specification means a group in which one hydrogen atom
within an amino group is substituted by the "C.sub.2-6 alkenyl
group" defined above. Specifically, examples of "mono-C.sub.2-6
alkenylamino group" include an ethenylamino group, a
1-propenylamino group, a 2-propenylamino group, a 1-butenylamino
group, a 2-butenylamino group, a 3-butenylamino group, a
2-methyl-1-propenylamino group, a pentenylamino group, a
3-methyl-2-butenylamino group, a hexenylamino group, a hexane
dienylamino group or the like, and preferably, an ethenylamino
group, a 1-propenylamino group, a 2-propenylamino group, a
1-butenylamino group, a 2-butenylamino group, a 3-butenylamino
group, a 2-methyl-1-propenylamino group, a 3-methyl-2-butenylamino
group or the like.
[0089] The term "mono-C.sub.2-6 alkynylamino group" used in the
present specification means a group in which one hydrogen atom
within an amino group is substituted by the "C.sub.2-6 alkynyl
group" defined above. Specifically, examples of "mono-C.sub.2-6
alkynylamino group" include an ethynylamino group, a
1-propynylamino group, a 2-propynylamino group, a 1-butynylamino
group, a 2-butynylamino group, a 3-butynylamino group, a
pentynylamino group, a hexynylamino group, a hexane diynylamino
group or the like, and preferably, an ethynylamino group, a
1-propynylamino group, a 2-propynylamino group, a 1-butynylamino
group, a 2-butynylamino group, a 3-butynylamino group or the
like.
[0090] The term "mono-C.sub.3-8 cycloalkylamino group" used in the
present specification means a group in which one hydrogen atom
within an amino group is substituted by the "C.sub.3-8 cycloalkyl
group" defined above. Specifically, examples of "mono-C.sub.3-8
cycloalkylamino group" include a cyclopropylamino group, a
cyclobutylamino group, a cyclopentylamino group, a cyclohexylamino
group, a cycloheptylamino group, a cyclooctylamino group or the
like, and preferably, a cyclopropylamino group, a cyclobutylamino
group, a cyclopentylamino group, a cyclohexylamino group or the
like.
[0091] The term "mono-C.sub.6-10 arylamino group" used in the
present specification means a group in which one hydrogen atom
within an amino group is substituted by the "C.sub.6-10 aryl group"
defined above. Specifically, examples of "mono-C.sub.6-10 arylamino
group" include a phenylamino group, a 1-naphthylamino group, a
2-naphthylamino group, an indenylamino group, an azulenylamino
group, a heptalenylamino group or the like, and preferably, a
phenylamino group, a 1-naphthylamino group, a 2-naphthylamino group
or the like.
[0092] The term "mono-C.sub.3-8 cycloalkyl C.sub.1-6 alkylamino
group" used in the present specification means a group in which one
hydrogen atom within an amino group is substituted by the
"C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group" defined above.
Specifically, examples of "mono-C.sub.3-8 cycloalkyl C.sub.1-6
alkylamino group" include a cyclopropylmethylamino group, a
cyclobutylmethylamino group, a cyclopentylmethylamino group, a
cyclohexylmethylamino group, a cyclopropylethylamino group, a
cyclobutylethylamino group, a cyclopentylethylamino group, a
cyclohexylethylamino group or the like.
[0093] The term "mono-C.sub.6-10 aryl C.sub.1-6 alkylamino group"
used in the present specification means a group in which one
hydrogen atom within an amino group is substituted by the
"C.sub.6-10 aryl C.sub.1-6 alkyl group" defined above.
Specifically, examples of "mono-C.sub.6-10 aryl C.sub.1-6
alkylamino group" include a benzyl amino group, a
1-naphthylmethylamino group, a 2-naphthylmethylamino group, a
phenethylamino group, a 1-naphthylethylamino group, a
2-naphthylethylamino group or the like.
[0094] The term "di-C.sub.1-6 alkylamino group" used in the present
specification means a group in which two hydrogen atoms within an
amino group are substituted by the identical to or different from
the "C.sub.1-6 alkyl groups" defined above. Specifically, examples
of "di-C.sub.1-6 alkylamino group" include a N,N-dimethylamino
group, a N,N-diethylamino group, a N,N-di-n-propylamino group, a
N,N-di-iso-propylamino group, a N,N-di-n-butylamino group, a
N,N-di-iso-butylamino group, a N,N-di-sec-butylamino group, a
N,N-di-tert-butylamino group, a N-ethyl-N-methylamino group, a
N-n-propyl-N-methylamino group, a N-iso-propyl-N-methylamino group,
a N-n-butyl-N-methylamino group, a N-iso-butyl-N-methylamino group,
a N-sec-butyl-N-methylamino group, a N-tert-butyl-N-methylamino
group or the like, and preferably, a N,N-dimethylamino group, a
N,N-diethylamino group, a N-ethyl-N-methylamino group or the
like.
[0095] The term "N--C.sub.2-6 alkenyl-N--C.sub.1-6 alkylamino
group" used in the present specification means a group in which one
of the hydrogen atoms within an amino group is substituted by the
"C.sub.2-6 alkenyl group" defined above, and the other hydrogen
atom is substituted by the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "N--C.sub.2-6 alkenyl-N--C.sub.1-6
alkylamino group" include a N-ethenyl-N-methylamino group, a
N-1-propenyl-N-methylamino group, a N-2-propenyl-N-methylamino
group, a N-1-butenyl-N-methylamino group, a
N-2-butenyl-N-methylamino group, a N-3-butenyl-N-methylamino group,
a N-2-methyl-1-propenyl-N-methylamino group, a
N-pentenyl-N-methylamino group, a
N-3-methyl-2-butenyl-N-methylamino group, a N-hexenyl-N-methylamino
group, a N-hexanedienyl-N-methylamino group or the like, and
preferably, a N-ethenyl-N-methylamino group, a
N-1-propenyl-N-methylamino group, a N-2-propenyl-N-methylamino
group, a N-1-butenyl-N-methylamino group, a
N-2-butenyl-N-methylamino group, a N-3-butenyl-N-methylamino group,
a N-2-methyl-1-propenyl-N-methylamino group, a
N-3-methyl-2-butenyl-N-methylamino a group or the like.
[0096] The term "N--C.sub.2-6 alkynyl-N--C.sub.1-6 alkylamino
group" used in the present specification means a group in which one
of the hydrogen atoms within an amino group is substituted by the
"C.sub.2-6 alkynyl group" defined above, and the other hydrogen
atom is substituted by the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "N--C.sub.2-6 alkynyl-N--C.sub.1-6
alkylamino group" include a N-ethynyl-N-methylamino group, a
N-1-propynyl-N-methylamino group, a N-2-propynyl-N-methylamino
group, a N-1-butynyl-N-methylamino group, a
N-2-butynyl-N-methylamino group, a N-3-butynyl-N-methylamino group,
a N-pentynyl-N-methylamino group, a N-hexynyl-N-methylamino group,
a N-hexanediynyl-N-methylamino group or the like, and preferably, a
N-ethynyl-N-methylamino group, a N-1-propynyl-N-methylamino group,
a N-2-propynyl-N-methylamino group, a N-1-butynyl-N-methylamino
group, a N-2-butynyl-N-methylamino group, a
N-3-butynyl-N-methylamino group or the like.
[0097] The term "N--C.sub.3-8 cycloalkyl-N--C.sub.1-6 alkylamino
group" used in the present specification means a group in which one
of the hydrogen atoms within an amino group is substituted by the
"C.sub.3-8 cycloalkyl group" defined above, and the other hydrogen
atom is substituted by the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "N--C.sub.3-8 cycloalkyl-N--C.sub.1-6
alkylamino group" include a N-cyclopropyl-N-methylamino group, a
N-cyclobutyl-N-methylamino group, a N-cyclopentyl-N-methylamino
group, a N-cyclohexyl-N-methylamino group, a
N-cycloheptyl-N-methylamino group, a N-cyclooctyl-N-methylamino
group or the like, and preferably, a N-cyclopropyl-N-methylamino
group, a N-cyclobutyl-N-methylamino group, a
N-cyclopentyl-N-methylamino group, a N-cyclohexyl-N-methylamino
group or the like.
[0098] The term "N--C.sub.6-10 aryl-N--C.sub.1-6 alkylamino group"
used in the present specification means a group in which one of the
hydrogen atoms within an amino group is substituted by the
"C.sub.6-10 aryl group" defined above, and the other hydrogen atom
is substituted by the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "N--C.sub.6-10 aryl-N--C.sub.1-6
alkylamino group" include a N-phenyl-N-methylamino group, a
N-1-naphthyl-N-methylamino group, a N-2-naphthyl-N-methylamino
group, a N-indenyl-N-methylamino group, a N-azulenyl-N-methylamino
group, a N-heptalenyl-N-methylamino group or the like, and
preferably, a N-phenyl-N-methylamino group, a
N-1-naphthyl-N-methylamino group, a N-2-naphthyl-N-methylamino
group or the like.
[0099] The term "N--C.sub.3-8 cycloalkyl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group" used in the present
specification means a group in which one of the hydrogen atoms
within an amino group is substituted by the "C.sub.3-8 cycloalkyl
C.sub.1-6 alkyl group" defined above, and the other hydrogen atom
is substituted by the "C.sub.1-6 alkyl group" defined above.
Specifically, examples of "N--C.sub.3-8 cycloalkyl C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group" include a
N-cyclopropylmethyl-N-methylamino group, a
N-cyclobutylmethyl-N-methylamino group, a
N-cyclopentylmethyl-N-methylamino group, a
N-cyclohexylmethyl-N-methylamino group, a
N-cyclopropylethyl-N-amino group, a N-cyclobutylethyl-N-methylamino
group, a N-cyclopentylethyl-N-methylamino group, a
N-cyclohexylethyl-N-methylamino group or the like.
[0100] The term "N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6
alkylamino group" used in the present specification means a group
in which one of the hydrogen atoms within an amino group is
substituted by the "C.sub.6-10 aryl C.sub.1-6 alkyl group" defined
above, and the other hydrogen atom is substituted by the "C.sub.1-6
alkyl group" defined above. Specifically, examples of
"N--C.sub.6-10 aryl C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group"
include a N-benzyl-N-methylamino group, a
N-1-naphthylmethyl-N-methylamino group, a
N-2-naphthylmethyl-N-methylamino group, a N-phenethyl-N-methylamino
group, a N-1-naphthylethyl-N-methylamino group, a
N-2-naphthylethyl-N-methylamino group or the like.
[0101] The term "halogen atom" used in the present specification
refers to a fluorine atom, a chlorine atom, a bromine atom or an
iodine atom, and preferably, a fluorine atom, a chlorine atom or a
bromine atom.
[0102] The term "heteroatom" used in the present specification
refers to a nitrogen atom, a sulfur atom or an oxygen atom.
[0103] The term "5- to 10-membered heterocyclic group" used in the
present specification means a monovalent group derived by removal
of any one hydrogen atom from the ring of an aromatic or a
non-aromatic that has one or a plurality of heteroatoms among the
atoms constituting the ring, the number of atoms constituting the
ring being 5 to 10. Specifically, examples of aromatic "5- to
10-membered heterocyclic group" include a furyl group (for
instance, a 2-furyl group, a 3-furyl group or the like), a thienyl
group (for instance, a 2-thienyl group, a 3-thienyl group or the
like), a pyrrolyl group (for instance, a 1-pyrrolyl group, a
2-pyrrolyl group, a 3-pyrrolyl group or the like), a pyridyl group
(for instance, a 2-pyridyl group, a 3-pyridyl group, a 4-pyridyl
group or the like), a pyrazinyl group, a pyridazinyl group (for
instance, a 3-pyridazinyl group, a 4-pyridazinyl group or the
like), a pyrimidinyl group (for instance, a 2-pyrimidinyl group, a
4-pyrimidinyl group, a 5-pyrimidinyl group or the like), a
triazolyl group (for instance, a 1,2,3-triazolyl group, a
1,2,4-triazolyl group or the like), a tetrazolyl group (for
instance, a 1H-tetrazolyl group, a 2H-tetrazolyl group or the
like), a thiazolyl group (for instance, a 2-thiazolyl group, a
4-thiazolyl group, a 5-thiazolyl group or the like), a pyrazolyl
group (for instance, a 3-pyrazolyl group, a 4-pyrazolyl group or
the like), an oxazolyl group (for instance, a 2-oxazolyl group, a
4-oxazolyl group, a 5-oxazolyl group or the like), an isooxazolyl
group (for instance, a 3-isooxazolyl group, a 4-isooxazolyl group,
a 5-isooxazolyl group or the like), an isothiazolyl group (for
instance, a 3-isothiazolyl group, a 4-isothiazolyl group, a
5-isothiazolyl group or the like), a quinolyl group (for instance,
a 5-quinolyl group, a 6-quinolyl group, a 7-quinolyl group, a
8-quinolyl group or the like), an isoquinolyl group (for instance,
a 5-isoquinolyl group, a 6-isoquinolyl group, a 7-isoquinolyl
group, a 8-isoquinolyl group or the like), a naphthyldinyl group
(for instance, a [1,5]naphthylidin-2-yl group, a
[1,5]naphthylidin-3-yl group, a [1,8]naphthylidin-2-yl group, a
[1,8]naphthylidin-3-yl group or the like), a quinoxalinyl group
(for instance, a 5-quinoxalinyl group, a 6-quinoxalinyl group, a
7-quinoxalinyl group, a 8-quinoxalinyl group or the like), a
cinnolinyl group (for instance, a 5-cinnolinyl group, a
6-cinnolinyl group, a 7-cinnolinyl group, a 8-cinnolinyl group or
the like), a quinazolinyl group (for instance, a 4-quinazolinyl
group, a 5-quinazolinyl group, a 6-quinazolinyl group, a
7-quinazolinyl group, a 8-quinazolinyl group or the like), an
imidazopyridyl group (for instance, an imidazo[1,2-a]pyridin-6-yl
group or the like), a benzothiazolyl group (for instance, a
benzothiazol-4-yl group, a benzothiazol-5-yl group, a
benzothiazol-6-yl group, a benzothiazol-7-yl group or the like), a
benzoxazolyl group (for instance, a benzoxazol-4-yl group, a
benzoxazol-5-yl group, a benzoxazol-6-yl group, a benzoxazol-7-yl
group or the like), a benzimidazolyl group (for instance, a
benzimidazol-4-yl group, a benzimidazol-5-yl group, a
benzimidazol-6-yl group, a benzimidazol-7-yl group or the like), an
indolyl group (for instance, an indol-4-yl group, an indol-5-yl
group, an indol-6-yl group, an indol-7-yl group or the like), a
pyrrolopyridyl group (for instance, a 1H-pyrrolo[2,3-b]pyridin-5-yl
group, a pyrrolo[3,2-b]pyridin-1-yl group or the like), a
thienopyridyl group (for instance, a thieno[2,3-b]pyridin-5-yl
group, a thieno[3,2-b]pyridin-6-yl group or the like), a
furopyridyl group (for instance, a furo[2,3-b]pyridin-5-yl group, a
furo[3,2-b]pyridin-6-yl group or the like), a
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group, a
benzothiadiazolyl group (for instance, a benzo[1, 2,
5]thiadiazol-5-yl group or the like), a benzoxadiazolyl group (for
instance, a benzo[1, 2, 5]oxadiazol-5-yl group or the like), a
pyridopyrimidinyl group (for instance, a
pyrido[2,3-d]pyrimidin-4-yl group or the like), a benzofuryl group
(for instance, a benzofuran-4-yl group, a benzofuran-5-yl group, a
benzofuran-6-yl group, a benzofuran-7-yl group or the like), a
benzothienyl group (for instance, a benzothiophen-4-yl group, a
benzothiophen-5-yl group, a benzothiophen-6-yl group, a
benzothiophen-7-yl group or the like), a benzo[1,3]dioxol group
(for instance, a benzo[1,3]dioxol-5-yl group or the like) or the
like. Specifically, examples of non-aromatic "5-10 membered
heterocyclic group" include a pyrrolidinyl group, a piperidinyl
group, a homopiperidinyl group, a piperazinyl group, a
homopiperazinyl group, a morpholinyl group, a thiomorpholinyl
group, a tetrahydrofuryl group, a tetrahydropyanyl group or the
like.
[0104] The term "5- to 10-membered heterocyclic group containing at
least one nitrogen atom" means a monovalent group derived by
removal of one hydrogen atom from any position on the ring of an
aromatic or a non-aromatic having from 1 to a plurality of
heteroatoms among the atoms constituting the ring, and having at
least one nitrogen atom, the number of atoms constituting the ring
being 5 to 10. Specifically, examples of "5- to 10-membered
heterocyclic group containing at least one nitrogen atom" include a
pyrrolyl group, a pyridyl group, a pyrazinyl group, a pyridazinyl
group, a pyrimidinyl group, a tetrazolyl group, a thiazolyl group,
a pyrazolyl group, an oxazolyl group, an isooxazolyl group, an
isothiazolyl group, a quinolyl group, an isoquinolyl group, a
naphthyldinyl group, a quinoxalinyl group, a cinnolinyl group, a
quinazolinyl group, an imidazopyridyl group, a benzothiazolyl
group, a benzoxazolyl group, a benzimidazolyl group, an indolyl
group, a pyrrolopyridyl group, a thienopyridyl group, a furopyridyl
group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group, a
benzothiadiazolyl group, a benzoxadiazolyl group, a
pyridopyrimidinyl group or the like.
[0105] The term "5- to 10-membered heterocyclic C.sub.1-6 alkyl
group" used in the present specification means a group in which any
hydrogen atom within the "C.sub.1-6 alkyl group" defined above is
substituted by the "5- to 10-membered heterocyclic group" defined
above.
[0106] Specifically, examples of "5- to 10-membered heterocyclic
C.sub.1-6 alkyl group" include a furylmethyl group, a thienylmethyl
group, a pyrrolylmethyl group, a pyridylmethyl group, a
triazolylmethyl group, a tetrazolylmethyl group, a thiazolylmethyl
group, a pyrazolylmethyl group, an oxazolylmethyl group, a
benzo[1,3]dioxol methyl group, a tetrahydrofurylmethyl group, a
furylethyl group, a thienylethyl group, a pyrrolylethyl group, a
pyridylethyl group, a triazolylethyl group, a tetrazolylethyl
group, a thiazolylethyl group, a pyrazolylethyl group, an
oxazolylethyl group, a benzo[1,3]dioxol ethyl group, a
tetrahydrofurylethyl group or the like.
[0107] The term "furyl C.sub.1-6 alkyl group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkyl group" defined above is substituted by a furyl
group. Specifically, examples of "furyl C.sub.1-6 alkyl group"
include a furylmethyl group, a furylethyl group or the like.
[0108] The term "thienyl C.sub.1-6 alkyl group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkyl group" defined above is substituted by a thienyl
group. Specifically, examples of "thienyl C.sub.1-6 alkyl group"
include a thienylmethyl group, a thienylethyl group or the
like.
[0109] The term "benzofuryl C.sub.1-6 alkyl group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkyl group" defined above is substituted by
a benzofuryl group. Specifically, examples of "benzofuryl C.sub.1-6
alkyl group" include a benzofurylmethyl group, a benzofurylethyl
group or the like.
[0110] The term "benzothienyl C.sub.1-6 alkyl group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkyl group" defined above is substituted by
a benzothienyl group. Specifically, examples of "benzothienyl
C.sub.1-6 alkyl group" include a benzothienylmethyl group, a
benzothienylethyl group or the like.
[0111] The term "5- to 10-membered heterocycle oxy group" used in
the present specification means a group in which an oxygen atom is
bonded to terminus of the "5-10 membered heterocyclic group"
defined above. Specifically, examples of "5- and 10-membered
heterocycle oxy group" include a furyloxy group, a thienyloxy
group, a pyrrolyloxy group, a pyridyloxy group, a triazolyloxy
group, a tetrazolyloxy group, a thiazolyloxy group, a pyrazolyloxy
group, an oxazolyloxy group, a benzo[1,3]dioxol oxy group, a
tetrahydrofuryloxy group or the like.
[0112] The term "5- to 10-membered heterocyclic C.sub.1-6 alkoxy
group" used in the present specification means a group in which any
hydrogen atom within the "C.sub.1-6 alkoxy group" defined above is
substituted by the "5- to 10-membered heterocyclic group" defined
above. Specifically, examples of "5- to 10-membered heterocyclic
C.sub.1-6 alkoxy group" include a furylmethoxy group, a
thienylmethoxy group, a pyrrolylmethoxy group, a pyridylmethoxy
group, a triazolylmethoxy group, a tetrazolylmethoxy group, a
thiazolylmethoxy group, a pyrazolylmethoxy group, an
oxazolylmethoxy group, a benzo[1,3]dioxol methoxy group, a
tetrahydrofurylmethoxy group, a furylethoxy group, a thienylethoxy
group, a pyrrolylethoxy group, a pyridylethoxy group, a
triazolylethoxy group, a tetrazolylethoxy group, a thiazolylethoxy
group, a pyrazolylethoxy group, an oxazolylethoxy group, a
benzo[1,3]dioxol ethoxy group, a tetrahydrofurylethoxy group or the
like.
[0113] The term "furyl C.sub.1-6 alkoxy group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkoxy group" defined above is substituted by a furyl
group. Specifically, examples of "furyl C.sub.1-6 alkoxy group"
include a furylmethoxy group, a furylethoxy group or the like.
[0114] The term "thienyl C.sub.1-6 alkoxy group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkoxy group" defined above is substituted by
a thienyl group. Specifically, examples of "thienyl C.sub.1-6
alkoxy group" include a thienylmethoxy group, a thienylethoxy group
or the like.
[0115] The term "pyridyl C.sub.1-6 alkoxy group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkoxy group" defined above is substituted by
a pyridyl group. Specifically, examples of "pyridyl C.sub.1-6
alkoxy group" include a pyridylmethoxy group, a pyridylethoxy group
or the like.
[0116] The term "5- to 10-membered heterocyclic C.sub.1-6 alkylthio
group" used in the present specification means a group in which any
hydrogen atom within the "C.sub.1-6 alkylthio group" defined above
is substituted by the "5- to 10-membered heterocyclic group"
defined above. Specifically, examples of "5- to 10-membered
heterocyclic C.sub.1-6 alkylthio group" include a furylmethylthio
group, a thienylmethylthio group, a pyrrolylmethylthio group, a
pyridylmethylthio group, a triazolylmethylthio group, a
tetrazolylmethylthio group, a thiazolylmethylthio group, a
pyrazolylmethylthio group, an oxazolylmethylthio group, a
benzo[1,3]dioxol methylthio group, a tetrahydrofurylmethylthio
group, a furylethylthio group, a thienylethylthio group, a
pyrrolylethylthio group, a pyridylethylthio group, a
triazolylethylthio group, a tetrazolylethylthio group, a
thiazolylethylthio group, a pyrazolylethylthio group, an
oxazolylethylthio group, a benzo[1,3]dioxol ethylthio group, a
tetrahydrofurylethylthio group or the like.
[0117] The term "mono-5- to 10-membered heterocyclic C.sub.1-6
alkylamino group" used in the present specification means a group
in which one hydrogen atom within an amino group is substituted by
the "5- to 10-membered heterocyclic C.sub.1-6 alkyl group" defined
above. Specifically, examples of "mono-5- to 10-membered
heterocyclic C.sub.1-6 alkylamino group" include a furylmethylamino
group, a thienylmethylamino group, a pyrrolylmethylamino group, a
pyridylmethylamino group, a triazolylmethylamino group, a
tetrazolylmethylamino group, a thiazolylmethylamino group, a
pyrazolylmethylamino group, an oxazolylmethylamino group, a
tetrahydrofurylmethylamino group, a furylethylamino group, a
thienylethylamino group, a pyrrolylethylamino group, a
pyridylethylamino group, a triazolylethylamino group, a
tetrazolylethylamino group, a thiazolylethylamino group, a
pyrazolylethylamino group, an oxazolylethylamino group, a
tetrahydrofurylethylamino group, a triazolyl-1-propylamino group or
the like.
[0118] The term "N-5- to 10-membered heterocyclic C.sub.1-6
alkyl-N--C.sub.1-6 alkylamino group" used in the present
specification means a group in which one of the hydrogen atoms
within an amino group is substituted by the "5- to 10-membered
heterocyclic C.sub.1-6 alkyl group" defined above and the other
hydrogen atom is substituted by the "C.sub.1-6 alkyl group" defined
above. Specifically, examples of "N-5- to 10-membered heterocyclic
C.sub.1-6 alkyl-N--C.sub.1-6 alkylamino group" include a
N-furylmethyl-N-methylamino group, a N-thienylmethyl-N-methylamino
group, a N-pyrrolylmethyl-N-methylamino group, a
N-pyridylmethyl-N-methylamino group, a
N-triazolylmethyl-N-methylamino group, a
N-tetrazolylmethyl-N-methylamino group, a
N-thiazolylmethyl-N-methylamino group, a
N-pyrazolylmethyl-N-methylamino group, a
N-oxazolylmethyl-N-methylamino group, a
N-tetrahydrofurylmethyl-N-methylamino group, a
N-furylethyl-N-methylamino group, a N-thienylethyl-N-methylamino
group, a N-pyrrolylethyl-N-methylamino group, a
N-pyridylethyl-N-methylamino group, a
N-triazolylethyl-N-methylamino group, a
N-tetrazolylethyl-N-methylamino group, a
N-thiazolylethyl-N-methylamino group, a
N-pyrazolylethyl-N-methylamino group, a
N-oxazolylethyl-N-methylamino group, a
N-tetrahydrofurylethyl-N-methylamino group or the like.
[0119] The term "C.sub.6-10 aryloxy C.sub.1-6 alkyl group" used in
the present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkyl group" defined above is substituted by
the "C.sub.6-10 aryloxy group" defined above. Specifically,
examples of "C.sub.6-10 aryloxy C.sub.1-6 alkyl group" include a
phenoxymethyl group, a 1-naphthyloxymethyl group, a
2-naphthyloxymethyl group, an indenyloxymethyl group, an
azulenyloxymethyl group, a heptalenyloxymethyl group or the like,
and preferably, a phenoxymethyl group, a 1-naphthyloxymethyl group,
a 2-naphthyloxymethyl group or the like.
[0120] The term "phenoxy C.sub.1-6 alkyl group" used in the present
specification means a group in which any hydrogen atom within the
"C.sub.1-6 alkyl group" defined above is substituted by a phenoxy
group. Specifically, examples of "phenoxy C.sub.1-6 alkyl group"
include a phenoxymethyl group or the like.
[0121] The term "5- to 10-membered heterocycle oxy C.sub.1-6 alkyl
group" used in the present specification means a group in which any
hydrogen atom within the "C.sub.1-6 alkyl group" defined above is
substituted by the "5- to 10-membered heterocycle oxy group".
Specifically, examples of "5- to 10-membered heterocycle oxy
C.sub.1-6 alkyl group" include a furyloxymethyl group, a
thienyloxymethyl group, a pyrrolyloxymethyl group, a
pyridyloxymethyl group, a triazolyloxymethyl group, a
tetrazolyloxymethyl group, a thiazolyloxymethyl group, a
pyrazolyloxymethyl group, an oxazolyloxymethyl group, a
benzo[1,3]dioxol oxymethyl group, a tetrahydrofuryloxymethyl group
or the like, and preferably, a furyloxymethyl group, a
thienyloxymethyl group, a pyrrolyloxymethyl group, a
pyridyloxymethyl group or the like.
[0122] The term "pyridyloxy C.sub.1-6 alkyl group" used in the
present specification means a group in which any hydrogen atom
within the "C.sub.1-6 alkyl group" defined above is substituted by
a pyridyl group. Specifically, examples of "pyridyloxy C.sub.1-6
alkyl group" include a pyridyloxymethyl group or the like.
[0123] The term "which may have a substituent" used in the present
specification means that a group may have from one to a plurality
of substituents combined at replaceable positions arbitrarily.
[0124] The term "having a substituent" used in the present
specification refers to having from one to a plurality of
substituents combined at replaceable positions arbitrarily.
[0125] The term "A" used in the present specification means a 5- to
10-membered heterocyclic group containing at least one nitrogen
atom (with the proviso that A may have 1 to 3 substituents selected
from the substituent group a-1 or a-2 defined above). Preferable
examples of "A" include an aromatic 5- to 10-membered heterocyclic
group containing at least one nitrogen atom, such as, a 3-pyridyl
group, a pyrazinyl group, a pyrimidinyl group, a pyrazolyl group, a
quinolyl group, an isoquinolyl group, a naphthyldinyl group, a
quinoxalinyl group, a cinnolinyl group, a quinazolinyl group, an
imidazopyridyl group, a benzothiazolyl group, a benzoxazolyl group,
a benzimidazolyl group, an indolyl group, a 1H-pyrrolopyridyl
group, a thienopyridyl group, a furopyridyl group, a
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group, a
benzothiadiazolyl group or a pyrido[2,3-d]pyrimidinyl group (with
the proviso that each above-mentioned group may have 1 to 3
substituents selected from the substituent groups a-1 and a-2
defined above).
[0126] The term "X" used in the present specification means a group
represented by the formula --NH--C(.dbd.Y)--(CH.sub.2).sub.n--, a
group represented by the formula
--C(.dbd.Y)--NH--(CH.sub.2).sub.n--, a group represented by the
formula --C(.dbd.Z)--(CH.sub.2).sub.n--, a group represented by the
formula --CH.sub.2--NH--(CH.sub.2).sub.n--, a group represented by
the formula --NH--CH.sub.2--(CH.sub.2).sub.n-- or a group
represented by the formula --Z--CH.sub.2--(CH.sub.2).sub.n--
(wherein Y, Z and n have the same meanings as defined above,
respectively). Preferable examples of "X" include a group
represented by the formula --NH--C(.dbd.Y)--CH.sub.2--, a group
represented by the formula --C(.dbd.Y)--NH--CH.sub.2--, a group
represented by the formula --CH.sub.2--NH-- or a group represented
by the formula --NH--CH.sub.2-- (wherein Y has the same meaning as
defined above).
[0127] The term "A.sup.1" used in the present specification means a
3-pyridyl group, a pyrazinyl group, a pyrimidinyl group, a
pyrazolyl group, a quinolyl group, an isoquinolyl group, a
naphthyldinyl group, a quinoxalinyl group, a cinnolinyl group, a
quinazolinyl group, an imidazopyridyl group, a benzothiazolyl
group, a benzoxazolyl group, a benzimidazolyl group, an indolyl
group, a pyrrolopyridyl group, a thienopyridyl group, a furopyridyl
group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group or a
benzothiadiazolyl group (with the proviso that each above-mentioned
group may have 1 to 3 substituents selected from the substituent
groups a-1 and a-2 defined above). Preferable examples of "A.sup.1"
include a 3-pyridyl group, a quinolyl group, a naphthyldinyl group,
a quinoxalinyl group, an imidazopyridyl group, a benzothiazolyl
group, a pyrrolopyridyl group, a thienopyridyl group or a
furopyridyl group (with the proviso that each above-mentioned group
may have 1 to 3 substituents selected from the substituent groups
a-1 and a-2 defined above), more preferably, a 3-pyridyl group, a
6-quinolyl group, a [1,5]naphthylidin-2-yl group, a 6-quinoxalinyl
group, an imidazo[1,2-a]pyridin-6-yl group, a benzothiazol-6-yl
group, a 1H-pyrrolo[2,3-b]pyridin-5-yl group, a
pyrrolo[3,2-b]pyridin-1-yl group, a thieno[2,3-b]pyridin-5-yl
group, a thieno[3,2-b]pyridin-6-yl group or a
furo[3,2-b]pyridin-6-yl group (with the proviso that each
above-mentioned group may have 1 to 3 substituents selected from
the substituent groups c-1 and c-2 defined above), still more
preferably, group represented by the formula:
##STR00019##
(wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 have the
same meanings as defined above, respectively), a 6-quinolyl group,
a [1,5]naphthylidin-2-yl group, a 6-quinoxalinyl group, an
imidazo[1,2-a]pyridin-6-yl group, a benzothiazol-6-yl group, a
pyrrolo[3,2-b]pyridin-1-yl group, a 1H-pyrrolo[2,3-b]pyridin-5-yl
group which may have one amino group, a thieno[2,3-b]pyridin-5-yl
group which may have one amino group, a thieno[3,2-b]pyridin-6-yl
group which may have one amino group or a furo[3,2-b]pyridin-6-yl
group which may have one amino group, and particularly preferably,
a group represented by the formula:
##STR00020##
(wherein R.sup.1, R.sup.2, R.sup.6 and R.sup.7 have the same
meanings as defined above, respectively), a 6-quinolyl group, a
[1,5]naphthylidin-2-yl group, an imidazo[1,2-a]pyridin-6-yl group
or a benzothiazol-6-yl group, most preferably 1) a group
represented by the formula:
##STR00021##
(wherein R.sup.11 has the same meaning as defined above) or 2)
group represented by the formula:
##STR00022##
(wherein R.sup.14 has the same meaning as defined above), a
6-quinolyl group, a [1,5]naphthylidin-2-yl group or an
imidazo[1,2-a]pyridin-6-yl group.
[0128] In addition, preferable examples of "A.sup.1" include a
3-pyridyl group, a pyrazinyl group, a pyrimidinyl group, a quinolyl
group, an isoquinolyl group, a naphthyldinyl group, a quinoxalinyl
group, a cinnolinyl group, a quinazolinyl group, an imidazopyridyl
group, a benzothiazolyl group, a benzoxazolyl group, a
benzimidazolyl group, an indolyl group, a pyrrolopyridyl group, a
thienopyridyl group, a furopyridyl group, a
2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group or a
benzothiadiazolyl group (with the proviso that A.sup.1 may have 1
to 3 substituents selected from the substituent groups a-1 and a-2
defined above), more preferably, a 3-pyridyl group, a pyrazinyl
group, a pyrimidinyl group, a quinolyl group, an isoquinolyl group,
a naphthyldinyl group, a quinoxalinyl group, a cinnolinyl group, a
quinazolinyl group, an imidazopyridyl group, a benzothiazolyl
group, a benzoxazolyl group, a benzimidazolyl group, an indolyl
group, a pyrrolopyridyl group, a thienopyridyl group, a furopyridyl
group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl group or a
benzothiadiazolyl group (with the proviso that A.sup.1 may have 1
to 3 substituents selected from the substituent groups c-1 and c-2
defined above), still more preferably, a 3-pyridyl group, a
pyrazinyl group, a pyrimidinyl group, a quinolyl group, an
isoquinolyl group, a naphthyldinyl group, a quinoxalinyl group, a
cinnolinyl group, a quinazolinyl group, an imidazopyridyl group, a
benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group,
an indolyl group, a pyrrolopyridyl group, a thienopyridyl group, a
furopyridyl group, a 2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-5-yl
group or a benzothiadiazolyl group (with the proviso that A.sup.1
may have 1 to 3 substituents selected from the substituent groups
c'-1 and c'-2 defined above).
[0129] Preferable examples of "a group represented by the formula
--C(.dbd.N--R.sup.a1) R.sup.a2", (wherein R.sup.a1 and R.sup.a2
have the same meanings as defined above, respectively) used in the
present specification includes a group represented by the formula
--C(.dbd.N--OH)R.sup.a2 (wherein R.sup.a2 has the same meaning as
defined above), and more preferably, a group represented by the
formula --C(.dbd.N--OH)CH.sub.3.
[0130] The term "X.sup.1" used in the present specification means a
group represented by the formula --NH--C(.dbd.O)--, a group
represented by the formula --C(.dbd.O)--NH--, a group represented
by the formula --NH--C(.dbd.S)--, a group represented by the
formula --C(.dbd.S)--NH--, a group represented by the formula
--NH--C(.dbd.NR.sup.Y1)-- or a group represented by the formula
--C(.dbd.R.sup.Y1)--NH-- (wherein R.sup.Y1 has the same meaning as
defined above). Preferable examples of "X.sup.1" include a group
represented by --C(.dbd.O)--NH-- or a group represented by the
formula --NH--C(.dbd.O)--, more preferably a group represented by
--C(.dbd.O)--NH--.
[0131] The term "E" used in the present specification refers to a
furyl group, a thienyl group, a pyrrolyl group, a phenyl group, a
pyridyl group, a tetrazolyl group, a thiazolyl group or a pyrazolyl
group (with the proviso that each above-mentioned group has 1 or 2
substituents selected from the substituent groups a-1 and a-2
defined above). Preferable examples of "E" include a furyl group, a
thienyl group, a pyrrolyl group, a phenyl group or a pyridyl group
(with the proviso that each above-mentioned group has 1 or 2
substituents selected from the substituent groups a-1 and a-2
defined above), more preferably, a furyl group, a thienyl group, a
pyrrolyl group, a phenyl group or a pyridyl group (with the proviso
that each above-mentioned group has 1 or 2 substituents selected
from the substituent groups e-1 and e-2 defined above), still more
preferably, a furyl group, a thienyl group, a pyrrolyl group, a
phenyl group or a pyridyl group (with the proviso that each
above-mentioned group has one substituent selected from the
substituent groups g-1 and g-2 defined above), particularly
preferably, a 2-furyl group, a 2-thienyl group, a 3-pyrrolyl group,
a phenyl group, a 2-pyridyl group or a 3-pyridyl group (with the
proviso that each above-mentioned group has one substituent
selected from the substituent groups g-1 and g-2 defined
above).
[0132] Examples of compound (1-a) include compounds in which the
"X.sup.1" defined above, the "A.sup.1" defined above and the "E"
defined above are combined arbitrarily; it is preferable that the
compound (1-a) be the compounds in which X.sup.1 represents a group
represented by the formula --C(.dbd.O)--NH-- or a group represented
by the formula --NH--C(.dbd.O)--,
[0133] (1) A.sup.1 represents a 3-pyridyl group and E represents a
furyl group;
[0134] (2) A.sup.1 represents a 3-pyridyl group and E represents a
thienyl group;
[0135] (3) A.sup.1 represents a 3-pyridyl group and E represents a
pyrrolyl group;
[0136] (4) A.sup.1 represents a 3-pyridyl group and E represents a
phenyl group;
[0137] (5) A.sup.1 represents a 3-pyridyl group and E represents a
pyridyl group;
[0138] (6) A.sup.1 represents a quinolyl group and E represents a
furyl group;
[0139] (7) A.sup.1 represents a quinolyl group and E represents a
thienyl group;
[0140] (8) A.sup.1 represents a quinolyl group and E represents a
pyrrolyl group;
[0141] (9) A.sup.1 represents a quinolyl group and E represents a
phenyl group;
[0142] (10) A.sup.1 represents a quinolyl group and E represents a
pyridyl group;
[0143] (11) A.sup.1 represents a naphthyldinyl group and E
represents a furyl group;
[0144] (12) A.sup.1 represents a naphthyldinyl group and E
represents a thienyl group;
[0145] (13) A.sup.1 represents a naphthyldinyl group and E
represents a pyrrolyl group;
[0146] (14) A.sup.1 represents a naphthyldinyl group and E
represents a phenyl group;
[0147] (15) A.sup.1 represents a naphthyldinyl group and E
represents a pyridyl group;
[0148] (16) A.sup.1 represents a quinoxalinyl group and E
represents a furyl group;
[0149] (17) A.sup.1 represents a quinoxalinyl group and E
represents a thienyl group;
[0150] (18) A.sup.1 represents a quinoxalinyl group and E
represents a pyrrolyl group;
[0151] (19) A.sup.1 represents a quinoxalinyl group and E
represents a phenyl group;
[0152] (20) A.sup.1 represents a quinoxalinyl group and E
represents a pyridyl group;
[0153] (21) A.sup.1 represents an imidazopyridyl group and E
represents a furyl group;
[0154] (22) A.sup.1 represents an imidazopyridyl group and E
represents a thienyl group;
[0155] (23) A.sup.1 represents an imidazopyridyl group and E
represents a pyrrolyl group;
[0156] (24) A.sup.1 represents an imidazopyridyl group and E
represents a phenyl group;
[0157] (25) A.sup.1 represents an imidazopyridyl group and E
represents a pyridyl group;
[0158] (26) A.sup.1 represents a benzothiazolyl group and E
represents a furyl group;
[0159] (27) A.sup.1 represents a benzothiazolyl group and E
represents a thienyl group;
[0160] (28) A.sup.1 represents a benzothiazolyl group and E
represents a pyrrolyl group;
[0161] (29) A.sup.1 represents a benzothiazolyl group and E
represents a phenyl group;
[0162] (30) A.sup.1 represents a benzothiazolyl group and E
represents a pyridyl group;
[0163] (31) A.sup.1 represents a 1H-pyrrolopyridyl group and E
represents a furyl group;
[0164] (32) A.sup.1 represents a 1H-pyrrolopyridyl group and E
represents a thienyl group;
[0165] (33) A.sup.1 represents a 1H-pyrrolopyridyl group and E
represents a pyrrolyl group;
[0166] (34) A.sup.1 represents a 1H-pyrrolopyridyl group and E
represents a phenyl group;
[0167] (35) A.sup.1 represents a 1H-pyrrolopyridyl group and E
represents a pyridyl group;
[0168] (36) A.sup.1 represents a thienopyridyl group and E
represents a furyl group;
[0169] (37) A.sup.1 represents a thienopyridyl group and E
represents a thienyl group;
[0170] (38) A.sup.1 represents a thienopyridyl group and E
represents a pyrrolyl group;
[0171] (39) A.sup.1 represents a thienopyridyl group and E
represents a phenyl group;
[0172] (40) A.sup.1 represents a thienopyridyl group and E
represents a pyridyl group;
[0173] (41) A.sup.1 represents a furopyridyl group and E represents
a furyl group;
[0174] (42) A.sup.1 represents a furopyridyl group and E represents
a thienyl group;
[0175] (43) A.sup.1 represents a furopyridyl group and E represents
a pyrrolyl group;
[0176] (44) A.sup.1 represents a furopyridyl group and E represents
a phenyl group or
[0177] (45) A.sup.1 represents a furopyridyl group and E represents
a pyridyl group (with the proviso that A.sup.1 may contain 1 to 3
substituents selected from the substituent groups a-1 and a-2
defined above, and E has 1 or 2 substituents selected from the
substituent group a-1 and a-2 defined above), more preferably,
compounds in which X.sup.1 represents a group represented by the
formula --C(.dbd.O)--NH--,
[0178] (1) A.sup.1 represents a 3-pyridyl group and E represents a
furyl group;
[0179] (2) A.sup.1 represents a 3-pyridyl group and E represents a
thienyl group;
[0180] (3) A.sup.1 represents a 3-pyridyl group and E represents a
pyrrolyl group;
[0181] (4) A.sup.1 represents a 3-pyridyl group and E represents a
phenyl group;
[0182] (5) A.sup.1 represents a 3-pyridyl group and E represents a
pyridyl group;
[0183] (6) A.sup.1 represents a 6-quinolyl group and E represents a
furyl group;
[0184] (7) A.sup.1 represents a 6-quinolyl group and E represents a
thienyl group;
[0185] (8) A.sup.1 represents a 6-quinolyl group and E represents a
pyrrolyl group;
[0186] (9) A.sup.1 represents a 6-quinolyl group and E represents a
phenyl group;
[0187] (10) A.sup.1 represents a 6-quinolyl group and E represents
a pyridyl group;
[0188] (11) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a furyl group;
[0189] (12) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a thienyl group;
[0190] (13) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a pyrrolyl group;
[0191] (14) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a phenyl group;
[0192] (15) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a pyridyl group;
[0193] (16) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a furyl group;
[0194] (17) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a thienyl group;
[0195] (18) A.sup.1 represents an imidazo[1,2-a]pyridine-6-yl group
and E represents a pyrrolyl group;
[0196] (19) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a phenyl group;
[0197] (20) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a pyridyl group;
[0198] (21) A.sup.1 represents a benzothiazol-6-yl group and E
represents a furyl group;
[0199] (22) A.sup.1 represents a benzothiazol-6-yl group and E
represents a thienyl group;
[0200] (23) A.sup.1 represents a benzothiazol-6-yl group and E
represents a pyrrolyl group;
[0201] (24) A.sup.1 represents a benzothiazol-6-yl group and E
represents a phenyl group or
[0202] (25) A.sup.1 represents a benzothiazol-6-yl group and E
represents a pyridyl group (with the proviso that A.sup.1 may
contain 1 to 3 substituents selected from the substituent groups
c-1 and c-2 defined above, and E has 1 or 2 substituents selected
from the substituent groups e-1 and e-2 defined above), still more
preferably, compounds in which X.sup.1 represents a group
represented by the formula --C(.dbd.O)--NH--,
[0203] (1) A.sup.1 represents a 3-pyridyl group and E represents a
2-furyl group;
[0204] (2) A.sup.1 represents a 3-pyridyl group and E represents a
2-thienyl group;
[0205] (3) A.sup.1 represents a 3-pyridyl group and E represents a
3-pyrrolyl group;
[0206] (4) A.sup.1 represents a 3-pyridyl group and E represents a
phenyl group;
[0207] (5) A.sup.1 represents a 3-pyridyl group and E represents a
2-pyridyl group;
[0208] (6) A.sup.1 represents a 3-pyridyl group and E represents a
3-pyridyl group;
[0209] (7) A.sup.1 represents a 6-quinolyl group and E represents a
2-furyl group;
[0210] (8) A.sup.1 represents a 6-quinolyl group and E represents a
2-thienyl group;
[0211] (9) A.sup.1 represents a 6-quinolyl group and E represents a
3-pyrrolyl group;
[0212] (10) A.sup.1 represents a 6-quinolyl group and E represents
a phenyl group;
[0213] (11) A.sup.1 represents a 6-quinolyl group and E represents
a 2-pyridyl group;
[0214] (12) A.sup.1 represents a 6-quinolyl group and E represents
a 3-pyridyl group;
[0215] (13) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a 2-furyl group;
[0216] (14) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a 2-thienyl group;
[0217] (15) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a 3-pyrrolyl group;
[0218] (16) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a phenyl group;
[0219] (17) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a 2-pyridyl group;
[0220] (18) A.sup.1 represents a [1,5]naphthylidin-2-yl group and E
represents a 3-pyridyl group;
[0221] (19) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a 2-furyl group;
[0222] (20) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a 2-thienyl group;
[0223] (21) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a 3-pyrrolyl group;
[0224] (22) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a phenyl group;
[0225] (23) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a 2-pyridyl group;
[0226] (24) A.sup.1 represents an imidazo[1,2-a]pyridin-6-yl group
and E represents a 3-pyridyl group;
[0227] (25) A.sup.1 represents a benzothiazol-6-yl group and E
represents a 2-furyl group;
[0228] (26) A.sup.1 represents a benzothiazol-6-yl group and E
represents a 2-thienyl group;
[0229] (27) A.sup.1 represents a benzothiazol-6-yl group and E
represents a 3-pyrrolyl group;
[0230] (28) A.sup.1 represents a benzothiazol-6-yl group and E
represents a phenyl group;
[0231] (29) A.sup.1 represents a benzothiazol-6-yl group and E
represents a 2-pyridyl group or
[0232] (29) A.sup.1 represents a benzothiazol-6-yl group and E
represents a 3-pyridyl group (with the proviso that A.sup.1 may
contain 1 to 3 substituents selected from the substituent groups
c-1 and c-2 defined above, and E has one substituent selected from
the substituent group g-1 and g-2 defined above).
[0233] Examples of compound (1-b) include compounds in which the
"X.sup.2" defined above, the "A.sup.2" defined above and "R.sup.10"
defined above are combined arbitrarily, preferably,
[0234] (1) compounds in which X.sup.2 represents a group
represented by the formula --O--CH.sub.2--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0235] (2) compounds in which X.sup.2 represents a group
represented by the formula --S--CH.sub.2--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0236] (3) compounds in which X.sup.2 represents a group
represented by the formula --C(.dbd.O)--CH.sub.2--, A.sup.2
represents a 6-quinolyl group and R.sup.10 represents a C.sub.6-10
aryloxy group;
[0237] (4) compounds in which X.sup.2 represents a group
represented by the formula --C(.dbd.O)--CH.sub.2--, A.sup.2
represents a 6-quinolyl group and R.sup.10 represents a C.sub.6-10
aryl C.sub.1-6 alkoxy group;
[0238] (5) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0239] (6) compounds in which X.sup.2 represents a group
represented by the formula --CH.sub.2--NH--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0240] (7) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
4-quinazolinyl group and R.sup.10 represents a C.sub.1-6 alkyl
group;
[0241] (8) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
4-quinazolinyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group or
[0242] (9) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
pyrido[2,3-d]pyrimidin-4-yl group which may have an amino group and
R.sup.10 represents a C.sub.6-10 aryl C.sub.1-6 alkoxy group, more
preferably,
[0243] (1) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0244] (2) compounds in which X.sup.2 represents a group
represented by the formula --CH.sub.2--NH--, A.sup.2 represents a
6-quinolyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group;
[0245] (3) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
4-quinazolinyl group and R.sup.10 represents a C.sub.1-6 alkyl
group;
[0246] (4) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
4-quinazolinyl group and R.sup.10 represents a C.sub.6-10 aryl
C.sub.1-6 alkoxy group or
[0247] (5) compounds in which X.sup.2 represents a group
represented by the formula --NH--CH.sub.2--, A.sup.2 represents a
pyrido[2,3-d]pyrimidin-4-yl group which may have an amino group and
R.sup.10 represents a C.sub.6-10 aryl C.sub.1-6 alkoxy group.
[0248] Examples of the term "salt" used in the present
specification include a salt with an inorganic acid, a salt with an
organic acid, a salt with an inorganic base, a salt with an organic
base, a salt with an acidic or basic amino acid or the like. Among
these salts, it is preferable that a salt used herein be a
pharmaceutically acceptable.
[0249] Preferable examples of the salt with the inorganic acid
include salts with hydrochloric acid, hydrobromic acid, sulfuric
acid, nitric acid, phosphoric acid or the like. Preferable examples
of the salt with the organic acid include salts with acetic acid,
succinic acid, fumaric acid, maleic acid, tartaric acid, citric
acid, lactic acid, stearic acid, benzoic acid, methanesulfonic
acid, ethanesulfonic acid, p-toluenesulfonic acid or the like.
Preferable examples of the salt with the inorganic base include
alkaline metal salts such as sodium salt and potassium salt,
alkaline earth metal salts such as calcium salt and magnesium salt,
aluminum salt, ammonium salt or the like. Preferable examples of
the salt with the organic base include salts with diethyl amine,
diethanolamine, meglumine, N,N-dibenzyl ethylenediamine or the
like.
[0250] Preferable examples of the salt with the acidic amino acid
include salts with aspartic acid, glutamic acid or the like.
Preferable examples of the salt with the basic amino acid include
salts with arginine, lysine, ornithine or the like.
[0251] The term "antifungal agent" used in the present
specification refers to a preventive agent or a therapeutic agent
for fungal infection.
[0252] The compounds according to the present invention, or salts
or hydrates thereof, can be formulated into tablets, powders, fine
granules, granules, coated tablets, capsulates, syrups, troches,
inhalants, suppositories, injections, ointments, eye ointments,
tapes, eye drops, nose drops, ear drops, cataplasms, lotions or the
like, by the conventional methods. Such formulation can be achieved
by using typical diluents, binders, lubricants, colorants,
flavorants, and, as necessary, stabilizers, emulsifiers,
absorbefacients, surfactants, pH modulators, preservatives,
antioxidants or the like, and materials commonly used as
ingredients of pharmaceutical preparations according to the
conventional methods. For example, an oral preparation can be
produced by combining a compound according to the present invention
or a pharmaceutically acceptable salt thereof with a diluent, and
if required, a binder, a disintegrating agent, a lubricant, a
colorant, a flavorant or the like, and formulating the mixture into
powders, fine granules, granules, tablets, coated tablets, capsules
or the like according to the conventional methods. Examples of the
materials include animal and vegetable oils such as soya bean oil,
beef tallow, and synthetic glyceride; hydrocarbons such as liquid
paraffin, squalane, and solid paraffin; ester oils such as
octyldodecyl myristate and iso-propyl myristate; higher alcohols
such as cetostearyl alcohol and behenyl alcohol; silicone resins;
silicone oils; surfactants such as polyoxyethylene fatty acids
ester, sorbitan fatty acid ester, polyoxyethylene sorbitan fatty
acid ester, polyoxyethylene hydrogenated castor oil, and
polyoxyethylene polyoxypropylene block co-polymer; water-soluble
polymers such as hydroxyethyl cellulose, polyacrylic acid,
carboxyvinyl polymer, polyethylene glycol, polyvinylpyrrolidone,
and methyl cellulose; lower alcohols such as ethanol and
isopropanol; polyhydric alcohols such as glycerol, propylene
glycol, dipropylene glycol, and sorbitol; sugars such as glucose
and sucrose; inorganic powder such as anhydrous silicic acid,
magnesium aluminum silicate, and aluminum silicate; and pure water.
Examples of the diluents include lactose, corn starch, white sugar,
glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide
or the like. Examples of the binders include polyvinyl alcohol,
polyvinyl ether, methylcellulose, ethylcellulose, gum Arabic,
tragacanth, gelatin, shellac, hydroxypropyl methylcellulose,
hydroxypropyl cellulose, polyvinylpyrrolidone, polypropylene
glycol-polyoxyethylene block co-polymer, and meglumine or the like.
Examples of disintegrating agents include starch, agar, gelatin
powder, crystalline cellulose, calcium carbonate, sodium
hydrogencarbonate, calcium citrate, dextrin, pectin, calcium
carboxymethyl cellulose or the like. Examples of lubricants include
magnesium stearate, talc, polyethylene glycol, silica, hydrogenated
vegetable oil or the like. Examples of colorants include those
pharmaceutically acceptable. Examples of flavorants include cocoa
powder, peppermint camphor, aromatic powder peppermint oil, Borneo
camphor, cinnamon powder or the like. Tablets and granules may be
coated with sugar, or if required, other appropriate coatings can
be made. Solutions, such as syrups or injectable preparations, to
be administered can be formulated by combining a compound according
to the present invention or a pharmaceutically acceptable salt
thereof with a pH modulator, a solubilizing agent, an isotonizing
agent or the like, and if required, with an auxiliary solubilizing
agent, a stabilizer or the like, according to the conventional
methods. Methods for manufacturing an external preparations are not
limited and such preparations can be manufactured by the
conventional methods. Specifically, various materials typically
used for manufacturing pharmaceuticals, quasi drugs, cosmetics or
the like can be used as base materials for the external
formulation. More specifically, examples of base materials to be
used include animal and vegetable oils, minerals oils, ester oils,
wax, higher alcohols, fatty acids, silicone oil, surfactants,
phospholipids, alcohols, polyhydric alcohols, water-soluble
polymers, clay minerals, pure water or the like. Furthermore,
external preparations of the present invention can contain, as
required, pH modulators, antioxidants, chelating agents,
antibacterial/antifungal agents, colorants, odoriferous substances
or the like. But this does not limit the type of base materials
that are to be used in the external preparations of the present
invention. If required, the preparation may contain differentiation
inducers, blood flow improving agents, antimicrobial agents,
antiphologistics, cell activators, vitamins, amino acids,
humectants, keratolytic agents or the like. The amount of the base
materials listed above is adjusted within a concentration range
used for producing typical external preparations.
[0253] When administering a compound according to the present
invention or a salt thereof, or a hydrate thereof, the forms of the
compounds are not limited in particular, and the compound can be
given orally or parenterally by the conventional method. For
instance, the compound can be administered as a dosage form such as
tablets, powders, granules, capsules, syrups, troches, inhalants,
suppositories, injections, ointments, eye ointments, tapes, eye
drops, nasal drops, ear drops, cataplasms and lotions.
[0254] Dose of a pharmaceutical of the present invention can be
selected appropriately according to symptom severity, age, sex,
body weight, forms of administration, type of salts, specific type
of disease or the like.
[0255] The does varies remarkably depending on the patient's
disease, symptom severity, age and sex, drug susceptibility or the
like. An oral preparation of the present invention can be generally
administered once or several time at a dose of from 1 to 10000
mg/adult/day, preferably from 10 to 2000 mg/adult/day. An injection
of the present invention can be generally administered at a dose of
from 0.1 to 10000 mg/adult/day, preferably from 1 to 2000
mg/adult/day.
[0256] The method for preparing compounds according to the present
invention represented by Formula (I) (hereinafter referred to as
compound (1)) will be described. The compounds according to the
present invention can be prepared by the conventional organic
synthesis methods. For instance, among the compounds (1), the
compounds represented by the following Formula (1a), Formula (2a),
Formula (3a), Formula (3b), Formula (3c), Formula (3d) and Formula
(3e) (hereinafter referred to as compound (1a), compound (2a),
compound (3a), compound (3b), compound (3c), compound (3d) and
compound (3e), respectively) can be prepared by the methods
described in the following [Preparation Method 1] to [Preparation
Method 3] or the like. In addition, conversion of substituents on A
and E of compound (1) according to the present invention can be
accomplished by the methods described in the following [Preparation
Method 4-1] to [Preparation Method 4-5] or the like.
[General Synthesis Method]
[Preparation Method 1] Representative Preparation Method for
Compound (1a)
##STR00023##
[0257] [wherein each symbol has the same meaning as defined
above.]
[Preparation Method 1-1] Amidation
##STR00024##
[0258] [wherein each symbol has the same meaning as defined
above.]
[0259] Compound (1b) which is a commercially available product can
be used, or compound (1b) can also be prepared from a commercially
available product by the well known method. In addition, compound
(1b) can also be prepared by the methods described in the
preparation examples among the following examples.
[0260] Compound (1c) which is a commercially available product can
be used, or compound (1c) can also be prepared from a commercially
available product by the well known method. In addition, compound
(1c) can also be prepared by the method described in the
preparation examples among the following examples or [Preparation
Method 1-2-1], or the like.
[Step 1]
[0261] This step is a step wherein compound (1b) and compound (1c)
are condensed in a solvent using a condensing agent to obtain
compound (1a). The solvent used is not limited in particular.
Examples of the solvent in this step include halogenated
hydrocarbons such as dichloromethane and chloroform; sulfoxides
such as dimethylsulfoxide; esters such as ethyl acetate; ethers
such as tetrahydrofuran and 1,4-dioxane; amides such as
N,N-dimethylformamide, and N,N-dimethylacetamide. Examples of the
condensing agent include Bop
(1H-1,2,3-benzotriazole-1-yloxy(tri(dimethylamino))phosphonium
hexafluorophosphate), WSC
(1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride),
DCC(N,N-dicyclohexylcarbodiimide), CDI (carbonyldiimidazole),
diethylphosphoryl cyanide or the like. Compound (1c) can be used in
amounts of 1 equivalent to 1.5 equivalents based on compound (1b).
The condensing agent can be used in amounts of 1 equivalent to 1.5
equivalents based on compound (1b). In addition, it is adequate to
add from 1 equivalent to excess amount of an organic base, for
instance, triethylamine or the like, as necessary. The reaction
temperature is from room temperature to 80.degree. C., and the
reaction time is from 10 minutes to 30 hours.
[0262] Furthermore, compound (1a) can also be prepared from
compound (1b) and compound (1c) by the method described in the
other method (1), (2) or (3) below.
[0263] Other method (1): Compound (1a) can be obtained by
converting compound (1b) into an acid chloride, then, reacting the
acid chloride and compound (1c). The step for obtaining the acid
chloride is carried out by reacting from 1 equivalent to excess
amount of acid chloride synthesis reagent based on compound (1b),
without solvent or in the presence of a solvent such as,
dichloromethane, benzene, toluene or the like. Catalytic amounts of
N,N-dimethylformamide may be added in the reaction system. Examples
of the acid chloride synthesis reagent include, for instance,
thionyl chloride, oxalyl chloride, phosphorus trichloride,
phosphorus pentachloride or the like. The reaction temperature is
from room temperature to reflux temperature, and the reaction time
is from 10 minutes to 24 hours.
[0264] The step for condensing the acid chloride and compound (1c)
is carried out by reacting the acid chloride and compound (1c) in a
solvent such as, for instance, dichloromethane, tetrahydrofuran,
N,N-dimethylformamide or the like, in the presence of 1 equivalent
to 3 equivalents of base based on the acid chloride. Examples of
the base include, for instance, an organic base such as
triethylamine, pyridine and the like or an inorganic base such as
potassium carbonate, cesium carbonate or the like. Compound (1c) is
used in the amounts of 1 equivalent to 1.5 equivalents based on the
acid chloride. The reaction time is from 10 minutes to 24 hours,
and the reaction temperature is from 0.degree. C. to reflux
temperature.
[0265] Other method (2): Compound (1a) can be obtained by
converting compound (1b) into mixed acid anhydride, then, reacting
the mixed acid anhydride with compound (1c).
[0266] The step for obtaining the mixed acid anhydride is carried
out by reacting compound (1b) and, for instance, chloroformates
such as ethyl chloroformate or the like, in the presence of a base
such as, for instance, triethylamine or the like. Chloroformates
and base are used in the amounts of 1 equivalent to 2 equivalents
based on compound (1b). The reaction time is from 10 minutes to 5
hours. The reaction temperature is from 0.degree. C. to room
temperature.
[0267] The step for condensing the mixed acid anhydride and
compound (1c) is carried out by reacting the mixed acid anhydride
and compound (1c) in a solvent such as, for instance,
dichloromethane, tetrahydrofuran, N,N-dimethylformamide or the
like. Compound (1c) is used in the amounts of 1 equivalent to 1.5
equivalents based on the mixed acid anhydride. The reaction time is
from 10 minutes to 24 hours, and the reaction temperature is from
0.degree. C. to 50.degree. C.
[0268] Other method (3): Compound (1a) can be obtained by
converting compound (1b) into an active ester, then, reacting the
active ester and compound (1c). The step for obtaining the active
ester is carried out by reacting compound (1b) and an active ester
synthesis reagent in a solvent such as, for instance, 1,4-dioxane,
tetrahydrofuran or the like, in the presence of a condensing agent
such as, for instance, DCC or the like. Examples of the active
ester synthesis reagent include, for instance, N-hydroxysuccinimide
or the like. The active ester synthesis reagent and the condensing
agent are used in the amounts of 1 equivalent to 1.5 equivalents
based on compound (1b). The reaction temperature is from 0.degree.
C. to room temperature. The reaction time is from 2 hours to 24
hours.
[0269] The step for condensing the active ester and compound (1c)
is carried out by reacting the active ester and compound (1c) in a
solvent such as, for instance, dichloromethane, tetrahydrofuran,
N,N-dimethylformamide or the like. Compound (1c) is used in the
amounts of 1 equivalent to 1.5 equivalents based on the active
ester. The reaction temperature is from 0.degree. C. to 50.degree.
C., and the reaction time is from 10 minutes to 24 hours.
[0270] Note that, after [Step 1], a substituent on A and E of
compound (1a) can be converted using a well known method.
Furthermore, a substituent on A of compound (1a) can also be
converted using a method described in [Preparation Method 4-1] or
[Preparation Method 4-4], and a substituent on E of compound (1a)
can also be converted using a method described in [Preparation
Method 4-2], [Preparation Method 4-3], [Preparation Method 4-5] or
the like.
[Preparation Method 1-2-1] Preparation Method for Compound (1c)
##STR00025##
[0271] [wherein E has the same meaning as defined above; L
represents a leaving group such as a halogen atom, a
methanesulfonyloxy group or a p-toluenesulfonyloxy group]
[0272] For each compound in the above step figure, a commercially
available product can be used as is, or it can also be prepared
from a commercially available product by a well known method. In
addition, it can be prepared using the method described in the
preparation examples among the examples and in [Preparation Method
1-2-2] to [Preparation Method 1-2-6]. Further, each compound in the
above step figure can also be prepared by converting a substituent
on E using the method described in [Preparation Method 4-2] to
[Preparation Method 4-5] or the like.
[Step 1-1]
[0273] The present step is a step wherein compound (1c-1) is
reduced to obtain compound (1c-2). Examples of the reducing agent
include, for instance, sodium borohydride, lithium borohydride,
lithium aluminum hydride or the like. Examples of the solvent
include alcohols such as, for instance, methanol, ethanol or the
like, and ethers such as, for instance, tetrahydrofuran, diethyl
ether or the like. The reducing agent is used in the amounts of 1
equivalent to 10 equivalents based on compound (1c-1). The reaction
temperature is from 0.degree. C. to reflux temperature, and the
reaction time is from 5 minutes to 24 hours.
[Step 1-2]
[0274] The present step is a step wherein a hydroxyl group of
compound (1c-2) is converted into a leaving group to obtain
compound (1c-3).
[0275] When L represents a methanesulfonyloxy group or
p-toluenesulfonyloxy group, compound (1c-3) can be obtained by
reacting compound (1c-2) and methanesulfonyl chloride or
p-toluenesulfonyl chloride in a solvent such as, for instance,
dichloromethane or the like, in the presence of an organic base
such as, for instance, triethylamine or the like. The organic base
is used in the amounts of 2 equivalents to 6 equivalents based on
compound (1c-2). Methanesulfonyl chloride or p-toluenesulfonyl
chloride is used in the amounts of 1 equivalent to 3 equivalents
based on compound (1c-2). The reaction temperature is from
0.degree. C. to room temperature, and the reaction time is from 10
minutes to 24 hours.
[0276] When L represents a chlorine atom, compound (1c-3) can be
obtained by action of a chlorination reagent such as, for instance,
thionyl chloride, oxalyl chloride or the like on compound (1c-2).
The chlorination reagent is used in the amounts of 1 equivalent to
excess amount based on compound (1c-2). The reaction temperature is
from 0.degree. C. to room temperature, and the reaction time is
from 10 minutes to 24 hours.
[Step 1-3]
[0277] The present step is a step wherein compound (1c-3) and
phthalimide potassium salt are reacted to obtain compound (1c-4).
Compound (1c-4) can be obtained by reacting compound (1c-3) and
phthalimide potassium salt in a solvent such as, for instance,
N,N-dimethylformamide or the like. Phthalimide is used in the
amounts of 1 equivalent to 2 equivalents based on compound (1c-3).
The reaction temperature is from room temperature to 160.degree. C.
The reaction time is from 10 minutes to 48 hours.
[Step 1-4]
[0278] The present step is a step for obtaining compound (1c-8)
from compound (1c-4). Compound (1c-8) can be obtained by adding
from 1 equivalent to excess amount of hydrazine hydrate based on
compound (1c-4) in a solvent such as, for instance, ethanol or the
like. The reaction temperature is from 80.degree. C. to reflux
temperature, and the reaction time is from 10 minutes to 24
hours.
[Step 1-5]
[0279] The present step is a step wherein compound (1c-2) and
phthalimide are reacted to obtain compound (1c-4). Compound (1c-4)
can be obtained by reacting compound (1c-2), phthalimide,
triphenylphosphine and diethyl azodicarboxylate or diisopropyl
azodicarboxylate, in a solvent such as, for instance,
dichloromethane, tetrahydrofuran or the like. Phthalimide,
triphenylphosphine and diethyl azodicarboxylate or diisopropyl
azodicarboxylate are used in the amounts of 1 equivalent to 2
equivalents based on compound (1c-2). The reaction temperature is
from -20.degree. C. to 80.degree. C., and the reaction time is from
5 minutes to 48 hours.
[Step 1-6]
[0280] The present step is a step wherein compound (1c-3) and an
amine protected with a tert-butoxycarbonyl group are reacted to
obtain compound (1c-5). Compound (1c-5) can be obtained by reacting
compound (1c-3) and the amine protected with the
tert-butoxycarbonyl group in a solvent such as, for instance,
N,N-dimethylformamide or the like, in the presence of a base such
as, for instance, sodium hydride or the like. The base is used in
the amounts of 1 equivalent to 2 equivalents based on compound
(1c-3). The amine protected with the tert-butoxycarbonyl group is
used in the amounts of 1 equivalent to 2 equivalents based on
compound (1c-3). The reaction temperature is from room temperature
to 80.degree. C., and the reaction time is from 1 hour to 24
hours.
[Step 1-7]
[0281] The present step is a step wherein the tert-butoxycarbonyl
group of compound (1c-5) is deprotected to obtain compound (1c-8).
Compound (1c-8) can be obtained by deprotecting the
tert-butoxycarbonyl group of compound (1c-5) without a solvent or
in a solvent such as, for instance, dichloromethane or the like, in
the presence of an acid such as trifluoroacetic acid or the like in
the amounts of 2 equivalents to excess amount based on compound
(1c-5). The reaction temperature is from 0.degree. C. to 60.degree.
C., and the reaction time is from 10 minutes to 24 hours.
[Step 1-8]
[0282] The present step is a step wherein the leaving group of
compound (1c-3) is converted into an azide group to obtain compound
(1c-6). Compound (1c-6) can be obtained by reacting compound (1c-3)
and an azidation reagent such as, for instance, sodium azide,
potassium azide or the like in a solvent such as, for instance,
N,N-dimethylformamide or the like. The azidation reagent is used in
the amounts of 1 equivalent to 5 equivalents based on compound
(1c-3). The reaction temperature is from room temperature to
80.degree. C., and the reaction time is from 10 minutes to 48
hours.
[Step 1-9]
[0283] The present step is a step wherein the azide group of
compound (1c-6) is reduced to obtain compound (1c-8). Compound
(1c-8) can be obtained by carrying out catalytic hydrogenation
using Lindlar catalyst in a solvent such as, for instance, ethanol
or the like. Lindlar catalyst is used in catalytic amount to excess
amount based on compound (1c-6). The reaction temperature is from
room temperature to 80.degree. C., the reaction time is from 30
minutes to 36 hours, and the reaction pressure is from 1 atm to 4
atm.
[0284] As other method, compound (1c-8) can be obtained by action
of triphenylphosphine in a solvent such as, for instance,
dichloromethane, tetrahydrofuran or the like. Triphenylphosphine is
used in the amounts of 1.0 equivalent to 2.0 equivalents based on
compound (1c-6).
[Step 1-10]
[0285] The present step is a step wherein a formyl group of
compound (1c-1) is converted into a cyano group to obtain compound
(1c-7). Compound (1c-7) can be obtained by reacting 1 equivalent to
3 equivalent of hydroxyamine hydrochloride based on compound (1c-1)
in a solvent such as, for instance, ethanol or the like, to obtain
an oxime, then, carrying out dehydration reaction by the action of
CDI on the oxime. CDI is used in the amounts of 1 equivalent to 5
equivalents based on the oxime. The reaction temperature is from
room temperature to reflux temperature, and the reaction time is
from 30 minutes to 24 hours.
[Step 1-11]
[0286] The present step is a step wherein a cyano group of compound
(1c-7) is reduced to obtain compound (1c-8). Compound (1c-8) can be
obtained either by carrying out a reduction reaction using a
reducing agent such as, for instance, lithium aluminum hydride,
diisobutylaluminum hydride or the like, or, by carrying out
catalytic hydrogenation under hydrogen atmosphere using a catalyst
such as, for instance, Raney nickel, palladium-carbon or the like.
The solvent used is not limited, however, when carrying out
reduction reaction using the reducing agent, ethers such as, for
instance, tetrahydrofuran, diethyl ether or the like, hydrocarbons
such as, for instance, toluene or the like, are used. When carrying
out catalytic hydrogenation, alcohols such as, for instance,
methanol, ethanol, propanol or the like are used. The reducing
agent is used in the amounts of 1 equivalent to 10 equivalents
based on compound (1c-7). The reaction temperature is from room
temperature to 80.degree. C., and the reaction time is from 10
minutes to 24 hours. The reaction pressure when carrying out
catalytic hydrogenation is from 1 atm to 4 atm.
[Step 1-12]
[0287] The present step is a step for obtaining compound (1c-8)
from compound (1c-1). Compound (1c-8) can be obtained by carrying
out catalytic hydrogenation using a catalyst such as Raney nickel
or the like, in a solvent containing ammonia, under hydrogen
atmosphere. Examples of the solvent include, but are not limited
to, alcohols such as methanol, ethanol, propanol or the like. The
reaction temperature is from room temperature to 80.degree. C., the
reaction time is from 1 hour to 36 hour, and the reaction pressure
is from 1 atm to 4 atm.
[Step 1-13]
[0288] The present step is a step wherein an acetal group on
compound (1c-9) is deprotected to obtain compound (1c-1). Compound
(1c-1) can be obtained by dissolving compound (1c-9) in an organic
solvent, and by action of an aqueous solution of acid such as, for
instance, hydrochloric acid, sulfuric acid, citric acid or the
like. Examples of the solvent include, but are not limited to, for
instance, methanol, ethanol, acetonitrile, tetrahydrofuran or the
like. The reaction temperature is from room temperature to
60.degree. C., and the reaction time is from 5 minutes to 24
hours.
[Step 1-14]
[0289] The present step is a step wherein an hydroxyl group of
compound (1c-2) is converted into an azide group to obtain compound
(1c-6). Compound (1c-6) can be obtained by reacting compound (1c-2)
and diphenylphosphoryl azide in a solvent such as, for instance,
benzene, toluene or the like, in the presence of an organic base
such as, for instance, 1,8-diazabicyclo[5,4,0]undec-7-ene. The
organic base is used in the amounts of 1 equivalent to 1.5
equivalents based on compound (1c-2). Diphenylphosphoryl azide is
used in the amounts of 1 equivalent to 1.5 equivalents based on
compound (1c-2). The reaction temperature is from room temperature
to 80.degree. C., and the reaction time is from 10 minutes to 48
hours.
[Step 1-26]
[0290] The present step is a step wherein compound (1c-30) is
formylated to obtain compound (1c-1). Compound (1c-1) can be
obtained by action of 1 equivalent to 1.5 equivalents of a strong
base based on compound (1c-30) for anionization, then, reacting a
formylation agent. Examples of the solvent include, for instance,
tetrahydrofuran, diethyl ether or the like. Examples of the strong
base include, for instance, n-butyl lithium or the like. Examples
of the formylation agent include, for instance,
N,N-dimethylformamide, N-formylmorpholine or the like. The
formylation agent is used in the amounts of 1 equivalent to 2
equivalents based on compound (1c-30). The reaction temperature is
from -80.degree. C. to room temperature, and the reaction time is
from 5 minutes to 12 hours.
[Step 1-27]
[0291] The present step is a step wherein compound (1c-30) is
cyanated to obtain compound (1c-7). Compound (1c-7) can be obtained
by reacting compound (1c-30) and zinc cyanide in a solvent such as,
for instance, N,N-dimethylformamide, N-methylpyrrolidinone or the
like, under nitrogen atmosphere, in the presence of a catalyst.
Examples of the catalyst include, for instance,
tetrakis(triphenylphosphine)palladium(0) or the like. Zinc cyanide
is used in the amounts of 1 equivalent to 2 equivalents based on
compound (1c-30). The catalyst is used in the amounts of 0.01
equivalents to 0.1 equivalents based on compound (1c-30). The
reaction temperature is from 50.degree. C. to reflux temperature,
and the reaction time is from 5 minutes to 24 hours.
[0292] Other method: Compound (1c-7) can be obtained by reacting
compound (1c-30) and copper cyanide in a solvent such as, for
instance, N,N-dimethylformamide and N-methylpyrrolidinone, under
nitrogen atmosphere. Copper cyanide is used in the amounts of 1
equivalent to excess amount based on compound (1c-30). The reaction
temperature is from 50.degree. C. to reflux temperature, and the
reaction time is from 10 minutes to 72 hours.
[Preparation Method 1-2-2] Preparation Method for Compound (1c-11),
which is Compound (1c-1)
##STR00026##
[wherein Q represents an oxygen atom or a sulfur atom; Ar.sup.1
represents a C.sub.6-10 aryl group that may have 1 or 2
substituents selected from the following substituent group i or an
aromatic 5-10 membered heterocyclic group that may have 1 to 3
substituents selected from the following substituent group i.
[0293] Substituent group i: a halogen atom, a cyano group, an amino
group, a carbamoyl group, a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylcarbonyl group, a C.sub.1-6 alkoxy-carbonyl group, a C.sub.1-6
alkylsulfonyl group, a mono-C.sub.6-10 arylamino group, a
trifluoromethyl group and a trifluoromethoxy group]
[0294] Compound (1c-10) which is a commercially available product
can be used as is. Compound (1c-10-1) which is a commercially
available product can be used as is, or it can also be prepared
from a commercially available product by a well known method.
[Step 1-15]
[0295] The present step is a step wherein compound (1c-10) and
compound (1c-10-1) are reacted to obtain compound (1c-11). Compound
(1c-11) can be obtained by reacting compound (1c-10) and compound
(1c-10-1) in a solvent such as, for instance,
N,N-dimethylformamide, dimethylsulfoxide or the like, in the
presence of a base such as, for instance, sodium hydride, potassium
carbonate, cesium carbonate or the like. Compound (1c-10-1) is used
in the amounts of 1 equivalent to 2 equivalents based on compound
(1c-10). The base is used in the amounts of 1 equivalent to 2
equivalents based on compound (1c-10). The reaction temperature is
from 0.degree. C. to 80.degree. C., and the reaction time is from 5
minutes to 1 hour.
[Preparation Method 1-2-3] Preparation Method for Compound (1c-13),
which is Compound (1c-1)
##STR00027##
[wherein V represents a C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.6-10 aryl group, a 5- to 10-membered heterocyclic group, a
C.sub.3-8 cycloalkyl C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group or a 5- to 10-membered heterocycle C.sub.1-6
alkyl group; W.sup.a represents a single bond or an oxygen
atom]
[0296] Compound (1c-12) which is a commercially available product
can be used as is. Compound (1c-12-1) which is a commercially
available product can be used as is, or it can also be prepared
from a commercially available product by a well known method.
[Step 1-16]
[0297] The present step is a step wherein compound (1c-12) and
compound (1c-12-1) are reacted to obtain compound (1c-13). Examples
of the solvent include, for instance, acetic acid or the like.
Compound (1c-12-1) is used in the amount of 1 equivalent based on
compound (1c-12). The reaction temperature is from 50.degree. C. to
110.degree. C., and the reaction time is from 5 minutes to 1
hour.
[Preparation Method 1-2-4] Preparation Method for Compound (1c-15),
which is Compound (1c-7)
##STR00028##
[wherein Q and Ar.sup.1 have the same meanings as defined
above.]
[0298] Compound (1c-14) which is a commercially available product
can be used as is. Compound (1c-10-1) which is a commercially
available product can be used as is, or it can also be prepared
from a commercially available product by a well known method.
[Step 1-17]
[0299] The present step is a step wherein compound (1c-14) and
compound (1c-10-1) are reacted to obtain compound (1c-15). Compound
(1c-15) can be obtained by reacting compound (1c-14) and compound
(1c-10-1) in a solvent such as, for instance,
N,N-dimethylformamide, dimethylsulfoxide or the like, in the
presence of a base such as, for instance, sodium hydride, potassium
carbonate, cesium carbonate or the like. Compound (1c-10-1) is used
in the amounts of 1 equivalent to 2 equivalents based on compound
(1c-14). The base is used in the amounts of 2 equivalent to 3
equivalents based on compound (1c-14). The reaction temperature is
from room temperature to 80.degree. C., and the reaction time is
from 1 hour to 72 hours.
[Preparation Method 1-2-5] Preparation Method for Compound (1c-17),
Compound (1c-19), Compound (1c-21), Compound (1c-23) and Compound
(1c-25), which are Compound (1c-7)
##STR00029##
[wherein V and Ar.sup.1 have the same meanings as defined above;
R.sup.w1 represents a hydrogen atom or a C.sub.1-6 alkyl group; Hal
represents a chlorine atom, a bromine atom or an iodine atom.]
[0300] Compound (1c-16), compound (1c-18), compound (1c-20),
compound (1c-22), compound (1c-24), compound (1c-16-1), compound
(1c-10-1), compound (1c-20-1) and compound (1c-22-1) which are
commercially available products can be used as is, or they can also
be prepared from commercially available products by a well known
method.
[Step 1-18]
[0301] The present step is a step wherein compound (1c-16) and
compound (1c-16-1) are subjected to a coupling reaction to obtain
compound (1c-17). Compound (1c-17) can be obtained by reacting
compound (1c-16) and compound (1c-16-1) in a solvent such as, for
instance, tetrahydrofuran, 1,4-dioxane, methanol, ethanol, toluene,
N,N-dimethylformamide or the like, in the presence of a base such
as, for instance, potassium carbonate, cesium carbonate, potassium
phosphate or the like, and a catalyst such as, for instance,
palladium(II) acetate, tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium(0),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)nickel(II) or the
like. The base is used in the amounts of 1.5 equivalents to excess
amount based on compound (1c-16). The catalyst is used in the
amounts of 0.05 equivalents to 0.3 equivalents based on compound
(1c-16).
[Step 1-19]
[0302] The present step is a step wherein compound (1c-18) and
compound (1c-10-1) are reacted to obtain compound (1c-19). Compound
(1c-19) can be obtained by reacting compound (1c-18) and compound
(1c-10-1) in a solvent such as dimethylsulfoxide or the like, in
the presence of a base such as potassium tert-butoxide or the like.
The base is used in the amounts of 1 equivalent to excess amount
based on compound (1c-18). The reaction temperature is from
80.degree. C. to 220.degree. C., and the reaction time is from 30
minutes to 48 hours.
[Step 1-20]
[0303] The present step is a step wherein compound (1c-20) and
compound (1c-20-1) are reacted to carry out reductive amination and
to obtain compound (1c-21). Compound (1c-21) can be obtained by
reacting compound (1c-20) and compound (1c-20-1) in a solvent such
as, for instance, tetrahydrofuran, methanol, ethanol or the like,
in the presence of a reducing agent such as, for instance, lithium
aluminum hydride, sodium borohydride, sodium cyanoborohydride,
triacetoxy sodium borohydride or the like, and acetic acid. The
reducing agent is used in the amounts of 1 equivalent to 2
equivalents based on compound (1c-20). The reaction temperature is
from room temperature to 60.degree. C., and the reaction time is
from 10 minutes to 24 hours.
[Step 1-21]
[0304] The present step is a step wherein compound (1c-22) and
compound (1c-22-1) are reacted to carry out reductive amination and
to obtain compound (1c-23). Compound (1c-23) can be prepared by a
method similar to [Step 1-20].
[Step 1-22]
[0305] The present step is a step wherein compound (1c-24) and
compound (1c-10-1) are reacted to obtain compound (1c-25). Compound
(1c-25) can be obtained by reacting compound (1c-24) and compound
(1c-10-1) in a solvent such as, for instance, dimethylsulfoxide or
the like, and in the presence of a base such as, for instance,
potassium carbonate, cesium carbonate or the like. The base is used
in the amounts of 1 equivalent to 3 equivalents based on compound
(1c-24). The reaction temperature is from room temperature to
80.degree. C., and the reaction time is from 10 minutes to 24
hours.
[Preparation Method 1-2-6] Preparation Method for Compound (1c-27),
which is Compound (1c-9), and Compound (1c-29), which is Compound
(1c-1)
##STR00030##
[wherein R.sup.w1, V, Q and Hal have the same meanings as defined
above; p1 is an integer of 1 or 2; T represents a hydrogen atom
when Q represents an oxygen atom, and a bromine atom when Q
represents a sulfur atom.]
[0306] Compound (1c-26) which is a commercially available product
can be used as is. Compound (1c-26-1) and compound (1c-22-1) which
are commercially available products can be used as is, or they can
also be prepared from commercially available products by a well
known method.
[Step 1-23]
[0307] The present step is a step wherein compound (1c-26) and
compound (1c-26-1) are reacted to obtain compound (1c-27). Compound
(1c-27) can be obtained by action of 1 equivalent of a strong base
based on compound (1c-26) for anionization, then, reacting with
compound (1c-26-1). Examples of the solvent include, for instance,
tetrahydrofuran, diethyl ether or the like. Examples of the strong
base include, for instance, n-butyl lithium or the like. The
reaction temperature is from -80.degree. C. to room
temperature.
[Step 1-24]
[0308] The present step is a step wherein compound (1c-26) and
compound (1c-22-1) are reacted to obtain compound (1c-28). Compound
(1c-28) can be obtained by action of 1 equivalent of a strong base
based on compound (1c-26) for anionization, then, reacting with
compound (1c-22-1). Examples of the solvent include, for instance,
tetrahydrofuran, diethyl ether or the like. Examples of the strong
base include, for instance, n-butyl lithium or the like. In
addition, 0.1 equivalent to 1 equivalent of copper(I) iodide or
copper(I) bromide based on compound (1c-26) may be added in the
reaction system. The reaction temperature is from -80.degree. C. to
room temperature.
[Step 1-25]
[0309] The present step is a step wherein elimination of a hydroxyl
group and deprotection of an acetal group of compound (1c-28) are
carried out simultaneously to obtain compound (1c-29). When
compound (1c-28) is treated with trimethylsilyliodide, elimination
of the hydroxyl group and deprotection of the acetal group occur
simultaneously, to give compound (1c-29). Trimethylsilyliodide is
used in the amounts of 2 equivalents to 6 equivalents based on
compound (1c-28). In addition, trimethylsilyliodide may be prepared
from trimethylsilyl chloride and sodium iodide in the reaction
solution and used as is. Examples of the solvent include, for
instance, acetonitrile or the like. The reaction temperature is
from 0.degree. C. to 60.degree. C., and the reaction time is from 5
minutes to 6 hours.
[0310] Other method: Compound (1c-29) can be obtained by converting
the hydroxyl group of compound (1c-28) into the acetyl group, then,
eliminating the acetyl group, and carrying out deprotection of an
acetal group. Conversion of the hydroxyl group into the acetyl
group can be carried out by using an acetylating reagent such as,
for instance, acetic anhydride, acetyl chloride or the like. A base
such as, for instance, N,N-dimethylaminopyridine, triethylamine,
pyridine or the like, in the amounts of 1 equivalent to excess
amount based on compound (1c-28) may be added in the reaction
system. Examples of the solvent include, for instance,
dichloromethane, ethyl acetate, N,N-dimethylformamide or the like.
In addition, pyridine, which is added as a base, may be used
directly as a solvent. An acetylating reagent is used in the
amounts of 1 equivalent to excess amount based on compound (1c-28).
The reaction temperature is from 0.degree. C. to 60.degree. C., and
the reaction time is from 1 hour to 36 hours. Elimination of the
acetyl group can be carried out, for instance, under hydrogen
atmosphere, in a solvent such as, for instance, ethanol, methanol
or the like, and using a catalyst such as for instance,
palladium-carbon, Raney nickel or the like. The reaction
temperature is from room temperature to 80.degree. C., and the
reaction time is from 5 hours to 36 hours. Deprotection of the
acetal group can be carried out by an analogous method to [Step
1-13].
[Preparation Method 2] Representative Preparation Method for
Compound (2a)
##STR00031##
[0311] [wherein each symbol has the same meaning as defined
above.]
[Preparation Method 2-1] Amidation
##STR00032##
[0312] [where each symbol has the same meaning as defined
above.]
[0313] Compound (2b) which is a commercially available product can
be used as is, or it can also be prepared from a commercially
available product by a well known method. In addition, it can also
be prepared using a method described in the preparation examples
among the examples.
[0314] Compound (2c) which is a commercially available product can
be used as is, or it can also be prepared from a commercially
available product by a well known method. In addition, it can also
be prepared by a method described in the preparation examples among
the examples or [Preparation Method 2-2-1] or the like.
[Step 2]
[0315] Compound (2a) is obtained by condensing compound (2b) and
compound (2c) in a solvent using a condensing agent. Compound (2a)
can be prepared by an analogous method to [Step 1].
[Preparation Method 2-2-1] Preparation Method for Compound (2c-2),
which is Compound (2c), and Compound (2c-5), which is Compound
(2c)
##STR00033##
[wherein E has the same meaning as defined above; p2 represents an
integer from 0 to 2.]
[0316] Compound (2c-1) which is a commercially available product
can be used as is, or it can also be prepared from a commercially
available product by a well known method.
[Step 2-1]
[0317] The present step is a step wherein compound (2c-1) is
oxidized to obtain compound (2c-2). Compound (2c-2) can be obtained
by dissolving compound (2c-1) in a mixed solvent of tert-butanol
and water (preferable mixing ratio being tert-butanol:water=10:1 to
2:1), and reacting with 3 equivalents to 10 equivalents of
2-methyl-2-butene, 1 equivalent to 2 equivalents of sodium chlorite
and 1 equivalent to 2 equivalents of sodium dihydrogenphosphate
based on compound (2c-1). The reaction temperature is the room
temperature, and the reaction time is from 10 minutes to 2
hours.
[0318] In addition, compound (2c-2) can also be prepared compound
(2c-1) by a method described in the following other method (1), (2)
or (3).
[0319] Other method (1): Compound (2c-2) can be obtained by
dissolving compound (2c-1) in a mixed solvent of tert-butanol and
water (preferable mixing ratio being tert-butanol:water=10:1 to
2:1), and reacting with 1 equivalent to 2 equivalents of potassium
permanganate and 1 equivalent to 2 equivalents of potassium
dihydrogenphosphate based on compound (2c-1). The reaction
temperature is room temperature, and the reaction time is from 10
minutes to 2 hours.
[0320] Other method (2): Compound (2c-2) can be obtained by
dissolving compound (2c-1) in a sodium hydroxide aqueous solution
and ethanol, and reacting with 1.5 equivalents to 2 equivalents of
silver nitrate based on compound (2c-1). The reaction temperature
is from 0.degree. C. to room temperature, and the reaction time is
from 5 minutes to 24 hours.
[0321] Other method (3): Compound (2c-2) can also be obtained by
dissolving compound (2c-1) in methanol and N,N-dimethylformamide,
and reacting with 1.0 equivalent to 1.5 equivalents of pyridinium
dichromate (PDC) based on compound (2c-1). The reaction temperature
is from -10.degree. C. to 40.degree. C., and the reaction time is
from 10 minutes to 24 hours.
[Step 2-2]
[0322] The present step is a step wherein compound (2c-1) is
extended by one carbon to obtain compound (2c-3). Compound (2c-3)
can be obtained in a solvent such as, for instance,
tetrahydrofuran, 1,4-dioxane or the like, at 10.degree. C. to room
temperature, by reacting 2 equivalents to 10 equivalents of
methoxymethyl triphenylphosphonium chloride and 2 equivalents to 10
equivalents of base (for instance, potassium tert-butoxide) based
on compound (2c-1) for 30 minutes to 2 hours, then adding compound
(2c-1) to this reaction solution, and reacting at room temperature
to reflux temperature for 30 minutes to 4 hours.
[Step 2-3]
[0323] The present step is a step wherein compound (2c-3) is
hydrolyzed to obtain compound (2c-4). Compound (2c-4) can be
obtained by dissolving compound (2c-3) in a solvent such as, for
instance, hydrous methanol, hydrous 1,4-dioxane or the like, adding
an acid such as, for instance, hydrochloric acid, p-toluenesulfonic
acid or the like, and reacting at 80.degree. C. to reflux
temperature for 10 minutes to 16 hours.
[Step 2-4]
[0324] The present step is a step wherein compound (2c-4) is
oxidized to obtain compound (2c-5). Compound (2c-5) can be prepared
by an analogous method to [Step 2-1].
[Preparation Method 2-2-2] Preparation Method for Compound (2c-7),
which is Compound (2c)
##STR00034##
[wherein E and n have the same meanings as defined above.]
[0325] Compound (2c-6) which is a commercially available product
can be used as is, or it can also be prepared from a commercially
available product by a well known method.
[Step 2-5]
[0326] The present step is a step wherein compound (2c-6) is
hydrolyzed to obtain compound (2c-7). Compound (2c-7) can be
obtained in an aqueous solution of acid such as, for instance,
hydrochloric acid and sulfuric acid or the like, or, in an aqueous
solution of alkali such as, for instance, sodium hydroxide,
potassium hydroxide or the like, by hydrolyzing compound (2c-6).
The reaction temperature is from room temperature to reflux
temperature, and the reaction time is from 10 minutes to 10
hours.
[Preparation Method 3] Representative Preparation Method for
Compound (3a), Compound (3b), Compound (3c), Compound (3d) and
Compound (3e)
##STR00035##
[0327] [wherein each symbol has the same meaning as defined
above.]
[Preparation Method 3-1] Representative Preparation Method for
Compound (3a) and Compound (3b)
##STR00036##
[0328] [wherein A, R.sup.Y, n, E and Hal have the same meanings as
defined above; G.sup.1 represent a C.sub.1-6 alkyl group that may
be substituted with a C.sub.6-10 aryl group.]
[Step 3-1]
[0329] The present process is a process wherein compound (1a) is
converted into thioamide to obtain compound (3a). Compound (3a) can
be obtained by reacting compound (1a) and
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide
(Lawesson's reagent). Examples of the solvent include, for
instance, tetrahydrofuran, toluene or the like. Lawesson's reagent
is used in the amounts of 1 equivalent to 5 equivalents based on
compound (1a). The reaction temperature is from room temperature to
reflux temperature, and the reaction time is from 10 minutes to 48
hours.
[Step 3-2]
[0330] The present step is a step wherein compound (3a) is
converted into thioimidate to obtain compound (3a-2). Compound
(3a-2) can be obtained by reacting compound (3a) and compound
(3a-1). Examples of the solvent include, for instance,
acetonitrile, tetrahydrofuran, toluene or the like. For compound
(3a-1), preferably, alkylating agents such as, for instance,
iodomethane, benzyl bromide, (bromomethyl)naphthalene or the like
can be used. Compound (3a-1) is used in the amounts of 1 equivalent
to 10 equivalents based on compound (3a). The reaction temperature
is from room temperature to reflux temperature, and the reaction
time is from 10 minutes to 48 hours.
[Step 3-3]
[0331] The present step is a step wherein compound (3a-2) is
converted into amidine to obtain compound (3b). Compound (3b) can
be obtained by reacting compound (3a-2) and compound (3a-3).
Examples of the solvent include, for instance, methanol, ethanol,
N,N-dimethylformamide, N-methylpyrrolidinone or the like. Examples
of compound (3a-3) include, preferably, alkoxy amines such as, for
instance, methoxylamine, benzyloxy amine, cyanamide or the like.
Compound (3a-3) is used in the amounts of 1 equivalent to 10
equivalents based on compound (3a-2). The reaction temperature is
from room temperature to reflux temperature, and the reaction time
is from 10 minutes to 48 hours.
[Preparation Method 3-2] Representative Preparation Method for
Compound (3c)
##STR00037##
[0332] [wherein each symbol has the same meaning as defined
above.]
[0333] Compound (3c-1) can be prepared using the method described
in [Preparation Method 1-1]. Compound (3c-2) and compound (3c-3)
which are commercially available products can be used as is, or
they can also be prepared from commercially available products by a
well known method.
[Step 3-4]
[0334] The present step is a step wherein compound (3c-1) is
reduced to obtain compound (3c). Compound (3c) can be obtained by
reacting compound (3c-1) in a solvent such as, for instance,
tetrahydrofuran or the like, in the presence of a reducing agent
such as, for instance, lithium aluminum hydride or the like. The
reducing agent is used in the amounts of 1 equivalent to 5
equivalents based on compound (3c-1). The reaction temperature is
from room temperature to reflux temperature, and the reaction time
is from 1 hour to 24 hours.
[Step 3-5]
[0335] The present step is a step wherein compound (3c-2) and
compound (3c-3) are reacted to carry out reductive amination and
obtain compound (3c). Compound (3c) can be prepared by an analogous
method to [Step 1-20].
[Preparation Method 3-3] Representative Preparation Method for
Compound (3d)
##STR00038##
[0336] [wherein each symbol has the same meaning as defined
above.]
[0337] Compound (3d-1) which is a commercially available product
can be used as is, or it can also be prepared from a commercially
available product by a well known method.
[Step 3-6]
[0338] The present step is a step wherein compound (2a) is reduced
to obtain compound (3d). Compound (3d) can be prepared by an
analogous method to [Step 3-4].
[Step 3-7]
[0339] The present step is a step wherein compound (2b) and
compound (3d-1) are reacted to carry out reductive amination and
obtain compound (3d). Compound (3d) can be prepared by an analogous
method to [Step 1-20].
[Preparation Method 3-3-1] Preparation Method for Compound (3d-3),
which is Compound (3d)
##STR00039##
[wherein each symbol has the same meaning as defined above.]
[Step 3-8]
[0340] The present step is a step wherein compound (3d-2) and
cyanamide are reacted to obtain compound (3d-3). Examples of the
solvent include, for instance, N,N-dimethylformamide,
N-methylpyrrolidinone or the like. Cyanamide is used in the amounts
of 2 equivalent to 5 equivalents based on compound (3d-2). The
reaction temperature is from room temperature to reflux
temperature, and the reaction time is from 10 minutes to 48
hours.
[Preparation Method 3-4] Representative Preparation Method for
Compound (3e)
##STR00040##
[0341] [wherein each symbol has the same meaning as defined
above.]
[0342] Compound (3e-1), compound (3c-2) and compound (3e-3) which
are commercially available products can be used as is, or they can
also be prepared from commercially available products by a well
known method.
[Step 3-9]
[0343] The present step is a step wherein compound (3e-1) is
converted into Grignard reagent, then, the Grignard reagent and
compound (3c-2) are reacted to obtain compound (3e-2). Compound
(3e-2) can be obtained by preparing the Grignard reagent of
compound (3e-1) in a solvent such as, for instance, tetrahydrofuran
or the like, in the presence of metallic magnesium and an initiator
such as, for instance, dibromoethane or the like, and reacting the
Grignard reagent and compound (3c-2). Metallic magnesium is used in
the amounts of 1 equivalent to 1.2 equivalents based on compound
(3e-1). The initiator is used in catalytic amounts based on
compound (3e-1). The reaction temperature is from 0.degree. C. to
reflux temperature, and the reaction time is from 10 minutes to 24
hours.
[Step 3-10]
[0344] The present step is a step wherein a hydroxyl group of
compound (3e-2) is oxidized to obtain compound (3e). Compound (3e)
can be obtained by reacting compound (3e-2) in a solvent such as,
for instance, chloroform, acetone or the like, in the presence of
an oxidizing agent such as, for instance, manganese dioxide or the
like. The oxidizing agent is used in the amounts of 2 equivalents
to 10 equivalents based on compound (3e-2). The reaction
temperature is from room temperature to reflux temperature, and the
reaction time is from 10 minutes to 24 hours.
[Step 3-11]
[0345] The present step is a step wherein compound (3e-1) is
converted into Grignard reagent, then, the Grignard reagent and
compound (3e-3) are reacted, and hydrolysis is carried out to
obtain compound (3e). Compound (3e) can be obtained by preparing
the Grignard reagent of compound (3e-1) in a solvent such as, for
instance, tetrahydrofuran or the like, in the presence of metallic
magnesium and an initiator such as, for instance, dibromoethane or
the like, reacting the Grignard reagent and compound (3c-2), and
hydrolyzing in the presence of acid. Metallic magnesium is used in
the amounts of 1 equivalent to 1.2 equivalents based on compound
(3e-1). The initiator is used in catalytic amounts based on
compound (3e-1). The reaction temperature is from 0.degree. C. to
reflux temperature, and the reaction time is from 10 minutes to 24
hours.
[Preparation Method 4-1] Conversion of Substituent on A in Compound
(1) (with the Proviso that A Represents an Aromatic 5- and
10-Membered Heterocyclic Group Containing at Least 1 Nitrogen
Atom)-1
##STR00041##
[wherein A, X (with the proviso that the case where X represents a
group represented by the formula --CH.sub.2--NH--(CH.sub.2).sub.n--
or a group represented by the formula
--NH--CH.sub.2--(CH.sub.2).sub.n-- are excluded; n represents an
integer from 0 to 3), E and Hal have the same meanings as defined
above; R.sup.N1 represents a C.sub.1-6 alkyl group, a C.sub.2-6
alkenyl group or a C.sub.2-6 alkynyl group; R.sup.N2 represents a
hydrogen atom or a C.sub.1-6 alkyl group; R.sup.a represents a
C.sub.2-6 alkenyl group, a C.sub.6-10 aryl group or an aromatic 5-
and 10-membered heterocyclic group; R.sup.b1 and R.sup.b2 may be
the same or different from each other, and represent a hydrogen
atom or a C.sub.1-6 alkyl group, or form a cyclic boric acid ester
together; R.sup.c1, R.sup.c2, R.sup.c3 and R.sup.c4 may be the same
or different from each other, and represent a hydrogen atom, a
C.sub.1-6 alkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.3-8 cycloalkyl group, a C.sub.6-10 aryl
group or a 5- to 10-membered heterocyclic group.]
[0346] Compound (4-1-1), compound (4-1-2), compound (4-1-3),
compound (4-1-4), compound (4-1-5) and compound (4-1-6) which are
commercially available products can be used as is, or they can also
be prepared from commercially available products by a well known
method.
[Step 4-1]
[0347] The present step is a step wherein compound (4-1) and
compound (4-1-1) are reacted to obtain compound (4-2). Examples of
the solvent include, for instance, dimethylsulfoxide,
tetrahydrofuran, toluene, acetonitrile, N,N-dimethylformamide or
the like. In addition, the reaction can also be carried out without
the solvent. The reaction is preferably carried out in a sealed
tube; the reaction time is from 1 hour to 60 hours, and the
reaction temperature is from 50.degree. C. to 200.degree. C. Note
that, an organic base such as, for instance,
N,N-diisopropylethylamine, triethylamine, pyridine,
1,8-diazabicyclo[5,4,0]undec-7-ene, inorganic base such as, for
instance, potassium carbonate, sodium carbonate, can be added in
the amounts of 2 equivalents to excess amount based on compound
(4-1).
[Step 4-2]
[0348] The present step is a step wherein compound (4-1) and
compound (4-1-2) are reacted to obtain compound (4-3). Compound
(4-3) can be obtained by reacting compound (4-1) and compound
(4-1-2) in the presence of a catalyst. Examples of the catalyst
include tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II) or the like. Examples
of the solvent include, toluene, 1,4-dioxane, xylene or the like.
Compound (4-1-2) is used in the amounts of 2 equivalent to 3
equivalents based on compound (4-1). The catalyst is used in the
amounts of 0.05 equivalents to 0.3 equivalents based on compound
(4-1). The reaction temperature is from 100.degree. C. to
140.degree. C., and the reaction time is from 1 hour to 24
hours.
[Step 4-3]
[0349] The present step is a step wherein compound (4-1) and
compound (4-1-3) are reacted to obtain compound (4-3). Compound
(4-3) can be obtained by reacting compound (4-1) and compound
(4-1-3) in the presence of a catalyst. Examples of the catalyst
include, for instance,
dichloro(1,1'-bis(diphenylphosphino)propane)nickel(II),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)nickel(II),
tetrakis(triphenylphosphine)palladium(0) or the like. Examples of
the solvent include, for instance, tetrahydrofuran, 1,4-dioxane or
the like. Compound (4-1-3) is used in the amounts of 3 equivalents
to excess amount based on compound (4-1). The catalyst is used in
the amounts of 0.05 equivalents to 0.3 equivalents based on
compound (4-1). The reaction temperature is from 0.degree. C. to
reflux temperature, and the reaction time is from 5 minutes to 24
hours.
[Step 4-4]
[0350] The present step is a step wherein compound (4-1) and
compound (4-1-4) are reacted to obtain compound (4-3). Compound
(4-3) can be obtained by reacting compound (4-1) and compound
(4-1-4) in the presence of a catalyst and a base. Examples of the
catalyst include, for instance, palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylideneacetone) dipalladium(0) or the like. To obtain
satisfactory results, a phosphorus ligand (for instance,
triphenylphosphine, tri-tert-butylphosphine or the like) may be
added in the amounts of 0.25 equivalents to 1.5 equivalents based
on compound (4-1). Examples of the basic include, for instance,
potassium carbonate, sodium carbonate, cesium carbonate, potassium
fluoride, cesium fluoride, potassium phosphate, sodium hydroxide,
barium hydroxide, potassium hydroxide or the like. The present
reaction is preferably carried out under an inert gas atmosphere
such as, for instance, nitrogen gas and argon gas. Examples of the
solvent include, for instance, tetrahydrofuran, 1,4-dioxane,
methanol, ethanol, toluene, water or the like. Depending on the
reagent used, quaternary ammonium salt such as tetrabutylammonium
bromide can be added. The catalyst is used in the amounts of 0.05
equivalents to 0.3 equivalents based on compound (4-1). The base is
used in the amounts of 2 equivalents to excess amount based on
compound (4-1). The reaction temperature is from room temperature
to reflux temperature, and the reaction time is from 30 minutes to
24 hours.
[Step 4-5]
[0351] The present step is a step wherein compound (4-1) and
compound (4-1-5) are reacted to obtain compound (4-4). Compound
(4-4) can be obtained by reacting compound (4-1) and compound
(4-1-5) in the presence of a catalyst and a base. Examples of the
catalyst include, for instance, palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylideneacetone) dipalladium (0) or the like. Examples of
the base include, for instance, triethylamine,
N,N-diisopropylethylamine, pyridine or the like. Examples of the
solvent include, for instance, tetrahydrofuran, acetonitrile,
1,4-dioxane, N,N-dimethylformamide, N-methylpyrrolidinone,
dimethylsulfoxide, toluene or the like. In addition, to obtain
satisfactory results, 0.1 equivalents to 0.3 equivalents of copper
(I) iodide or tetrabutylammonium fluoride may be added based on
compound (4-1). Compound (4-1-5) is used in the amounts of 1
equivalent to 5 equivalents based on compound (4-1). The catalyst
is used in the amounts of 0.05 equivalents to 0.3 equivalents based
on compound (4-1). The base is used in the amounts of 2 equivalents
to 5 equivalents based on compound (4-1). The reaction temperature
is from room temperature to 150.degree. C., and the reaction time
is from 30 minutes to 24 hours.
[Step 4-6]
[0352] The present step is a step wherein a triple bond in compound
(4-4) is reduced into a double bond to obtain compound (4-5).
Compound (4-5) can be obtained using a catalyst such as, for
instance, Lindlar catalyst, palladium-barium sulfate or the like,
in a solvent such as, for instance, tetrahydrofuran, ethyl acetate,
acetonitrile, methanol, ethanol or the like, under hydrogen
atmosphere. The preferable solvent is ethyl acetate. To obtain
satisfactory results, 0.1 equivalents to 1 equivalents of quinoline
may be added based on compound (4-4). The catalyst is used in
catalytic amount to excess amount based on compound (4-4). The
reaction temperature is room temperature, the reaction time is from
15 minutes to 24 hours, and reaction pressure is from 1 atm to 4
atm.
[Step 4-7]
[0353] The present step is a step wherein compound (4-5) is reduced
to obtain compound (4-6). Compound (4-6) can be obtained using a
catalyst such as, for instance, palladium-carbon, Raney nickel,
platinum dioxide or the like, in a solvent such as, for instance,
tetrahydrofuran, ethyl acetate, acetonitrile, methanol, ethanol or
the like, under hydrogen atmosphere. The catalyst is used in
catalytic amount to excess amount based on compound (4-5). The
reaction temperature is room temperature, the reaction time is from
5 minutes to 24 hours, and the reaction pressure is from 1 atm to 4
atm.
[Step 4-8]
[0354] The present step is a step wherein compound (4-4) is reduced
to obtain compound (4-6). Compound (4-6) can be prepared by an
analogous method to [Step 4-7].
[Step 4-9]
[0355] The present step is a step wherein compound (4-1) and
compound (4-1-6) are reacted to obtain compound (4-7). Compound
(4-7) can be obtained by reacting compound (4-1) and compound
(4-1-6) in the presence of a catalyst and a base. Examples of the
catalyst include, for instance, palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II),
tris(dibenzylideneacetone)dipalladium (0) or the like. Examples of
the base include, for instance, triethylamine,
N,N-diisopropylethylamine, N,N-dicyclohexylmethylamine or the like.
Examples of the solvent include, for instance, acetonitrile,
tetrahydrofuran, 1,4-dioxane, benzene, toluene, xylene,
N,N-dimethylformamide, N-methylpyrrolidinone or the like. In
addition, to obtain satisfactory results, 0.25 equivalents to 1.5
equivalents of a phosphorus ligand (for instance,
triphenylphosphine, tri-tert-butylphosphine,
2-(di-tert-butylphosphino)biphenyl or the like) may be added based
on compound (4-1). Compound (4-1-6) is used in the amounts of 1
equivalent to 4 equivalents based on compound (4-1). The catalyst
is used in the amounts of 0.05 equivalents to 0.3 equivalents based
on compound (4-1). The base is used in the amounts of 2 equivalents
to 5 equivalents based on compound (4-1). The reaction temperature
is from room temperature to 150.degree. C., the reaction time is
from 5 minutes to 24 hours.
[Step 4-10]
[0356] The present step is a step wherein compound (4-7) is reduced
to obtain compound (4-8). Compound (4-8) can be prepared by an
analogous method to [Step 4-7].
[Preparation Method 4-2] Conversion of Substituent on E in Compound
(1)-1
##STR00042##
[0357] [wherein A, X (with the proviso that the case where X
represents a group represented by the formula
--CH.sub.2--NH--(CH.sub.2).sub.n-- or a group represented by the
formula --NH--CH.sub.2--(CH.sub.2).sub.n-- are excluded; n
represents an integer from 0 to 3), E, Hal, R.sup.a, R.sup.b1,
R.sup.b2, R.sup.c1, R.sup.c2, R.sup.c3, R.sup.c4, R.sup.w1, V and
Ar.sup.1 have the same meanings as defined above.]
[0358] Compound (4-1-2), compound (4-1-3), compound (4-1-4),
compound (4-1-5), compound (4-1-6), compound (1c-20-1) and compound
(1c-10-1) which are commercially available products can be used as
is, or they can also be prepared from commercially available
products by a well known method.
[Step 4-11]
[0359] The present step is a step wherein compound (4-9) and
compound (4-1-2) are reacted to obtain compound (4-10). Compound
(4-10) can be prepared by an analogous method to [Step 4-2].
[Step 4-12]
[0360] The present step is a step wherein compound (4-9) and
compound (4-1-3) are reacted to obtain compound (4-10). Compound
(4-10) can be prepared by an analogous method to [Step 4-3].
[Step 4-13]
[0361] The present step is a step wherein compound (4-9) and
compound (4-1-4) are reacted to obtain compound (4-10). Compound
(4-10) can be prepared by an analogous method to [Step 4-4].
[Step 4-14]
[0362] The present step is a step wherein compound (4-9) and
compound (4-1-5) are reacted to obtain compound (4-11). Compound
(4-11) can be prepared by an analogous method to [Step 4-5].
[Step 4-15]
[0363] The present step is a step wherein a triple bond of compound
(4-11) is reduced into a double bond to obtain compound (4-12).
Compound (4-12) can be prepared by an analogous method to [Step
4-6].
[Step 4-16]
[0364] The present step is a step wherein compound (4-12) is
reduced to obtain compound (4-13). Compound (4-13) can be prepared
by an analogous method to [Step 4-7].
[Step 4-17]
[0365] The present step is a step wherein compound (4-11) is
reduced to obtain compound (4-13). Compound (4-13) can be prepared
by an analogous method to [Step 4-8].
[Step 4-18]
[0366] The present step is a step wherein compound (4-9) and
compound (4-1-6) are reacted to obtain compound (4-14). Compound
(4-14) can be prepared by an analogous method to [Step 4-9].
[Step 4-19]
[0367] The present step is a step wherein compound (4-14) is
reduced to obtain compound (4-15). Compound (4-15) can be prepared
by an analogous method to [Step 4-10].
[Step 4-20]
[0368] The present step is a step wherein compound (4-9) and
compound (1c-20-1) are reacted to obtain compound (4-16). Compound
(4-16) can be obtained by reacting compound (4-9) and compound
(1c-20-1) in a solvent such as, for instance, tetrahydrofuran,
benzene, toluene, xylene or the like, in the presence of a catalyst
such as for instance, tris(dibenzylideneacetone)dipalladium(0),
dichloro(1,1'-bis(diphenylphosphino)ferrocene)palladium(II),
palladium(II) acetate, a phosphorus ligand such as, for instance,
2,2-bis(diphenylphosphino)-1,1'-binaphthyl, and a base such as, for
instance, sodium tert-butoxide. Compound (1c-20-1) is used in the
amounts of 1 equivalent to 3 equivalents based on compound (4-9).
Catalyst is used in the amounts of 0.05 equivalents to 0.3
equivalents based on compound (4-9). The base is used in the
amounts of 1.5 equivalent to excess amount based on compound (4-9).
The phosphorus ligand is used in the amounts of 0.25 equivalents to
1.5 equivalents based on compound (4-9). The reaction temperature
is 50.degree. C. to reflux temperature, and the reaction time is
from 1 hour to 48 hours.
[Step 4-21]
[0369] The present step is a step wherein compound (4-9) and
compound (1c-10-1) are reacted to obtain compound (4-17). Compound
(4-17) can be obtained by reacting compound (4-9) and compound
(1c-10-1) in a solvent such as, for instance, tetrahydrofuran,
toluene or the like, in the presence of a catalyst such as, for
instance, copper(I) chloride, copper(I) iodide or the like, and a
base such as, for instance, potassium carbonate, cesium carbonate,
potassium phosphate, pyridine or the like. Compound (1c-10-1) is
used in the amounts of 1 equivalent to 3 equivalents based on
compound (4-9). Catalyst is used in the amounts of 0.5 equivalents
to 3 equivalents based on compound (4-9). The base is used in the
amounts of 2 equivalents to 10 equivalents based on compound (4-9).
The reaction temperature is 50.degree. C. to reflux temperature,
and the reaction time is from 1 hour to 48 hours.
[0370] Other Method for [Step 4-20] and [Step 4-21]
[0371] When E represent a furyl group or a thienyl group, compound
(4-16) or compound (4-17) can be obtained respectively by reacting
compound (4-9) and compound (1c-20-1) or compound (1c-10-1) in a
solvent such as, for instance, dimethylsulfoxide,
N-methylpyrrolidone or the like, in the presence of a catalyst such
as, for instance, copper(I) chloride or the like, a base such as,
for instance, cesium carbonate and
2,2,6,6-tetramethyl-3,5-heptanedione. Compound (1c-20-1) or
compound (1c-10-1) is used in the amounts of 1 equivalent to 3
equivalents based on compound (4-9). The catalyst is used in the
amounts of 0.5 equivalents to 3 equivalents based on compound
(4-9). The base is used in the amounts of 2 equivalents to 10
equivalents based on compound (4-9). The reaction temperature is
80.degree. C. to reflux temperature, and the reaction time is from
1 hour to 24 hours.
[Preparation Method 4-3] Conversion of Substituent on E in Compound
(1)-2
##STR00043##
[0372] [wherein A, X (with the proviso that the cases where X
represents a group represented by the formula
--CH.sub.2--NH--(CH.sub.2).sub.n-- or a group represented by the
formula --NH--CH.sub.2--(CH.sub.2).sub.n-- are excluded; n
represents an integer from 0 to 3), E, R.sup.a, Hal, R.sup.w1, p1
and V have the same meanings as defined above.]
[0373] Compound (4-18-1) and compound (1c-26-1) which are
commercially available products can be used as is, or they can also
be prepared from commercially available products by a well known
method.
[Step 4-22]
[0374] The present step is a step wherein compound (4-18) and
compound (4-18-1) are reacted to obtain compound (4-19). Compound
(4-19) can be obtained by reacting compound (4-18) and compound
(4-18-1) in the presence of a catalyst and a base. Examples of the
catalyst include a cuprous catalyst such as, for instance, copper
(II) acetate. Examples of the base include, for instance,
triethylamine, N,N-diisopropylethylamine or the like. Examples of
the solvent include, for instance, dichloromethane,
tetrahydrofuran, toluene or the like. It is preferable to use
dichloromethane. The present reaction is preferably carried out in
the presence of oxygen. To obtain satisfactory results, molecular
sieves 4A may be added. Compound (4-18-1) is used in the amounts of
1 equivalent to 4 equivalents based on compound (4-18). The
catalyst is used in the amounts of 0.1 equivalents to 0.3
equivalents based on compound (4-18). The base is used in the
amounts of 2 equivalents to excess amount based on compound (4-18).
The reaction temperature is from room temperature to 50.degree. C.,
the reaction time is from 24 hours to 5 days.
[Step 4-23]
[0375] The present step is a step wherein compound (4-18) and
compound (1c-26-1) are reacted to obtain compound (4-20). Compound
(4-20) can be obtained by reacting compound (4-18) and compound
(1c-26-1) in a solvent such as, for instance,
N,N-dimethylformamide, N-methylpyrrolidinone, tetrahydrofuran or
the like, in the presence of a base such as, for instance,
potassium carbonate, cesium carbonate, sodium hydride or the like.
To obtain satisfactory results, a catalytic amount of sodium iodide
or potassium iodide may be added. The reaction temperature is from
room temperature to 160.degree. C., and the reaction time is from
10 minutes to 48 hours.
[0376] Another method is based on the technique that uses the
Mitsunobu reaction. Compound (4-20) can be obtained by reacting
compound (4-18), compound (1c-26-1), triphenylphosphine and diethyl
azodicarboxylate or diisopropyl azodicarboxylate in a solvent such
as, for instance, dichloromethane, tetrahydrofuran or the like.
Compound (1c-26-1) is used in the amounts of 1 equivalent to 1.5
equivalents based on compound (4-18). Triphenylphosphine is used in
the amounts of 1 equivalent to 1.5 equivalents based on compound
(4-18). Diethyl azodicarboxylate or diisopropyl azodicarboxylate is
used in the amounts of 1 equivalent to 1.5 equivalents based on
compound (4-18). The reaction temperature is from room temperature
to reflux temperature, and the reaction time is from 5 minutes to
24 hours.
[Preparation Method 4-4] Conversion of Substituent on A in Compound
(1) (with the Proviso that A Represents an Aromatic 5- to
10-Membered Heterocyclic Group Containing at Least 1 Nitrogen
Atom)-2
##STR00044##
[wherein A, X (with the proviso that the cases where X represents a
group represented by the formula --CH.sub.2--NH--(CH.sub.2).sub.n--
or a group represented by the formula
--NH--CH.sub.2--(CH.sub.2).sub.n-- are excluded; n represents an
integer from 0 to 3), E and Hal have the same meanings as defined
above; R.sup.d and R.sup.e are the same or different from each
other, and represent C.sub.1-6 alkyl groups.]
[Step 4-24]
[0377] The present step is a step wherein compound (4-1) and
compound (4-24-1) are reacted to obtain compound (4-21). The
present reaction is preferably carried out under an inert gas
atmosphere; the solvent for use varies depending on the starting
materials and reagents used; for instance, N-methylpyrrolidinone,
1,4-dioxane or the like can be used. Examples of the catalyst
include, for instance, palladium(II) acetate,
tetrakis(triphenylphosphine)palladium(0),
dichlorobis(triphenylphosphine)palladium(II) or
tris(dibenzylideneacetone)dipalladium(0) or the like. To obtain
satisfactory results, of phosphorus ligand, preferably, for
instance, triphenylphosphine, tri-tert-butylphosphine,
diphenylphosphino ferrocene or the like may be added. Compound
(4-24-1) is used in the amounts of 1 equivalent to 10 equivalents
based on compound (4-1). The catalyst is used in the amounts of
0.001 equivalents to 0.2 equivalents based on compound (4-1). The
phosphorus ligand is used in the amounts of 0.001 equivalents to
0.4 equivalents based on compound (4-1). The reaction temperature
is from room temperature to reflux temperature, and the reaction
time is from 10 minutes to 24 hours.
[Preparation Method 4-5] Conversion of Substituent on E in Compound
(1)-3
##STR00045##
[0378] [wherein A, X (with the proviso that the cases where X
represents a group represented by the formula
--CH.sub.2--NH--(CH.sub.2).sub.n-- or a group represented by the
formula --NH--CH.sub.2--(CH.sub.2).sub.n-- are excluded; n
represents an integer from 0 to 3), E, Hal, R.sup.d and R.sup.e
have the same meanings as defined above.]
[Step 4-25]
[0379] The present step is a step wherein compound (4-9) and
compound (4-24-1) are reacted to obtain compound (4-22). Compound
(4-22) can be prepared by an analogous method to [Step 4-24].
(Preparation Method for Compound (4-24-1))
##STR00046##
[0380] [wherein L, R.sup.d and R.sup.e have the same meanings as
defined above.]
[0381] Compound (4-24-2), compound (4-24-5) and compound (4-24-6)
which are commercially available products can be used as is, or
they can also be prepared from commercially available products by a
well known method.
[Step 4-24-1]
[0382] The present step is a step wherein compound (4-24-2) and
compound (4-24-5) are reacted to obtain compound (4-24-1). Compound
(4-24-1) can be obtained in a solvent such as, for instance,
tetrahydrofuran, by abstracting a hydrogen atom from compound
(4-24-2) with a strong base such as for instance, lithium
diisopropyl amide, and then reacting with compound (4-24-5).
Examples of compound (4-24-5) include, for instance, chloromethyl
ethyl ether, chloromethyl benzyl ether or the like. The strong base
is used in the amounts of 1 equivalent to 2 equivalents based on
compound (4-24-2). Compound (4-24-5) is used in the amounts of 1
equivalent to 2 equivalents based on compound (4-24-2). The
reaction temperature is from -78.degree. C. to reflux temperature,
and the reaction time is from 1 hour to 24 hours.
[Step 4-24-2]
[0383] The present step is a step wherein compound (4-24-2) and a
formaldehyde equivalent are reacted to obtain compound (4-24-3).
Compound (4-24-3) can be obtained in a solvent such as, for
instance, tetrahydrofuran, by abstracting an hydrogen atom from
compound (4-24-2) with a base such as, for instance, lithium
diisopropyl amide, and then reacting with paraformaldehyde. The
strong base is used in the amounts of 1 equivalent to 2 equivalents
based on compound (4-24-2). The formaldehyde equivalent is used in
the amounts of 1 equivalent to 2 equivalents based on compound
(4-24-2). The reaction temperature is -78.degree. C. to reflux
temperature, and the reaction time is from 1 hour to 24 hours.
[Step 4-24-3]
[0384] The present step is a step wherein a hydroxyl group of
compound (4-24-3) is converted into a leaving group to obtain
compound (4-24-4).
[0385] When L represents a methane sulfonyloxy group, a
p-toluenesulfonyloxy group, or the like, compound (4-24-4) can be
obtained in a solvent such as, for instance, dichloromethane, by
reacting compound (4-24-3) and a sulfonyl halide such as methane
sulfonyl chloride or p-toluenesulfonyl chloride, in the presence of
an organic base such as, for instance, triethylamine. The organic
base is used in the amounts of 1 equivalent to 3 equivalents based
on compound (4-24-3). The sulfonyl halide is used in the amounts of
1 equivalent to 2 equivalents based on compound (4-24-3). The
reaction temperature is from 0.degree. C. to reflux temperature,
and the reaction time is from 10 minutes to 24 hours.
[0386] When L represents a bromine atom or an iodine atom, compound
(4-24-4) can be obtained in a solvent such as, for instance,
dichloromethane, by action of a halogenation agent such as, for
instance, carbon tetrabromide, N-bromosuccinimide or
N-iodosuccinimide on compound (4-24-3), in the presence of
triphenylphosphine. Triphenylphosphine is used in the amounts of 1
equivalent to 2 equivalents with based on compound (4-24-3). The
halogenation agent is used in the amounts of 1 equivalent to 2
equivalents with respect to compound (4-24-3). The reaction
temperature is from 0.degree. C. to room temperature, and the
reaction time is from 10 minutes to 24 hours.
[Step 4-24-4]
[0387] The present step is a process wherein compound (4-24-4) and
compound (4-24-6) are reacted to obtain compound (4-24-1). Compound
(4-24-1) can be obtained in a solvent such as for instance,
N,N-dimethylformamide, abstracting a hydrogen atom from compound
(4-24-4) using a base such as, for instance, sodium hydride, and
reacting with compound (4-24-6). Compound (4-24-6) is used in the
amounts of 1 equivalent to 10 equivalents based on compound
(4-24-4). The base is used in the amounts of 1 equivalent to 10
equivalents based on compound (4-24-4). The reaction temperature is
from 0.degree. C. to reflux temperature, and the reaction time is
from 10 minutes to 24 hours.
EXAMPLES
[0388] The compounds according to the present invention can be
prepared by a method described in, for instance, the following
Preparation Examples and Examples. With the proviso that these are
illustrative, and that the compounds according to the present
invention is not to be limited in any way to the following specific
examples.
Preparation Example A-1
2-Amino-6-chloro-nicotinic acid
[0389] To liquid ammonia (approximately 20 mL) was added
2,6-dichloro-nicotinic acid (0.38 g, 2 mmol) and copper(I) iodide
(720 mg, 3.8 mmol) at -78.degree. C. in a sealed tube, and the
solution was heated for 25 hours (the temperature of the oil bath
was 115.degree. C.). The temperature of the oil bath was raised to
125.degree. C., which was further heated for 14 hours 30 minutes.
The reaction mixture was allowed to room temperature, and ammonia
was evaporated. Methanol was added, insoluble matter was removed by
filtration, and the filtrate was concentrated to obtain the title
compound (0.25 g, 1.45 mmol, 72%) as a solid.
[0390] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.63 (1H,
d, J=8.0 Hz), 7.55 (2H, brs), 8.02 (1H, d, J=8.0 Hz).
Preparation Example A-2
2-Amino-nicotinic acid methyl ester
[0391] 2-Amino-nicotinic acid (10.0 g, 72.4 mmol) was dissolved in
a mixed solution of methanol (200 mL) and sulfuric acid (10 mL),
and the solution was stirred under reflux for 35 hours. A saturated
aqueous solution of sodium bicarbonate was added to the reaction
solution at 0.degree. C., which was extracted with ethyl acetate,
the organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography to obtain the
title compound (5.26 g, 34.6 mmol, 48%) as a white solid.
[0392] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.89 (3H,
s), 6.63 (1H, ddd, J=1.1, 4.8, 7.7 Hz), 8.13 (1H, dd, J=1.6, 7.7
Hz), 8.22 (1H, dd, J=1.8, 4.8 Hz).
Preparation Example A-3
2-Amino-5-nitro-nicotinic acid methyl ester
[0393] 2-Amino-nicotinic acid methyl ester (1.00 g, 6.57 mmol)
described in Preparation Example A-2 was dissolved at 0.degree. C.
in a mixed solution of nitric acid (0.7 mL) and sulfuric acid (2.6
mL), which was stirred at 0.degree. C. for 40 minute and at room
temperature for 19 hours, then, further stirred at 70.degree. C.
for 4 hours. A saturated aqueous solution of sodium bicarbonate was
added to the reaction solution at 0.degree. C., which was extracted
with ethyl acetate and tetrahydrofuran, the organic layer was
washed with brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated in vacuo. Methanol was added to the residue,
the precipitated solid was filtered to obtain the title compound
(459 mg, 2.33 mmol, 35%) as a white solid.
[0394] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.86 (3H,
s), 8.14 (1H, brs), 8.62 (1H, brs), 8.68 (1H, d, J=2.7 Hz), 9.04
(1H, d, J=2.9 Hz).
Preparation Example A-4
2-Amino-6-chloronicotinic acid
[0395] Tris(2-(2-methoxyethoxy)ethyl)amine (3.0 mL, 9.4 mmol) was
added to a mixture of 2,6-dichloronicotinic acid (40 g (90%
purity), 0.19 mol), acetamide (80 g, 1.4 mol), potassium carbonate
(78 g, 0.56 mol), copper(I) chloride (0.93 g, 9.4 mmol) and xylene
(80 mL), which was stirred overnight at 145.degree. C. After
cooling, copper(I) chloride (0.46 g, 4.6 mmol) was added to the
reaction solution, which was stirred overnight at 145.degree. C.
After cooling the reaction solution to 105.degree. C., water (100
mL) was added, the solution was stirred for 1 hour at the same
temperature, and cooled down to room temperature. 5N hydrochloric
acid (150 mL) was added, the solution was neutralized with a citric
acid aqueous solution, then, ethyl acetate was added, and the
solution was filtered through Celite pad. The organic layer was
washed with brine, then, the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography (ethyl
acetate), recrystallization by the ethyl acetate-hexane was carried
out to obtain the title compound (1.4 g, 8.3 mmol, 4.5%) as white
crystal.
[0396] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.61 (1H,
d, J=8.1 Hz), 7.53 (2H, brs), 8.01 (1H, d, J=8.1 Hz).
Preparation Example A-5
2-Amino-6-(2-hydroxy-ethoxy)-nicotinic acid
[0397] To ethyleneglycol (0.50 mL) was added sodium hydride (70 mg,
1.7 mmol, 60% in oil), catalytic amount of copper(I) iodide and
2-amino-6-chloronicotinic acid (30 mg, 0.17 mmol), which was
stirred for 3 hours at 110.degree. C., then, further stirred
overnight at 80.degree. C. After cooling, water, diethyl ether and
aqueous ammonia was added to the reaction solution, which was then
partitioned, the aqueous layer was neutralized with citric acid,
then, extracted with dichloromethane. The organic layer was washed
with brine, then dried over anhydrous magnesium sulfate. The
solvent was evaporated in vacuo to obtain the title compound (14
mg).
Preparation Example A-6
2-Amino-6-ethoxy-nicotinic acid
[0398] The title compound (35 mg) was obtained from ethanol (0.50
mL) and 2-amino-6-chloro-nicotinic acid (30 mg, 0.17 mmol)
according to an analogous method to Preparation Example A-5.
Preparation Example A-7
2-Amino-6-isopropoxy-nicotinic acid
[0399] The title compound (60 mg) was obtained from isopropanol
(0.50 mL) and 2-amino-6-chloro-nicotinic acid (30 mg, 0.17 mmol)
according to an analogous method to Preparation Example A-5.
Preparation Example A-8
2-Amino-6-chloro-nicotinic acid methyl ester
[0400] To methanol (50 mL) were added concentrated sulfuric acid
(25 mL) and 2-amino-6-chloro-nicotinic acid (4.3 g, 25 mmol)
described in Preparation Example A-1 (or A-4) on an ice bath, which
was stirred at 70.degree. C. for 5 hours. After cooling, an aqueous
solution of sodium bicarbonate (90 g) was added to neutralize. The
resulting solid was filtered to obtain the title compound (3.2 g,
17 mmol, 68%) as a light brown solid.
[0401] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.88 (3H,
s), 6.62 (1H, d, J=8.2 Hz), 8.05 (1H, d, J=8.1 Hz).
Preparation Example A-9
Tributyl-methoxymethyl-stannane
[0402] To a mixture of diisopropylamine (9.4 mL, 67 mmol) and
tetrahydrofuran (150 mL) was added n-butyl lithium (2.4M n-hexane
solution, 25 mL, 61 mmol) dropwise at -78.degree. C., which was
stirred for 30 minutes at the same temperature. Tributyltin hydride
(16 mL, 61 mmol) was added dropwise at the same temperature, the
solution was then stirred for 30 minutes on ice. The reaction
solution was brought to -78.degree. C., chloromethyl methyl ether
(4.6 mL, 61 mmol) was added dropwise thereto, the solution was then
gradually warmed to room temperature. Water (100 mL) was added to
the reaction solution, which was then extracted with diethyl ether
(300 mL). The organic layer was washed with brine, then, evaporated
in vacuo. The residue was purified by neutral silica gel column
chromatography (heptane/ethyl acetate=30/1), and the title compound
(18 g, 0.52 mmol, 86%) was obtained as a colorless oil.
[0403] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.88-0.93
(15H, m), 1.26-1.35 (6H, m), 1.47-1.55 (6H, m), 3.30 (3H, s), 3.71
(2H, t, J=6.8 Hz).
Preparation Example A-10
2-Amino-6-methoxymethyl-nicotinic acid methyl ester
[0404] A mixture of 2-amino-6-chloro-nicotinic acid methyl ester
described in Preparation Example A-8 (1.4 g, 7.6 mmol),
tributyl-methoxymethyl-stannane (3.1 g, 9.1 mmol) described in
Preparation Example A-9, tetrakis(triphenylphosphine)palladium (440
mg, 0.38 mmol) and N-methylpyrrolidinone (20 mL) was stirred at
130.degree. C. for 3.5 hours. The reaction solution was allowed to
cool, an aqueous solution of potassium fluoride and ethyl acetate
were added thereto on an ice bath, followed by filtering through
Celite pad. The organic layer was washed with brine, then,
evaporated in vacuo. The residue was purified by silica gel column
chromatography (heptane/ethyl acetate=2/1), and the title compound
(0.93 g, 4.7 mmol, 63%) was obtained as a light brown oil.
[0405] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.47 (3H,
s), 3.88 (3H, s), 4.41 (2H, s), 6.74 (1H, d, J=7.9 Hz), 8.14 (1H,
d, J=7.9 Hz).
Preparation Example A-11
2-Amino-6-methoxymethyl-nicotinic acid
[0406] Lithium hydroxide monohydrate (1.2 g, 29 mmol) was added to
a mixture of 2-amino-6-methoxymethyl-nicotinic acid methyl ester
described in Preparation Example A-10 (2.9 g, 15 mmol),
tetrahydrofuran (30 mL), methanol (7.5 mL), and water (7.5 mL),
which was then stirred overnight at room temperature. Acetic acid
(1.7 mL, 29 mmol) was added to the reaction solution and the
solvent was evaporated in vacuo. After filtration using silica gel
(methanol/ethyl acetate=1/3) and the solvent was evaporated in
vacuo, the residue was washed with water, and the title compound
(2.1 g, 12 mmol, 80%) was obtained as a pale yellow solid.
[0407] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.32 (3H,
s), 4.29 (2H, s), 6.61 (1H, d, J=7.9 Hz), 7.16 (2H, br s), 8.02
(1H, d, J=7.9 Hz).
Preparation Example A-12
2-(2-Cyanoethyl)-3,3-diaminopropenoic acid ethyl ester
[0408] (1-Ethoxyformimidoyl) 1-acetic acid ethyl ester
hydrochloride (50 g, 0.26 mol) was suspended in an ammonia-ethanol
solution (300 mL; prepared by saturating ethanol with ammonia gas
at room temperature), which was then stirred at room temperature
for 4 hours. After the reaction was completed, the precipitated
salt was removed by filtration, and the filtrate was concentrated
in vacuo at room temperature to reach 1/3 of the amount.
Hydrochloric acid-methanol (130 mL; hydrochloric acid content:
7.5%) was added to this filtrate, the solution was then
concentrated under a reduced pressure to obtain 3,3-diamino-acrylic
acid ethyl ester hydrochloride (40 g, 0.24 mol, 92%) as a
solid.
[0409] The resulting 3,3-diamino-acrylic acid ethyl ester
hydrochloride (2.2 g, 13.2 mmol) was suspended in tetrahydrofuran
(40 mL), triethylamine (2 mL, 14.3 mmol) and acrylonitrile (1.2 mL,
19.3 mmol) were added thereto, and the solution was refluxed for 6
hours. After the reaction was completed, the resulting
triethylamine hydrochloride was filtered, and the filtrate was
concentrated to obtain the title compound (0.6 g, 3.3 mmol,
25%).
[0410] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.26 (3H, t,
J=7.2 Hz), 2.42-2.49 (2H, m), 2.50-2.57 (2H, m), 4.12 (2H, q, J=7.2
Hz), 4.22 (2H, brs), 6.45 (2H, brs).
Preparation Example A-13
2,6-Diamino-4,5-dihydronicotinic acid ethyl ester
[0411] A solution of 2-(2-cyanoethyl) 3,3-diaminopropenoic acid
ethyl ester described in Preparation Example A-12 (0.55 g, 3 mmol)
in tetrahydrofuran (7 mL) was added dropwise to a suspension of
sodium hydride (208 mg, 5.2 mmol, 60% in oil) in tetrahydrofuran (7
mL), and the solution was stirred for 19 hours 20 minutes under
reflux. After the reaction was completed, the reaction solution was
poured into an ice water, which was then extracted with ethyl
acetate. The organic layer was dried over anhydrous magnesium
sulfate, then, concentrated to obtain the title compound as a crude
product (0.188 g, 1 mmol, 34%).
[0412] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.27 (3H, t,
J=7.2 Hz), 2.28-2.34 (2H, m), 2.46-2.52 (2H, m), 4.14 (2H, q, J=7.2
Hz).
Preparation Example A-14
2,6-Diamino-nicotinic acid ethyl ester
[0413] To a solution of 2,6-diamino-4,5-dihydronicotinic acid ethyl
ester described in Preparation Example A-13 (4.5 g, 24.6 mmol) in
tetrahydrofuran (300 mL) was added
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (5.6 g, 24.7 mmol), which
was then stirred for 40 minutes at room temperature. The residue
obtained by concentrating the reaction solution was then purified
by NH silica gel column chromatography (ethyl acetate) to obtain a
solid of the target compound. This solid was washed with hexane and
dried to obtain the title compound (3.1 g, 17.1 mmol, 69.5%).
[0414] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.35 (3H, t,
J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 4.60 (2H, brs), 5.82 (1H, d,
J=8.4 Hz), 7.90 (1H, d, J=8.4 Hz).
Preparation Example A-15
2,6-Diamino-nicotinic acid
[0415] 2,6-Diamino-nicotinic acid ethyl ester described in
Preparation Example A-14 (2 g, 11 mmol) was dissolved in ethanol
(15 mL), an aqueous solution of 1N sodium hydroxide (15 mL) was
added thereto, followed by stirring for 2 hours under reflux. The
reaction solution was allowed to room temperature, ethanol was then
removed by evaporation, the residue was cooled on an ice bath, then
neutralized with 1N hydrochloric acid. The precipitated solid was
collected by filtration, washed with water, then, dried to obtain
the title compound (1.72 g, 11 mmol, quantitatively).
[0416] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.70 (1H,
d, J=8.4 Hz), 6.31 (2H, brs), 6.58-7.12 (1H, brs), 7.62 (1H, d,
J=8.4 Hz).
Preparation Example A-16
2-Amino-6-vinyl-nicotinic acid methyl ester
[0417] 2-Amino-6-chloro-nicotinic acid methyl ester (2.95 g, 15.8
mmol), vinyl tri-n-butyltin (5.01 g, 1.58 mmol) and
tetrakis(triphenylphosphine)palladium(0) (1.83 g, 1.58 mmol) were
suspended in xylene (15 mL), and heated for 1 hour at 130.degree.
C. The reaction mixture was allowed to room temperature, water and
ethyl acetate were added thereto, this mixture was filtered through
Celite pad, then, the filtrate thereof was partitioned. The organic
layer was separated, the solvent was evaporated in vacuo, and the
residue was purified by silica gel column chromatography to obtain
the title compound (1.87 g, 10.5 mmol, 66%) as a white solid.
[0418] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.81 (3H,
s), 5.54 (1H, dd, J=1.6, 10.4 Hz), 6.24 (1H, dd, J=1.6, 17.2 Hz),
6.65 (1H, dd, J=10.4, 17.2 Hz), 6.76 (1H, d, J=8.0 Hz), 7.16 (1H,
brs), 8.04 (1H, d, J=8.0 Hz).
Preparation Example A-17
2-Amino-6-(2-cyanoethyl)-nicotinic acid methyl ester
[0419] To a solution of 2-amino-6-vinyl-nicotinic acid methyl ester
(760 mg, 4.26 mmol) in tetrahydrofuran (76 mL) was added a solution
of diethyl aluminum cyanide in toluene (12.8 mL, 12.8 mmol)
dropwise under sodium chloride--an ice bath cooling, at an internal
temperature of -5.degree. C. or below, then, the solution was
gradually allowed to room temperature and stirred overnight. The
reaction solution was partitioned into an aqueous solution of
saturated ammonium chloride and ethyl acetate. This organic layer
was separated, washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, the residue was
purified by silica gel column chromatography, and the title
compound (180 mg, 0.878 mmol, 21%) was obtained as a yellow
oil.
[0420] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.80 (2H, t,
J=7.2 Hz), 2.97 (2H, t, J=7.2 Hz), 3.88 (3H, s), 6.53 (1H, d, J=8.0
Hz) 8.07 (1H, d, J=8.0 Hz).
Preparation Example A-18
2-Amino-6-(2-cyanoethyl)-nicotinic acid
[0421] To a solvent mixture of 2N-sodium hydroxide aqueous solution
(5 mL) and methanol (5 mL) was added
2-amino-6-(2-cyanoethyl)-nicotinic acid methyl ester (90 mg, 0.439
mmol), and the solution was stirred for 18 hours at room
temperature. This mixed solution was neutralized with
5N-hydrochloric acid, then, extracted with ethyl acetate. This
organic layer was dried over anhydrous magnesium sulfate, then, the
solvent was evaporated in vacuo, and the title compound (68 mg,
0.355 mmol, 81%) was obtained as a yellowish brown solid.
[0422] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.86 (4H,
bs), 6.54 (1H, d, J=8.0 Hz), 7.18 (2H, bs), 7.98 (1H, d, J=8.0
Hz).
Preparation Example A-19
2-Amino-6-(2-ethoxy-vinyl)-nicotinic acid methyl ester
[0423] To a solution of ethyl ethynyl ether (3.6 g, 25.7 mmol) in
tetrahydrofuran (10 mL) was added catechol borane (3.08 g, 25.7
mmol) on an ice bath. Immediately, the cold bath was removed, the
reaction mixture was allowed to room temperature, and then, the
solution was stirred for 1.5 hours under reflux. This reaction
mixture was allowed to room temperature. To this mixture solution
were added 2-amino-6-chloro-nicotinic acid methyl ester (1.6 g,
8.57 mmol), sodium hydroxide powder (1.13 g, 28.3 mmol),
tetrakis(triphenylphosphine)palladium(0) (0.99 g, 0.857 mmol) and
dioxane (20 mL), which was then stirred for 2 hours under reflux.
The reaction mixture was allowed to room temperature, and
partitioned into water and ethyl acetate. The organic layer was
separated, the solvent was evaporated in vacuo, the residue was
purified by silica gel column chromatography, and the title
compound (1.30 g, 5.85 mmol, 68%) was obtained as a brown
solid.
[0424] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.27 (3H,
t, J=7.2 Hz), 3.77 (3H, s), 3.95 (2H, q, J=7.2 Hz), 5.75 (1H, d,
J=12.8 Hz), 6.49 (1H, d, J=8.4 Hz), 7.02 (2H, brs), 7.63 (1H, d,
J=12.8 Hz), 7.89 (1H, d, J=8.4 Hz).
Preparation Example A-20
2-Amino-6-(2-hydroxy-ethyl)-nicotinic acid methyl ester
[0425] 2-Amino-6-(2-ethoxy-vinyl)-nicotinic acid methyl ester (1.07
g, 4.81 mmol) was dissolved in 5N-hydrochloric acid (25 mL),
ethanol (20 mL) and tetrahydrofuran (5 mL), and the solution was
stirred for 3 hours under reflux. This reaction mixture was allowed
to room temperature, and neutralized with a aqueous solution of
saturated sodium bicarbonate, then, sodium borohydride (1 g, 26.5
mmol) was added to this reaction mixture, which was then stirred
for 20 minutes at room temperature. Ethyl acetate was added
thereto, followed by filtrating through Celite pad. This filtrate
was partitioned. This organic layer was separated, the solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography, and the title compound (350 mg, 1.92 mmol, 40%) was
obtained as a brown oil.
[0426] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.72 (2H,
t, J=6.8 Hz), 3.71 (2H, q, J=6.8 Hz), 3.79 (3H, s), 4.66 (1H, t,
J=6.8 Hz), 6.53 (1H, d, J=8.0 Hz), 7.12 (2H, brs), 7.95 (1H, d,
J=8.0 Hz).
Preparation Example A-21
2-Amino-6-(2-fluoro-ethyl)-nicotinic acid methyl ester
[0427] A solution of (bis(2-methoxyethyl)amino)sulfur trifluoride
(2.39 g, 10.8 mmol) in dichloromethane (30 mL) was cooled with a
dry ice-methanol bath, and 2-amino-6-(2-hydroxyethyl)-nicotinic
acid methyl ester (50 mg, 0.255 mmol) was added thereto dropwise.
After dropwise addition the cold bath was immediately removed, and
the solution was gradually allowed to room temperature. Water and
ethyl acetate were added to the reaction solution, which was then
partitioned. The organic layer was separated, the solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography, and the title compound (4 mg, 0.020 mmol, 7.9%) was
obtained as a white solid.
[0428] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.97 (2H,
td, J=6.0, 26.0 Hz), 3.80 (3H, s), 4.77 (2H, td, J=6.0, 47.2 Hz),
6.58 (1H, d, J=8.0 Hz), 7.16 (2H, bs), 8.00 (1H, d, J=8.0 Hz).
Preparation Example A-22
2-Amino-6-(2-fluoro-ethyl)-nicotinic acid
[0429] 2-Amino-6-(2-fluoro-ethyl)-nicotinic acid methyl ester (77
mg, 0.387 mmol) was dissolved in an aqueous solution of 2N sodium
hydroxide (5 mL) and methanol (5 mL), and the solution was stirred
for 20 minutes at room temperature. This mixture solution was
neutralized with 5N hydrochloric acid, then, extracted with ethyl
acetate. The organic layer was separated, the solvent was
evaporated in vacuo, and the title compound (64 mg, 0.348 mmol,
90%/65% purity) was obtained as a white solid.
[0430] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.97 (2H,
td, J=6.0, 26.0 Hz), 4.77 (2H, td, J=6.0, 47.2 Hz), 6.57 (1H, d,
J=8.0 Hz), 7.98 (1H, d, J=8.0 Hz).
Preparation Example A-23
Tributyl-ethoxymethyl-stannane
[0431] The title compound (2.8 g, 8.0 mmol, 67%) was obtained as a
colorless oil from chloromethyl ethyl ether (1.1 mL, 12 mmol)
according to an analogous method to Preparation Example A-9.
[0432] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.87-0.92
(15H, m), 1.16 (3H, t, J=7.0 Hz), 1.26-1.35 (6H, m), 1.43-1.55 (6H,
m), 3.36 (2H, q, J=7.0 Hz), 3.74 (2H, t, J=6.5 Hz).
Preparation Example A-24
2-Amino-6-ethoxymethyl-nicotinic acid methyl ester
[0433] The title compound (0.35 g, 1.7 mmol, 39%) was obtained as a
pale yellow solid from tributyl-ethoxymethyl-stannane (2.0 g, 6.3
mmol) described in Preparation Example A-23 and
2-amino-6-chloro-nicotinic acid methyl ester described in
Preparation Example A-8 (0.80 g, 4.3 mmol) according to an
analogous method to Preparation Example A-10.
[0434] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.28 (3H, t,
J=7.0 Hz), 3.61 (2H, q, J=7.0 Hz), 3.88 (3H, s), 4.45 (2H, s), 6.41
(2H, br s), 6.78 (1H, d, J=7.9 Hz), 8.13 (1H, d, J=8.1 Hz).
Preparation Example A-25
2-Amino-6-ethoxymethyl-nicotinic acid
[0435] The title compound (180 mg, 0.92 mmol, 57%) was obtained as
a pale yellow solid from 2-amino-6-ethoxymethyl-nicotinic acid
methyl ester (330 mg, 1.6 mmol) described in Preparation Example
A-24 according to an analogous method to Preparation Example
A-11.
[0436] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.15 (3H,
t, J=7.1 Hz), 3.51 (2H, q, J=7.0 Hz), 4.33 (2H, s), 6.64 (1H, d,
J=7.9 Hz), 8.02 (1H, d, J=7.9 Hz).
Preparation Example A-26
Tributyl-isopropoxymethyl-stannane
[0437] To a mixture of isopropanol (2 mL) and tetrahydrofuran (2
mL) was added sodium hydride (66%, 58 mg, 1.6 mmol) on an ice bath,
then, the solution was stirred for 20 minutes at room temperature.
To the reaction solution was added a solution of
tributyl-iodomethyl-stannane (230 mg, 0.53 mmol), synthesized
according to the document (Synthetic Communications, Vol. 24, No.
8, pp. 1117-1120), in tetrahydrofuran (1 mL) dropwise on an ice
bath, then, N,N-dimethylformamide (0.5 mL) was added thereto,
followed by stirring overnight at room temperature. The reaction
solution was partitioned into water (20 mL) and diethyl ether (50
mL). The organic layer was separated, washed with brine, and then,
evaporated in vacuo. The residue was purified by neutral silica gel
column chromatography (heptane:ethyl acetate=30:1), and the title
compound (63 mg, 0.17 mmol, 32%) was obtained as a colorless
oil.
[0438] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.87-0.91
(15H, m), 1.11 (6H, d, J=6.0 Hz), 1.26-1.35 (6H, m), 1.47-1.53 (6H,
m), 3.28-3.31 (1H, m), 3.69 (2H, t, J=7.6 Hz).
Preparation Example A-27
Butoxymethyl-tributyl-stannane
[0439] The title compound (220 mg, 0.58 mmol, 99%) was obtained as
a colorless oil from tributyl-iodomethyl-stannane (250 mg, 0.58
mmol) according to an analogous method to Preparation Example
A-26.
[0440] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.87-0.93
(18H, m), 1.26-1.38 (8H, m), 1.47-1.55 (8H, m), 3.30 (2H, t, J=6.5
Hz), 3.73 (2H, t, J=6.5 Hz).
Preparation Example A-28
Tributyl-propoxymethyl-stannane
[0441] The title compound (230 mg, 0.63 mmol, 97%) was obtained as
a colorless oil from tributyl-iodomethyl-stannane (280 mg, 0.65
mmol) according to an analogous method to Preparation Example
A-26.
[0442] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.87-0.91
(18H, m), 1.26-1.35 (6H, m), 1.47-1.58 (8H, m), 3.27 (2H, t, J=6.5
Hz), 3.73 (2H, t, J=6.5 Hz).
Preparation Example A+-1
Sodium
4-(((2-Aminopyridine-3-carbonyl)-amino)-methyl)-phenolate
[0443] To a solution of 4-hydroxybenzaldehyde (10 g, 81.9 mmol) in
methanol (45 mL) was added Raney nickel (3 g) and 7N aqueous
ammonia solution (45 mL), and the solution was stirred under
hydrogen atmosphere (1 atm) at room temperature for 21 hours. The
reaction solution was filtered through Celite pad to remove the
catalyst, the filtrate was concentrated, and 4-aminomethyl-phenol
(10 g, quantitatively) was obtained as a pale green solid.
[0444] Then, a solution of 2-aminonicotinic acid (3.0 g, 21.7 mmol)
in N,N-dimethylformamide (30 mL) was cooled with an ice water,
1-hydroxybenzotriazole (3.51 g, 26 mmol),
(3-dimethylaminopropyl)-ethyl-carbodiimide (4.04 g, 26 mmol) and a
solution of the resulting 4-aminomethyl-phenol (3.0 g, 21.7 mmol)
in N,N-dimethylformamide (20 mL) were added, and the solution was
stirred for 18 hours at this temperature. The reaction solution was
partitioned into brine, the organic layer was dried over anhydrous
magnesium sulfate, and the solvent was evaporated. The residue was
dissolved in ethyl acetate, filtration was carried out using NH
silica gel, and the filtrate was concentrated. The residue was
dissolved in methanol (90 mL), 1N sodium hydroxide (17.8 mL, 17.8
mmol) was added thereto, followed by stirring at room temperature
for an hour and a half The reaction solution was concentrated in
vacuo, and the title compound (5.66 g) was obtained as a pale
yellow solid.
Preparation Example A+-2
(6-Amino-5-((5-(3-fluoro-phenoxy)-thiophene-2-ylmethyl)-carbamoyl)-pyridin-
e-2-yl)-carbamic acid tert-butyl ester
[0445] To a solution of 6-amino-nicotinic acid (270 mg, 2.0 mmol)
and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine (400 mg, 1.8
mmol) in N,N-dimethylformamide (10 mL) were added
benzotriazole-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (870 mg, 2.0 mmol) and triethylamine (0.50 mL,
3.6 mmol), and the solution was stirred for 30 minutes at
60.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, and the organic layer was
washed twice with water. Silica gel was added to the organic layer,
the solvent was evaporated in vacuo for adsorption, purification
was carried out with NH silica gel column chromatography (ethyl
acetate, then ethyl acetate:methanol=10:1), and
6-amino-N-(5-(3-fluoro-phenoxy)-thiophen-2-yl)-methylnicotinamide
(270 mg, 0.79 mmol, 43.9%) was obtained.
[0446] To the resulting
6-amino-N-(5-(3-fluoro-phenoxy)-thiophen-2-yl)-methylnicotinamide
(270 mg, 0.79 mmol) were added di-tert-butyldicarbonate (210 mg,
0.94 mmol) and tert-butyl alcohol (15 mL), and the solution was
stirred for 16.5 hours at room temperature. NH silica gel was added
to the reaction solution, solvent was evaporated in vacuo for
adsorption, purification was carried out by NH silica gel column
chromatography (hexane:ethyl acetate=4:1 then 1:1), and the title
compound (250 mg, 0.54 mmol, 68.3%) was obtained as a white
solid.
[0447] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.46 (9H,
s), 4.52 (2H, d, J=5.6 Hz), 6.55-6.59 (1H, m), 6.78-6.82 (1H, m),
6.88-7.00 (4H, m), 7.36-7.44 (1H, m), 7.85 (1H, d, J=8.8 Hz), 8.15
(1H, d, J=8.8 Hz), 8.70 (1H, s), 9.14 (1H, t, J=5.6 Hz), 10.1 (1H,
s).
Preparation Example A+-3
(6-Amino-5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridin--
2-yl)-methyl-carbamic acid tert-butyl ester
[0448] To a solution of
(6-amino-5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridin-
e-2-yl)-carbamic acid tert-butyl ester described in Preparation
Example A+-2 (125 mg, 0.27 mmol) and methyl iodide (43 mg, 0.29
mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (12
mg, 0.29 mmol, 60% in oil) on an ice bath, and the solution was
stirred for 1 hour at room temperature. NH silica gel was added to
the reaction solution, the solvent was evaporated in vacuo for
adsorption, purification was carried out by NH silica gel column
chromatography (hexane:ethyl acetate=4:1 then 2:1), and the title
compound (87 mg, 0.19 mmol, 70.5%) was obtained as a colorless
oil.
[0449] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.46 (9H,
s), 3.31 (3H, s), 4.53 (2H, d, J=5.6 Hz), 6.57 (1H, d, J=3.6 Hz),
6.81 (1H, d, J=3.6 Hz), 6.86-7.00 (3H, m), 7.36-7.44 (1H, m), 7.76
(1H, d, J=8.8 Hz), 8.14 (1H, dd, J=2.0, 8.8 Hz), 8.80 (1H, d, J=2.0
Hz), 9.22 (1H, t, J=5.6 Hz).
Preparation Example A+-4
(6-Amino-5-((5-benzyl-thiophen-2-ylmethyl)-carbamoyl)-pyridine-2-yl)-carba-
moylmethyl-carbamic acid tert-butyl ester
[0450] To a solution of 6-aminonicotinic acid (340 mg, 2.4 mmol)
and C-(5-benzyl-thiophen-2-yl)-methylamine described in Preparation
Example 42 (450 mg, 2.2 mmol) in N,N-dimethylformamide (5 mL) were
added benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (1.1 g, 2.4 mmol) and triethylamine (0.62 mL,
4.4 mmol), and the solution was stirred at 60.degree. C. for 1
hour. Water and ethyl acetate were added to the reaction solution,
which was then partitioned, and the organic layer was washed twice
with water. Silica gel was added to the organic layer, the solvent
was evaporated in vacuo adsorption, purification was carried out by
NH silica gel column chromatography (hexane:ethyl acetate=1:1, then
ethyl acetate, then ethyl acetate:methanol=10:1), and
6-amino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide (210 mg, 0.65
mmol, 29.5%) was obtained. Then, according to an analogous method
to Preparation Example A+-2, from the resulting
6-amino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide (210 mg, 0.65
mmol),
(5-((5-benzyl-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-yl)-carbam-
ic acid tert-butyl ester (120 mg, 0.28 mmol, 43.0%) was obtained as
a colorless oil.
[0451] To a solution of this oil (60 mg, 0.14 mmol) in
N,N-dimethylformamide (5 mL) were added sodium hydride (6.8 mg,
0.14 mmol, 60% in oil) and bromoacetamide (23 mg, 0.16 mmol), and
the solution was stirred for 25 hours room temperature. Water and
ethyl acetate were added to the reaction solution, which was then
partitioned, the organic layer was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (hexane:ethyl
acetate=1:1, then ethyl acetate, then ethyl acetate:methanol=20:1),
and the title compound (23 mg, 0.047 mmol, 33.5%) was obtained as a
colorless oil.
[0452] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.43 (9H,
s), 4.04 (2H, s), 4.49-4.54 (4H, m), 6.69 (1H, d, J=3.6 Hz), 6.79
(1H, d, J=3.6 Hz), 6.94 (1H, s), 7.16-7.30 (5H, m), 7.38 (1H, s),
7.87 (1H, d, J=8.8 Hz), 8.10-8.16 (1H, m), 8.68-8.73 (1H, m), 9.13
(1H, t, J=5.6 Hz).
Preparation Example A+-5
6-Chloro-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-nicotinamide
[0453] 6-chloro-nicotinic acid (100 mg, 0.58 mmol), triethylamine
(0.194 mL, 1.39 mmol) and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (308 mg, 0.696 mmol) were dissolved in
N,N-dimethylformamide (3 mL),
C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)-methylamine (142 mg, 0.695
mmol) described in Preparation Example 59 was added, and the
solution was stirred for 15 hours 10 minutes at room temperature.
After the reaction was completed, the reaction solution was poured
into brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then the
solution was concentrated, the resulting residue was purified by NH
silica gel column chromatography (ethyl acetate:hexane=1:1), and
the title compound (0.14 g, 0.39 mmol, 67%) was obtained.
[0454] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.42 (2H, d,
J=4.8 Hz), 5.02 (2H, s), 5.99-6.09 (1H, m), 6.16-6.18 (1H, m), 6.56
(1H, d, J=8.0 Hz), 6.57 (1H, brs), 6.64-6.68 (2H, m), 6.78-6.83
(1H, m), 6.91-6.94 (1H, m), 6.96-7.02 (1H, m), 7.27-7.33 (1H, m),
7.49 (1H, d, J=8.0 Hz).
Preparation Example A+-6
2-(Ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0455] To a solution of 2-aminonicotinic acid (3245 mg, 23.49 mmol)
in N,N-dimethylformamide (200 mL) were added
C-(5-phenoxy-thiophen-2-yl)methylamine (5305 mg, 25.84 mmol)
described in Preparation Example 24,
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (12.49 g, 28.19 mmol) and triethylamine (7.86
mL, 56.38 mmol), and the solution was stirred for 2 days at room
temperature. Water was added to the reaction mixture, which was
then extracted with ethyl acetate, the organic layer was
sequentially washed with an aqueous solution of saturated sodium
bicarbonate, water, then brine, the solvent was evaporated in
vacuo, and 2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
(4999 mg, 15.36 mmol, 65%) was obtained as crude product.
[0456] To a solution of the resulting
2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (602 mg,
1.85 mmol) in ethanol (40 mL) were added 5,5-dimethylhydantoin (260
mg, 2.04 mmol), 37% formic acid aqueous solution (3.00 mL, 23.6
mmol), and the solution was stirred under reflux for 1 hour. Water
was added to the reaction mixture, which was then extracted with
ethyl acetate, the organic layer was sequentially washed with water
and brine, dried over anhydrous sodium sulfate, and then,
evaporated in vacuo. The resulting residue was purified by silica
gel chromatography (hexane-ethyl acetate), and the title compound
(430 mg, 1.12 mmol, 61%) was obtained.
[0457] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.03 (3H,
t, J=6.8 Hz), 3.41 (2H, q, J=6.8 Hz), 4.48 (2H, d, J=5.6 Hz), 4.90
(2H, d, J=7.2 Hz), 6.49 (1H, d, J=3.6 Hz), 6.68 (1H, dd, J=4.8, 7.6
Hz), 6.77 (1H, d, J=3.6 Hz), 7.06-7.14 (3H, m), 7.33-7.38 (2H, m),
7.94 (1H, dd, J=1.6, 7.6 Hz), 8.19 (1H, dd, J=1.6, 4.8 Hz), 8.91
(1H, t, J=7.2 Hz), 9.16-9.20 (1H, m).
Preparation Example A+-7
2-Chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0458] To a solution of 2-chloro nicotinic acid (1182 mg, 7.50
mmol) in N,N-dimethylformamide (3 mL) were added
C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation
Example 24 (1693 mg, 8.25 mmol), benzotriazol-1-yloxy
tris(dimethylamino)phosphonium hexafluorophosphate (3987 mg, 9.0
mmol) and triethylamine (2.5 mL, 18.0 mmol), and the solution was
stirred at 60.degree. C. for 2 days. Water was added to the
reaction mixture, which was then extracted with ethyl acetate, and
then concentrated. The residue was purified by silica gel column
chromatography, and the title compound (1181 mg, 3.43 mmol, 46%)
was obtained.
[0459] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.51 (2H,
d, J=5.2 Hz), 6.52 (1H, d, J=3.6 Hz), 6.80 (1H, d, J=3.6 Hz),
7.07-7.16 (3H, m), 7.30-7.45 (2H, m), 7.47 (1H, dd, J=4.8, 7.6 Hz),
7.87 (1H, dd, J=1.6, 7.6 Hz), 8.46 (1H, dd, J=1.6, 4.8 Hz), 9.20
(1H, t, J=5.2 Hz).
Preparation Example A+-8
N-(4-Benzyloxy-benzyl)-6-(ethoxymethyl-amino)-nicotinamide
[0460] To a solution of 6-aminonicotinic acid (130 mg, 0.941 mmol)
and 4-benzyloxy-benzylamine (201 mg, 0.941 mmol) described in
Preparation Example 1 in N,N-dimethylformamide (5 mL), was added
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (624 mg, 1.41 mmol) and triethylamine (394
.mu.l, 2.82 mmol), and the solution was stirred for 40 minutes at
80.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, and the organic layer was
washed twice with water. The solvent was evaporated in vacuo, ethyl
acetate was added to the residue, a white insoluble matter was
collected by filtration, and
6-amino-N-(4-benzyloxy-benzyl)-nicotinamide (202 mg, 0.606 mmol,
64%) was obtained.
[0461] To a solution of the resulting
6-amino-N-(4-benzyloxy-benzyl)-nicotinamide (200 mg, 0.556 mmol) in
ethanol (10 mL) were added 5,5-dimethylimidazophospho-2,4-dione (85
mg, 0.66 mmol) and 37% formaldehyde aqueous solution (1 mL), and
the solution was stirred for 1 hour under reflux. Water and ethyl
acetate were added to the reaction solution, which was then
partitioned, and the organic layer was washed twice. NH silica gel
was added to the organic layer, the solvent was evaporated in vacuo
for adsorption, purification was carried out by NH silica gel
column chromatography (ethyl acetate), and the title compound (95
mg, 0.243 mmol, 40%) was obtained as a white solid.
[0462] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.20 (3H, t,
J=7.0 Hz), 3.55 (2H, q, J=7.0 Hz), 4.56 (2H, d, J=5.5 Hz), 4.84
(2H, s), 5.07 (2H, s), 5.68 (1H, brs), 6.14 (1H, brs), 6.62 (1H, d,
J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.22-7.35 (4H, m), 7.27-7.44
(3H, m), 7.93 (1H, dd, J=2.4, 8.8 Hz), 8.54 (1H, d, J=2.4 Hz).
Preparation Example A+-9
2-Amino-5-nitro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0463] 2-Amino-5-nitro-nicotinic acid methyl ester (48.4 mg, 0.245
mmol) described in Preparation Example A-3 and lithium hydroxide
monohydrate (10.3 mg, 0.245 mmol) were dissolved in a solvent
mixture of tetrahydrofuran (1 mL), methanol (0.1 mL) and water (0.1
mL), and the solution was stirred for 17 hours at room temperature.
The solvent was evaporated in vacuo, and 2-amino-5-nitro-nicotinic
acid was obtained as a lithium salt.
[0464] Then, the resulting lithium salt of
2-amino-5-nitro-nicotinic acid,
C-(5-phenoxy-thiophen-2-yl)-methylamine (60 mg, 0.29 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (162 mg, 0.367 mmol) and triethylamine (103
.mu.l, 0.735 mmol) were dissolved in N,N-dimethylformamide (2.0
mL), and the solution was stirred for 6 hours at room temperature.
Water was added to the reaction solution, which was then extracted
with ethyl acetate, and the organic layer was washed with water and
brine. The solvent was evaporated in vacuo, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:1), and the title compound (87 mg, 0.24 mmol, 96%) was
obtained as a pale yellow solid.
[0465] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.49 (2H,
d, J=5.5 Hz), 6.50 (1H, d, J=3.7 Hz), 6.80 (1H, d, J=3.1 Hz), 7.08
(2H, d, J=7.7 Hz), 7.13 (1H, t, J=7.5 Hz), 7.37 (2H, t, J=7.5 Hz),
8.76 (1H, d, J=2.2 Hz), 8.96 (1H, d, J=1.7 Hz), 9.51 (1H, t, J=5.5
Hz).
Preparation Example A+-10
2,5-Diamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0466]
2-Amino-5-nitro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (74
mg, 0.20 mmol) described in Preparation Example A+-9, an iron
powder (56 mg, 1.0 mmol) and ammonium chloride (21 mg, 0.40 mmol)
were suspended in a solvent mixture of ethanol (2 mL) and water
(0.5 mL), the solution was stirred at 60.degree. C. for 3 hours,
then, it was stirred at 90.degree. C. for 6 hours. The reaction
solution was cooled to room temperature, then, it was filtered
through Celite pad. The filtrate was evaporated in vacuo, the
residue was purified by reverse phase high performance liquid
chromatography (acetonitrile-water: mobile phase (containing 0.1%
trifluoroacetic acid) was used), and the title compound (54.4 mg)
was obtained as a trifluoroacetic acid salt.
[0467] MS m/e (ESI) 341.26 (MH.sup.+)
Preparation Example A+-11
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0468] 2-Amino-6-chloro-nicotinic acid (400 mg, 2.31 mmol)
described in Preparation Example A-1 was dissolved in
N,N-dimethylformamide (10 mL), triethylamine (0.78 mL, 5.6 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.23 g, 2.8 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine (572 mg, 2.8 mmol)
described in Preparation Example 35 were added thereto, and the
solution was stirred for 13 hours 30 minutes at room temperature.
After the reaction was completed, the reaction solution was poured
into brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the resulting residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1), and the title
compound (380 mg, 1.05 mmol, 46%) was obtained.
[0469] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.47 (2H,
d, J=6.0 Hz), 6.50 (1H, d, J=4.0 Hz), 6.64 (1H, d, J=8.0 Hz), 6.78
(1H, d, J=4.0 Hz), 7.07-7.17 (3H, m), 7.36-7.41 (2H, m), 7.53 (2H,
brs), 7.93 (1H, d, J=8.0 Hz), 9.11 (1H, t, J=6.0 Hz).
Preparation Example A+-12
2-Amino-6-(2-amino-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinam-
ide
[0470]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
(150 mg, 0.417 mmol) described in Preparation Example A+-11,
ethane-1,2-diamine (418 .mu.l, 6.25 mmol) were dissolved in a
mixture solution of dimethylsulfoxide (2 mL) and
N,N-diisopropylethylamine (1 mL), and the solution was stirred at
120.degree. C. for 15 hours. The reaction solution was cooled to
room temperature, water was added, then extracted with ethyl
acetate and tetrahydrofuran, the organic layer was washed with
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated in vacuo, tetrahydrofuran and NH silica gel were added
to the residue, the solvent was evaporated in vacuo adsorption,
purification was carried out by NH silica gel column chromatography
(ethyl acetate:methanol=10:1), and the title compound (95 mg, 0.25
mmol, 59%) was obtained as a white solid.
[0471] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.64 (2H,
t, J=6.4 Hz), 3.16-3.22 (2H, m), 4.41 (2H, d, J=5.7 Hz), 5.70 (1H,
d, J=8.6 Hz), 6.48 (1H, d, J=3.8 Hz), 6.67 (1H, brs), 6.72 (1H, d,
J=3.8 Hz), 7.02 (2H, s), 7.08 (2H, d, J=8.6 Hz), 7.14 (1H, t, J=7.3
Hz), 7.38 (2H, dd, J=7.3, 8.6 Hz), 7.59 (1H, d, J=8.6 Hz), 8.38
(1H, t, J=5.7 Hz).
Preparation Example A+-13
2-Amino-6-(2-(4-nitro-phenylamino)-ethylamino)-N-(5-phenoxy-thiophen-2-ylm-
ethyl)-nicotinamide
[0472]
2-Amino-6-(2-amino-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-ni-
cotinamide (25 mg, 65 .mu.mol) described in Preparation Example
A+-12, 4-fluoronitrobenzene (7.6 .mu.l, 71 mmol) and
N,N-diisopropylethylamine (22.7 .mu.l, 130 mmol) were dissolved in
dimethylsulfoxide (0.5 mL), the solution was stirred for 3.5 hours
at room temperature, and then, the solution was stirred for 15.5
hours at 70.degree. C. The reaction solution was cooled to room
temperature, water was added, the solution was extracted with ethyl
acetate, the organic layer was washed with brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
residue was purified by reverse phase high performance liquid
chromatography (mobile phase:acetonitrile-water (containing 0.1%
trifluoroacetic acid) was used), and the title compound (23 mg) was
obtained as a trifluoroacetic acid salt.
[0473] MS m/e (ESI) 505.37 (MH.sup.+)
Preparation Example A+-14
2-Amino-6-(1-ethoxyvinyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[0474] 1-Ethoxyvinyl(tri-n-butyl)tin (0.47 mL, 1.4 mmol) was added
to a mixture of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
(170 mg, 0.46 mmol) described in Preparation Example A+-11,
tetrakis(triphenylphosphine)palladium(0) (54 mg, 0.046 mmol) and
xylene (5 mL), and the solution was stirred for 2.5 hours at
130.degree. C. After cooling, water and ethyl acetate were added to
the reaction solution for extraction, and the solution was washed
with brine. The solvent was evaporated in vacuo, then, the residue
was purified by NH silica gel column chromatography (hexane:ethyl
acetate=2:1), and the title compound (150 mg, 0.38 mmol, 82%) was
obtained as a pale yellow solid.
[0475] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.42 (3H,
t, J=7.0 Hz), 3.93 (2H, q, J=7.0 Hz), 4.35 (1H, d, J=1.8 Hz), 4.65
(2H, d, J=5.3 Hz), 5.37 (1H, d, J=1.8 Hz), 6.30-6.32 (3H, m), 6.39
(1H, d, J=3.7 Hz), 6.74 (1H, d, J=3.8 Hz), 7.00 (1H, d, J=8.1 Hz),
7.08-7.13 (3H, m), 7.30-7.35 (2H, m), 7.59 (1H, d, J=8.1 Hz).
Preparation Example A+-15
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-tributylstanyl-nicotinamide
[0476] To a mixture of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
(1.1 g, 3.0 mmol) described in Preparation Example A+-11,
tetrakis(triphenylphosphine)palladium(0) (170 mg, 0.15 mmol) and
xylene (5 mL) was added bis(tri n-butyl tin) (9.1 mL, 18 mmol), and
the solution was stirred at 135.degree. C. for 2 hours. After
cooling, the reaction solution was directly purified by neutral
silica gel column chromatography (hexane:ethyl acetate=3:1), then,
the resulting crude product was washed with hexane cooled to
0.degree. C. to obtain the title compound (600 mg, 0.98 mmol, 33%)
as a colorless oil.
[0477] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.86-0.90
(9H, m), 1.05-1.09 (6H, m), 1.27-1.36 (6H, m), 1.50-1.58 (6H, m),
4.64 (1H, d, J=5.5 Hz), 6.26-6.30 (4H, m), 6.38 (1H, d, J=3.8 Hz),
6.73-6.74 (2H, m), 7.08-7.12 (3H, m), 7.31-7.36 (3H, m).
Preparation Example A+-16
2-Amino-5-iodo-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide
[0478] 2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide (250
mg, 0.768 mmol) obtained from 2-aminonicotinic acid and
C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation
Example 24 according to an analogous method to Preparation Example
A+-5, and N-iodosuccinimide (190 mg, 0.845 mmol) were dissolved in
tetrahydrofuran (5 mL), and the solution was stirred for 16 hours
at room temperature. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C.,
which was then extracted with ethyl acetate, the organic layer was
washed with brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated in vacuo, residue was purified by NH silica
gel column chromatography (hexane:ethyl acetate=1:1), and title
compound (45 mg, 0.10 mmol, 13%) was obtained as a pale yellow
solid.
[0479] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, J=5.7 Hz), 6.49 (1H, d, J=3.7 Hz), 6.77 (1H, d, J=3.8 Hz), 7.08
(2H, d, J=7.7 Hz), 7.13 (1H, t, J=7.3 Hz), 7.23 (2H, s), 7.37 (2H,
t, J=7.3 Hz), 8.15 (1H, d, J=2.2 Hz), 8.21 (1H, d, J=1.8 Hz), 9.13
(1H, d, J=5.7 Hz).
Preparation Example A+-17
2-Amino-N-(3-hydroxybenzyl)-nicotinamide
[0480] The title compound (0.63 g, 2.6 mmol, 53%) was obtained as a
white solid from 3-aminomethylphenol (0.60 g, 4.9 mmol) described
in Preparation Example 130 and 2-aminonicotinic acid (0.67 g, 4.9
mmol) according to an analogous method to Preparation Example
Q+-1.
[0481] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.34 (2H,
d, J=5.9 Hz), 6.56-6.61 (2H, m), 6.69-6.71 (2H, m), 7.06-7.10 (3H,
m), 7.93 (1H, dd, J=1.8, 7.8 Hz), 8.06 (1H, dd, J=1.8, 4.8 Hz),
8.91 (1H, t, J=6.0 Hz), 9.30 (1H, s).
Preparation Example A+-18
2-Amino-N-(4-benzyloxy-benzyl)-6-chloro-nicotinamide
[0482] The title compound (0.43 g, 1.2 mmol, 28%) was obtained as a
white solid from 14-benzyloxy-benzylamine (0.90 g, 4.2 mmol)
described in Preparation Example and 2-amino-6-chloro-nicotinic
acid (1.5 g, 8.4 mmol) described in Preparation Example A-1 (or
A-4) according to an analogous method to Preparation Example
Q+-1.
[0483] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.33 (2H,
d, J=5.7 Hz), 5.06 (2H, s), 6.61 (1H, d, J=8.1 Hz), 6.94 (2H, d,
J=8.6 Hz), 7.20 (2H, d, J=8.4 Hz), 7.28-7.31 (1H, m), 7.34-7.38
(2H, m), 7.41 (2H, d, J=7.5 Hz), 7.49 (2H, brs), 7.95 (1H, d, J=8.1
Hz), 8.92-8.95 (1H, m).
Preparation Example A+-19
5-Bromo-thiophene-2-carbaldehyde oxime
[0484] To a mixture of 2-bromo-5-formylthiophene (2.5 mL, 21 mmol)
and pyridine (25 mL) was added hydroxylamine hydrochloride (2.2 g,
32 mmol) on an ice bath, then, the solution was stirred overnight
at room temperature. This reaction mixture was concentrated in
vacuo, then, partitioned with water (50 mL), ethyl acetate (50 mL)
then 1N hydrochloric acid solution (50 mL). The organic layer was
separated, sequentially washed with an aqueous solution of
saturated sodium bicarbonate and brine, and then, dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was washed with heptane-ethyl acetate (30:1), and the
title compound (4.3 g, 21 mmol, 98%) was obtained as a light brown
solid.
[0485] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.07 (1H, d,
J=4.0 Hz), 7.11 (1H, d, J=4.0 Hz), 7.62 (1H, s), 8.35 (1H, br
s).
Preparation Example A+-20
5-Bromo-thiophene-2-carbonitrile
[0486] To a mixture of 5-bromo-thiophene-2-carbaldehyde oxime
described in Preparation Example A+-19 (1.3 g, 6.2 mmol) and
tetrahydrofuran (15 mL) were acetic acid (1.4 mL, 25 mmol) and
acetic anhydride (1.5 mL, 15 mmol) at room temperature, then,
stirred at 50.degree. C. for 2 hours, and further stirred at
70.degree. C. for 8 hours. After cooling this reaction mixture, the
solution was concentrated in vacuo. The residue was purified by
NH-silica gel column chromatography (heptane:ethyl acetate=8:1),
and the title compound (1.0 g, 5.4 mmol, 88%) was obtained as a
colorless solid.
[0487] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.11 (1H, d,
J=4.0 Hz), 7.40 (1H, d, J=4.0 Hz).
Preparation Example A+-21
C-(5-Bromo-thiophen-2-yl)-methylamine
[0488] To a mixture of lithium aluminum hydride (1.6 g, 4 .mu.mol)
and tetrahydrofuran (45 mL) was aluminum chloride (6.1 g, 46 mmol)
on an ice bath, then, the solution was stirred for 1 hour at room
temperature. The reaction solution was cooled to -20.degree. C., a
solution of 5-bromo-thiophene-2-carbonitrile described in
Preparation Example A+-20 (4.3 g, 25 mmol) in tetrahydrofuran (5
mL) was added dropwise at the same temperature. After stirring at
2.degree. C. for 20 minutes, the reaction solution was cooled to
-10.degree. C., and while maintaining the internal temperature at
0.degree. C. or lower, tetrahydrofuran (300 mL) and 28% aqueous
ammonia solution (5 mL) were added thereto. Anhydrous magnesium
sulfate was added to the reaction solution, which was then filtered
using a filter paper, and then, concentrated in vacuo. The residue
was purified by NH-silica gel column chromatography (ethyl
acetate), and the title compound (840 mg, 4.4 mmol, 85%) was
obtained as a colorless oil.
[0489] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.99 (2H,
s), 6.67 (1H, d, J=3.7 Hz), 6.88 (1H, d, J=3.7 Hz).
Preparation Example A+-22
2-Amino-N-(5-bromo-thiophen-2-ylmethyl)-6-methoxymethyl-nicotinamide
[0490] To a solution of C-(5-bromo-thiophen-2-yl)-methylamine (250
mg, 1.3 mmol) in N,N-dimethylformamide (5 mL) were added
tiethylamine (0.54 mL, 3.9 mmol), 2-amino-6-methoxymethyl-nicotinic
acid (240 mg, 1.3 mmol) described in Preparation Example A-11, and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (690 mg, 1.6 mmol) sequentially on an ice bath,
then, the solution was stirred for 2 days at room temperature. The
reaction solution was partitioned in water and ethyl acetate. The
organic layer was separated, the solvent was evaporated in vacuo.
The residue was purified by silica gel column chromatography
(heptane:ethyl acetate=4:1), and the title compound (370 mg, 1.0
mmol, 79%) was obtained as a white solid.
[0491] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.40 (2H, s), 4.67 (2H, d, J=5.7 Hz), 6.33 (1H, br s), 6.38
(2H, br s), 6.71 (1H, d, J=7.9 Hz), 6.79 (1H, d, J=3.7 Hz), 6.91
(1H, d, J=3.9 Hz), 7.59 (1H, d, J=7.9 Hz).
Preparation Example A+-23
2-Amino-N-(4-bromo-benzyl)-6-methoxymethyl-nicotinamide
[0492] The title compound (1.9 g, 5.4 mmol, 86%) was obtained as a
pale yellow solid from 2-amino-6-methoxymethyl-nicotinic acid (1.2
g, 6.3 mmol) described in Preparation Example A-11 and
4-bromobenzylamine hydrochloride (1.5 g, 6.9 mmol) according to an
analogous method to Preparation Example A+-22.
[0493] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.40 (2H, s), 4.55 (2H, d, J=5.7 Hz), 6.30 (1H, br s), 6.39
(2H, br s), 6.70 (1H, d, J=7.9 Hz), 7.22 (2H, d, J=8.2 Hz), 7.48
(2H, d, J=8.4 Hz), 7.60 (1H, d, J=7.9 Hz).
Preparation Example A+-24
2-Amino-N-(4-((Z)-2-ethoxy-vinyl)-benzyl)-6-methoxymethyl-nicotinamide
[0494] A mixture of (2-ethoxy-vinyl)-tributyl-stannane (37 mg, 0.10
mmol) synthesized according to WO02/018368,
2-amino-N-(4-bromo-benzyl)-6-methoxymethyl-nicotinamide (30 mg,
0.086 mmol) described in Preparation Example A+-23,
tri-o-tolylphosphine (6.5 mg, 0.021 mmol), palladium acetate (0.96
mg, 0.0043 mmol), tetrabutylammonium chloride (24 mg, 0.086 mmol)
and N-methylpyrrolidinone (1 mL) was stirred at 125.degree. C. for
1 hour. The reaction solution was allowed to cool, an aqueous
solution of potassium fluoride was added on an ice bath, the
solution was filtered through Celite pad. The filtrate was
partitioned with ethyl acetate. The organic layer was separated,
washed with brine, then, evaporated in vacuo. The residue was
purified by silica gel column chromatography (heptane:ethyl
acetate=1:2), and the title compound (12 mg, 0.035 mmol, 35%) was
obtained as a colorless solid.
[0495] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.36 (3H, d,
J=7.1 Hz), 3.45 (3H, s), 3.99 (2H, q, J=7.1 Hz), 4.39 (2H, s), 4.55
(2H, d, J=5.5 Hz), 5.21 (1H, d, J=7.0 Hz), 6.21-6.23 (2H, m), 6.40
(2H, br s), 6.68 (1H, d, J=7.9 Hz), 7.26 (2H, d, J=8.3 Hz),
7.57-7.59 (3H, m).
Preparation Example A+-25
2-Amino-6-methoxymethyl-N-(3-hydroxybenzyl)-nicotinamide
[0496] 2-Amino-6-methoxymethylcotinic acid (500 mg, 2.74 mmol),
3-hydroxybenzylamine (405 mg, 3.29 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.33 mg, 3.01 mmol) and triethylamine (555 mg,
5.48 mmol) were added to dimethylsulfoxide (20 mL), and the
solution was stirred for 15 minutes at 60.degree. C. Water and
ethyl acetate were added to the reaction mixture, which was then
partitioned. The aqueous layer was extracted once with ethyl
acetate, the ethyl acetate layers were combined and the solvent was
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1, then ethyl acetate). The
resulting residue was purified by NH silica gel column
chromatography (ethyl acetate). The resulting residue was
solidified from hexane-ethyl acetate, and the title compound (490
mg, 1.71 mmol, 62.2%) was obtained as a pale yellow solid.
[0497] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.34 (3H,
s), 4.30 (2H, s), 4.35 (2H, d, J=6.0 Hz), 6.61 (2H, d, J=8.0 Hz),
6.70 (1H, s), 6.71 (1H, d, J=8.0 Hz), 7.10 (1H, dd, J=8.0, 8.0 Hz),
7.13 (2H, brs), 7.99 (1H, d, J=8.0 Hz), 8.91 (1H, t, J=6.0 Hz),
9.31 (1H, s).
Preparation Example A+-26
2-Amino-6-methoxymethyl-N-(4-hydroxybenzyl)-nicotinamide
[0498] The title compound (506 mg, 1.76 mmol, 64.3%) was obtained
as a pale yellow solid from 2-amino-6-methoxymethylcotinic acid
(500 mg, 2.74 mmol) and 4-hydroxybenzylamine (506 mg, 4.11 mmol)
according to an analogous method to Preparation Example A+-25.
[0499] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.34 (3H,
s), 4.29 (2H, s), 4.30 (2H, d, J=6.0), 6.59 (1H, d, J=7.6 Hz), 6.70
(2H, d, J=7.4 Hz), 7.10 (2H, d, J=7.4 Hz), 7.12 (2H, brs), 7.95
(1H, d, J=7.6 Hz), 8.84 (1H, t, J=6.0 Hz), 9.27 (1H, s).
Preparation Example AA-1
3,5-Diamino-pyrazine-2-carboxylic acid methyl ester
[0500] To a solution of 3,5-diamino-6-chloro-pyrazine-2-carboxylic
acid methyl ester (8.00 g, 39.5 mmol) in tetrahydrofuran (150 mL)
were added tetrakis(triphenylphosphine)palladium(0) (2.28 g, 1.98
mmol), formic acid (2.24 mL, 59.3 mmol) and triethylamine (16.5 mL,
119 mmol) at 0.degree. C. under nitrogen atmosphere, then, the
solution was stirred at 125.degree. C. for 12 hours. The reaction
solution was cooled to room temperature, and a solid precipitated.
This solid was collected by filtration, and the title compound
(10.7 g, quantitatively) was obtained as a crude product of a white
solid.
[0501] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.70 (3H,
s), 6.95 (2H, brs), 7.21 (1H, s).
Preparation Example AA-2
3,5-Diamino-pyrazine-2-carboxylic acid
[0502] Lithium hydroxide monohydrate (2.50 g, 59.5 mmol) was added
to 3,5-diamino-pyrazine-2-carboxylic acid methyl ester (10.0 g,
59.5 mmol) described in Preparation Example AA-1 in a mixture
solvent of tetrahydrofuran (100 mL), methanol (10 mL) and water (10
mL) at room temperature. The solution was stirred at room
temperature for 17 hours, then, an aqueous solution of 5N sodium
hydroxide (15 mL) was added thereto, followed by further stirring
for 4.5 hours under reflux. The reaction solution was cooled to
room temperature, and partitioned in 5N hydrochloric acid solution
and ethyl acetate. The organic layer was separated, washed with
brine, and then, dried over anhydrous magnesium sulfate. The
organic layer was filtered, then, the solvent was evaporated in
vacuo, and the title compound (3.34 g, 36%) was obtained as a crude
product of a white solid.
[0503] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.93 (2H,
brs), 7.20 (1H, s).
Preparation Example B-1
4-Amino-5-hydroxy-carbonyl-2-n-propylamino-pyrimidine
[0504] 4-Amino-2-chloro-5-cyano-pyrimidine (300 mg, 1.94 mmol) and
n-propyl amine (5 g, 84.6 mmol) were mixed and stirred for 10
minutes at 60.degree. C. The reaction solution was directly
purified by silica gel column chromatography, and a 2-propylamino
compound (300 mg, 1.69 mmol, 101%) was obtained as a brown solid.
This solid was suspended in concentrated sulfuric acid (3 mL) and
water (3 mL), and the solution was stirred for 1.5 hours at
130.degree. C. This mixture was alkalinized with an aqueous
solution of saturated sodium bicarbonate, then, the aqueous layer
was washed with ethyl acetate. Then, this aqueous layer was
neutralized with citric acid, and extracted with a mixture solvent
of acetate-methanol. This organic layer was separated, then, the
solvent was evaporated, and the title compound (44 mg, 0.224 mmol,
12%) was obtained as a white solid.
[0505] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 0.87 (3H,
t, J=7.2 Hz), 1.49 (2H, qt, J=7.2, 7.2 Hz), 3.18 (2H, q, J=7.2 Hz),
6.98 (2H, bs), 8.14 (1H, bs), 8.35 (1H, s).
Preparation Example C-1
Potassium salt of 2-Cyano-3-hydroxy-acrylic acid ethyl ester
[0506] To a solution of potassium ethoxide (9.8 g, 116 mmol) in
ethanol (180 mL) were added a solution of cyano ethyl acetate ester
(13.2 g, 117 mmol) and formic acid ethyl ester (30 g, 405 mmol) in
ethanol (20 mL), and the solution was stirred for 2 hours under
reflux. The reaction solution was allowed to room temperature, the
precipitated solid was collected by filtration and dried, and the
title compound (18 g, 100 mmol, 85%) was obtained.
[0507] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.13 (3H,
t, J=7.2 Hz), 3.96 (2H, q, J=7.2 Hz), 9.18 (1H, s).
Preparation Example C-2
1-(Pyrrolidino)-2-(2-carbethoxy-2-cyanoethylene)cyclopentene
[0508] Potassium salt of 2-cyano-3-hydroxy-acrylic acid ethyl ester
described in Preparation Example C-1 (18 g, 0.1 mol) was dissolved
in dichloromethane (80 mL), phosphorus pentachloride (20.9 g, 0.1
mol) was added, and the solution was stirred for 2 hours under
reflux. After the reaction was completed, the residue obtained by
evaporating dichloromethane was subjected to distillation in vacuo,
and ethyl(chloromethylene)cyanoacetate (9.5 g, 56 mmol) was
obtained.
[0509] To a solution of 1-pyrrolidinocyclopentene (10.2 g, 74 mmol)
and triethylamine (10 mL, 72 mmol) in dichloromethane (200 mL) was
added a solution of the resulting
ethyl(chloromethylene)cyanoacetate (9.5 g, 56 mmol) in
dichloromethane (20 mL) dropwise while stirring at from -20.degree.
C. to -25.degree. C. The solution was stirred at room temperature
for 50 minutes, water (20 mL) was added thereto, followed by
further stirring for 5 minutes. The reaction mixture was
partitioned, the organic layer was dried over anhydrous magnesium
sulfate, then concentrated, and the title compound (6 g, 23 mmol,
23%) was obtained.
[0510] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.19 (3H,
t, J=7.2 Hz), 1.76-1.86 (2H, m), 1.86-2.04 (4H, m), 2.73 (2H, t,
J=7.6 Hz), 2.88 (2H, t, J=7.2 Hz), 3.60-3.71 (4H, m), 4.09 (2H, q,
J=7.2 Hz), 7.97 (1H, brs).
Preparation Example C-3
1-Amino-2-(2-carbethoxy-2-cyanoethylene)cyclopentene
[0511] 1-(Pyrrolidino)-2-(2-carbethoxy-2-cyanoethylene)cyclopentene
(6 g, 23 mmol) described in Preparation Example C-2 was dissolved
in ethanol saturated with ammonia (75 mL; was saturated at room
temperature using ammonia gas), and the solution was stirred for 19
hours at room temperature. The reaction solution was concentrated
and the title compound (4.8 g, 23 mmol, quantitatively) was
obtained.
[0512] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.21 (3H,
t, J=7.2 Hz), 1.74-1.83 (2H, m), 2.48-2.54 (2H, m), 2.72-2.78 (2H,
m), 4.12 (2H, q, J=7.2 Hz), 8.09-8.47 (1H, brs).
Preparation Example C-4
2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
ethyl ester
[0513] 1-Amino-2-(2-carboethoxy-2-cyanoethylene)cyclopentene (0.8
g, 3.9 mmol) described in Preparation Example C-3 was dissolved in
ethanol (27 mL), sodium ethoxide (0.12 g, 1.8 mmol) was added
thereto, followed by stirring for 16 hours under reflux. The
reaction mixture was allowed to room temperature, poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then, the
residue obtained by concentration was purified by silica gel column
chromatography (ethyl acetate:hexane=1:2), and the title compound
(0.63 g, 3.1 mmol, 79%) was obtained.
[0514] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.38 (3H, t,
J=7.2 Hz), 2.04-2.13 (2H, m), 2.79-2.88 (4H, m), 4.32 (2H, q, J=7.2
Hz), 6.16-6.32 (2H, brs), 7.96 (1H, s).
Preparation Example C-5
2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
[0515] 2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic
acid ethyl ester (0.2 g, 0.97 mmol) described in Preparation
Example C-4 was dissolved in ethanol (15 mL), an aqueous solution
of 1N sodium hydroxide (7.5 mL) was added thereto, followed by
heating at 100.degree. C. for 30 minutes. The reaction solution was
allowed to room temperature, then cooled on an ice bath, and
neutralized with 1N hydrochloric acid. The precipitated solid was
collected by filtration, rinsed with water, then dried, and the
title compound (143 mg, 0.8 mmol, 83%) was obtained.
[0516] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.94-2.03
(2H, m), 2.71-2.76 (4H, m), 7.84 (1H, s).
Preparation Example D-1
[1,5]Naphthylidine-2-carboxylic acid
[0517] 5-Amino-2-chloro pyridine (10 g, 0.078 mol) and oxalacetic
acid diethyl ester (14.7 g, 0.078 mol) were stirred at 90.degree.
C. for 7 hours. The reaction solution was allowed to room
temperature, ethyl acetate was added thereto, the precipitated
yellow solid was removed by filtration, and the filtrate was
concentrated. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and
2-(6-chloro-pyridin-3-ylamino)-buto-2-enedioic acid diethyl ester
(4.8 g, 21%) was obtained as a yellow oil.
[0518] The resulting 2-(6-chloro-pyridin-3-ylamino)-buto-2-enedioic
acid diethyl ester (4.8 g, 16.1 mmol) was added to Dowtherm A
(Dowtherm A; trademark) (300 mL), and the solution was stirred at
210.degree. C. for 5 hours. The reaction solution was allowed to
room temperature, hexane was added thereto, the precipitated solid
was collected, washed with hexane, then, dried in vacuo to obtain
6-chloro-4-hydroxy-[1,5]naphthylidine-2-carboxylic acid ethyl ester
(1.38 g, 34%) as a pale brown solid.
[0519] To the resulting
6-chloro-4-hydroxy-[1,5]naphthylidine-2-carboxylic acid ethyl ester
(502 mg, 1.99 mmol) was added thionyl chloride (10 mL), and the
solution was stirred for 7 hours under reflux. Excess thionyl
chloride was evaporated in vacuo,
4,6-dichloro-[1,5]naphthylidine-2-carboxylic acid ethyl ester (522
mg, 97%) was obtained as a pale brown solid. Under nitrogen
atmosphere, a portion of the resulting solid (200 mg, 0.738 mmol)
was dissolved in dimethylsulfoxide (30 mL),
tetrakis(triphenylphosphine)palladium(0) (171 mg, 0.148 mmol) and
formic acid sodium (251 mg, 3.69 mmol) were added thereto, followed
by stirring at 100.degree. C. for 4 hours. The reaction solution
was allowed to room temperature, ethyl acetate and water were added
for partitioning, the organic layer was washed with water and dried
over anhydrous magnesium sulfate. The solvent was evaporated, then,
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate), and [1,5]naphthylidine-2-carboxylic acid
ethyl ester (49 mg, 33%) was obtained as a colorless solid.
[0520] The resulting solid was dissolved in methanol (1.0 mL), an
aqueous solution of 1N sodium hydroxide (0.3 mL) was added thereto,
followed by stirring at room temperature for 30 minutes. Water was
added to the reaction solution, the pH was adjusted from 3 to 4
using 1N hydrochloric acid, the solution was extracted with ethyl
acetate, dried over anhydrous magnesium sulfate, and the solvent
was evaporated to obtain the title compound (29 mg, 69%) as a white
solid.
Preparation Example E-1
Quinoline-6-carboxylic acid cyanomethyl-amide
[0521] To a solution of quinoline-6-carboxylic acid (500 mg, 2.9
mmol) and amino acetonitrile hydrochloride (320 mg, 3.4 mmol) in
N,N-dimethylformamide (10 mL) were added
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (1.5 g, 3.48 mmol) and triethylamine (1.2 mL,
8.7 mmol), and the solution was stirred at 60.degree. C. for 10
minutes. Ethyl acetate and water was added to the reaction
solution, which was then partitioned, the organic layer was washed
twice with water. Silica gel was added to the organic layer, the
solvent was evaporated in vacuo for adsorption, purified by NH
silica gel column chromatography (ethyl acetate), and the title
compound (420 mg, 2.0 mmol, 68.9%) was obtained as a light brown
solid.
[0522] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.43 (2H,
d, J=5.6 Hz), 7.65 (1H, dd, J=4.0, 8.4 Hz), 8.14 (1H, d, J=8.8 Hz),
8.18-8.22 (1H, m), 8.30-8.35 (1H, m), 8.58 (1H, d, J=1.2 Hz),
9.02-9.05 (1H, m), 9.49 (1H, t, J=5.6 Hz).
Preparation Example E+-1
Quinoline-6-carboxylic acid 4-hydroxybenzylamide
[0523] Trifluoroacetic acid (5 mL) and thioanisole (3 drops) were
added to quinoline-6-carboxylic acid 4-benzyloxybenzylamide (2.67
g, 7.25 mmol) synthesized in Example E-8, the solution was stirred
at room temperature for 14 hours, followed by stirring at
50.degree. C. for 4 hours, lastly, and the solution was stirred at
70.degree. C. for 3 hours. The reaction solution was allowed to
room temperature, then, was neutralized with an aqueous solution of
saturated sodium bicarbonate, extracted with ethyl acetate and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
the residue was purified by NH silica gel column chromatography
(ethyl acetate), and the title compound (433 mg, 22%) was obtained
as a colorless solid.
Preparation Example E+-2
Quinoline-6-carboxylic acid (5-bromo-furan-2-ylmethyl)-amide
[0524] The title compound (1.0 g, 3.0 mmol, 75.5%) was obtained as
a white solid from C-(5-bromo-furan-2-yl)-methylamine (700 mg, 4.0
mmol) and quinoline-6-carboxylic acid (700 mg, 4.0 mmol) according
to an analogous method to Example Q-6.
[0525] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.49 (2H,
d, J=5.6 Hz), 6.38-6.41 (1H, m), 6.50 (1H, d, J=3.6 Hz), 7.60 (1H,
dd, J=4.0, 8.4 Hz), 8.06 (1H, d, J=8.8 Hz), 8.17 (1H, dd, J=2.0,
8.8 Hz), 8.44-8.48 (1H, m), 8.52 (1H, d, J=2.0 Hz), 8.97 (1H, dd,
J=1.6, 4.0 Hz), 9.23 (1H, t, J=5.6 Hz).
Preparation Example E+-3
Quinoline-6-carboxylic acid 4-benzylamino-benzylamide
[0526] 4-Benzylamino-benzonitrile (472 mg, 2.27 mmol) described in
Preparation Example 89 was dissolved at 0.degree. C. in
tetrahydrofuran (20 mL), and lithium aluminum hydride (430 mg, 11.3
mmol) was added thereto. The solution was stirred overnight at room
temperature, then, at 0.degree. C., water (430 .mu.l), an aqueous
solution of 5N sodium hydroxide (430 .mu.l) and water (1.29 mL)
were sequentially added to the solution. The reaction solution was
filtered through Celite pad, the solvent was then evaporated in
vacuo, (4-aminomethyl-phenyl)-benzylamine (475 mg, 2.24 mmol, 99%)
was obtained as an oil.
[0527] The resulting (4-aminomethyl-phenyl)-benzylamine (162 mg,
0.763 mmol), quinoline-6-carboxylic acid (132 mg, 0.736 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (506 mg, 1.14 mmol) and triethylamine (319
.mu.l, 2.29 mmol) were dissolved in N,N-dimethylformamide (4.0 mL),
and the solution was stirred for 2 hours at room temperature. Water
was added to the reaction solution, which was then extracted with
ethyl acetate, the organic layer was washed with water and brine
and dried over anhydrous magnesium sulfate. The solvent was
evaporated in vacuo, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate=1:1), and the title
compound (224 mg, 0.610 mmol, 80%) was obtained as a white
solid.
[0528] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.23 (2H,
d, J=6.0 Hz), 4.33 (2H, d, J=6.0 Hz), 6.18 (1H, t, J=6.1 Hz), 6.51
(2H, d, J=8.6 Hz), 7.03 (2H, d, J=8.6 Hz), 7.18 (1H, t, J=7.0 Hz),
7.25-7.34 (4H, m), 7.58 (1H, dd, J=4.1, 8.3 Hz), 8.04 (1H, d, J=8.8
Hz), 8.16 (1H, dd, J=1.8, 9.0 Hz), 8.43 (1H, d, J=7.0 Hz), 8.49
(1H, d, J=2.0 Hz), 8.95 (1H, dd, J=1.8, 5.0 Hz), 9.04 (1H, t, J=5.5
Hz).
Preparation Example E+-4
Quinoline-6-carboxylic acid 3-hydroxybenzylamide
[0529] Thioanisole (1.7 mL, 14 mmol) was added to a mixture of
quinoline-6-carboxylic acid 3-benzyloxybenzylamide (1.3 g, 3.6
mmol) and trifluoroacetic acid (8 mL) on an ice bath, and the
solution was stirred for 4 hours at room temperature. The solvent
was evaporated in vacuo, then water, an aqueous solution of
saturated sodium bicarbonate, ethyl acetate and tetrahydrofuran
were added to the residue for extraction, the organic layer was
washed with brine, then, dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, recrystallized from ethyl
acetate-methanol, and the title compound (0.64 g, 2.3 mmol, 64%)
was obtained as a white crystal.
[0530] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, J=5.9 Hz), 6.60-6.63 (1H, m), 6.75-6.77 (2H, m), 7.10 (1H, t,
J=8.1 Hz), 7.60 (1H, dd, J=4.2, 8.2 Hz), 8.07 (1H, d, J=8.8 Hz),
8.20 (1H, dd, J=2.0, 8.8 Hz), 8.45-8.47 (1H, m), 8.54 (1H, d, J=1.8
Hz), 8.97 (1H, dd, J=1.7, 4.2 Hz), 9.23 (1H, t, J=5.8 Hz), 9.33
(1H, s).
Preparation Example E+-5
Quinoline-6-carboxylic acid 4-phenylethynyl-benzylamide
[0531] Quinoline-6-carboxylic acid 4-bromobenzylamide (1.3 g, 68%)
was obtained from quinoline-6-carboxylic acid (1.0 g, 5.8 mmol) and
4-bromobenzylamine hydrochloride (1.3 g, 5.8 mmol) according to an
analogous method to Preparation Example A+-5 (with the proviso that
reaction was carried out at 80.degree. C.).
[0532] N,N-diisopropylethylamine (0.31 mL, 1.8 mmol) was added to a
mixture of the resulting quinoline-6-carboxylic acid
4-bromobenzylamide (200 mg, 0.59 mmol), ethynylbenzene (0.077 mL,
0.70 mmol), copper(I) iodide (catalytic amount),
tetrakis(triphenylphosphine)palladium(0) (68 mg, 0.059 mmol) and
N-methylpyrrolidinone (4 mL), and the solution was stirred at
100.degree. C. for 30 minutes, and at 120.degree. C. for 50
minutes. After cooling, water, ethyl acetate, tetrahydrofuran and
29% aqueous ammonia solution were added to the reaction mixture for
extraction, the organic layer was washed with brine, then, the
solvent was evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane:ethyl acetate=1:4), then, the
resulting crudely purified product was washed with diethyl ether to
obtain the title compound (50 mg, 0.14 mmol, 24%) as a white
solid.
[0533] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=5.7 Hz), 7.39-7.41 (5H, m), 7.52 (4H, d, J=6.8 Hz), 7.60 (1H,
dd, J=3.8, 8.1 Hz), 8.08 (1H, d, J=8.6 Hz), 8.21 (1H, d, J=8.8 Hz),
8.47 (1H, d, J=7.9 Hz), 8.56 (1H, s), 8.97 (1H, d, J=4.0 Hz), 9.33
(1H, brs).
Preparation Example E+-6
Quinoline-6-carboxylic acid 4-[1,3]-dioxolan-2-yl-benzylamide
[0534] The title compound (1.31 g, 3.92 mmol, 77%) was obtained as
a white solid from 4-[1,3]dioxolan-2-yl-benzylamine described in
Preparation Example 120 (970 mg, 5.60 mmol) and
quinoline-6-carboxylic acid (913 mg, 5.09 mmol) according to an
analogous method to Preparation Example Q+-1.
[0535] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.90-4.02
(4H, m), 4.54 (2H, d, J=5.9 Hz), 5.69 (1H, s), 7.35-7.40 (4H, m),
7.60 (1H, dd, J=4.2, 8.2 Hz), 8.07 (1H, d, J=9.0 Hz), 8.2 (1H, dd,
J=1.9, 9.0 Hz), 8.46 (1H, d, J=8.1 Hz), 8.54 (1H, d, J=1.5 Hz),
8.97 (1H, dd, J=1.7, 4.2 Hz), 9.29 (1H, t, J=5.7 Hz).
Preparation Example E+-7
Quinoline-6-carboxylic acid 4-formyl-benzylamide
[0536] Quinoline-6-carboxylic acid 4-[1,3]dioxolan-2-yl-benzylamide
described in Preparation Example E+-6 (1.30 g, 3.89 mmol) was
dissolved in a mixture solution of tetrahydrofuran (20 mL), water
(10 mL) and sulfuric acid (3 mL), the solution was stirred for 2
hours under reflux. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C., the
solution was extracted with ethyl acetate and tetrahydrofuran. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, and the solvent was evaporated in vacuo. Ethyl acetate was
added to the residue, the precipitated solid was filtered, and the
title compound (700 mg, 2.41 mmol, 62%) was obtained as a white
solid.
[0537] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.63 (2H,
d, J=5.7 Hz), 7.57 (2H, d, J=7.9 Hz), 7.61 (1H, t, J=4.1 Hz), 7.88
(2H, dd, J=1.8, 8.4 Hz), 8.09 (1H, d, J=8.8 Hz), 8.21 (1H, dd,
J=2.0, 8.8 Hz), 8.48 (1H, d, J=7.9 Hz), 8.56 (1H, d, J=1.5 Hz),
8.98 (1H, dd, J=1.8, 4.2 Hz), 9.39 (1H, t, J=6.0 Hz), 9.97 (1H,
s).
Preparation Example E+-8
Quinoline-6-carboxylic acid 3-bromobenzylamide
[0538] The title compound (1.4 g, 4.0 mmol, 70%) was obtained as a
white solid from 3-bromobenzylamine hydrochloride (1.3 g, 5.8 mmol)
and quinoline-6-carboxylic acid (1.0 g, 5.8 mmol) according to an
analogous method to Preparation Example Q+-1.
[0539] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.68 (2H, d,
J=5.7 Hz), 6.75 (1H, brs), 7.23 (1H, t, J=7.8 Hz), 7.31-7.34 (1H,
m), 7.43-7.45 (1H, m), 7.47 (1H, dd, J=4.2, 8.2 Hz), 7.53-7.54 (1H,
m), 8.07 (1H, dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.22-8.24
(1H, m), 8.34 (1H, d, J=1.8 Hz), 8.99 (1H, dd, J=1.8, 4.2 Hz).
Preparation Example E+-9
Quinoline-6-carboxylic acid 4-bromobenzylamide
[0540] The title compound (1.3 g, 3.9 mmol, 68%) was obtained as a
white solid from 4-bromobenzylamine hydrochloride (1.3 g, 5.8 mmol)
and quinoline-6-carboxylic acid (1.0 g, 5.8 mmol) according to an
analogous method to Preparation Example Q+-1.
[0541] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.67 (2H, d,
J=5.9 Hz), 6.63 (1H, brs), 7.26-7.29 (2H, m), 7.47-7.51 (3H, m),
8.06 (1H, dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.22-8.25
(1H, m), 8.33 (1H, d, J=2.0 Hz), 8.99 (1H, dd, J=1.7, 4.2 Hz).
Preparation Example E+-10. Quinoline-6-carbothioic acid
4-benzyloxy-benzylamide
[0542] To a solution of 6-quinoline carboxylic acid (100 mg, 0.577
mmol) in tetrahydrofuran (50 mL) was added
N,N'-dicyclohexylcarbodiimide (1.90 g, 11.7 mmol), and the solution
was stirred for 1 hour at room temperature. Then, a solution of
4-benzyloxybenzylamine described in Preparation Example 1 (2.49 g,
11.7 mmol) in tetrahydrofuran was added thereto, followed by
stirring overnight at room temperature. The solvent was evaporated,
the residue was purified by NH silica gel column chromatography
(hexane:ethyl acetate), and quinoline-6-carboxylic acid
4-benzyloxy-benzylamide (4.31 g, quantitatively) was obtained as a
white solid.
[0543] A mixture of the resulting quinoline-6-carboxylic acid
4-benzyloxy-benzylamide (310 mg, 0.84 mmol),
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide
(Lawesson's reagent) (1.4 g, 3.4 mmol) and tetrahydrofuran (10 mL)
was refluxed for 1 hour. After cooling, the solvent was evaporated
in vacuo, dichloromethane was added to the residue, which was
purified by NH silica gel column chromatography (hexane:ethyl
acetate=1:1), and the title compound (55 mg, 0.14 mmol, 17%) was
obtained as a pale yellow solid.
[0544] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.93 (2H,
d, J=4.6 Hz), 5.09 (2H, s), 6.99 (2H, d, J=8.8 Hz), 7.26-7.44 (7H,
m), 7.58 (1H, dd, J=4.2, 8.2 Hz), 8.01 (1H, d, J=9.0 Hz), 8.13 (1H,
dd, J=2.1, 8.9 Hz), 8.29 (1H, d, J=1.8 Hz), 8.46 (1H, d, J=8.2 Hz),
8.94 (1H, dd, J=1.6, 4.2 Hz), 10.9 (1H, brs).
Preparation Example F-1
3-Acetyl-4-amino-benzoic acid methyl ester
[0545] To a solution of 4-amino-3-iodo-benzoic acid methyl ester
(11.30 g, 40.77 mmol) in toluene (300 mL) were added
tributyl(1-ethoxyvinyl)tin (16.5 mL, 48.9 mmol) and
tetrakis(triphenylphosphine)palladium(0) (9422 mg, 8.154 mmol)
under nitrogen atmosphere, and the solution was stirred at
105.degree. C. for 7 hours. After cooling to room temperature,
water was added, the mixture was extracted with ethyl
acetate-tetrahydrofuran, the organic layer was washed with water,
and then, evaporated. The residue was dissolved in 280 mL of
tetrahydrofuran, 2N hydrochloric acid (80 mL) was added thereto,
followed by stirring for 3 hours at room temperature. The reaction
mixture was cooled on an ice bath, an aqueous solution of 2N sodium
hydroxide (80 mL) was added, an aqueous solution of saturated
sodium bicarbonate was further added, and the solution was
extracted with ethyl acetate. An aqueous solution of 10% potassium
fluoride was added to the organic layer, and the solution was
stirred for 3 hours at room temperature. The organic layer was
separated, washed with brine, then evaporated, the residue was
purified by silica gel column chromatography (hexane-ethyl
acetate), and title compound (6.42 g, 33.2 mmol, 81.4%) was
obtained.
[0546] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.64 (3H,
s), 3.89 (3H, s), 6.63 (1H, d, J=8.8 Hz), 7.91 (1H, dd, J=2.0, 8.8
Hz), 8.47 (1H, d, J=2.0 Hz).
Preparation Example F-2
4-oxo-1,4-dihydro-cinnoline-6-carboxylic acid methyl ester
[0547] To a solution of 3-acetyl-4-amino-benzoic acid methyl ester
(2063 mg, 10.68 mmol) in acetic acid (39 mL) was added sulfuric
acid (6.5 mL) on an ice bath, then, an aqueous solution (6.5 mL) of
sodium nitrite (922 mg, 13.35 mmol) was added thereto, followed by
stirring on the ice for 1 hour, and at room temperature for 2 days.
The reaction mixture was concentrated until it reached half of the
amount, water was added, then an aqueous solution of 2N sodium
hydroxide was added on an ice bath to adjust the pH to 5. The
insoluble matter was separated by filtration, then, the filtrate
was extracted with ethyl acetate, the organic layer was dried over
sodium sulfate and then evaporated. Diethyl ether was added to the
resulting residue for solidification, the resulting solid was
washed with diethyl ether, and 365 mg of the title compound (1.78
mmol, 16.6%) was obtained.
[0548] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.88 (3H,
s), 7.66 (1H, d, J=8.8 Hz), 7.82 (1H, s), 8.24 (1H, d, J=8.8 Hz),
8.58 (1H, s), 13.7 (1H, brs).
Preparation Example F-3
4-Chloro-cinnoline-6-carboxylic acid methyl ester
[0549] Thionyl chloride (5 mL, 68.5 mmol) and N,N-dimethylformamide
(3 drops) were added to 4-oxo-1,4-dihydro-cinnoline-6-carboxylic
acid methyl ester (212 mg, 1.04 mol), and the solution was stirred
for 1.15 hours under reflux. Toluene was added to the reaction
mixture, which was then evaporated in vacuo. Ethyl acetate was
added to the residue the organic layer was washed with an ice
water, dried over anhydrous magnesium sulfate, then, evaporated in
vacuo, and the title compound (192 mg, 0.862 mmol, 82.9%) was
obtained. This was used in the next reaction without
purification.
[0550] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.97 (3H,
s), 8.43 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=8.8 Hz), 8.72 (1H, s),
9.73 (1H, s).
Preparation Example F-4
Cinnoline-6-carboxylic acid methyl ester
[0551] To a solution of 4-chloro-cinnoline-6-carboxylic acid methyl
ester (192 mg, 0.863 mmol) in dimethylsulfoxide (30 mL) were added
sodium formate (70 mg, 1.04 mmol),
tetrakis(triphenylphosphine)palladium(0) (198 mg, 0.702 mmol) and
N,N-diisopropylethylamine (0.21 mL, 1.21 mmol), and the mixture was
stirred for 1.5 hours at 90.degree. C. After cooling to room
temperature, water was added, ethyl acetate extraction was carried
out, the organic layer was washed with water and brine, then, after
drying over anhydrous sodium sulfate, the organic layer was
evaporated. The resulting solid was washed with diethyl ether,
then, purified by silica gel column chromatography (hexane-ethyl
acetate), and the title compound (16 mg, 0.089 mmol, 10%) was
obtained.
[0552] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.03 (3H,
s), 7.97 (1H, dd, J=0.8, 6.0 Hz), 8.42 (1H, J=0.8, 8.0 Hz),
8.59-8.63 (2H, m), 9.43 (1H, dd, J=0.8, 6.0 Hz).
Preparation Example G-1
Isoquinoline-6-carboxylic acid
[0553] A solution prepared by adding
(4-bromobenzylydene)-(2,2-diethoxyethyl) amine (synthesized from
4-bromobenzaldehyde, according to the method described in J. Org.
Chem., vol. 48, 3344-3346 (1983)) (51.4 g, 0.189 mmol) to an
ice-cold concentrated sulfuric acid (20 g) was added to a solution
prepared by adding diphosphorus pentoxide (40 g) to an ice-cold
concentrated sulfuric acid (360 g), and the solution was stirred at
160.degree. C. for 2 hours. The reaction solution was gradually
cooled to 0.degree. C., the solution was filtered through Celite
pad, the filtrate was neutralized with sodium carbonate. This
solution was further filtrated through Celite pad, this filtrate
was extracted with ethyl acetate and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the residue was purified
by silica gel column chromatography (hexane:ethyl acetate), and
6-bromoisoquinoline (482 mg, 1.2%) was obtained as an orange
oil.
[0554] Next, to a solution of 6-bromoisoquinoline (382 mg, 1.84
mmol) in N,N-dimethylformamide (3.8 mL) were added zinc cyanide
(431 mg, 3.67 mmol) and tetrakis(triphenylphosphine)palladium(0)
(42 mg, 0.0367 mmol) under nitrogen atmosphere, and the mixture was
stirred at 100.degree. C. for 1 hour.
Tetrakis(triphenylphosphine)palladium(0) (42 mg, 0.0367 mmol) was
further added, and the mixture was stirred for 2.5 hours at
100.degree. C. The reaction mixture was allowed to room
temperature, ethyl acetate and water were added for extraction, the
organic layer was washed with water and dried over anhydrous
magnesium sulfate. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and
isoquinoline-6-carbonitrile (234 mg, 83%) was obtained as a yellow
solid.
[0555] Lastly, isoquinoline-6-carbonitrile (51 mg, 0.331 mmol) was
dissolved in diethyleneglycol (1.0 mL), potassium hydroxide (9 mg,
0.166 mmol) was added thereto, followed by stirring at 160.degree.
C. for 3 hours. The reaction mixture was allowed to room
temperature, neutralized using hydrochloric acid, extracted with
ethyl acetate, dried over anhydrous magnesium sulfate, then, the
solvent was evaporated. Water was added to the residue, the
precipitated solid was collected, washed with water, dried in
vacuo, so as to obtain the title compound (12 mg, 21%) as a yellow
solid.
Preparation Example H-1
4-Chloro-quinazoline-6-carboxylic acid ethyl ester
[0556] The title compound (380 mg, 1.61 mmol, 88%) was obtained
from 4-oxo-dihydroquinazoline-6-carboxylic acid ethyl ester (396
mg, 1.81 mmol) according to an analogous method to Preparation
Example F-3.
[0557] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.34 (3H,
t, J=7.2 Hz), 4.35 (2H, q, J=7.2 Hz), 7.78 (1H, d, J=8.4 Hz), 8.29
(1H, dd, J=2.0, 8.4 Hz), 8.37 (1H, s), 8.64 (1H, d, J=2.0 Hz).
Preparation Example H-2
Quinazoline-6-carboxylic acid ethyl ester
[0558] The title compound (79 mg, 0.39 mmol, 24%) was obtained from
4-chloro-quinazoline-6-carboxylic acid ethyl ester (380 mg, 1.61
mmol) according to an analogous method to Preparation Example
F-4.
[0559] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.47 (3H, t,
J=7.6 Hz), 4.48 (2H, t, J=7.6 Hz), 8.11 (1H, d, J=8.8 Hz), 8.53
(1H, dd, J=2.0, 8.8 Hz), 8.71 (1H, d, J=2.0 Hz), 9.42 (1H, s), 9.52
(1H, s).
Preparation Example H-3
Quinazoline-6-carboxylic acid
[0560] To a solution of quinazoline-6-carboxylic acid ethyl ester
(79 mg, 0.391 mmol) in ethanol (4 mL) was added an aqueous solution
of 1N sodium hydroxide (4 mL), and the solution was stirred for 1
hour at room temperature. 1N Hydrochloric acid was added to the
reaction mixture to adjust the pH to 4, and the solution was
evaporated in vacuo. Ethanol was added to the residue, and the
organic layer was concentrated. The residue was dissolved in an
ethyl acetate-tetrahydrofuran mixture solvent, dried over anhydrous
magnesium sulfate, then, evaporated in vacuo, and
quinazoline-6-carboxylic acid (15 mg, 0.086 mmol, 22%) was
obtained. This was used in the next reaction without
purification.
[0561] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 8.09 (1H,
d, J=8.8 Hz), 8.44 (1H, dd, J=2.0, 8.8 Hz), 8.83 (1H, d, J=2.0 Hz),
9.39 (1H, s), 9.79 (1H, s).
Preparation Example I-1
Quinoxaline-6-carboxylic acid
[0562] To a solution of quinoxaline-6-carboxylic acid methyl ester
(2084 mg, 11.07 mmol) in ethanol (25 mL) was added an aqueous
solution of 1N sodium hydroxide (25 mL), and the solution was
stirred for 4 hours under reflux. 1N Hydrochloric acid was added to
the reaction mixture to adjust the pH to 4, then, the precipitated
solid was collected by filtration, washed with water and
isopropanol, then dried to obtain the title compound (1477 mg,
8.479 mmol, 76.6%) as a solid.
[0563] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 8.18 (1H,
d, J=8.4 Hz), 8.29 (1H, dd, J=8.4, 1.2 Hz), 8.61 (1H, d, J=1.2 Hz),
9.00-9.07 (2H, m).
Preparation Example J-1
2,2-Dimethyl-N-pyridin-2-yl-propionamide
[0564] 2-Aminopyridine (3.1 g, 33 mmol) and triethylamine (6.9 mL,
49 mmol) was dissolved in dichloromethane (40 mL),
2,2-dimethylpropionyl chloride (4.5 mL, 36 mmol) was added on an
ice bath, and the solution was stirred for 2 hours at the same
temperature. Water was added thereto for extraction, the organic
layer was sequentially washed with an aqueous solution of saturated
sodium bicarbonate and brine, then, dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, and the title
compound (6.0 g, 34 mmol, 102%) was obtained as a white solid.
[0565] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.27 (9H,
s), 7.03 (1H, ddd, J=1.1, 4.9, 7.3 Hz), 7.68-7.72 (1H, m), 8.02
(1H, s), 8.23-8.27 (2H, m).
Preparation Example J-2
N-(3-formylpyridin-2-yl)-2,2-dimethylpropionamide
[0566] To a mixture solution of tert-butyl lithium (1.5M pentane
solution, 10 mL, 15 mmol) and diethyl ether (50 mL) was added a
solution of 2,2-dimethyl-N-pyridin-2-yl-propionamide described in
Preparation Example J-1 (900 mg, 5.0 mmol) in diethyl ether (10 mL)
dropwise at -78.degree. C., and the solution was stirred for 90
minutes at the same temperature. At the same temperature,
morpholine-4-carbaldehyde (1.0 mL, 10 mmol) was added dropwise, and
the solution was warmed gradually to room temperature. Water and
tetrahydrofuran were added to the reaction mixture for extraction,
the organic layer was washed with brine, then, the solvent was
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:4), and the title compound
(880 mg, 4.3 mmol, 85%) was obtained as a white solid.
[0567] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.38 (9H,
s), 7.21 (1H, dd, J=4.9, 7.6 Hz), 8.05 (1H, dd, J=2.0, 7.5 Hz),
8.69 (1H, dd, J=2.0, 4.9 Hz), 9.94 (1H, s), 10.9 (1H, brs).
Preparation Example J-3
(2-Aminopyridin-3-yl)-methanol
[0568] A mixture solution of
N-(3-formylpyridin-2-yl)-2,2-dimethylpropionamide described in
Preparation Example J-2 (500 mg, 2.4 mmol) and an aqueous solution
of 5N sodium hydroxide (7 mL) was refluxed for 90 minutes. After
cooling, ethyl acetate and tetrahydrofuran were added for
extraction, the organic layer was washed with brine, then, the
solvent was evaporated in vacuo. The residue was purified by silica
gel column chromatography (methanol:ethyl acetate=1:5), and the
title compound (160 mg, 1.2 mmol, 53%) was obtained as a pale
yellow solid.
[0569] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.31 (2H,
s), 5.13 (1H, brs), 5.62 (2H, s), 6.51 (1H, dd, J=5.0, 7.3 Hz),
7.34-7.36 (1H, m), 7.81-7.82 (1H, m).
Preparation Example J-4
2-Aminopyridine-3-carbaldehyde
[0570] To a mixture of (2-aminopyridin-3-yl)-methanol described in
Preparation Example J-3 (130 mg, 1.1 mmol) and dichloromethane (10
mL) was added manganese dioxide (1.3 g, 15 mmol) at room
temperature, and the solution was stirred overnight. The reaction
solution was filtered through Celite pad, then, the solvent was
evaporated in vacuo, and the title compound (108 mg, 0.88 mmol,
83%) was obtained as a white solid.
[0571] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 6.75 (1H,
dd, J=4.9, 7.5 Hz), 7.83 (1H, dd, J=1.9, 7.5 Hz), 8.23 (1H, dd,
J=1.9, 4.9 Hz), 9.86 (1H, s).
Preparation Example J-5
2-Hydroxy-[1,8]naphthylidine-3-carboxylic acid ethyl ester
[0572] To a mixture of 2-aminopyridine-3-carbaldehyde described in
Preparation Example J-4 (8.0 mg, 0.066 mmol) and ethanol (2 mL)
were added diethylmalonate (0.50 mL, 3.3 mmol) and piperidine (0.20
mL, 2.0 mmol), and the solution was stirred overnight at 70.degree.
C. The solvent was evaporated in vacuo, the residue was purified by
silica gel column chromatography (methanol:ethyl acetate=1:10), and
the title compound (9.2 mg, 0.042 mmol, 64%) was obtained as a
white solid.
[0573] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.43 (3H, t,
J=7.1 Hz), 4.45 (2H, q, J=7.1 Hz), 7.28 (1H, dd, J=4.9, 7.8 Hz),
8.04 (1H, dd, J=1.7, 7.9 Hz), 8.48 (1H, s), 8.87-8.88 (1H, m),
12.16 (1H, brs).
Preparation Example J-6
2-Trifluoromethane sulfonyloxy-[1,8]naphthylidine-3-carboxylic acid
ethyl ester
[0574] To a mixture of 2-hydroxy-[1,8]naphthylidine-3-carboxylic
acid ethyl ester described in Preparation Example J-5 (95 mg, 0.44
mmol), dichloromethane (4 mL) and N,N-dimethylformamide (0.5 mL)
were added N-phenyl-bis(trifluoromethanesulfonimide) (230 mg, 0.65
mmol), triethylamine (0.18 mL, 1.3 mmol) and catalytic amount of
4-(dimethylamino)pyridine, and the solution was stirred for 2.5
hours at room temperature. The solvent was evaporated in vacuo, the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1), and the title compound (22 mg, 0.063
mmol, 14%) was obtained as a white solid.
[0575] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.49 (3H, t,
J=7.1 Hz), 4.54 (2H, q, J=7.1 Hz), 7.69 (1H, dd, J=4.3, 8.2 Hz),
8.41 (1H, dd, J=2.0, 8.4 Hz), 9.09 (1H, s), 9.28 (1H, dd, J=2.0,
4.2 Hz).
Preparation Example J-7
[1,8]Naphthylidine-3-carboxylic acid ethyl ester
[0576] To a mixture of
2-trifluoromethanesulfonyloxy-[1,8]naphthylidine-3-carboxylic acid
ethyl ester described in Preparation Example J-6 (22 mg, 0.063
mmol), tetrakis(triphenylphosphine)palladium(0) (7.3 mg, 0.0063
mmol), and 1-methyl-2-pyrrolidinone (1.5 mL) were added
N,N-diisopropylethylamine (0.033 mL, 0.19 mmol) and formic acid
(0.0036 mL, 0.094 mmol), and the solution was stirred for 45
minutes at 100.degree. C. After cooling, filtration was carried out
using NH silica gel, and the filtrate was evaporated in vacuo.
Water, ethyl acetate and tetrahydrofuran were added to the residue
for extraction, the organic layer was washed with brine, the
solvent was then evaporated in vacuo. The residue was purified by
silica gel column chromatography (ethyl acetate), and the title
compound (8.1 mg, 0.040 mmol, 64%) was obtained as a white
solid.
[0577] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.49 (3H, t,
J=7.1 Hz), 4.51 (2H, q, J=7.1 Hz), 7.61 (1H, dd, J=4.3, 8.2 Hz),
8.34 (1H, dd, J=2.0, 8.2 Hz), 8.91 (1H, d, J=2.2 Hz), 9.25 (1H, dd,
J=2.0, 4.2 Hz), 9.69 (1H, d, J=2.4 Hz).
Preparation Example K-1
2-Methyl-benzoxazole-6-carboxylic acid methyl ester
[0578] To a solution of 4-amino-3-hydroxy-benzoic acid methyl ester
(2085 mg, 12.47 mmol) in xylene (200 mL) were added acetyl chloride
(1.06 mL, 14.96 mmol), pyridinium p-toluenesulfonate (940 mg, 3.74
mmol) and triethylamine (2.09 mL, 14.96 mmol), and the solution was
stirred for 8.5 hours under reflux. Ethyl acetate was added to the
reaction mixture, which was then washed with water, dried over
anhydrous magnesium sulfate, then, evaporated in vacuo, the
resulting residue was purified by silica gel chromatography
(hexane-ethyl acetate), and the title compound (1917 mg, 10.02
mmol, 80.4%) was obtained.
[0579] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.69 (3H,
s), 3.96 (3H, s), 7.68 (1H, d, J=8.4 Hz), 8.05 (1H, dd, J=1.2, 8.4
Hz), 8.17 (1H, d, J=1.2 Hz).
Preparation Example K-2
2-Methyl-benzoxazole-6-carboxylic acid
[0580] To a solution of 2-methyl-benzoxazole-6-carboxylic acid
methyl ester (301 mg, 1.57 mmol) in ethanol (10 mL) was added an
aqueous solution of 2N sodium hydroxide (10 mL), and the mixture
was stirred for 2 hours at room temperature. 2N Hydrochloric acid
was added to the reaction mixture to adjust the pH to 4, and the
solution was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous sodium sulfate, then,
evaporated in vacuo, and the title compound (270 mg, 1.52 mmol,
97%) was obtained. This was used in the next reaction without
purification.
[0581] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.64 (3H,
s), 7.73 (1H, d, J=8.0 Hz), 7.93 (1H, dd, J=1.2, 8.0 Hz), 8.15 (1H,
d, J=1.2 Hz).
Preparation Example O-1
2,3-Dihydro-1H-pyrrolo [2,3-b]pyridine-5-carbonitrile
[0582] 1H-Pyrrolo[2,3-b]pyridine (1.0 g, 8.46 mmol) and 10%
palladium-carbon (500 mg) were dissolved in a mixture of formic
acid (10 mL) and triethylamine (10 mL), and the solution was
stirred at 70.degree. C. for 17 hours. To this reaction mixture was
further added 10% palladium-carbon (270 mg), and the mixture was
stirred at 70.degree. C. for 2 hours. The reaction mixture was
cooled to room temperature, then an aqueous solution of 5N sodium
hydroxide was added thereto, the solution was extracted with ethyl
acetate and tetrahydrofuran, and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was purified by silica gel column chromatography (ethyl
acetate:methanol=10:1), and 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(614 mg, 5.11 mmol, 60%) was obtained as a pale yellow solid.
[0583] The resulting 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (614 mg,
5.11 mmol) and N-bromosuccinimide (1.09 g, 6.13 mmol) were
dissolved in N,N-dimethylformamide (12 mL), and the solution was
stirred for 2.5 hours at room temperature. An aqueous solution of
saturated sodium bicarbonate was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (hexane:ethyl
acetate=3:1), and 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(370 mg, 1.86 mmol, 36%) was obtained as a white solid.
[0584] The resulting 5-bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
(345 mg, 1.73 mmol), zinc cyanide (305 mg, 2.60 mmol) and
tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.173 mmol) were
dissolved in dimethylsulfoxide (7 mL), and the solution was stirred
at 120.degree. C. for 4 hours under nitrogen atmosphere. The
reaction solution was cooled to room temperature, water and ethyl
acetate were added to the reaction solution, the organic layer was
separated, the organic layer was washed with brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was purified by silica gel column chromatography (ethyl
acetate), and the title compound (167 mg, 1.15 mmol, 66%) was
obtained as a light brown solid.
[0585] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.01 (2H,
t, J=8.6 Hz), 3.58 (2H, t, J=8.6 Hz), 7.46 (1H, s), 7.63 (1H, s),
8.10 (1H, s).
Preparation Example O-2
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
[0586] The title compound (259 mg, quantitatively) was obtained as
a white solid from
2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carbonitrile described in
Preparation Example O-1 (167 mg, 1.15 mmol) according to an
analogous method to Preparation Example T-6.
[0587] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.00 (2H,
t, J=8.6 Hz), 3.56 (2H, t, J=8.6 Hz), 7.25 (1H, s), 7.59 (1H, s),
8.30 (1H, s).
Preparation Example P-1
6-Oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester
[0588] To a suspension of 6-hydroxy-nicotinic acid (5.00 g, 35.9
mmol) in ethanol (60 mL) was added 1N hydrochloric acid (20 mL),
which was then stirred at 110.degree. C. for 3 hours. The reaction
solution was cooled to 0.degree. C., then, an aqueous solution of
saturated sodium bicarbonate was added, the solution was extracted
with ethyl acetate and tetrahydrofuran, and the organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (ethyl acetate), and the title compound (3.90 g,
23.3 mmol, 65%) was obtained as a white solid.
[0589] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.27 (3H,
t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 6.36 (1H, d, J=9.7 Hz), 7.79
(1H, dd, J=2.6, 9.7 Hz), 8.03 (1H, d, J=2.6 Hz).
Preparation Example P-2
5-Iodo-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl ester
[0590] The title compound (2.82 g, 9.62 mmol, 80%) was obtained as
a white solid from 6-oxo-1,6-dihydro-pyridine-3-carboxylic acid
ethyl ester described in Preparation Example P-1 (2.00 g, 12.0
mmol) according to an analogous method to Preparation Example
A+-16.
[0591] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.28 (3H,
t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 8.09 (1H, s), 8.36 (1H, d,
J=2.4 Hz).
Preparation Example P-3
6-oxo-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic
acid ethyl ester
[0592] 5-Iodine-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid ethyl
ester described in Preparation Example P-2 (1.00 g, 3.41 mmol),
trimethylsilylacetylene (626 .mu.l, 4.43 mmol), palladium(II)
acetate (7.66 mg, 34 mmol), triphenylphosphine (17.9 mg, 68 mmol),
copper(I) iodide (13 mg, 68 mmol) and butylamine (674 .mu.l, 6.82
mmol) were suspended in tetrahydrofuran (6 mL), and the mixture was
stirred at 40.degree. C. for 16 hours under nitrogen atmosphere.
The reaction mixture was cooled to room temperature, then, water
was added thereto, the solution was extracted with ethyl acetate,
and the organic layer was washed with brine. The organic layer was
dried over anhydrous magnesium sulfate, then, the solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1), and the title compound
(551 mg, 2.09 mmol, 61%) was obtained as a light brown solid.
[0593] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 0.22 (9H,
s), 1.27 (3H, t, J=7.1 Hz), 4.23 (2H, q, J=7.1 Hz), 7.91 (1H, d,
J=2.4 Hz), 8.07 (1H, d, J=2.4 Hz).
Preparation Example P-4
Furo[2,3-b]pyridine-5-carboxylic acid ethyl ester
[0594]
6-oxo-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic
acid ethyl ester described in Preparation Example P-3 (545 mg, 2.07
mmol) and copper(I) iodide (5.9 mg, 31 .mu.mol) were suspended in
ethanol (7 mL) and triethylamine (3 mL), and the mixture was
stirred at 75.degree. C. for 20 hours. The reaction mixture was
cooled to room temperature, then, potassium carbonate (572 mg, 4.14
mmol) was added to the reaction mixture, which was further stirred
at 75.degree. C. for 5 hours. The reaction mixture was cooled to
0.degree. C., then, water was added, the precipitated solid was
filtered, and the title compound (303 mg) was obtained as a brown
solid. In addition, ethyl acetate was added to the mother liquor
for extraction, the organic layer was washed with brine, then,
dried over anhydrous magnesium sulfate, the solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1), and the title compound
(33 mg, 0.17 mmol) was obtained as a white solid.
[0595] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.36 (3H,
t, J=7.1 Hz), 4.38 (2H, q, J=7.1 Hz), 7.16 (1H, d, J=2.4 Hz), 8.25
(1H, d, J=2.2 Hz), 8.69 (1H, d, J=1.8 Hz), 8.87 (1H, d, J=2.0
Hz).
Preparation Example Q+-1
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-(3-fluorophenoxy)thiophene-2-ylmethyl) amide
[0596] To a solution of imidazo[1,2-a]pyridine-6-carboxylic acid
(87 mg, 0.54 mmol) and
C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine (120 mg, 0.54 mmol)
in N,N-dimethylformamide (5 mL) were added
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (240 mg, 0.54 mmol) and triethylamine (0.15 mL,
1.08 mmol), and the solution was stirred for 40 minutes at
80.degree. C. Water and ethyl acetate were added to the reaction
mixture for extraction, and the organic layer was washed twice with
water. Silica gel was added to the organic layer, solvent was
evaporated in vacuo for adsorption, purification was carried out by
silica gel column chromatography (hexane:ethyl acetate=1:1, then
ethyl acetate), and the title compound (90 mg, 0.25 mmol, 45.4%)
was obtained as a light brown oil.
[0597] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.55 (2H,
d, J=5.6 Hz), 6.58 (1H, d, J=4.0 Hz), 6.83 (1H, d, J=4.0 Hz),
6.90-7.00 (3H, m), 7.40 (1H, ddd, J=8.0, 8.0, 8.0 Hz), 7.57-7.66
(3H, m), 8.04 (1H, s), 9.12 (1H, d, J=0.8 Hz), 9.20 (1H, t, J=5.6
Hz).
Preparation Example R-1
2,6-Diamino-5-iodo-nicotinic acid ethyl ester
[0598] To a solution of 2,6-diamino-nicotinic acid ethyl ester
described in Preparation Example A-14 (1.4 g, 7.7 mmol) in
N,N-dimethylformamide (15 mL) was added N-iodosuccinimide (2.09 g,
9.3 mmol), and the solution was stirred for 1 hour at room
temperature. The reaction mixture was poured into an aqueous
solution of saturated sodium thiosulfate pentahydrate, and the
solution was extracted with ethyl acetate. The organic layer was
washed with brine, dried over anhydrous magnesium sulfate, and then
evaporated. The resulting residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:1) and the title compound
(0.84 g, 2.7 mmol, 35.5%) was obtained.
[0599] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.36 (3H, t,
J=7.2 Hz), 4.27 (2H, q, J=7.2 Hz), 5.10 (2H, brs), 8.23 (1H,
s).
Preparation Example R-2
6-Amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester
[0600] Catechol borane (2.7 mL, 1M tetrahydrofuran solution, 2.7
mmol) was added dropwise to ethoxyacetylene (0.7 mL, 40% hexane
solution, 2.83 mmol) on an ice bath, and the mixture was stirred
for 1 hour at room temperature. The mixture was further heated at
70.degree. C. and stirred for 2 hours, and allowed to room
temperature. A solution of 2,6-diamino-5-iodo-nicotinic acid ethyl
ester described in Preparation Example R-1 (415 mg, 1.35 mmol) in
tetrahydrofuran (5.5 mL), tetrakis(triphenylphosphine)palladium (0)
(48 mg, 0.042 mmol) and sodium hydroxide (160 mg, 4 mmol, powder)
were added thereto, followed by stirring for 7 hours 30 minutes
under reflux. The reaction mixture was allowed to room temperature,
2N hydrochloric acid (4.7 mL, 9.4 mmol) was added thereto, followed
by stirring for 60 hours at room temperature. After the reaction
was completed, the reaction mixture was evaporated, and extracted
using diethyl ether. The aqueous layer was fractionated,
neutralized on an ice bath with an aqueous solution of 5N sodium
hydroxide, then, was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, then evaporated,
the resulting residue was purified by silica gel column
chromatography (ethyl acetate:hexane=2:1), and the title compound
(97 mg, 0.47 mmol, 35%) was obtained.
[0601] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.41 (3H, t,
J=7.2 Hz), 4.36 (2H, q, J=7.2 Hz), 6.28-6.42 (3H, m), 6.99-7.02
(1H, m), 8.49 (1H, s), 9.19 (1H, brs).
Preparation Example R-3
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine
[0602] 1H-Pyrrolo[2,3-b]pyridine (1.00 g, 8.46 mmol) and 10%
palladium-carbon (500 mg) were dissolved in a mixture of formic
acid (10 mL) and triethylamine (10 mL), and the mixture was stirred
at 70.degree. C. for 87 hours. To this reaction mixture was further
added 10% palladium-carbon (400 mg), and the solution was stirred
for 9.5 hours at 70.degree. C. The reaction mixture was cooled to
room temperature, an aqueous solution of 5N sodium hydroxide was
added thereto, the solution was extracted with ethyl acetate and
tetrahydrofuran, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by silica gel column chromatography (ethyl
acetate:methanol=10:1), and the title compound (219 mg, 1.82 mmol,
22%) was obtained as a pale yellow solid.
[0603] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.94 (2H,
t, J=8.4 Hz), 3.43 (2H, t, J=8.4 Hz), 6.27 (1H, s), 6.39 (1H, dd,
J=5.3, 7.0 Hz), 7.22 (1H, d, J=7.0 Hz), 7.66 (1H, d, J=4.9 Hz).
Preparation Example R-4
5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine
[0604] 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine described in
Preparation Example R-3 (15 mg, 0.13 mmol) and N-bromosuccinimide
(24 mg, 0.14 mmol) were dissolved in N,N-dimethylformamide (0.5
mL), and the solution was stirred for 15 hours at room temperature.
An aqueous solution of saturated sodium bicarbonate was added to
the reaction solution at 0.degree. C., which was then extracted
with ethyl acetate, the organic layer was washed with brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=5:1), and the title compound
(12 mg, 60 .mu.mol, 48%) was obtained as a white solid.
[0605] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.98 (2H,
t, J=8.8 Hz), 3.48 (2H, t, J=8.8 Hz), 6.60 (1H, s), 7.37 (1H, d,
J=1.1 Hz), 7.71 (1H, d, J=2.4 Hz).
Preparation Example R-5
5-Bromo-1H-pyrrolo[2,3-b]pyridine
[0606] 5-Bromo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine (600 mg, 3.01
mmol) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone described in
Preparation Example R-4 (753 mg, 3.3 .mu.mol) was dissolved in
toluene (15 mL), and the solution was refluxed for 40 minutes under
nitrogen atmosphere. The reaction solution was cooled to room
temperature, water and ethyl acetate were added thereto, the
organic layer was partitioned, the organic layer was washed with
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=5:1), and the title compound
(260 mg, 1.32 mmol, 44%) was obtained as a white solid.
[0607] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.40-6.48
(1H, m), 7.50-7.60 (1H, m), 8.20 (1H, s), 8.30 (1H, s), 11.9 (1H,
s).
Preparation Example R-6
1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile
[0608] 5-Bromo-1H-pyrrolo[2,3-b]pyridine described in Preparation
Example R-5 (90 mg, 0.46 mmol), zinc cyanide (80 mg, 0.69 mmol) and
tetrakis(triphenylphosphine)palladium(0) (53 mg, 46 mmol) were
dissolved in N-methyl-2-pyrrolidinone (2 mL), and the mixture was
stirred for 4.5 hours at 110.degree. C. under nitrogen atmosphere.
The reaction mixture was cooled to room temperature, water and
ethyl acetate were added to the reaction mixture, the organic layer
was partitioned, the organic layer was washed with brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated in
vacuo, the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=5:1), and the title compound (48 mg, 0.34
mmol, 73%) was obtained as a white solid.
[0609] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.55-6.68
(1H, m), 7.65-7.78 (1H, m), 8.52 (1H, s), 8.60 (1H, s), 12.3 (1H,
brs).
Preparation Example R-7
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
[0610] The title compound (47 mg, 0.29 mmol, 88%) was obtained as a
white solid from 1H-pyrrolo[2,3-b]pyridine-5-carbonitrile described
in Preparation Example R-6 (47 mg, 0.33 mmol) according to an
analogous method to Preparation Example T-6.
[0611] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.57-6.63
(1H, m), 7.55-7.62 (1H, m), 8.51 (1H, s), 8.79 (1H, s), 12.0 (1H,
s), 12.7 (1H, brs).
Preparation Example S-1
3-Amino-2-bromopyridine
[0612] 2-Bromo-3-nitropyridine (3 g, 15 mmol) was dissolved in a
mixture solution of tetrahydrofuran (15 mL) and water (5 mL), then
iron powder (1 g, 18 mmol) and ammonium chloride (2 g, 37 mmol)
were added thereto, followed by stirring at from 60.degree. C. to
70.degree. C. for 5 hours. After the reaction was completed, the
reaction mixture was filtered through Celite pad, brine was added,
and the solution was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, then evaporated,
the resulting residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4), and the title compound
(2.6 g, 15 mmol, quantitatively) was obtained.
[0613] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.47 (2H,
brs), 7.07-7.09 (2H, m), 7.54 (1H, dd, J=2.0, 3.6 Hz).
Preparation Example S-2
(2-Bromo-pyridin-3-yl)carbamic acid ethyl ester
[0614] 3-Amino-2-bromopyridine described in Preparation Example S-1
(1.4 g, 8.1 mmol) was dissolved in pyridine (10 mL), ethyl
chloroformate (0.93 mL, 9.7 mmol) was added dropwise on an ice
bath, and the solution was stirred for 2 hours at room temperature.
After the reaction was completed, the reaction solution was poured
into brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
evaporated, the resulting residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:4), and the title compound
(0.56 g, 2.3 mmol, 28%) was obtained.
[0615] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.22 (3H,
t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz), 7.43 (1H, dd, J=4.8, 8.0 Hz),
7.92 (1H, dd, J=1.6, 8.0 Hz), 8.17 (1H, dd, J=1.6, 4.8 Hz), 9.10
(1H, brs).
Preparation Example S-3
(2-Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl
ester
[0616] A mixture of (2-bromo-pyridin-3-yl)carbamic acid ethyl ester
described in Preparation Example S-2 (395 mg, 1.6 mmol),
dichlorobis(triphenylphosphine)palladium(II) (20 mg, 0.028 mmol),
triethylamine (0.25 mL, 1.8 mmol), copper(I) iodide (10 mg, 0.05
mmol) and trimethylsilylacetylene (0.131 mL, 2.4 mmol) was placed
in a sealed tube, and heated at 100.degree. C. for 4 hours. After
the reaction was completed, the reaction mixture was poured into
water, which was then extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, then evaporated,
the resulting residue was purified by silica gel column
chromatography (ethyl acetate:hexane=1:2), and the title compound
(0.42 g, 1.6 mmol, quantitatively) was obtained.
[0617] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 0.24 (9H,
s), 1.21 (3H, t, J=7.2 Hz), 4.12 (2H, q, J=7.2 Hz), 7.38 (1H, dd,
J=4.8, 8.4 Hz), 7.88-7.96 (1H, m), 8.29 (1H, dd, J=1.6, 4.8 Hz),
8.82 (1H, brs).
Preparation Example S-4
1H-Pyrrolo[3,2-b]pyridine
[0618] (2-Trimethylsilanylethynyl-pyridin-3-yl)carbamic acid ethyl
ester described in Preparation Example S-3 (0.42 g, 1.6 mmol) was
dissolved in ethanol (8 mL), sodium ethoxide (204 mg, 3 mmol) was
added thereto, followed by stirring for 1 hour under reflux. After
the reaction was completed, the reaction mixture was poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
evaporated, the resulting solid was washed with solvent
(diethylether:hexane=1:2), and the title compound (0.12 g, 1 mmol,
63.5%) was obtained.
[0619] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.50-6.54
(1H, m), 7.06 (1H, dd, J=4.8, 8.4 Hz), 7.58-7.62 (1H, m), 7.72-7.76
(1H, m), 8.26-8.30 (1H, m), 11.2 (1H, brs).
Preparation Example T-1
3-Dichloromethyl-2-nitro-thiophene
[0620] To a solution of potassium tert-butoxide (23.0 mL, 1.0M
tetrahydrofuran solution, 23.2 mmol) in N,N-dimethyl formamide (20
mL) were added a mixture solution of 2-nitro-thiophene (1.00 g,
7.74 mmol) in chloroform (682 .mu.l, 8.51 mmol) and
N,N-dimethylformamide (2 mL) dropwise at -78.degree. C., the
solution was stirred for 5 minutes, and then, methanol and acetic
acid were added at 0.degree. C. Brine was added to the reaction
solution, which was then extracted with ethyl acetate. The solvent
was evaporated in vacuo, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1), and the title
compound (1.54 g, 7.26 mmol, 94%) was obtained as a light brown
solid.
[0621] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.54 (1H, d,
J=5.7 Hz), 7.57 (1H, d, J=5.7 Hz), 7.64 (1H, s).
Preparation Example T-2
2-nitro-thiophene-3-carbaldehyde
[0622] 3-Dichloromethyl-2-nitro-thiophene described in Preparation
Example T-1 (1.54 g, 7.26 mmol) was dissolved in formic acid (10
mL), and the solution was refluxed for 24 hours under nitrogen
atmosphere. An aqueous solution of 5N sodium hydroxide was added to
the reaction solution at 0.degree. C., which was then extracted
with ethyl acetate, the organic layer was washed with brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=10:1), and the title compound
(472 mg, 3.00 mmol, 41%) was obtained as a light brown solid.
[0623] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.49 (1H, d,
J=5.5 Hz), 7.54 (1H, d, J=5.7 Hz), 10.62 (1H, s).
Preparation Example T-3
[0624] 2-(2-Nitro-thiophen-3-yl)-[1,3]-dioxolane
2-Nitro-thiophene-3-carbaldehyde described in Preparation Example
T-2 (367 mg, 2.33 mmol), ethane-1,2-diol (651 .mu.l, 11.7 mmol) and
toluene-4-sulfonic acid monohydrate (40 mg, 0.233 mmol) were
dissolved in toluene (8 mL), and the solution was stirred for 2.5
hours under reflux. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C.,
which was then extracted with ethyl acetate, the organic layer was
washed with brine, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (hexane:ethyl
acetate=5:1), and the title compound (304 mg, 1.51 mmol, 65%) was
obtained as a white solid.
[0625] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.07-4.15
(4H, m), 6.51 (1H, s), 7.25 (1H, d, J=5.5 Hz), 7.45 (1H, d, J=5.5
Hz).
Preparation Example T-4
2-Amino-thiophene-3-carbaldehyde
[0626] 2-(2-Nitro-thiophen-3-yl)-[1,3]dioxolane described in
Preparation Example T-3 (150 mg, 0.746 mmol), iron powder (208 mg,
3.73 mmol) and ammonium chloride (80 mg, 1.49 mmol) were suspended
in a mixture solvent of ethanol (3 mL) and water (0.75 mL), and the
mixture was stirred at 90.degree. C. for 5 hours. The reaction
mixture was cooled to room temperature, then, filtered through
Celite pad. The filtrate was evaporated in vacuo, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=5:1), and the title compound (38 mg, 0.30 mmol, 40%) was
obtained as a red oily substance.
[0627] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 6.19 (1H, d,
J=5.7 Hz), 6.67 (2H, brs), 6.90 (1H, d, J=5.7 Hz), 9.69 (1H,
s).
Preparation Example T-5
6-Amino-thieno[2,3-b]pyridine-5-carbonitrile
[0628] 2-Amino-thiophene-3-carbaldehyde described in Preparation
Example T-4 (38 mg, 0.30 mmol) and malononitrile (20 mg, 0.30 mmol)
were dissolved in ethanol (1 mL) to which piperidine (several
drops) had been added, and the solution was stirred for 1 hour
under reflux. The reaction solution was cooled to room temperature,
and the solvent was evaporated in vacuo. The residue was purified
by NH silica gel column chromatography (hexane:ethyl acetate=10:1),
and the title compound (50 mg, 0.29 mmol, 96%) was obtained as a
white solid.
[0629] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 7.00 (2H,
s), 7.18 (1H, d, J=6.0 Hz), 7.42 (1H, d, J=6.0 Hz), 8.40 (1H,
s).
Preparation Example T-6
6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid
[0630] 6-Amino-thieno[2,3-b]pyridine-5-carbonitrile described in
Preparation Example T-5 (104 mg, 0.594 mmol) was dissolved in a
mixture solution of water (1.5 mL) and sulfuric acid (1.5 mL), and
the solution was stirred for 3 hours under reflux. An aqueous
solution of 5N sodium hydroxide was added to the reaction solution
at 0.degree. C., to neutralize the solution. The precipitated solid
was filtered, and title compound (65 mg, 0.33 mmol, 56%) was
obtained as a pale yellow solid.
[0631] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 7.19 (1H,
d, J=5.9 Hz), 7.25 (1H, d, J=6.0 Hz), 8.48 (1H, s).
Preparation Example T-7
6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid methyl ester
[0632] 6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid (44 mg, 0.23
mmol) was dissolved in a mixture solution of methanol (1 mL) and
sulfuric acid (0.5 mL), and the solution was stirred for 24 hours
under reflux. An aqueous solution of saturated sodium bicarbonate
was added to the reaction solution at 0.degree. C., which was then
extracted with ethyl acetate, the organic layer was washed with
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated in vacuo, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate=2:1), and the title
compound (34 mg, 0.16 mmol, 72%) was obtained as a white solid.
[0633] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.93 (3H,
s), 7.09 (1H, d, J=6.0 Hz), 7.11 (1H, d, J=6.0 Hz), 8.54 (1H,
s).
Preparation Example T-8
6-Oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid methyl
ester
[0634] 6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid methyl ester
described in Preparation Example T-7 (10 mg, 48 mmol) and sodium
nitrite (10 mg, 144 mmol) were dissolved in phosphinic acid (0.5
mL), and the solution was stirred at 0.degree. C. for 1 hour. An
aqueous solution of saturated sodium bicarbonate was added to the
reaction solution at 0.degree. C., which was then extracted with
ethyl acetate, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=1:1), and the title compound (10 mg, 48 mmol,
quantitatively) was obtained as a white solid.
[0635] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.03 (3H,
s), 7.21 (1H, d, J=5.9 Hz), 7.34 (1H, d, J=6.0 Hz), 8.61 (1H, s),
11.4 (1H, s).
Preparation Example T-9
6-trifluoromethanesulfonyloxy-thieno[2,3-b]pyridine-5-carboxylic
acid methyl ester
[0636] 6-Oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carboxylic acid
methyl ester described in Preparation Example T-8 (9 mg, 43 mmol),
N-phenyltrifluoromethanesulfonimide (23 mg, 65 mmol) and
dimethyl-pyridin-4-yl-amine (catalytic amount) were dissolved in
dichloromethane (0.5 mL), and the solution was stirred for 18.5
hours at room temperature. Water was added to the reaction
solution, which was then extracted with ethyl acetate, the organic
layer was washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, the residue was
purified by NH silica gel column chromatography (hexane:ethyl
acetate=3:1), and the title compound (10 mg, 29 mmol, 68%) was
obtained as a white solid.
[0637] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.03 (3H,
s), 7.43 (1H, d, J=5.9 Hz), 7.73 (1H, d, J=5.9 Hz), 8.87 (1H,
s).
Preparation Example T-10
Thieno[2,3-b]pyridine-5-carboxylic acid methyl ester
[0638]
6-Trifluoromethanesulfonyloxy-thieno[2,3-b]pyridine-5-carboxylic
acid methyl ester described in Preparation Example T-9 (10 mg, 29
mmol), tetrakis(triphenylphosphine)palladium(0) (3.4 mg, 2.9 mmol),
formic acid (1.7 .mu.l, 44 mmol) and N,N-diisopropylethylamine (15
.mu.l, 87 mmol) were dissolved in 1-methyl-2-pyrrolidone (0.5 mL),
and the mixture was stirred for 1.5 hours at 100.degree. C. The
reaction mixture was cooled to room temperature, water and ethyl
acetate were added, the organic layer was partitioned, the organic
layer was washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, the residue was
purified by NH silica gel column chromatography (hexane:ethyl
acetate=5:1), and the title compound (7 mg, quantitatively) was
obtained as a white solid.
[0639] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.99 (3H,
s), 7.36 (1H, d, J=6.4 Hz), 7.62 (1H, d, J=6.0 Hz), 8.70 (1H, d,
J=1.6 Hz), 9.17 (1H, d, J=2.0 Hz).
Preparation Example U-1
Thiophen-3-yl-carbamic acid tert-butyl ester
[0640] Thiophene-3-carboxylic acid (2.50 g, 19.5 mmol),
diphenylphosphoryl azide (4.62 mL, 21.5 mmol), triethylamine (3.26
mL, 23.4 mmol) were dissolved in tert-butanol (50 mL), and the
solution was stirred for 3.5 hours under reflux. Water was added to
the reaction solution at 0.degree. C., which was then extracted
with ethyl acetate, the organic layer was washed with brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=10:1), and the title compound
(3.33 g, 16.7 mmol, 86%) was obtained as a white solid.
[0641] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.46 (9H,
s), 6.97 (1H, d, J=5.2 Hz), 7.16 (1H, s), 7.38 (1H, m), 9.61 (1H,
s).
Preparation Example U-2
(2-Formyl-thiophen-3-yl)-carbamic acid tert-butyl ester
[0642] Thiophen-3-yl-carbamic acid tert-butyl ester described in
Preparation Example U-1 (1.00 g, 5.02 mmol) was dissolved in
tetrahydrofuran (20 mL), to which n-butyl lithium (2.47M hexane
solution, 4.47 mL, 11.0 mmol) was added at -78.degree. C., and the
mixture was stirred at -78.degree. C. for 1 hour.
N,N-dimethylformamide (466 .mu.l, 6.02 mmol) was added to the
reaction mixture at -78.degree. C., and the solution was stirred
for 1 hour at room temperature. Water was added to the reaction
solution, which was then extracted with ethyl acetate, the organic
layer was washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1), and the title compound (1.14 g, quantitatively) was
obtained as a colorless oil.
[0643] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.50 (9H,
s), 7.60 (1H, d, J=5.3 Hz), 8.02 (1H, d, J=5.3 Hz), 9.94 (1H, s),
10.1 (1H, s).
Preparation Example U-3
5-Amino-thieno[3,2-b]pyridine-6-carbonitrile
[0644] (2-Formyl-thiophen-3-yl)-carbamic acid tert-butyl ester
described in Preparation Example U-2 (500 mg, 2.20 mmol) and
malononitrile (153 mg, 2.3 .mu.mol) were dissolved in a solution of
ethanol (10 mL) to which piperidine (catalytic amount) had been
added, and the mixture was stirred for 1 hour under reflux. The
reaction mixture was cooled to room temperature, the precipitated
solid was filtered, and title compound (215 mg, 1.23 mmol, 56%) was
obtained as a white solid.
[0645] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.76 (2H,
s), 7.22 (1H, dd, J=0.73, 5.5 Hz), 8.22 (1H, d, J=5.5 Hz), 8.64
(1H, s).
Preparation Example U-4
5-Amino-thieno[3,2-b]pyridine-6-carboxylic acid
[0646] The title compound (200 mg) was obtained as a white solid
from 5-amino-thieno[3,2-b]pyridine-6-carbonitrile described in
Preparation Example U-3 (208 mg, 1.19 mmol) according to an
analogous method to Preparation Example T-6.
[0647] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 7.27 (1H,
dd, J=0.73, 5.5 Hz), 8.28 (1H, d, J=5.5 Hz), 8.92 (1H, s).
Preparation Example U+-1
5-Oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[0648] The title compound (17 mg, 44 mmol, 46%) was obtained as a
white solid from 5-amino-thieno[3,2-b]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide described in Preparation
Example U-4 (37 mg, 97 mmol) according to an analogous method to
Preparation Example T-8
[0649] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.59 (2H,
d, J=5.9 Hz), 6.49 (1H, d, J=3.8 Hz), 6.79 (1H, d, J=3.7 Hz),
7.07-7.15 (4H, m), 7.37 (2H, t, J=7.7 Hz), 8.15 (1H, d, J=5.5 Hz),
8.94 (1H, s), 10.3 (1H, m), 13.0 (1H, s).
Preparation Example U+-2
Trifluoromethanesulfonic acid
6-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-thieno[3,2-b]pyridin-5-yl
ester
[0650] The title compound (11 mg, 21 mmol, 68%) was obtained as a
white solid from
5-oxo-4,5-dihydro-thieno[3,2-b]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide described in Preparation
Example U+-1 (12 mg, 31 mmol) according to an analogous method to
Preparation Example T-9 (with the proviso that
N,N-dimethylformamide was used instead of dichloromethane).
[0651] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.53 (2H,
d, J=5.5 Hz), 6.53 (1H, d, J=3.8 Hz), 6.83 (1H, d, J=4.4 Hz), 7.09
(2H, d, J=8.6 Hz), 7.13 (1H, t, J=7.7 Hz), 7.37 (2H, t, J=7.7 Hz),
7.65 (1H, d, J=5.5 Hz), 8.50 (1H, d, J=5.7 Hz), 8.97 (1H, s),
9.39-9.44 (1H, m).
Preparation Example W-1
Dithiocarbonic acid O-ethyl ester S-quinolin-6-yl ester
[0652] To a solution of quinolin-6-yl amine (2.88 g, 20 mmol) and
HBF.sub.4 aqueous solution (48% W/W, 11 mL) in tetrahydrofuran (100
mL) was added 3-methyl-1-nitrosooxy-butane (10.7 mL, 60 mmol)
dropwise under nitrogen atmosphere at from -10.degree. C. to
-15.degree. C., then, the mixture was stirred for 1 hour. At from
-10.degree. C. to -15.degree. C., diethyl ether (200 mL) was added
dropwise, the precipitated solid was collected by filtration,
washed with diethyl ether, dried, and quinolin-6-diazonium
tetrafluoroborate (6.85 g) was obtained as a yellow-red solid.
[0653] Next, to a solution of potassium O-ethyl dithiocarbonate
(802 mg, 5 mmol), water (20 mL) and diethyl ether (30 mL) was added
quinolin-6-diazonium tetrafluoroborate (665 mg, 2 mmol) dropwise on
an ice bath, then, the solution was stirred for 18 hours. To this
reaction mixture was added water (100 mL), then the solution was
extracted with diethyl ether (50 mL), and washed with brine (150
mL). The organic layer was dried over anhydrous magnesium sulfate,
filtered, then, evaporation in vacuo was carried out, and a residue
of red oil (0.462 g) was obtained. This residue in the amount of
0.2 g was purified by thin layer silica gel chromatography
(hexane:ethyl acetate=1:1), and the title compound (50 mg, 0.2
mmol) was obtained as a pale yellow oil.
[0654] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 1.31
(3H, t, J=7.2 Hz), 4.66 (2H, q, J=7.2 Hz), 7.60 (1H, dd, J=8.4, 4.4
Hz), 7.86 (1H, m), 8.13 (1H, d, J=8.8 Hz), 8.18 (1H, m), 8.41 (1H,
m), 9.01 (1H, m).
[0655] MS m/e (ESI) 360 (MH.sup.+)
Preparation Example X-1
4-Chloro-quinazoline
[0656] Phosphorus oxychloride (64 mL, 687 mmol) and phosphorus
pentachloride (14.89 g, 71.50 mmol) were added to
4-hydroxyquinazoline (7.94 g, 52.3 mmol), and the solution was
stirred for 20 minutes under reflux. The reaction mixture was
evaporated in vacuo, and the residue was dissolved in chloroform.
The chloroform solution was poured on an ice bath, concentrated
aqueous ammonia was added to adjust the pH to 10, then, the
solution was partitioned. The aqueous layer was extracted with
chloroform, and the combined chloroform layers were washed with
water. The organic layer was dried over anhydrous magnesium
sulfate, then, evaporated in vacuo, and the title compound (8.03 g,
48.8 mmol, 93%) was obtained. This was used in the next reaction
without purification.
[0657] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 7.64 (1H,
dd, J=7.2, 8.0 Hz), 7.81 (1H, d, J=8.0 Hz), 7.93 (1H, ddd, J=0.8,
7.2, 8.0 Hz), 8.16 (1H, dd, J=0.8, 8.0 Hz), 8.86 (1H, brs).
Preparation Example Z-1
Quinoline-6-carbaldehyde
[0658] n-Butyl lithium (19.2 mL; 1.5M hexane solution) was added
dropwise to a solution of 6-bromoquinoline (5 g, 24.0 mmol) in
diethyl ether (20 mL) that had been cooled to -70.degree. C. under
nitrogen atmosphere, a solution of N,N-dimethylformamide (3.7 mL,
48.0 mmol) in diethyl ether was further added, and the solution was
stirred at -70.degree. C. for 2 hours. The reaction solution was
allowed to room temperature, then, an aqueous solution of saturated
ammonium chloride was added, the solution was extracted with ethyl
acetate and dried over anhydrous magnesium sulfate. The solvent was
evaporated, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and the title compound (320
mg, 8.5%) was obtained as a yellow oil.
[0659] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.52-7.56
(1H, m), 8.21-8.22 (2H, m), 8.33-8.36 (1H, m), 8.37 (1H, s),
9.06-9.07 (1H, m), 10.2 (1H, s).
Preparation Example Z-2
4-Bromo-1-butyl-2-methylbenzene
[0660] Aluminum chloride (38.9 g, 0.292 mol) was portionwise added
to a solution of 3-bromotoluene (25 g, 0.146 mol) and n-butyryl
chloride (22.9 mL, 0.129 mol) in carbon disulfide (100 mL) that had
been cooled with an ice water, and the solution was stirred for 18
hours while gradually allowing to room temperature. The reaction
solution was poured into a mixture solution of an ice water (120
mL) and concentrated hydrochloric acid (10 mL), and the solution
was stirred for 10 minutes. Then, the solution was extracted with
hexane, washed with water and an aqueous solution of saturated
sodium bicarbonate and dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and
1-(4-bromo-2-methyl-1-phenyl)-butane-1-one (7.77 g, 22%) was
obtained as a pale yellow oil. To a solution of the resulting
compound in diethyleneglycol (40 mL), were added hydrazine
monohydrate (4.52 g, 90.2 mmol) and potassium hydroxide (4.16 g,
74.1 mmol), then the solution was stirred at 80.degree. C. for 2
hours, and further stirred at 160.degree. C. overnight. The
reaction solution was allowed to room temperature, hexane and water
were added for partitioning, the organic layer was washed with
water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, then, the residue was purified by silica
gel column chromatography (hexane:ethyl acetate), and the title
compound (5.01 g, 69%) was obtained as a colorless oil.
[0661] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.90 (3H, t,
J=0.2 Hz), 1.32-1.36 (2H, m), 1.51-1.55 (2H, m), 2.27 (3H, s), 2.52
(2H, t, J=7.6 Hz), 6.98 (1H, d, J=8.0 Hz), 7.23 (1H, dd, J=2.0 Hz,
8.0 Hz), 7.26-7.27 (1H, m).
Preparation Example Z+-1
(4-Butyl-3-methyl-phenyl)-quinolin-6-yl-metanol
[0662] Magnesium (83 mg, 3.40 mmol),
4-bromo-1-butyl-2-methylbenzene (722 mg, 3.18 mmol) and, as an
initiator, catalytic amount of 1,2-dibromoethane were added to
tetrahydrofuran (2.5 mL) under nitrogen atmosphere, and the mixture
was stirred for 10 minutes under reflux. This mixture was cooled to
0.degree. C., a solution of quinoline-6-carbaldehyde (100 mg, 6.36
mmol) in tetrahydrofuran (12 mL) was added thereto, followed by
stirring for 1 hour at this temperature. An aqueous solution of
saturated ammonium chloride was added to the reaction mixture,
which was extracted with chloroform and dried over anhydrous
magnesium sulfate. The solvent was evaporated, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate), and the title compound (152 mg, 78%) was obtained as a
yellow solid.
[0663] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.93 (3H, t,
J=7.2 Hz), 1.34-1.43 (2H, m), 1.49-1.57 (2H, m), 1.64 (1H, brs),
2.28 (3H, s), 2.57 (2H, t, J=8.0 Hz), 5.97 (1H, brs), 7.10-7.17
(3H, m), 7.38-7.42 (1H, m), 7.66-7.68 (1H, m), 7.93 (1H, s),
8.03-8.05 (1H, m), 8.16-8.18 (1H, m), 8.87-8.88 (1H, m).
Preparation Example Z+-2
Quinoline-6-carboxylic acid (4-benzyloxy phenyl)-amide
[0664] To a solution of 6-quinolinecarboxylic acid (500 mg, 2.89
mmol) and 4-benzyloxyphenylamine (681 mg, 2.89 mmol) in
dichloromethane (25 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.53 g, 3.47 mmol) and triethylamine (0.96 mL,
6.94 mmol), and the solution was stirred overnight at room
temperature. The solvent was evaporated, the residue was purified
by NH silica gel column chromatography (hexane:ethyl acetate), and
the title compound (194 mg, 19%) was obtained as a white solid.
[0665] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.11 (2H,
s), 7.00-7.02 (2H, m), 7.32-7.45 (5H, m), 7.48-7.51 (1H, m),
7.57-7.59 (2H, m), 7.86 (1H, brs), 8.11-8.14 (1H, m), 8.19-8.21
(1H, m), 8.26-8.28 (1H, m), 8.38-8.39 (1H, m), 9.00-9.01 (1H,
m).
Preparation Example Z+-3
4-Benzyloxy-N-quinolin-6-yl-benzamide
[0666] To a solution of 6-aminoquinoline (500 mg, 3.47 mmol) and
4-benzyloxybenzoic acid (792 mg, 3.47 mmol) in dichloromethane (25
mL) were added benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.84 g, 4.16 mmol) and triethylamine (0.58 mL,
4.16 mmol), and the solution was stirred overnight at room
temperature. The solvent was evaporated, the residue was purified
by NH silica gel column chromatography (hexane:ethyl acetate), and
the title compound (218 mg, 18%) was obtained as a white solid.
[0667] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.16 (2H,
s), 7.08-7.10 (2H, m), 7.36-7.47 (6H, m), 7.65-7.68 (1H, m),
7.89-7.91 (2H, m), 7.97 (1H, brs), 8.08-8.10 (1H, m), 8.15-8.17
(1H, m), 8.49-8.50 (1H, m), 8.84-8.86 (1H, m).
Preparation Example 1
4-Benzyloxybenzylamine
[0668] Potassium phthalimide (20 g, 0.108 mol) was added to a
solution obtained by dissolving 4-benzyloxybenzyl chloride (25 g,
0.107 mol) in N,N-dimethylformamide (75 mL), and the solution was
stirred for 3 hours under reflux. The reaction solution was allowed
to room temperature, then, ethyl acetate and water were added for
partitioning, the organic layer was washed with water and dried
over anhydrous magnesium sulfate. The solvent was evaporated, and
2-(4-benzyloxybenzyl)-isoindol-1,3-dione (37 g, quantitatively) was
obtained as a pale brown solid.
[0669] Next, to a solution of the resulting
2-(4-benzyloxybenzyl)-isoindol-1,3-dione (37 g, 0.107 mol) in
ethanol (1 L) was added hydrazine monohydrate (8.04 g, 0.161 mol),
and the solution was stirred for 8 hours under reflux. The reaction
solution was allowed to room temperature, then, water was added,
and ethanol was evaporated in vacuo. Ethyl acetate and water were
added to the residue for partitioning, the organic layer was washed
with water, an aqueous solution of 2N sodium hydroxide and water,
in this order, and dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate=2:1; hereinafter, the
NH silica gel used was manufactured by Fuji Silysia), and the title
compound (15 g, 64%) was obtained as a white solid.
Preparation Example 2
3-Benzyloxybenzylamine
[0670] To a solution of 3-benzyloxybenzyl alcohol (3.0 g, 14.0
mmol) in dichloromethane (30 mL) was added methanesulfonyl chloride
(1.39 mL, 16.8 mmol) and triethylamine (2.34 mL, 16.8 mmol) on an
ice bath, and the solution was stirred overnight. The reaction
solution was diluted with dichloromethane, washed with aqueous
solution of 5% sodium bicarbonate, and then, dried over anhydrous
magnesium sulfate. The solvent was evaporated, then, the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=10:1), and 1-benzyloxy-3-chloromethyl-benzene (2.2 g, 67%)
was obtained as a colorless oil.
[0671] Next, to a solution of iminodicarboxylic acid di-tert-butyl
ester (2.12 g, 8.76 mmol) in N,N-dimethylformamide (13 mL) was
added sodium hydride (0.39 g, 9.86 mmol, 60% in oil), the solution
was stirred at 60.degree. C. for 6 hours,
1-benzyloxy-3-chloromethyl-benzene (1.0 g, 4.30 mmol) was added,
and the solution was further stirred at 60.degree. C. for 4 hours.
The reaction solution was allowed to room temperature, then,
dichloromethane and water were added for partitioning, and the
organic layer was dried over anhydrous magnesium sulfate. The
solvent was evaporated, then, the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=10:1), and
(3-benzyloxybenzyl) iminodicarboxylic acid di-tert-butyl ester (691
mg, 39%) was obtained as a pale yellow oil.
[0672] Lastly, (3-benzyloxybenzyl) iminodicarboxylic acid
di-tert-butyl ester (691 mg, 1.67 mmol) was cooled on an ice bath,
trifluoroacetic acid (3 mL) was added, and the solution was stirred
for 30 minutes. An aqueous solution of saturated sodium bicarbonate
was added to the reaction solution, which was then extracted with
ethyl acetate and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the title compound (292 mg, 82%) was
obtained as a white waxy solid. This was used in the next reaction
without further purification.
Preparation Example 3
4-Phenoxybenzylamine
[0673] A solution of sodium borohydride (2.20 g, 58.3 mmol) and
concentrated sulfuric acid in diethyl ether (1.6 mL) was added to a
solution of 4-phenoxybenzoic acid (5.0 g, 23.3 mmol) in
tetrahydrofuran (20 mL) that had been cooled on an ice bath, and
the solution was stirred for 4 hours at room temperature. The
reaction solution was cooled on an ice bath, methanol was added,
then, the solution was allowed to room temperature and stirred for
30 minutes. This reaction solution was cooled again, ethyl acetate
and an aqueous solution of 2N sodium hydroxide were added for
partitioning, the organic layer was washed with 10% sodium chloride
water, dried over anhydrous magnesium sulfate, and the solvent was
evaporated to obtain 4-phenoxybenzyl alcohol (4.66 g,
quantitatively) as a colorless solid. This 4-phenoxybenzyl alcohol
was used to carry out an analogous reaction to Preparation Example
2, and the title compound (886 mg) was obtained as a pale brown
solid.
Preparation Example 4
3-Phenoxybenzylamine
[0674] The title compound was obtained as a pale brown solid from
3-phenoxybenzyl alcohol according to a similar method to
Preparation Example 2.
Preparation Example 5
C-Biphenyl-3-yl-methylamine
[0675] To a solution of 3-cyanophenylboronic acid (1.0 g, 6.81
mmol) and bromobenzene (1.07 g, 6.81 mmol) in N,N-dimethylformamide
(100 mL) were added tetrakis(triphenylphosphine)palladium(0) (0.393
g, 0.341 mmol) and cesium carbonate (2.77 g, 8.5 .mu.mol) under
nitrogen atmosphere, and the mixture was stirred for 4 hours under
reflux. The reaction mixture was allowed to room temperature, ethyl
acetate and water were added for partitioning, the organic layer
was washed with water and dried over anhydrous magnesium sulfate.
The solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=10:1), and
biphenyl-3-carbonitrile (821 mg, 67%) was obtained as a yellow
solid.
[0676] Next, a solution of the resulting biphenyl-3-carbonitrile
(821 mg, 4.58 mmol) in tetrahydrofuran (5 mL) was added to a
solution of lithium aluminum hydride (0.435 g, 11.5 mmol) in
tetrahydrofuran (5 mL) that had been cooled on an ice bath, and the
solution was stirred for 6 hours at room temperature. The reaction
solution was cooled on an ice bath, a mixture solution of methanol
and water (9:1) was added thereto, an aqueous solution of saturated
ammonium chloride was further added, filtration was carried out
through Celite pad and insoluble matter was removed. The filtrate
was partitioned, the organic layer was dried over anhydrous
magnesium sulfate, and the title compound (527 mg, 63%) was
obtained as a brown oil. This was used in the next reaction without
further purification.
Preparation Example 6
4-(3-Fluorobenzyloxy)-benzylamine
[0677] To a solution of 4-cyanophenol (3.0 g, 25.2 mmol) and
3-fluorobenzyl bromide (3.1 mL, 25.2 mmol) in N,N-dimethylformamide
(30 mL) was added potassium carbonate (8.71 g, 63.0 mmol), and the
mixture was stirred for 1 hour at room temperature. Ethyl acetate
and water were added to the reaction mixture, which was then
partitioned, the organic layer was washed with water, then, dried
over anhydrous magnesium sulfate, and the solvent was evaporated to
obtain 4-(3-fluorobenzyloxy)-benzonitrile (5.31 g, 93%) as a
colorless solid.
[0678] Next, to a solution of lithium aluminum hydride (1.25 g,
133.0 mmol) in tetrahydrofuran (15 mL) was added a solution of
4-(3-fluorobenzyloxy)-benzonitrile (218 mg, 0.615 mmol) in
tetrahydrofuran (12 mL) on an ice bath, and the solution was
stirred at room temperature for 19 hours. A mixture solvent of
methanol and water (9:1) was added to the reaction solution, an
aqueous solution of saturated ammonium chloride was further added,
and the solution was stirred on an ice bath for 30 minutes. This
solution was filtered through Celite pad, and insoluble matter was
removed. The filtrate was partitioned, and the organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated,
and the title compound (1.33 g, 44%) was obtained as a yellow
solid. This was used in the next reaction without further
purification.
Preparation Example 7
C-(4-Phenoxy-pyridin-2-yl)-methylamine
[0679] To a solution of 4-phenoxypyridine (3.0 g, 17.5 mmol) in
dichloromethane (500 mL) was added 3-chloro-perbenzoic acid (5.18
g, 21.0 mmol) on an ice bath, and the solution was stirred for 22
hours. An aqueous solution of saturated sodium thiosulfate and an
aqueous solution of saturated sodium bicarbonate were added to the
reaction solution, the solution was stirred at room temperature for
10 minutes, then, the organic layer was separated, washed with
brine and dried over anhydrous magnesium sulfate. The solvent was
evaporated, and 4-phenoxy-pyridine N-oxide (3.3 g, quantitatively)
was obtained as a pale yellow solid.
[0680] The resulting solid (3.3 g, 17.6 mmol) was dissolved in
acetonitrile (18 mL), trimethylsilyl cyanide (6.6 mL, 52.8 mmol)
and triethylamine (4.9 mL, 35.2 mmol) were added, and the solution
was stirred for 5 hours under reflux. The solvent was evaporated,
the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=4:1), and 4-phenoxy-pyridine-2-carbonitrile
(2.5 g, 73%) was obtained as a pale yellow solid.
[0681] Next, to a solution of lithium aluminum hydride (725 mg, 19
.mu.mol) in tetrahydrofuran (6.0 mL) was portionwise added a
solution of the resulting 4-phenoxy-pyridine-2-carbonitrile (1.5 g,
7.65 mmol) in tetrahydrofuran (3 mL) on an ice bath, and the
solution was stirred at room temperature for 15 hours. A mixture
solvent of methanol and water (9:1) was added to the reaction
solution, an aqueous solution of saturated ammonium chloride was
further added, the solution was extracted with ethyl acetate, dried
over anhydrous magnesium sulfate, then, the solvent was evaporated
to obtain the title compound (730 mg, 48%) as a pale brown oil.
This was used in the next reaction without further
purification.
Preparation Example 8
3-(4-Fluorophenoxy)-benzylamine
[0682] The title compound (790 mg, quantitatively) was obtained as
a pale yellow solid from 3-(4-fluorophenoxy)benzyl bromide (944 mg,
3.36 mmol) according to a similar technique to Preparation Example
1.
Preparation Example 9
3-(4-Methoxyphenoxy)benzylamine
[0683] To a solution of 3-(4-methoxyphenoxy)benzaldehyde (5.0 g,
21.9 mmol) in methanol (35 mL) was added a solution of sodium
borohydride (0.86 g, 22.8 mmol) in an aqueous solution of 2N sodium
hydroxide (2.5 mL), and the mixture was stirred at room temperature
for 30 minutes. Water was added to the reaction mixture, which was
neutralized with acetic acid, then, extracted with ethyl acetate,
washed with brine, then, dried over anhydrous magnesium sulfate,
and the solvent was evaporated to obtain
(3-(4-methoxy-phenoxy)-phenyl)-metanol (5.3 g, quantitatively) as a
colorless oil.
[0684] To a solution of the obtained
(3-(4-methoxy-phenoxy)-phenyl)-metanol (2.0 g, 8.73 mmol) in
dichloromethane (20 mL) was added methanesulfonyl chloride (0.81
mL, 10.5 mmol) and triethylamine (1.46 mL, 10.5 mmol) on an ice
bath, and the solution was stirred for 19 hours. The reaction
solution was diluted with dichloromethane, washed with an aqueous
solution of 5% sodium bicarbonate, dried over anhydrous magnesium
sulfate, and the solvent was evaporated to obtain methanesulfonic
acid 3-(4-methoxy-phenoxy)benzyl ester (2.4 g, 89%) as a pale brown
oil.
[0685] Next, the title compound (859 mg, 89%) was obtained as a
pale yellow solid from the resulting methanesulfonic acid
3-(4-methoxy-phenoxy)benzyl ester (2.4 g, 7.78 mmol) according to a
similar technique to Preparation Example 1.
Preparation Example 10
3-(3-Trifluoromethyl-phenoxy)-benzylamine
[0686] The title compound (2.63 g) was obtained as a brown oil from
3-(3-(trifluoromethyl)phenoxy)benzaldehyde (5.01 g, 18.8 mmol)
according to an analogous method to Preparation Example 9.
Preparation Example 11
3-(3-Fluoro-phenoxy)-benzylamine
[0687] To a solution of 3-fluoro-phenol (500 mg, 4.46 mmol) and
3-fluoro-benzonitrile (540 mg, 4.46 mmol) in dimethylsulfoxide (1.0
mL) was added potassium tert-butoxide (500 mg, 4.46 mmol), and the
solution was stirred at 140.degree. C. for 3 hours. The reaction
solution was allowed to room temperature, ethyl acetate and water
were added for partitioning, the organic layer was washed with
water and dried over anhydrous magnesium sulfate. The solvent was
evaporated, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=4:1), and
3-(3-fluoro-phenoxy)-benzonitrile (313 mg, 33%) was obtained as a
yellow solid.
[0688] Next, to a solution of lithium aluminum hydride (139 mg,
3.68 mmol) in tetrahydrofuran (3.0 mL) was added a solution of the
resulting 3-(3-fluoro-phenoxy)-benzonitrile (313 mg, 1.47 mmol) in
tetrahydrofuran (1 mL) on an ice bath, and the solution was stirred
at room temperature for 18 hours. A mixture solvent of methanol and
water (9:1) was added to the reaction solution, an aqueous solution
of saturated ammonium chloride was further added thereto, followed
by stirring at room temperature for 10 minutes, then, extracted
with ethyl acetate, dried over anhydrous magnesium sulfate, then,
the solvent was evaporated to obtain the title compound (285 mg,
89%) as a yellow oil.
Preparation Example 12
4-(Furan-2-ylmethoxy)-benzylamine
[0689] To a solution of 4-cyanophenol (2.0 g, 16.8 mmol) in
dichloromethane (20 mL) were added triphenyl phosphine (6.6 g, 25.2
mmol), furfuryl alcohol (1.65 g, 16.8 mmol) and diethyl
azodicarboxylate (3.97 mL, 25.2 mmol) on an ice bath, and the
solution was stirred at room temperature for 16 hours. The reaction
solution was directly purified by silica gel column chromatography
(hexane:ethyl acetate), the obtained crudely purified product was
further purified by NH silica gel column chromatography
(hexane:ethyl acetate), 4-furan-2-ylmethoxy)-benzonitrile (106 mg,
3%) was obtained as a pale yellow solid.
[0690] Next, to a solution of lithium aluminum hydride (50 mg, 1.33
mmol) in tetrahydrofuran (1.0 mL) was added a solution of the
resulting 4-furan-2-ylmethoxy)-benzonitrile (106 mg, 0.532 mmol) in
tetrahydrofuran (1 mL) on an ice bath, and the solution was stirred
at room temperature for 4 hours. A mixture solvent of methanol and
water (9:1) was added to the reaction solution, an aqueous solution
of saturated ammonium chloride was further added, the solution was
extracted with ethyl acetate, dried over anhydrous magnesium
sulfate, then, the solvent was evaporated to obtain the title
compound (76 mg, 70%) as a yellow solid.
Preparation Example 13
4-(Thiophen-2-ylmethoxy)-benzylamine
[0691] To a solution of 2-thiophenemethanol (2.0 g, 17.5 mmol) in
dichloromethane (20 mL) were added methanesulfonyl chloride (1.63
mL, 21.0 mmol) and triethylamine (2.93 mL, 21.0 mmol) on an ice
bath, and the solution was stirred for 13 hours. The reaction
solution was diluted with dichloromethane, washed with an aqueous
solution of 5% sodium bicarbonate, dried over anhydrous magnesium
sulfate, and the solvent was evaporated to obtain methanesulfonic
acid 2-thiophen-2-ylmethyl ester (2.4 g) as a brown oil.
[0692] Next, to a solution of the resulting methanesulfonic acid
2-thiophen-2-ylmethyl ester (2.4 g, 12.6 mmol) and p-cyanophenol
(1.50 g, 12.6 mmol) in N,N-dimethylformamide (25 mL) was added
potassium carbonate (4.35 g, 32.5 mmol), and the solution was
stirred at room temperature for 13 hours. Ethyl acetate and water
were added to the reaction solution, which was then separated, the
organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was evaporated, the residue was
purified by NH silica gel column chromatography (hexane ethyl
acetate=4:1), and 4-(thiophen-2-ylmethoxy)-benzonitrile (1.88 g)
was obtained as a white solid.
[0693] In addition, to a solution of lithium aluminum hydride (220
mg, 5.80 mmol) in tetrahydrofuran (2.5 mL) was added a solution of
the resulting 4-(thiophene-2-ylmethoxy)-benzonitrile (500 mg, 2.32
mmol) in tetrahydrofuran (1 mL) on an ice bath, and the solution
was stirred at room temperature for 4 hours. A mixture solvent of
methanol and water (9:1) was added to the reaction solution, an
aqueous solution of saturated ammonium chloride was further added,
the solution was extracted with ethyl acetate, dried over anhydrous
magnesium sulfate, then, the solvent was evaporated to obtain the
title compound (415 mg, 82%) as a colorless solid.
Preparation Example 14
4-(Thiophen-3-ylmethyl)-benzylamine
[0694] The title compound (419 mg) was obtained as a pale brown
solid from 3-thiophenemethanol according to an analogous method to
Preparation Example 13.
Preparation Example 15
4-((S)-1-Phenyl-ethoxy)-benzylamine
[0695] To a solution of 4-bromobenzonitrile (500 mg, 2.75 mmol) and
S-(-)-.alpha.-phenylethylalcohol (403 mg, 3.30 mmol) in toluene (5
mL) were added sodium hydride (220 mg, 5.49 mmol; 60% in oil),
tris(dibenzylideneacetone)dipalladium(0) (38 mg, 0.0413 mmol) and
2,2-bis(di-p-tolylphosphino)-1,1-binaphthyl (67 mg, 0.099 mmol),
and the solution was stirred at 70.degree. C. for 4 hours. The
reaction solution was allowed to room temperature, ethyl acetate
and water were added for partitioning, the organic layer was washed
with water and dried over anhydrous magnesium sulfate. The solvent
was evaporated, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and
4-(1-phenyl-ethoxy)-benzonitrile (159 mg, 26%) was obtained as a
colorless oil.
[0696] Next, to a solution of lithium aluminum hydride (68 mg, 1.78
mmol) in tetrahydrofuran (5.0 mL) was added a solution of the
resulting 4-(1-phenyl-ethoxy)-benzonitrile (159 mg, 0.712 mmol) in
tetrahydrofuran (1 mL) on an ice bath, which was stirred under
reflux for 2 hours. The reaction solution was allowed to room
temperature, a mixture solvent of methanol and water (9:1) was
added, an aqueous solution of saturated ammonium chloride was
further added, then, ethyl acetate and water were added for
partitioning, the organic layer was dried over anhydrous magnesium
sulfate, then, the solvent was evaporated to obtain the title
compound (172 mg, quantitatively) as a yellow oily substance.
Preparation Example 16
C-(6-Phenoxy-pyridin-2-yl)-methylamine
[0697] To a solution of 2,6-dibromopyridine (20 g, 84.4 mmol) and
phenol (7.94 g, 84.4 mmol) in dimethylsulfoxide (200 mL) was added
potassium tert-butoxide (9.47 g, 84.4 mmol), and the solution was
stirred at 160.degree. C. for 7 hours. The reaction solution was
allowed to room temperature, ethyl acetate and water were added for
partitioning, the organic layer was washed with water and dried
over anhydrous magnesium sulfate. The solvent was evaporated, the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=10:1), and 2-bromo-6-phenoxy-pyridine (19.6
g, 93%) was obtained as a yellow solid.
[0698] Next, to a solution of the resulting
2-bromo-6-phenoxy-pyridine (1.0 g, 4.0 mmol) in
N,N-dimethylformamide (30 mL) were added zinc cyanide (940 mg, 8.0
mmol) and tetrakis(triphenylphosphine)palladium(0) (924 mg, 0.8
mmol) under nitrogen atmosphere, and the mixture was stirred at
100.degree. C. for 1 hour. The reaction mixture was allowed to room
temperature, ethyl acetate and water were added for partitioning,
the organic layer was washed with water and dried over anhydrous
magnesium sulfate. The solvent was evaporated, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=10:1), and 6-phenoxy-pyridine-2-carbonitrile (524 mg, 67%)
was obtained as a white solid.
[0699] 10% Palladium-carbon (50 mg) was added to a solution of the
resulting 6-phenoxy-pyridine-2-carbonitrile (100 mg, 0.5 .mu.mol)
in methanol (5.0 mL), the mixture was stirred at room temperature
for 24 hours under hydrogen atmosphere (1 atm). The catalyst was
removed by filtration, and the filtrate was concentrated to obtain
the title compound (65 mg, 64%) as a colorless oil.
Preparation Example 17
C-(5-(3-bromophenoxy)-thiophen-2-yl)-methylamine
[0700] To a solution of 5-nitrothiophene-2-carbonitrile (1.79 g,
11.6 mmol) and 3-bromophenol (2.00 g, 11.6 mmol) in
dimethylsulfoxide (22 mL) was added potassium carbonate (1.76 g,
12.8 mmol), and the solution was stirred at 70.degree. C. for 3
hours. The reaction solution was allowed to room temperature, ethyl
acetate and water were added for partitioning, the organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane ethyl acetate=10:1), and
5-(3-bromophenoxy)-thiophene-2-carbonitrile (2.00 g, 62%) was
obtained as a yellow oil.
[0701] Next, to a solution of lithium aluminum hydride (204 mg,
5.39 mmol) in tetrahydrofuran (10 mL) was added a solution of the
resulting 5-(3-bromophenoxy)-thiophene-2-carbonitrile (1.01 g, 3.59
mmol) in tetrahydrofuran (10 mL), and the solution was stirred at
room temperature for 2 hours. Then, lithium aluminum hydride (68
mg, 1.80 mmol) was added, and the solution was further stirred at
room temperature for 1 hour. Water was added to the reaction
solution, which was then extracted with ethyl acetate, dried over
anhydrous magnesium sulfate, and the solvent was evaporated to
obtain a mixture of the title compound and debrominated compound
(740 mg) as a pale brown oil. As this mixture cannot be purified,
it was used in the next reaction without purification.
Preparation Example 18
C-(5-(3-Benzyloxy-phenoxy)-thiophen-2-yl)-methylamine
[0702] To a solution of resorcinol (10 g, 90.8 mmol) in
N,N-dimethylformamide (100 mL) was added potassium carbonate (12.6
g, 90.8 mmol) and benzyl bromide (10.8 mL, 90.8 mmol), and the
mixture was stirred at 60.degree. C. for 2 hours. The reaction
mixture was allowed to room temperature, ethyl acetate and water
were added for partitioning, the organic layer was washed with
water and dried over anhydrous magnesium sulfate. The solvent was
evaporated, then, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and 3-benzyloxy-phenol (6.0
g, 33%) was obtained as a pale brown oil.
[0703] To a solution of the resulting 3-benzyloxy-phenol (2.6 g,
13.0 mmol) and a 5-nitrothiophene-2-carbonitrile (2.0 g, 13.0 mmol)
in dimethylsulfoxide (25 mL) was added potassium carbonate (1.98 g,
14.0 mmol), and the solution was stirred at 70.degree. C. for 3
hours. The reaction solution was allowed to room temperature, ethyl
acetate and water were added for partitioning, the organic layer
was washed with water and dried over anhydrous magnesium sulfate.
The solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane ethyl acetate=10:1), and
5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile (110 mg, 2.8%) was
obtained as a pale brown solid.
[0704] Next, to a solution of lithium aluminum hydride (27 mg,
0.716 mmol) in tetrahydrofuran (2.0 mL) was added a solution of
5-(3-benzyloxy-phenoxy)-thiophene-2-carbonitrile obtained above
(110 mg, 0.358 mmol) in tetrahydrofuran (1 mL), and the solution
was stirred at room temperature for 3 hours. Water was added to the
reaction solution, which was then extracted with ethyl acetate,
dried over anhydrous magnesium sulfate, and the solvent was
evaporated to obtain the title compound (80 mg, 72%) as a red
solid. This compound was used in the next reaction without
purification.
Preparation Example 19
(4-Aminomethylphenyl)-benzyl-amine
[0705] To a mixture of sodium tert-butoxide (7.44 g, 77.4 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.38 g, 0.415 mmol) and
rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.172 g, 0.277 mmol)
was added a solution of 4-bromobenzonitrile (10 g, 55.3 mmol) and
benzylamine (11.8 g, 0.11 mol) in toluene (100 mL) under nitrogen
atmosphere, and the solution was stirred at 80.degree. C. for 5
hours. The reaction solution was allowed to room temperature, then,
filtrated through Celite pad to remove insoluble matter, and the
filtrate was concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and 4-benzyl
amino-benzonitrile (11.1 g, 96%) was obtained as a yellow
solid.
[0706] Next, to a solution of lithium aluminum hydride (911 mg,
24.0 mmol) in tetrahydrofuran (60 mL) was added a solution of the
resulting 4-benzyl amino-benzonitrile (2.0 g, 9.61 mmol) in
tetrahydrofuran (5 mL), and the solution was stirred at room
temperature for 3 hours. Water was added to the reaction solution,
which was then extracted with ethyl acetate, dried over anhydrous
magnesium sulfate, and the solvent was evaporated to obtain the
title compound (2.0 g, quantitatively) as an orange oil. This
compound was used in the next reaction without purification.
Preparation Example 20
(4-Aminomethyl-phenyl)-phenyl-amine
[0707] To a mixture of sodium tert-butoxide (7.44 g, 77.4 mmol),
tris(dibenzylideneacetone)dipalladium(0) (0.38 g, 0.415 mmol) and
rac-2,2-bis(diphenylphosphino)-1,1-binaphthyl (0.172 g, 0.277 mmol)
was added a solution of 4-bromobenzonitrile (10 g, 55.3 mmol) and
benzylamine (6.5 mL, 0.11 mol) in toluene (100 mL) under nitrogen
atmosphere, and the solution was stirred at 80.degree. C. for 5
hours. The reaction mixture was allowed to room temperature, then,
filtered through Celite pad to remove insoluble matter, and the
filtrate was concentrated. The residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and
4-phenylamino-benzonitrile (6.7 g, 63%) was obtained as a yellow
solid.
[0708] Next, to a solution of lithium aluminum hydride (1.17 g,
30.9 mmol) in tetrahydrofuran (60 mL) was added a solution of the
obtained 4-phenylamino-benzonitrile (2.0 g, 10.3 mmol) in
tetrahydrofuran (5 mL), and the solution was stirred at room
temperature for 22 hours. Water was added to the reaction solution,
which was then extracted with ethyl acetate, dried over anhydrous
magnesium sulfate, and the solvent was evaporated to obtain the
title compound (2.0 g, 98%) as an orange oil. This compound was
used in the next reaction without purification.
Preparation Example 21
(4-Aminomethyl-benzyl)-phenylamine
[0709] To a solution of 4-cyanobenzaldehyde (10 g, 76.3 mmol) and
aniline (4.48 mL, 76.3 mmol) in tetrahydrofuran (370 mL) were added
acetic acid (21.9 mL, 0.383 mol) and triacetoxy sodium borohydride
(32.3 g, 0.153 mol), and the solution was stirred at room
temperature for 1 hour. Ethyl acetate and water were added to the
reaction solution, which was then partitioned, the organic layer
was washed with water and dried over anhydrous magnesium sulfate.
The solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and
4-phenylaminomethyl-benzonitrile) (5.1 g, 32%) was obtained as a
pale yellow solid.
[0710] Next, to a solution of lithium aluminum hydride (0.91 g, 24
mmol) in tetrahydrofuran (60 mL) was added a solution of the
resulting 4-phenylaminomethyl-benzonitrile (2.0 g, 9.6 .mu.mol) in
tetrahydrofuran (5 mL), and the solution was stirred at room
temperature for 2 hours. Water was added to the reaction solution,
which was then extracted with ethyl acetate, dried over anhydrous
magnesium sulfate, and the solvent was evaporated to obtain the
title compound (1.98 g, 97%) as a yellow oil. This compound was
used in the next reaction without purification.
Preparation Example 22
5-(3-Fluorophenoxy)thiophene-2-carbonitrile
[0711] 5-Nitrothiophene-2-carbonitrile (2 g, 13 mmol),
3-fluorophenol (1.75 g, 15.6 mmol) and potassium carbonate (3.6 g,
26 mmol) were suspended in dimethylsulfoxide (15 mL), and the
mixture was stirred at room temperature for 16 hours. Water and
ethyl acetate were added for partitioning, silica gel was added to
the organic layer, and the solvent was evaporated in vacuo for
adsorption. Purification was carried out by silica gel column
chromatography (hexane:ethyl acetate=10:1), and the title compound
(670 mg, 3.1 mmol, 23.5%) was obtained as an oil.
[0712] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.83 (1H,
d, J=4.0 Hz), 7.08-7.26 (2H, m), 7.18-7.24 (1H, m), 7.49 (1H, ddd,
J=8.0, 8.0, 8.0 Hz), 7.81 (1H, d, J=4.0 Hz).
Preparation Example 23
C-(5-(3-Fluorophenoxy)thiophen-2-yl)methylamine
[0713] To a solution of 5-(3-fluorophenoxy)thiophene-2-carbonitrile
described in Preparation Example 22 (670 mg, 3 mmol) in
tetrahydrofuran (30 mL) was added lithium aluminum hydride (460 mg,
12 mmol), and the solution was stirred at room temperature for 16
hours. Water and ethyl acetate were added to the reaction solution,
which was then partitioned, the organic layer was filtered with NH
silica gel, the filtrate was evaporated in vacuo, and the title
compound (570 mg, 2.42 mmol, 80.7%) was obtained as a brown
oil.
[0714] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.08 (2H,
brs), 3.80 (2H, s), 6.54 (1H, d, J=3.6 Hz), 6.66-6.70 (1H, m),
6.88-6.99 (3H, m), 7.39 (1H, ddd, J=8.0, 8.0, 8.0 Hz).
Preparation Example 24
C-(5-Phenoxy thiophen-2-yl)methylamine
[0715] 5-Nitrothiophene-2-carbonitrile (0.80 g, 5.2 mmol), phenol
(1.0 g, 10.4 mmol) and potassium carbonate (2.2 g, 15.6 mmol) were
suspended in dimethylsulfoxide (30 mL), and the mixture was stirred
at room temperature for 15.5 hours. Water and ethyl acetate were
added for partitioning, and the organic layer was washed three
times with water. NH silica gel was added to the organic layer, the
solvent was evaporated in vacuo for adsorption, purification was
carried out by NH silica gel column chromatography (hexane:ethyl
acetate=8:1), and 5-phenoxythiophene-2-carbonitrile (720 mg, 3.6
mmol, 69.2%) was obtained as a colorless oil.
[0716] To a solution of this oil in tetrahydrofuran (40 mL) was
added lithium aluminum hydride (540 mg, 14.4 mmol), and the mixture
was stirred for 30 minutes at room temperature. Water and ethyl
acetate were added to the reaction mixture, which was then
partitioned, silica gel was added to the organic layer, the solvent
was evaporated in vacuo for adsorption, purification was carried
out by silica gel column chromatography (ethyl acetate, then ethyl
acetate:methanol=4:1), and the title compound (570 mg, 2.8 mmol,
77.2%) was obtained as a light brown oil.
[0717] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.34 (2H,
brs), 3.78-3.82 (2H, m), 6.47 (1H, d, J=4.0 Hz), 6.65-6.68 (1H, m),
7.04-7.14 (3H, m), 7.34-7.40 (2H, m).
Preparation Example 25
5-Phenoxy thiophene-2-carbonitrile
[0718] 5-Nitro-thiophene-2-carbonitrile (1.5 g, 9.7 mmol), phenol
(1.8 g, 19.4 mmol) and potassium carbonate (4.0 g, 29.1 mmol) were
suspended in dimethylsulfoxide (20 mL), and the mixture was stirred
for 50 minutes at 60.degree. C., followed by further stirring
overnight at room temperature. Water and ethyl acetate were added
to the reaction mixture, which was then partitioned, the organic
layer was washed 4 times with water, then, NH silica gel was added
to the organic layer, the solvent was evaporated in vacuo for
adsorption, purification was carried out by NH silica gel column
chromatography (hexane, then hexane:ethyl acetate=20:1, then 10:1),
and the title compound (1.4 g, 7.0 mmol, 72.1%) was obtained as a
pale yellow oil.
[0719] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.75 (1H,
d, J=4.0 Hz), 7.23-7.31 (3H, m), 7.42-7.49 (2H, m), 7.78 (1H, d,
J=4.0 Hz).
Preparation Example 26
C-(5-Phenoxy thiophen-2-yl)methylamine
[0720] To a solution of 5-phenoxythiophene-2-carbonitrile described
in Preparation Example 25 (1.4 g, 7.0 mmol) in tetrahydrofuran (30
mL) was added lithium aluminum hydride (1.1 g, 28 mmol), and the
solution was stirred at room temperature for 25 minutes. Water and
ethyl acetate were added to the reaction solution, this mixed
solution was filtered through Celite pad, furthermore, the organic
layer was partitioned. The solvent was evaporated in vacuo, and the
title compound (1.29 g, 6.3 mmol, 89.9%) was obtained as a brown
oil.
[0721] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.92 (2H,
brs), 3.74-3.80 (2H, m), 6.46 (1H, d, J=3.6 Hz), 6.62-6.66 (1H, m),
7.02-7.14 (3H, m), 7.32-7.39 (2H, m).
Preparation Example 27
5-(4-Fluorophenoxy)thiophene-2-carbonitrile
[0722] 5-Nitrothiophene-2-carbonitrile (2.0 g, 13 mmol),
4-fluorophenol (2.9 g, 26 mmol) and potassium carbonate (5.4 g, 39
mmol) were suspended in dimethylsulfoxide (30 mL), and the mixture
was stirred for 30 minutes at 60.degree. C. Water and ethyl acetate
were added to the reaction mixture, which was then separated, the
organic layer was washed with water twice, then, NH silica gel was
added to the organic layer, the solvent was evaporated in vacuo for
adsorption, purification was carried out by NH silica gel column
chromatography (hexane:ethyl acetate=20:1), and the title compound
(3.7 g, containing 4-fluorophenol) was obtained as a brown oil.
[0723] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.68-6.76
(2H, m), 7.26-7.38 (3H, m), 7.74-7.80 (1H, m).
Preparation Example 28
C-(5-(4-Fluorophenoxy)thiophen-2-yl)methylamine
[0724] To a solution of 5-(4-fluorophenoxy)thiophene-2-carbonitrile
described in Preparation Example 27 (containing 4-fluorophenol)
(3.7 g) in tetrahydrofuran (40 mL) was added lithium aluminum
hydride (1.3 g, 34 mmol), and the solution was stirred at room
temperature for 30 minutes. Water and ethyl acetate were added to
the reaction solution, which was then partitioned, the solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (ethyl acetate, then ethyl acetate:methanol=4:1),
and the title compound (1.2 g, 5.4 mmol) was obtained as a brown
oil.
[0725] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.00 (2H,
brs), 3.75-3.80 (2H, m), 6.44-6.48 (1H, m), 6.62-6.67 (1H, m),
7.08-7.14 (2H, m), 7.16-7.24 (2H, m).
Preparation Example 29
5-m-Tolyloxy-thiophene-2-carbonitrile
[0726] The title compound (960 mg, 4.47 mmol, 68.7%) was obtained
as a yellow oil from 5-nitro-thiophene-2-carbonitrile (1.0 g, 6.5
mmol) and 3-methylphenol (1.4 g, 13 mmol) according to an analogous
method to Preparation Example 27.
[0727] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.31 (3H,
s), 6.73 (1H, dd, J=0.8, 4.0 Hz), 7.03-7.06 (1H, m), 7.07-7.12 (2H,
m), 7.33 (1H, dd, J=8.0, 8.0 Hz), 7.77 (1H, dd, J=0.8, 4.0 Hz).
Preparation Example 30
C-(5-m-Tolyloxy-thiophen-2-yl)-methylamine
[0728] The title compound (900 mg, 4.10 mmol, 91.7%) was obtained
as a reddish brown oil from 5-m-tolyloxy thiophene-2-carbonitrile
described in Preparation Example 29 (960 mg, 4.47 mmol) according
to an analogous method to Preparation Example 28.
[0729] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.03 (2H,
brs), 2.34 (3H, s), 3.85 (2H, s), 6.51-6.54 (1H, m), 6.71-6.74 (1H,
m), 6.90-7.03 (3H, m), 7.31 (1H, dd, J=8.0, 8.0 Hz).
Preparation Example 31
5-p-Tolyloxy-thiophene-2-carbonitrile
[0730] The title compound (1.0 g, 4.65 mmol, 71.5%) was obtained as
a yellow oil from 5-nitro-thiophene-2-carbonitrile (1.0 g, 6.5
mmol) and 4-methylphenol (1.4 g, 13 mmol) according to an analogous
method to Preparation Example 27.
[0731] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.30 (3H,
s), 6.69-6.71 (1H, m), 7.15-7.18 (2H, m), 6.24-6.28 (2H, m),
7.15-7.78 (1H, m).
Preparation Example 32
C-(5-p-Tolyloxy thiophen-2-yl)methylamine
[0732] The title compound (780 mg, 3.56 mmol, 76.5%) was obtained
as a reddish brown oil from 5-p-tolyloxy thiophene-2-carbonitrile
described in Preparation Example 31 (1.0 g, 4.65 mmol) according to
an analogous method to Preparation Example 28.
[0733] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.06 (2H,
br), 2.22 (3H, s), 3.76 (2H, s), 6.41 (1H, d, J=3.6 Hz), 6.62 (1H,
d, J=3.6 Hz), 6.90-6.98 (2H, m), 7.15-7.18 (2H, m).
Preparation Example 33
[0734] 2-(4-(3-Fluoro-phenoxy)-thiophen-2-yl)-[1,3]-dioxolane
2-(4-Bromo-thiophen-2-yl)-[1,3]dioxolane (1.0 g, 4.3 mmol),
3-fluorophenol (0.95 g, 8.6 mmol),
2,2,6,6-tetramethyl-3,5-heptanedione (0.078 g, 0.43 mmol),
copper(I) chloride (0.21 g, 2.7 mmol) and cesium carbonate (2.8 g,
8.6 mmol) were suspended in N-methylpyrrolidone (10 mL) under a
nitrogen stream, and the mixture was stirred for 4.5 hours at
120.degree. C. To this suspension was added
2,2,6,6-tetramethyl-3,5-heptanedione (0.12 g, 0.65 mmol), and the
solution was further stirred for 8 hours at 140.degree. C. The
reaction mixture was filtered through Celite pad, then, water and
ethyl acetate were added for partitioning, and the organic layer
was washed with water twice. NH silica gel was added to the organic
layer, the solvent was evaporated in vacuo for adsorption to NH
silica gel, purification was carried out by NH silica gel column
chromatography (hexane, then hexane:ethyl acetate=30:1), and the
title compound (280 mg, 1.05 mmol, 24.4%) was obtained as a
colorless oil.
[0735] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.88-3.96
(2H, m), 3.96-4.04 (2H, m), 5.98 (1H, s), 6.82-6.88 (2H, m),
6.91-6.97 (1H, m), 7.04-7.05 (1H, m), 7.09 (1H, d, J=2.0 Hz),
7.35-7.42 (1H, m).
Preparation Example 34
4-(3-Fluorophenoxy)thiophene-2-carbaldehyde
[0736] To a solution of
2-(4-(3-fluoro-phenoxy)-thiophen-2-yl)-[1,3]dioxolane described in
Preparation Example 33 (280 mg, 1.05 mmol) in methanol (10 mL) was
added citric acid aqueous solution (10 mL), and the solution was
stirred at room temperature for 30 minutes. The reaction solution
was neutralized with an aqueous solution of sodium bicarbonate, the
solution was extracted with ethyl acetate, the organic layer was
dried over anhydrous sodium sulfate, the solvent was evaporated in
vacuo, and the title compound (210 mg, 0.95 mmol, 90%) was obtained
as a colorless oil.
[0737] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.88-7.03
(3H, m), 7.38-7.46 (1H, m), 7.67 (1H, d, J=1.6 Hz), 7.88 (1H, d,
J=1.6 Hz), 9.86 (1H, s).
Preparation Example 35
(C-(4-(3-Fluorophenoxy)thiophen-2-yl)methylamine
[0738] 4-(3-Fluorophenoxy)thiophene-2-carbaldehyde described in
Preparation Example 34 (210 mg, 0.95 mmol) was dissolved in 7N
ammonia/methanol (30 mL), Raney nickel (500 mg) was added thereto,
followed by stirring for 19 hours under hydrogen atmosphere at room
temperature. The reaction mixture was filtered through Celite pad,
Raney nickel was removed, silica gel was added to the filtrate,
then, the solvent was evaporated in vacuo, for adsorption on silica
gel, purification by silica gel chromatography (ethyl acetate, then
ethyl acetate:methanol=4:1) was carried out, and the title compound
(70 mg, 0.32 mmol) was obtained as a pale yellow oil.
[0739] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.11 (2H,
brs), 3.82 (2H, s), 6.75 (1H, s), 6.80-6.95 (4H, m), 7.33-7.41 (1H,
m).
Preparation Example 36
2-(5-(4-Fluoro-benzyl)-thiophen-2-yl)-[1,3]-dioxolane
[0740] n-Butyl lithium (2.6N hexane solution, 3.3 mL, 8.47 mmol)
was added dropwise to a solution of
2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (1.8 g, 7.7 mmol) in
tetrahydrofuran (20 mL) that had been cooled to from -75.degree. to
-70.degree. C., and the solution was stirred for 30 minutes.
4-Fluorobenzyl bromide (1.1 mL, 8.47 mmol) was added dropwise to
this reaction solution while keeping it at -70.degree. C. or less.
After completion of dropwise addition, the reaction solution was
gradually allowed to room temperature. Water and ethyl acetate were
added to the reaction solution, which was then partitioned, silica
gel was added to the organic layer, which was then evaporated in
vacuo for adsorption, purification by silica gel column
chromatography (hexane, then hexane:ethyl acetate=20:1, then 10:1)
was carried out, and the title compound (560 mg, 2.04 mmol, 26.4%)
was obtained as a brown oil.
[0741] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.84-3.98
(4H, m), 4.08 (2H, s), 5.90 (1H, s), 6.75-6.78 (1H, m), 7.00 (1H,
d, J=3.6 Hz), 7.08-7.15 (2H, m), 7.25-7.30 (2H, m).
Preparation Example 37
5-(4-Fluoro-benzyl)-thiophene-2-carbaldehyde
[0742] To a solution of
2-(5-(4-fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in
Preparation Example 36 (560 mg, 2.04 mmol) in methanol (20 mL) was
added citric acid aqueous solution (20 mL), and the solution was
stirred at room temperature for 30 minutes. Ethyl acetate and water
were added to the reaction solution, which was then partitioned,
the organic layer was washed with water twice, dried over anhydrous
sodium sulfate, the solvent was evaporated in vacuo, and title
compound (460 mg, 2.09 mmol) was obtained as a brown oil.
[0743] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.22 (2H,
s), 7.08-7.18 (3H, m), 7.29-7.36 (2H, m), 7.83-7.87 (1H, m), 9.79
(1H, s).
Preparation Example 38
C-(5-(4-Fluorobenzyl)thiophen-2-yl)methylamine
[0744] 7N ammonia/methanol (30 mL) and Raney nickel (500 mg) were
added to 5-(4-fluorobenzyl)thiophene-2-carbaldehyde described in
Preparation Example 37 (460 mg, 2.09 mmol), and the mixture was
stirred for 14 hours under hydrogen atmosphere at room temperature.
The catalyst was removed by filtering through Celite pad, then,
purification by silica gel column chromatography (ethyl acetate,
then ethyl acetate:methanol=4:1) was carried out, and the title
compound (70 mg, 0.316 mol, 15.1%) was obtained as an oil.
[0745] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.20 (2H,
brs), 3.78 (2H, s), 4.03 (2H, s), 6.58-6.80 (2H, m), 7.00-7.38 (4H,
m).
Preparation Example 39
5-Benzyl-furan-2-carbaldehyde
[0746] n-Butyl lithium (2.44N hexane solution, 15 mL, 39.6 mmol)
was added dropwise to a solution of 2-furan-2-yl-[1,3]dioxolane (5
g, 36 mmol) in tetrahydrofuran (30 mL) that had been cooled to from
-75.degree. C. to -70.degree. C., and the solution was stirred for
1 hour. Benzyl bromide (4.7 mL, 39.6 mmol) was added dropwise to
this solution at from -75.degree. C. to -70.degree. C. After
completion of dropwise addition, the cold bath was removed, and the
solution was gradually allowed to room temperature. Water and ethyl
acetate were added to the reaction mixture for partitioning, silica
gel was added to the organic layer, which was then evaporated in
vacuo to adsorb the reaction mixture, purification by silica gel
column chromatography (hexane:ethyl acetate=50:1, then 6:1) was
carried out, and 2-(5-benzyl-furan-2-yl)-[1,3]dioxolane (3.8 g,
16.5 mmol, 45.9%) was obtained as a yellow oil.
[0747] The resulting 2-(5-benzyl-furan-2-yl)-[1,3]dioxolane (3.8 g,
16.5 mmol) was suspended in a mixture solution of methanol (15 mL),
tetrahydrofuran (10 mL) and 2N hydrochloric acid (15 mL), and the
solution was stirred at room temperature for 2 hours. Ethyl acetate
and an aqueous solution of sodium bicarbonate were added to the
reaction solution, which was then partitioned, the organic layer
was washed with water twice and dried over anhydrous sodium
sulfate. The solvent was evaporated, and the title compound (2.5 g,
13 mmol) was obtained as a brown oil.
[0748] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.09 (2H,
s), 6.45-6.48 (1H, m), 7.20-7.35 (5H, m), 7.45 (1H, d, J=3.6 Hz),
9.46 (1H, s).
Preparation Example 40
2-(5-Benzyl-thiophen-2-yl)-[1,3]-dioxolane
[0749] The title compound (520 mg, 2.1 mmol, 41.4%) was obtained as
a colorless oil from benzyl bromide according to an analogous
method to Preparation Example 36.
[0750] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.84-3.90
(2H, m), 3.90-3.98 (2H, m), 4.08 (2H, s), 5.90 (1H, s), 6.75-6.78
(1H, m), 7.00 (1H, d, J=3.6 Hz), 7.18-7.32 (5H, m).
Preparation Example 41
5-Benzyl-thiophene-2-carbaldehyde
[0751] The title compound (containing impurity, 460 mg) was
obtained as a colorless oil from
2-(5-benzyl-thiophen-2-yl)-[1,3]dioxolane described in Preparation
Example 40 (520 mg, 2.1 mmol) according to an analogous method to
Preparation Example 37.
[0752] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.22 (2H,
s), 7.11 (1H, d, J=3.6 Hz), 7.20-7.34 (5H, m), 7.85 (1H, d, J=3.6
Hz), 9.79 (1H, s).
Preparation Example 42
C-(5-benzyl-thiophen-2-yl)-methylamine
[0753] The title compound (270 mg) was obtained as a brown oil from
5-benzyl-thiophene-2-carbaldehyde described in Preparation Example
41 (containing impurity, 460 mg, 2.27 mmol) according to an
analogous method to Preparation Example 38.
[0754] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.85 (2H,
brs), 3.75 (2H, s), 4.01 (2H, s), 6.65-6.72 (2H, m), 7.15-7.30 (5H,
m).
Preparation Example 43
2-(5-(3-Chloro-benzyl)-thiophen-2-yl)-[1,3]-dioxolane
[0755] n-Butyl lithium (2.6N hexane solution, 15.6 mL, 39 mmol) was
added dropwise to a solution of
2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (7.0 g, 30 mmol) in
tetrahydrofuran (40 mL) at from -75.degree. to -68.degree. C., and
the solution was stirred for 20 minutes. 3-Chlorobenzyl bromide
(4.3 mL, 33 mmol) was added dropwise to this reaction solution at
from -75.degree. C. to -68.degree. C., and the solution was stirred
for 20 minutes. The cold bath was removed, and the reaction
solution was gradually allowed to room temperature. Water and ethyl
acetate were added to the reaction solution, which was then
partitioned, the solvent was evaporated, the residue was purified
by NH silica gel column chromatography (hexane:ethyl acetate=20:1),
and the title compound (1.6 g, 5.7 mmol, 19.0%) was obtained as a
yellow oil.
[0756] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.82-4.00
(4H, m), 4.11 (2H, s), 5.91 (1H, s), 6.78-6.80 (1H, m), 7.01 (1H,
d, J=3.6 Hz), 7.19-7.36 (4H, m).
Preparation Example 44
5-(3-Chloro-benzyl)-thiophene-2-carbaldehyde
[0757] To a solution of
2-(5-(3-chloro-benzyl)-thiophen-2-yl)-[1,3]dioxolane described in
Preparation Example 43 (1.6 g, 5.7 mmol) in methanol (20 mL) was
added citric acid aqueous solution (20 mL), and the solution was
stirred at room temperature for 20 minutes. An aqueous solution of
sodium bicarbonate and ethyl acetate were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water twice and dried over anhydrous magnesium sulfate. The
solvent was evaporated, and the title compound (1.2 g, 5.08 mmol,
89.2%) was obtained as a yellow oil.
[0758] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.25 (2H,
s), 7.12-7.15 (1H, m), 7.24-7.40 (4H, m), 7.86 (1H, d, J=3.6 Hz),
9.80 (1H, s).
Preparation Example 45
C-(5-(3-Chloro-benzyl)-thiophen-2-yl)-methylamine
[0759] To a solution of 5-(3-chloro-benzyl)thiophene-2-carbaldehyde
described in Preparation Example 44 (1.2 g, 5.08 mmol) in 7N
ammonia/methanol (40 mL) was added Raney nickel (2 g), and the
solution was stirred at room temperature for 17 hours under
hydrogen atmosphere. The reaction solution was filtered through
Celite pad, the catalyst was removed, then, this filtrate was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (ethyl acetate, then ethyl acetate:methanol=5:1),
and the title compound (740 mg, 3.12 mmol, 61.4%) was obtained as a
brown oil.
[0760] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.94 (2H,
brs), 3.76 (2H, s), 4.06 (2H, s), 6.69-6.72 (2H, m), 7.18-7.34 (4H,
m).
Preparation Example 46
5-(4-Chloro-phenoxy)-furan-2-carbaldehyde
[0761] To a solution of 4-chlorophenol (4.4 g, 33.6 mmol) in
dimethylsulfoxide (30 mL) was added sodium hydride (1.34 g, 33.6
mmol, 60% in oil), and the solution was stirred at room temperature
for 10 minutes. 5-Nitrofuran-2-carbaldehyde (4.0 g, 28 mmol) was
added to this reaction solution, and the solution was stirred at
room temperature for 5 minutes. Water and ethyl acetate were added
to the reaction solution, which was then partitioned, and the
organic layer was washed with water 6 times. The solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (hexane, then hexane:ethyl acetate=10:1, then 4:1),
and the title compound (3.3 g, 14.9 mmol, 53.0%) was obtained as a
yellow oil.
[0762] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.89-5.93
(1H, m), 7.30-7.36 (2H, m), 7.50-7.60 (3H, m), 9.35-9.38 (1H,
m).
Preparation Example 47
C-(5-(4-Chloro-phenoxy)-furan-2-yl)-methylamine
[0763] The title compound (200 mg, 0.90 mmol, 8.7%) was obtained as
a brown oil from 5-(4-chloro-phenoxy)-furan-2-carbaldehyde
described in Preparation Example 46 (2.3 g, 10.3 mmol) according to
an analogous method to Preparation Example 38.
[0764] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.56 (2H,
s), 5.73 (1H, d, J=3.2 Hz), 6.18 (1H, d, J=3.2 Hz), 7.03-7.08 (2H,
m), 7.40-7.45 (2H, m).
Preparation Example 48
5-Phenoxy-furan-2-carbaldehyde
[0765] The title compound (2.3 g, 12.2 mmol, 43.5%) was obtained as
a light brown oil from phenol (3.2 g, 33.6 mmol) and
5-nitro-furan-2-carbaldehyde (4.0 g, 28 mmol) according to an
analogous method to Preparation Example 46.
[0766] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.85 (1H,
d, J=4.0 Hz), 7.25-7.33 (3H, m), 7.45-7.50 (2H, m), 7.57 (1H, d,
J=4.0 Hz), 9.34 (1H, s).
Preparation Example 49
C-(5-Phenoxy-furan-2-yl)-methylamine
[0767] The title compound (250 mg, 1.32 mmol, 24.9%) was obtained
as a yellow oil from 5-phenoxy-furan-2-carbaldehyde described in
Preparation Example 48 (1.0 g, 5.3 mmol) according to an analogous
method to Preparation Example 38.
[0768] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.98 (2H,
brs), 3.56 (2H, s), 5.67 (1H, d, J=3.2 Hz), 6.16-6.18 (1H, m),
6.99-7.04 (2H, m), 7.10-7.16 (1H, m), 7.34-7.40 (2H, m).
Preparation Example 50
5-(3-Fluoro-phenoxy)-furan-2-carbaldehyde
[0769] The title compound (1.5 g, 7.3 mmol, 52.1%) was obtained as
a yellow oil from 3-fluorophenol (1.9 g, 16.8 mmol) and
5-nitro-furan-2-carbaldehyde (2.0 g, 14 mmol) according to an
analogous method to Preparation Example 46.
[0770] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.97-6.00
(1H, m), 7.10-7.20 (2H, m), 7.24-7.30 (1H, m), 7.48-7.55 (1H, m),
7.59 (1H, d, J=3.6 Hz) 9.37 (1H, s).
Preparation Example 51
(5-(3-Fluoro-phenoxy)-furan-2-yl)-methanol
[0771] To a solution of 5-(3-fluoro-phenoxy)-furan-2-carbaldehyde
described in Preparation Example 50 (1.5 g, 7.3 mmol) in
tetrahydrofuran (20 mL) was added sodium borohydride (280 mg, 7.3
mmol), and the solution was stirred at room temperature for 1 hour.
Water and ethyl acetate were added to the reaction solution, which
was then partitioned, the organic layer was washed with water
twice, and the organic layer was filtered through a glass filter
lined with silica gel. The solvent was evaporated in vacuo, and the
title compound (1.5 g, 7.2 mmol) was obtained as a pale yellow
oil.
[0772] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.29 (2H,
d, J=6.0 Hz), 5.17 (1H, t, J=6.0 Hz), 5.78-5.82 (1H, m), 6.78-6.82
(1H, m), 6.85-6.95 (2H, m), 6.98-7.04 (1H, m), 7.40-7.46 (1H,
m).
Preparation Example 52
2-(5-(3-Fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane
[0773] n-Butyl lithium (2.44N hexane solution, 6.4 mL, 16.9 mmol)
was added dropwise to a solution of
2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (3.0 g, 13 mmol) in
tetrahydrofuran (30 mL) at from -75.degree. C. to -69.degree. C.,
and the solution was stirred for 17 minutes. 3-Fluorobenzyl bromide
(1.7 mL, 14.3 mmol) was added dropwise to this reaction solution at
from -75.degree. C. to -69.degree. C. After dropwise addition was
completed, the reaction solution was gradually allowed to room
temperature. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, the organic layer was
concentrated in vacuo, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=20:1), and the title
compound (478 mg, 1.81 mmol, 13.9%) was obtained as a brown
oil.
[0774] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.82-4.00
(4H, m), 4.13 (2H, s), 5.91 (1H, s), 6.78-6.80 (1H, m), 7.00-7.10
(4H, m), 7.30-7.37 (1H, m).
Preparation Example 53
5-(3-Fluoro-benzyl)-thiophene-2-carbaldehyde
[0775] An aqueous solution of saturated citric acid (20 mL) was
added to a solution of
2-(5-(3-fluoro-benzyl)thiophen-2-yl)-[1,3]dioxolane described in
Preparation Example 52 (670 mg, 2.53 mmol) in methanol (20 mL), and
the solution was stirred at room temperature for 30 minutes. Water
and ethyl acetate were added to the reaction solution, which was
then partitioned, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, and the
title compound (485 mg, 2.2 mmol, 87.0%) was obtained as a brown
oil.
[0776] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.25 (2H,
s), 7.03-7.18 (4H, m), 7.30-7.40 (1H, m), 7.86 (1H, dd, J=1.6, 3.6
Hz), 9.80 (1H, d, J=1.6 Hz).
Preparation Example 54
2-(5-(3-Chloro-benzyl)-furan-2-yl)-[1,3]dioxolane
[0777] The title compound (1.34 g, 5.07 mmol, 14.1%) was obtained
as a yellow oil from 2-furan-2-yl-[1,3]dioxolane (5.0 g, 36 mol)
and 3-chlorobenzyl bromide (5.2 mL, 39.6 mmol) according to an
analogous method to Preparation Example 36.
[0778] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.84-4.02
(6H, m), 5.76 (1H, s), 6.10-6.12 (1H, m), 6.41 (1H, d, J=3.2 Hz),
7.16-7.20 (1H, m), 7.26-7.36 (3H, m).
Preparation Example 55
5-(3-Chloro-benzyl)furan-2-carbaldehyde
[0779] The title compound (1.03 g, 4.68 mmol, 82.1%) was obtained
as a yellow oil from
2-(5-(3-chloro-benzyl)-furan-2-yl)-[1,3]dioxolane described in
Preparation Example 54 (1.34 g, 5.07 mmol) according to an
analogous method to Preparation Example 37.
[0780] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.11 (2H,
s), 6.48-6.51 (1H, m), 7.20-7.24 (1H, m), 7.28-7.37 (3H, m), 7.46
(1H, d, J=3.2 Hz), 9.46-9.49 (1H, m).
Preparation Example 56
C-(5-(3-Chloro-benzyl)-furan-2-yl)-methylamine
[0781] The title compound (690 mg, 3.12 mmol, 66.6%) was obtained
as a yellow oil from 5-(3-Chloro-benzyl)-furan-2-carbaldehyde
described in Preparation Example 55 (1.03 g, 4.68 mmol) according
to an analogous method to Preparation Example 38.
[0782] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.90 (2H,
brs), 3.57 (2H, s), 3.92 (2H, s), 6.01 (1H, d, J=2.8 Hz), 6.07 (1H,
d, J=2.8 Hz), 7.16-7.20 (1H, m), 7.24-7.34 (3H, m).
Preparation Example 57
1-Benzyl-1H-pyrrole-3-carbaldehyde
[0783] Benzylamine (540 mg, 5.00 mmol) and acetic acid (10 mL) were
added to 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (1 g, 6.25
mmol), and the solution was stirred for 20 minutes at 90.degree. C.
Water and ethyl acetate were added to the reaction solution, which
was then partitioned, the organic layer was washed with an aqueous
solution 2N sodium hydroxide once and with water twice, filtered
with a glass filter lined with silica gel, the filtrate was
evaporated in vacuo, and title compound (800 mg, 4.3 mmol, 68.8%)
was obtained as a brown oil.
[0784] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.18 (2H,
s), 6.46 (1H, dd, J=2.0, 2.0 Hz), 6.97 (1H, dd, J=2.0, 2.0 Hz),
7.24-7.37 (5H, m), 7.71 (1H, dd, J=2.0, 2.0 Hz), 9.63 (1H, s).
Preparation Example 58
1-(3-Fluoro-benzyl)-1H-pyrrole-3-carbaldehyde
[0785] The title compound (2.33 g, 11.4 mmol, 71.7%) was obtained
as an oil from 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (2.6 g,
16 mmol) and 3-fluorobenzylamine (2.0 g, 16 mmol) according to an
analogous method to Preparation Example 57.
[0786] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.20 (2H,
s), 6.44-6.48 (1H, m), 6.98-7.02 (1H, m), 7.07-7.17 (3H, m),
7.36-7.42 (1H, m), 7.74 (1H, d, J=1.6 Hz), 9.63 (1H, s).
Preparation Example 59
C-(1-(3-Fluoro-benzyl)-1H-pyrrol-3-yl)-methylamine
[0787] 7N Ammonia/methanol (40 mL) and Raney nickel(2 g) were added
to 1-(3-fluoro-benzyl)-1H-pyrrole-3-carbaldehyde described in
Preparation Example 58 (1.0 g, 4.9 mmol), and the solution was
stirred for 18 hours under hydrogen atmosphere at room temperature.
The catalyst was removed by filtering through Celite pad, then, NH
silica gel was added to the filtrate, the solvent was evaporated in
vacuo for adsorption, purification by NH silica gel column
chromatography (hexane:ethyl acetate=2:1, then 1:1, then ethyl
acetate) was carried out, and the title compound (530 mg, 2.5 mmol,
53.0%) was obtained as a brown oil.
[0788] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.50 (2H,
s), 5.01 (2H, s), 5.95 (1H, d, J=2.0 Hz), 6.64 (1H, d, J=1.2 Hz),
6.69-6.74 (1H, m), 6.92-7.10 (3H, m), 7.32-7.38 (1H, m).
Preparation Example 60
1-Benzo[1,3]-dioxol-5-ylmethyl-1H-pyrrole-3-carbaldehyde
[0789] The title compound (2.0 g, 8.7 mmol, 69.8%) was obtained as
a brown oil from 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (2.0
g, 12.5 mmol) and C-benzo[1,3]dioxol-5-ylmethylamine) (1.9 g, 12.5
mmol) according to an analogous method to Preparation Example
57.
[0790] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.04 (2H,
s), 5.97 (2H, s), 6.42-6.45 (1H, m), 6.80-7.00 (4H, m), 7.69-7.72
(1H, m), 9.61 (1H, s).
Preparation Example 61
C-(1-benzo[1,3]dioxol-5-ylmethyl-1H-pyrrol-3-yl)-methylamine
[0791] The title compound (1.5 g, 6.5 mmol, 74.7%) was obtained as
a light green oil from
1-benzo[1,3]dioxol-5-ylmethyl-1H-pyrrole-3-carbaldehyde described
in Preparation Example 60 (2.0 g, 8.7 mmol) according to an
analogous method to Preparation Example 59.
[0792] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.37 (2H,
brs), 3.48 (2H, brs), 4.87 (2H, s), 5.90 (1H, s), 5.95 (2H, s),
6.60 (1H, s), 6.66-6.72 (2H, m), 6.75 (1H, s), 6.83 (1H, d, J=7.6
Hz).
Preparation Example 62
1-Phenethyl-1H-pyrrol-3-carbaldehyde
[0793] The title compound (840 mg, 4.2 mmol, 84%) was obtained as a
brown oil from 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (1.0 g,
6.25 mmol) and phenethyl amine (600 mg, 5.0 mmol) according to an
analogous method to Preparation Example 57.
[0794] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.03 (2H,
t, J=7.2 Hz), 4.19 (2H, t, J=7.2 Hz), 6.38-6.42 (1H, m), 6.37-6.82
(1H, m), 7.15-7.30 (5H, m), 7.54-7.60 (1H, m), 9.57 (1H, s).
Preparation Example 63
1-Benzyloxy-1H-pyrrole-3-carbaldehyde
[0795] The title compound (500 mg, 2.5 mmol, 13.1%) was obtained as
a yellow oil from 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (3.0
g, 19 mmol) and O-benzyl hydroxylamine (2.3 g, 19 mmol) according
to an analogous method to Preparation Example 57.
[0796] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.24 (2H,
s), 6.35-6.48 (1H, m), 7.05-7.08 (1H, m), 7.28-7.43 (5H, m),
7.74-7.77 (1H, m), 9.55 (1H, s).
Preparation Example 64
(1-Benzyloxy-1H-pyrrol-3-yl)-methanol
[0797] To a solution of 1-benzyloxy-1H-pyrrole-3-carbaldehyde
described in Preparation Example 63 (500 mg, 2.5 mmol) in
tetrahydrofuran (10 mL) was added lithium aluminum hydride (75 mg,
1.97 mmol), and the solution was stirred at room temperature for 10
minutes. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, silica gel was added to the
organic layer, the solvent was evaporated in vacuo for adsorption,
purification by silica gel column chromatography (hexane:ethyl
acetate=2:1) was carried out, and the title compound (168 mg, 0.828
mmol, 33.1%) was obtained as a colorless oil.
[0798] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.22 (2H,
d, J=5.6 Hz), 4.60 (1H, t, J=5.6 Hz), 5.10 (2H, s), 5.78-5.81 (1H,
m), 6.75-6.78 (1H, m), 6.78-6.81 (1H, m), 7.37-7.42 (5H, m).
Preparation Example 65
(5-[1,3]Dioxolan-2-yl-thiophen-2-yl)-(5-methyl-thiophen-2-yl)-methanol
[0799] n-Butyl lithium (2.44N hexane solution, 7.4 mL, 17.9 mmol)
was added dropwise to a solution of
2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (4.0 g, 17 mmol) in
tetrahydrofuran (50 mL) at from -75.degree. C. to -70.degree. C.,
and the solution was stirred for 10 minutes.
5-Methylthiophene-2-carbaldehyde (2.4 g, 18.7 mmol) was further
added dropwise to the reaction solution at from -75.degree. C. to
-70.degree. C. After dropwise addition was completed, the reaction
solution was gradually allowed to room temperature. Water and ethyl
acetate were added to the reaction mixture, which was then
partitioned, and the solvent was evaporated. The residue was
purified by NH silica gel column chromatography (hexane:ethyl
acetate=4:1, then 2:1), and the title compound (2.0 g, 7.09 mmol,
41.7%) was obtained as a brown oil.
[0800] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.38 (3H,
s), 3.88-4.04 (4H, m), 5.95 (1H, s), 6.04-6.08 (1H, m), 6.43-6.46
(1H, m), 6.60-6.63 (1H, m), 6.75 (1H, d, J=3.6 Hz), 6.83 (1H, d,
J=3.6 Hz), 7.02 (1H, d, J=3.6 Hz).
Preparation Example 66
5-(5-Methyl-thiophen-2-ylmethyl)-thiophene-2-carbaldehyde
[0801] Sodium iodide (6.4 g, 42.6 mmol) and trimethylsilyl chloride
(4.6 g, 42.6 mmol) were suspended in acetonitrile (100 mL) on an
ice bath, and
(5-[1,3]dioxolane-2-ylthiophen-2-yl)-(5-methyl-thiophen-2-yl)-methanol
described in Preparation Example 65 (2.0 g, 7.09 mmol) was added
dropwise. After dropwise addition was completed, the reaction
solution was gradually allowed to room temperature. A solution
obtained by dissolving an aqueous solution of 2N sodium hydroxide
(10.6 mL) and sodium thiosulfate pentahydrate (530 mg, 2.13 mmol)
in water (5 mL) was added to the reaction solution that had been
cooled on an ice bath, and the solution was stirred. Water and
ethyl acetate were added to the reaction solution, which was then
partitioned, and the organic layer was concentrated in vacuo. The
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=20:1), and the title compound (790 mg, 3.56
mmol, 50.2%) was obtained as a brown oil.
[0802] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.38 (3H,
s), 4.38 (2H, s), 6.62-6.67 (1H, m), 6.76-6.80 (1H, m), 7.12-7.16
(1H, m), 7.85-7.90 (1H, m), 9.83 (1H, s).
Preparation Example 67
(5-(5-Methyl-thiophen-2-ylmethyl)-thiophen-2-yl)-methanol
[0803] To a solution of
5-(5-methyl-thiophen-2-ylmethyl)-thiophene-2-carbaldehyde described
in Preparation Example 66 (790 mg, 3.56 mmol) in tetrahydrofuran (5
mL) was added lithium aluminum hydride (41 mg, 1.06 mmol), and the
mixture was stirred at room temperature for 10 minutes. Water and
ethyl acetate were added to the reaction mixture, which was then
partitioned, the organic layer was filtered with a glass filter
lined with silica gel, the filtrate was evaporated in vacuo, and
the title compound (640 mg, 2.86 mmol, 80.3%) was obtained as a
light brown oil.
[0804] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.36 (3H,
s), 4.20 (2H, s), 4.52 (2H, d, J=6.0 Hz), 5.33 (1H, t, J=6.0 Hz),
6.56-6.63 (1H, m), 6.66-6.76 (3H, m).
Preparation Example 68
(5-[1,3]-Dioxolan-2-yl-thiophen-2-yl)-(5-methyl-furan-2-yl)-methanol
[0805] The title compound (4.2 g, 16 mmol) was obtained as a
reddish brown oil from 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane
(4.0 g, 17 mmol) and 5-methyl-furan-2-carbaldehyde (1.9 g, 17 mmol)
according to an analogous method to Preparation Examples 65.
[0806] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.22 (3H,
s), 3.89-3.96 (2H, m), 3.98-4.06 (2H, m), 5.83 (1H, d, J=4.8 Hz),
5.96-6.02 (2H, m), 6.11-6.13 (1H, m), 6.22-6.24 (1H, m), 6.82-6.84
(1H, m), 7.02-7.05 (1H, m).
Preparation Example 69
5-(5-Methyl-furan-2-ylmethyl)-thiophene-2-carbaldehyde
[0807] The title compound (400 mg, 1.9 mmol, 11.8%) was obtained as
a brown oil from
5-[1,3]dioxolan-2-yl-thiophen-2-yl)-(5-methyl-furan-2-yl)-methanol
described in Preparation Example 68 (4.2 g, 16 mmol) according to
an analogous method to Preparation Example 66.
[0808] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.21 (3H,
s), 4.24 (2H, s), 5.98-6.02 (1H, m), 6.12-6.14 (1H, m), 7.13 (1H,
d, J=3.6 Hz), 7.89 (1H, d, J=3.6 Hz), 9.82 (1H, s).
Preparation Example 70
(5-(5-Methyl-furan-2-ylmethyl)-thiophen-2-yl)-methanol
[0809] The title compound (210 mg, 1.0 mmol, 52.6%) was obtained as
a brown oil from
5-(5-methyl-furan-2-ylmethyl)-thiophene-2-carbaldehyde described in
Preparation Example 69 (400 mg, 1.9 mmol) according to an analogous
method to Preparation Example 67.
[0810] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.20 (3H,
s), 4.05 (2H, s), 4.53 (2H, d, J=5.6 Hz), 5.33 (1H, t, J=5.6 Hz),
5.94-5.98 (1H, m), 6.02 (1H, d, J=2.8 Hz), 6.70-6.77 (2H, m).
Preparation Example 71
Benzofuran-2-yl-(5-[1,3]-dioxolan-2-yl-thiophen-2-yl)-methanol
[0811] The title compound (7.2 g, 23.8 mmol, 91.5%) was obtained as
a yellow oil from 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane (6.0 g,
26 mmol) and benzofuran-2-carbaldehyde (3.8 g, 26 mmol) according
to an analogous method to Preparation Example 65.
[0812] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.88-4.06
(4H, m), 5.98 (1H, s), 6.08-6.11 (1H, m), 6.59 (1H, d, J=5.2 Hz),
6.78 (1H, s), 6.95 (1H, d, 3.6 Hz), 7.07 (1H, d, J=3.6 Hz),
7.20-7.30 (2H, m), 7.52 (1H, d, J=8.0 Hz), 7.61 (1H, d, J=7.2
Hz).
Preparation Example 72
(5-Benzofuran-2-ylmethyl-thiophene)-methanol
[0813] (Benzofuran-2-ylmethyl)-thiophene-2-carbaldehyde (1.3 g, 5.4
mmol, 54.5%) was obtained as a brown oil from
benzofuran-2-yl-(5-[1,3]dioxolan-2-yl-thiophen-2-yl)-methanol
described in Preparation Example 71 (3.0 g, 9.9 mmol) according to
an analogous method to Preparation Example 66, Using this oil (1.2
g) according to an analogous method to Preparation Example 67, the
title compound (900 mg, 3.7 mmol, 68.5%) was obtained as a brown
oil.
[0814] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.32 (2H,
s), 4.55 (2H, d, J=5.6 Hz), 5.36 (1H, t, J=5.6 Hz), 6.67 (1H, s),
6.80 (1H, d, J=3.2 Hz), 6.83 (1H, d, J=3.2 Hz), 7.17-7.27 (2H, m),
7.50 (1H, d, J=8.0 Hz), 7.56 (1H, d, J=7.2 Hz).
Preparation Example 73
1-Phenyl-1H-pyrrole-3-carbaldehyde
[0815] The title compound (1.2, 7.0 mmol, 70%) was obtained as a
brown oil from 2,5-dimethoxy-tetrahydrofuran-3-carbaldehyde (2.0 g,
12.5 mmol) and aniline (930 mg, 10 mmol) according to an analogous
method to Preparation Example 57.
[0816] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.67-6.70
(1H, m), 7.32-7.39 (1H, m), 7.48-7.55 (3H, m), 7.65-7.70 (2H, m),
8.22-8.26 (1H, m), 9.77 (1H, s).
Preparation Example 74
C-(1-Phenyl-1H-pyrrol-3-yl)-methylamine
[0817] The title compound (580 mg, 3.37 mmol, 48.1%) was obtained
as a light green oil from 1-phenyl-1H-pyrrole-3-carbaldehyde
described in Preparation Example 73 (1.2 g, 7.0 mmol) according to
an analogous method to Preparation Example 59.
[0818] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.58 (2H,
s), 6.19-6.22 (1H, m), 7.16-7.22 (2H, m), 7.24-7.28 (1H, m),
7.38-7.44 (2H, m), 7.47-7.52 (2H, m).
Preparation Example 75
(3-Phenoxy-benzyl)-carbamic acid phenyl ester
[0819] To a solution of phenyl chloroformate (0.29 mL, 2.3 mmol) in
tetrahydrofuran (10 mL) were added 3-phenoxybenzylamine described
in Preparation Example 4 (0.5 g, 2.5 mmol) and triethylamine (0.35
mL, 2.5 mmol) dropwise on an ice bath, and then, the solution was
stirred at room temperature for 4 hours. The reaction solution was
poured into brine, the solution was extracted with ethyl acetate
and concentrated, and the title compound (0.7 g, 2.2 mmol, 88%) was
obtained.
[0820] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.24 (2H,
d, J=6.0 Hz), 6.87-7.49 (14H, m), 8.29 (1H, t, J=6.0 Hz).
Preparation Example 76
5-(2,4-Difluoro-phenoxy)-furan-2-carbaldehyde
[0821] To a solution of 2,4-difluorophenol (6.54 mL, 68.0 mmol) in
dimethylsulfoxide (70 mL) was sodium hydride (4534 mg, 68.0 mmol,
60% in oil), which was then stirred for 40 minutes.
5-Nitro-2-furaldehyde (8000 mg, 56.7 mmol) was added to the
reaction solution, and the solution was stirred at room temperature
for 2 hours. Water was added to the reaction mixture, which was
then extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over anhydrous magnesium sulfate, and
then, concentrated in vacuo. The resulting residue was purified by
silica gel chromatography (hexane:ethyl acetate), and the title
compound (4134 mg, 18.44 mmol, 33%) was obtained.
[0822] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.54 (1H, d,
J=3.6 Hz), 6.90-7.03 (2H, m), 7.21 (1H, d, J=3.6 Hz), 7.24-7.31
(1H, m), 9.40 (1H, s).
Preparation Example 77
C-(5-(2,4-Difluoro-phenoxy)-furan-2-yl)-methylamine
[0823] To a solution of
5-(2,4-difluoro-phenoxy)-furan-2-carbaldehyde (2060 mg, 9.19 mmol)
in 7N ammonia/methanol solution (100 mL) was added Raney nickel
(5.9 g), and the mixture was stirred for 24 hours at room
temperature under hydrogen atmosphere. The reaction mixture was
filtered through Celite pad, and the filtrate was concentrated in
vacuo. The residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate), and the title compound (1814
mg, 88.06 mmol, 87.7%) was obtained as a yellow oil.
[0824] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.70 (2H,
brs), 3.55 (2H, s), 5.55 (1H, d, J=3.2 Hz), 6.13 (1H, d, J=3.2 Hz),
7.05-7.22 (1H, m), 7.21-7.28 (1H, m), 7.43-7.50 (1H, m).
Preparation Example 78
5-(2,5-Difluoro-phenoxy)-furan-2-carbaldehyde
[0825] To a solution of 2,5-difluorophenol (3360 mg, 25.83 mmol) in
N,N-dimethylformamide (60 mL) was sodium hydride (1032 mg, 25.83
mmol, 60% in oil), which was then stirred for 1 hour.
5-Bromo-2-furaldehyde (3826 mg, 21.52 mmol) was added to the
reaction solution, and the solution was stirred at 60.degree. C.
for 12 hours. Water was added to the reaction mixture, which was
then extracted with ethyl acetate. The organic layer was washed
with water and brine, dried over anhydrous magnesium sulfate, and
then, concentrated in vacuo. The resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate), and the title
compound (1104 mg, 4.92 mmol, 22.9%) was obtained.
[0826] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.67 (1H, d,
J=3.6 Hz), 6.93-7.04 (2H, m), 7.15-7.22 (1H, m), 7.24 (1H, d, J=3.6
Hz), 9.43 (1H, s).
Preparation Example 79
C-(5-(2,5-Difluoro-phenoxy)-furan-2-yl)-methylamine
[0827] The title compound (2353 mg, 10.50 mmol, 97%) was obtained
from 5-(2,5-difluoro-phenoxy)-furan-2-carbaldehyde (2402 mg, 11.65
mmol) according to an analogous method to Preparation Example
77.
[0828] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.72 (2H,
brs), 3.56 (2H, s), 5.71 (1H, d, J=3.2 Hz), 6.17 (1H, d, J=3.2 Hz),
7.01-7.12 (2H, m), 7.41-7.50 (1H, m).
Preparation Example 80
2-Benzyloxy-thiophene
[0829] To a solution of benzyl alcohol (3.45 mL, 33.3 mmol) in
1,2-dimethoxyethane (80 mL) was added n-butyl lithium (2.6M hexane
solution, 13.5 mL, 33.3 mmol) dropwise, which was then stirred for
10 minutes. Copper(I) chloride (5210 mg, 49.45 mmol) was added
thereto, followed by stirring for 10 minutes on an ice bath, then,
it was stirred for 2.5 hours at room temperature. 2-Iodothiophene
(4995 mg, 23.78 mmol) and pyridine 320 mL were further added, and
the solution was stirred for 13 hours under reflux. Ethyl acetate
was added to the reaction mixture, which was sequentially washed
with 1N hydrochloric acid, an aqueous solution of sodium hydrogen
sulfate and brine, dried over anhydrous magnesium sulfate, and
then, concentrated in vacuo. The resulting residue was purified by
silica gel chromatography (hexane-ethyl acetate), and the title
compound (420 mg, 2.2 .mu.mol, 9.5%) was obtained.
[0830] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.08 (2H,
s), 6.28 (1H, dd, J=1.6, 4.0 Hz), 6.57 (1H, dd, J=1.6, 5.6 Hz),
6.71 (1H, dd, J=4.0, 5.6 Hz), 7.30-7.47 (5H, m).
Preparation Example 81
5-Benzyloxy-thiophene-2-carbonitrile
[0831] To a solution of 2-benzyloxy-thiophene (184 mg, 0.967 mmol)
in diethyl ether (4 mL) was added n-butyl lithium (2.47M hexane
solution, 0.47 mL, 1.16 mmol) at -78.degree. C. under nitrogen
atmosphere, then, the solution was stirred for 1.5 hours on an ice
bath. The solution was cooled again to -78.degree. C.,
N,N-dimethylformamide (487 .mu.l, 4.84 mmol) was added, and the
solution was stirred for 45 minutes while warming to room
temperature. An aqueous solution of saturated ammonium chloride was
added to the reaction mixture, which was then extracted with ethyl
acetate. The organic layer was washed with brine, dried over
anhydrous magnesium sulfate, then, filtered with silica gel, the
filtrate was concentrated in vacuo, and
5-benzyloxy-thiophene-2-carbaldehyde (171 mg) was obtained.
[0832] The resulting 5-benzyloxy-thiophene-2-carbaldehyde (171 mg)
was dissolved in N,N-dimethylformamide (4 mL), pyridine (82 .mu.l,
1.02 mmol) and hydroxylamine hydrochloride (65 mg, 0.94 mmol) were
added thereto, followed by stirring for 30 minutes at 60.degree.
C., then, cooled on an ice bath. 1,1'-Carbonyldiimidazole (635 mg,
3.92 mmol) was added, the solution was warmed again to 60.degree.
C. and stirred for 35 minutes, triethylamine (272 .mu.l, 1.96 mmol)
was added, and the solution was further stirred for 30 minutes. The
reaction mixture was cooled to room temperature, water was added,
and the solution was extracted with ethyl acetate. The organic
layer was sequentially washed with an aqueous solution of oxalic
acid, an aqueous solution of saturated sodium bicarbonate and
brine, dried over anhydrous sodium sulfate, and then, concentrated
in vacuo. The resulting residue was purified by silica gel
chromatography (hexane-ethyl acetate), and the title compound (30
mg, 0.14 mmol, 14%) was obtained.
[0833] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.15 (2H,
s), 6.28 (1H, d, J=4.0 Hz), 7.32 (1H, d, J=4.0 Hz), 7.38-7.48 (5H,
m).
Preparation Example 82
2-(5-(3-Fluoro-benzyl)-furan-2-yl)-[1,3]-dioxolane
[0834] n-Butyl lithium (2.66M hexane solution, 25.5 mL, 67.88 mmol)
was added dropwise to a solution of 2-(1,3-dioxolan-2-yl)furan
(8272 mg, 59.03 mmol) in tetrahydrofuran (160 mL) that had been
cooled to -78.degree. C. solution under nitrogen atmosphere, which
was then stirred for 10 minutes. To this solution was added a
solution of 3-fluorobenzyl bromide (14.50 g, 76.73 mmol) in
tetrahydrofuran (60 mL) dropwise, which was then stirred for 1 hour
at -78.degree. C., and for 1.25 hours at room temperature. An
aqueous solution of saturated ammonium chloride was added to the
reaction mixture, which was extracted with diethyl ether. The
organic layer was washed with brine, dried over anhydrous sodium
sulfate, and then, concentrated in vacuo. The obtained residue was
purified by silica gel chromatography (hexane-ethyl acetate), and a
mixture of the title compound and 2-(1,3-dioxolane-2-yl)furan (8033
mg), which is the starting material, was obtained.
Preparation Example 83
5-(3-Fluoro-benzyl)-furan-2-carbaldehyde
[0835] To a solution of a mixture of
2-(5-(3-fluoro-benzyl)-furan-2-yl)-[1,3]dioxolane and
2-(1,3-dioxolan-2-yl)furan (8033 mg) in methanol (80 mL) was added
an aqueous solution of oxalic acid (22 g, 115 mmol) (80 mL), and
the solution was stirred at room temperature for 1 hour. Water was
added to the reaction mixture, which extracted with diethyl ether,
the organic layer was sequentially washed with an aqueous solution
of saturated sodium bicarbonate, water and brine, dried over
anhydrous sodium sulfate, and then, concentrated in vacuo. The
resulting residue was purified by silica gel chromatography
(hexane-ethyl acetate), and the title compound (4084 mg, 20.0 mmol,
34%) was obtained.
[0836] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.07 (2H,
s), 6.23 (1H, d, J=4.0 Hz), 6.90-7.10 (3H, m), 7.18 (1H, d, J=4.0
Hz), 7.25-7.37 (1H, m), 9.56 (1H, s).
Preparation Example 84
C-(5-(3-Fluoro-benzyl)-furan-2-yl)-methylamine
[0837] The title compound (4104 mg, 20.0 mmol, 100%) was obtained
from 5-(3-fluoro-benzyl)-furan-2-carbaldehyde (4084 mg, 20.0 mmol)
according to an analogous method to Preparation Example 77.
[0838] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.60 (2H,
brs), 3.31 (2H, s), 3.93 (2H, s), 5.97-6.11 (2H, m), 6.82-7.15 (3H,
m), 7.20-7.41 (1H, m).
Preparation Example 85
2-(3-[1,2,3] Triazol-2-yl-propyl)-isoindol-1,3-dione
[0839] To a solution of 1H-1,2,3-triazole (2000 mg, 28.96 mmol) in
N,N-dimethylformamide (60 mL) was added sodium hydride (1159 mg,
28.96 mmol, 60% in oil), which was stirred for 30 minutes.
N-(3-Bromopropyl)phthalimide (7057 mg, 26.32 mmol) and potassium
iodide (431 mg, 2.63 mmol) were added thereto, and the solution was
stirred for 3 hours at 70.degree.. Water was added to the reaction
mixture, which was then extracted with ethyl acetate. The organic
layer was washed with water and brine, dried over anhydrous
magnesium sulfate, and then, concentrated in vacuo. The resulting
residue was purified by silica gel chromatography
(dichloromethane-ethyl acetate), and the title compound (3526 mg,
13.75 mmol, 47%) was obtained.
[0840] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.19-2.28
(2H, m), 3.65 (2H, t, J=6.8 Hz), 4.51 (2H, t, J=6.8 Hz), 7.74 (2H,
s), 7.80-7.89 (4H, m).
Preparation Example 86
3-[1,2,3]Triazol-2-yl-propyl amine
[0841] To a mixture solution of
2-(3-[1,2,3]triazol-2-yl-propyl)-isoindol-1,3-dione (1782 mg, 6.95
mmol) in methanol-tetrahydrofuran (5:4, 27 mL) was added hydrazine
monohydrate (371 .mu.l, 7.65 mmol), and the solution was stirred
for 5 days at room temperature. Methanol (8 mL) was added thereto,
followed by further stirring for 3.25 hours under reflux. The
reaction mixture was filtered, and the filtrate was concentrated.
The resulting residue was dissolved in tetrahydrofuran, adsorbed
onto NH silica gel, purified by NH silica gel chromatography (ethyl
acetate-methanol), and the title compound (491 mg, 1.36 mmol,
19.6%) was obtained.
[0842] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.85-1.93
(2H, m), 2.46-2.51 (2H, m), 4.42-4.52 (2H, m), 7.75 (2H, s).
Preparation Example 87
3-Benzyl amino-benzonitrile
[0843] 3-Bromo-benzonitrile (500 mg, 2.75 mmol), benzylamine (360
.mu.l, 3.30 mmol), 2,2-bis(diphenylphosphino)-1,1'-binaphthyl (8.6
mg, 14 mmol), tris(dibenzylideneacetone)dipalladium(0) (19 mg, 21
mmol) and sodium tert-butoxide (370 mg, 3.85 mmol) were suspended
in toluene (10 mL), and the mixture was stirred at 80.degree. C.
for 22 hours under nitrogen atmosphere. The reaction mixture was
filtered through Celite pad, then, the filtrate was evaporated in
vacuo, the residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=15:1), and the title compound
(331 mg, 1.59 mmol, 58%) was obtained as a pale yellow oil.
[0844] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.33 (2H,
m), 4.34 (1H, s), 6.79-6.83 (2H, m), 6.97 (1H, dt, J=1.2, 7.7 Hz),
7.22 (1H, t, J=8.1 Hz), 7.29-7.39 (5H, m).
Preparation Example 88
4-Phenylamino-benzonitrile
[0845] The title compound (460 mg, 2.37 mmol, 86%) was obtained as
a white solid from 4-bromo-benzonitrile (500 mg, 2.75 mmol) and
phenylamine (300 .mu.l, 3.30 mmol) according to an analogous method
to Preparation Example 87.
[0846] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 6.04 (1H,
s), 6.97 (2H, d, J=8.8 Hz), 7.12 (1H, t, J=7.3 Hz), 7.17 (2H, d,
J=7.7 Hz), 7.36 (2H, t, J=7.5 Hz), 7.48 (2H, d, J=8.8 Hz).
Preparation Example 89
4-Benzylamino-benzonitrile
[0847] The title compound (472 mg, 2.27 mmol, 83%) was obtained as
a pale yellow solid from 4-bromo-benzonitrile (500 mg, 2.75 mmol)
and benzylamine (360 .mu.l, 3.30 mmol) according to an analogous
method to Preparation Example 87.
[0848] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 4.38 (2H,
d, J=5.5 Hz), 4.58 (1H, s), 6.59 (2H, d, J=8.8 Hz), 7.29-7.39 (5H,
m), 7.42 (2H, d, J=8.8 Hz).
Preparation Example 90
2-(3-Bromo-phenyl)-[1,3]dioxolane
[0849] 3-Bromobenzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol
(6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186
mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution
was stirred under reflux for 4 hours. An aqueous solution of
saturated sodium bicarbonate was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine, and the organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=20:1), and the title compound
(4.79 g, 20.9 mmol, 97%) was obtained as a colorless oil.
[0850] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.02-4.05
(2H, m), 4.07-4.13 (2H, m), 5.79 (1H, s), 7.23-7.27 (1H, m), 7.40
(1H, d, J=7.7 Hz), 7.49 (1H, dt, J=1.1, 7.1 Hz), 7.64 (1H, s).
Preparation Example 91
2-(3-Phenylsulfanyl-phenyl)-[1,3]-dioxolane
[0851] 2-(3-Bromo-phenyl)-[1,3]dioxolane described in Preparation
Example 90 (515 mg, 2.25 mmol) was dissolved in tetrahydrofuran (10
mL) under nitrogen atmosphere, n-butyl lithium (2.47M hexane
solution, 1.64 mL, 4.05 mmol) was added at -78.degree. C., the
solution was stirred for 15 minutes, then, diphenyldisulphide (540
mg, 2.48 mmol) was added thereto, followed by stirring for 3 hours.
The reaction solution was cooled to 0.degree. C., water was added,
the solution was extracted with ethyl acetate, the organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=20:1), and
the title compound (402 mg, 1.56 mmol, 69%) was obtained as a
colorless oil.
[0852] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.01-4.06
(2H, m), 4.09-4.14 (2H, m), 5.76 (1H, s), 7.22-7.39 (8H, m), 7.48
(1H, s).
Preparation Example 92
3-Phenylsulfanyl-benzaldehyde
[0853] 2-(3-Phenylsulfanyl-phenyl)-[1,3]dioxolane described in
Preparation Example 91 (396 mg, 1.53 mmol) was dissolved in a
mixture solution of ethanol (5 mL), water (5 mL), tetrahydrofuran
(5 mL) and sulfuric acid (1 mL), and the solution was stirred for
2.5 hours under reflux. The reaction solution was cooled to
0.degree. C., an aqueous solution of saturated sodium bicarbonate
was added thereto, the solution was extracted with ethyl acetate,
the organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=20:1), and the title compound (323 mg, 1.5 .mu.mol, 98%)
was obtained as a colorless oil.
[0854] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.31-7.39
(3H, m), 7.41-7.50 (3H, m), 7.52 (1H, d, J=7.9 Hz), 7.71 (1H, d,
J=7.3 Hz), 7.76 (1H, s), 9.94 (1H, s).
Preparation Example 93
(3-Phenylsulfanyl-phenyl)-methanol
[0855] 3-Phenylsulfanyl-benzaldehyde described in Preparation
Example 92 (321 mg, 1.49 mmol) was dissolved in ethanol (6 mL),
sodium borohydride (113 mg, 2.98 mmol) was added thereto at
0.degree. C., followed by stirring at room temperature for 3 hours.
Water was added to the reaction solution, which was then extracted
with ethyl acetate, the organic layer was washed with brine and
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=5:1), and the title compound
(220 mg, 1.02 mmol, 68%) was obtained as a colorless oil.
[0856] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.73 (2H,
s), 4.66 (1H, s), 7.18-7.37 (9H, m).
Preparation Example 94
2-(3-Phenylsulfanyl-benzyl)-isoindol-1,3-dione
[0857] (3-Phenylsulfanyl-phenyl)-methanol described in Preparation
Example 93 (212 mg, 0.980 mmol), phthalimide (144 mg, 0.980 mmol),
diethylazodicarboxylate (170 .mu.l, 1.08 mmol) and
triphenylphosphine (308 mg, 1.18 mmol) were dissolved in
tetrahydrofuran (4 mL), and the solution was stirred overnight at
room temperature. Water was added to the reaction solution, which
was then extracted with ethyl acetate, the organic layer was washed
with brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated in vacuo, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate=10:1), and the title
compound (124 mg, 0.359 mmol, 37%) was obtained as a solid.
[0858] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.80 (2H,
s), 7.17-7.36 (9H, m), 7.73 (2H, dd, J=2.9, 5.3 Hz), 7.86 (2H, dd,
J=2.9, 5.3 Hz).
Preparation Example 95
3-Phenylsulfanyl-benzylamine
[0859] 2-(3-Phenylsulfanyl-benzyl)-isoindole-1,3-dione described in
Preparation Example 94 (123 mg, 0.356 mmol) was dissolved in
ethanol (3 mL), hydrazine monohydrate (518 .mu.l, 10.7 mmol) was
added at 0.degree. C., and the solution was stirred under reflux
for 2 hours. Water was added to the reaction solution at 0.degree.
C., which was then extracted with ethyl acetate, the organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by NH
silica gel column chromatography (ethyl acetate), and the title
compound (75 mg, 0.35 mmol, 98%) was obtained as a colorless
oil.
[0860] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.83 (2H,
s), 7.19-7.36 (9H, m).
Preparation Example 96
2-(4-Bromo-phenyl)-[1,3]dioxolane
[0861] 4-Bromo-benzaldehyde (4.00 g, 21.6 mmol), ethane-1,2-diol
(6.03 mL, 108 mmol) and toluene-4-sulfonic acid monohydrate (186
mg, 1.08 mmol) were dissolved in toluene (80 mL), and the solution
was stirred under reflux for 4 hours. An aqueous solution of
saturated sodium bicarbonate was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine, and the organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=20:1), and the title compound
(4.66 g, 20.3 mmol, 94%) was obtained as a colorless oil.
[0862] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.01-4.05
(2H, m), 4.07-4.13 (2H, m), 5.77 (1H, s), 7.35 (2H, d, J=8.2 Hz),
7.51 (2H, d, J=8.4 Hz).
Preparation Example 97
2-(4-Benzylsulfanyl-phenyl)-[1,3]-dioxolane
[0863] The title compound (568 mg, 2.09 mmol, 48%) was obtained as
a solid from 2-(4-bromo-phenyl)-[1,3]dioxolane described in
Preparation Example 96 (1.00 g, 4.37 mmol) and benzyl disulphide
(1.18 g, 4.81 mmol) according to an analogous method to Preparation
Example 91.
[0864] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.02-4.04
(2H, m), 4.10-4.13 (2H, m), 4.13 (2H, s), 5.76 (1H, s), 7.23-7.27
(1H, m), 7.28-7.32 (6H, m), 7.37 (2H, d, J=8.2 Hz).
Preparation Example 98
4-Benzylsulfanyl-benzaldehyde
[0865] The title compound (462 mg, 2.02 mmol, 97%) was obtained as
a white solid from 2-(4-benzyl sulfanyl-phenyl)-[1,3]dioxolane
described in Preparation Example 97 (568 mg, 2.09 mmol) according
to an analogous method to Preparation Example 92.
[0866] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 4.24 (2H,
s), 7.26-7.40 (7H, m), 7.75 (2H, d, J=8.6 Hz), 9.92 (1H, s).
Preparation Example 99
(4-Benzylsulfanyl-phenyl)-methanol
[0867] The title compound (406 mg, 1.76 mmol, 87%) was obtained as
a white solid from 4-benzylsulfanyl-benzaldehyde described in
Preparation Example 98 (462 mg, 2.02 mmol) according to an
analogous method to Preparation Example 93.
[0868] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.11 (2H,
s), 4.65 (2H, d, J=4.4 Hz), 7.20-7.35 (8H, m), 7.37 (1H, d, J=4.4
Hz).
Preparation Example 100
2-(4-Benzylsulfanyl-benzyl)-isoindol-1,3-dione
[0869] The title compound (563 mg, 1.57 mmol, 89%) was obtained as
a white solid from (4-benzylsulfanyl)-methanol described in
Preparation Example 99 (406 mg, 1.76 mmol) according to an
analogous method to Preparation Example 94.
[0870] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.09 (2H,
s), 4.79 (2H, s), 7.20-7.35 (5H, m), 7.24 (2H, d, J=8.2 Hz), 7.32
(2H, d, J=8.1 Hz), 7.71 (2H, dd, J=2.9, 5.3 Hz), 7.84 (2H, dd,
J=2.9, 5.3 Hz).
Preparation Example 101
4-Benzylsulfanyl-benzylamine
[0871] The title compound (260 mg, 1.13 mmol, 72%) was obtained as
a white solid from 2-(4-benzylsulfanyl-benzyl)-isoindol-1,3-dione
described in Preparation Example 100 (563 mg, 1.57 mmol) according
to an analogous method to Preparation Example 95.
[0872] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.83 (2H,
s), 4.10 (2H, s), 7.20 (2H, d, J=8.6 Hz), 7.19-7.32 (7H, m).
Preparation Example 102
(5-Phenylaminomethyl-furan-2-yl)-methanol
[0873] Acetic acid 5-formyl-furan-2-ylmethyl ester (2.00 g, 11.9
mmol), aniline (1.63 mL, 17.9 mmol) and triacetoxy sodium
borohydride (5.04 g, 23.8 mmol) were suspended in a mixture
solution of tetrahydrofuran (40 mL) and acetic acid (1 mL) at
0.degree. C., and the mixture was stirred at room temperature for 7
hours. An aqueous solution of saturated sodium bicarbonate was
added to the reaction solution at 0.degree. C., which was then
extracted with ethyl acetate and tetrahydrofuran, the organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=1:1), and a
mixture of acetic acid 5-phenylaminomethyl-furan-2-ylmethyl ester
and aniline (2.91 g) was obtained as a pale yellow oil.
[0874] Then, the resulting mixture of acetic acid
5-phenylaminomethyl-furan-2-ylmethyl ester and aniline (2.91 g) as
well as potassium carbonate (3.28 g, 23.7 mmol) were suspended in
methanol (60 mL), and the solution was stirred overnight at room
temperature. The reaction solution was evaporated in vacuo, water
and ethyl acetate were added to the residue, the organic layer was
partitioned, washed with brine and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, the residue was
purified by NH silica gel column chromatography (hexane:ethyl
acetate=1:1), and the title compound (1.99 g, 9.79 mmol, 82%) was
obtained as a colorless oil.
[0875] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.04 (1H,
brs), 4.31 (2H, s), 4.59 (2H, d, J=5.9 Hz), 6.19 (1H, d, J=3.1 Hz),
6.23 (1H, d, J=3.1 Hz), 6.68 (2H, d, J=7.5 Hz), 6.75 (1H, t, J=7.3
Hz), 7.19 (2H, t, J=7.3 Hz).
Preparation Example 103
2-(5-phenylaminomethyl-furan-2-ylmethyl)-isoindol-1,3-dione
[0876] The title compound (603 mg, 1.81 mmol, 23%) was obtained as
a pale yellow solid from (5-phenylaminomethyl-furan-2-yl)-methanol
described in Preparation Example 102 (1.58 g, 7.77 mmol) according
to an analogous method to Preparation Example 94.
[0877] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.25 (2H,
s), 4.82 (2H, s), 6.14 (1H, d, J=3.1 Hz), 6.28 (1H, d, J=3.1 Hz),
6.63 (2H, d, J=7.5 Hz), 6.70 (1H, t, J=7.3 Hz), 7.14 (2H, t, J=7.3
Hz), 7.72 (2H, dd, J=3.1, 5.3 Hz), 7.87 (2H, dd, J=3.1, 5.3
Hz).
Preparation Example 104
(5-Aminomethyl-furan-2-ylmethyl)-phenyl-amine
[0878] The title compound (92 mg, 0.46 mmol, 60%) was obtained as a
pale yellow oil from
2-(5-phenylaminomethyl-furan-2-ylmethyl)-isoindol-1,3-dione
described in Preparation Example 103 (251 mg, 0.755 mmol) according
to an analogous method to Preparation Example 95.
[0879] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.79 (2H,
s), 4.28 (2H, s), 6.06 (1H, d, J=3.1 Hz), 6.15 (1H, d, J=3.1 Hz),
6.68 (2H, d, J=7.7 Hz), 6.74 (1H, t, J=7.3 Hz), 7.19 (2H, t, J=7.3
Hz).
Preparation Example 105
(2-(5-[1,3]-Dioxolan-2-yl-furan-2-yl)-ethyl)-phenylamine
[0880] 5-[1,3]Dioxolan-2-yl-furan-2-carbaldehyde (2.03 g, 12
.mu.mol), trimethylsulfonium bromide (1.90 g, 12.1 mmol) and
potassium hydroxide (779 mg, 13.9 mmol) were suspended in
acetonitrile (75 mL), and the solution was stirred overnight at
room temperature. Water was added to the reaction solution, which
was then extracted with ethyl acetate, the organic layer was washed
with brine and dried over anhydrous magnesium sulfate. The solvent
was evaporated in vacuo, 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane
(2.25 g) was obtained as a pale yellow oil.
[0881] The resulting 2-(5-oxiranyl-furan-2-yl)-[1,3]dioxolane (2.25
g) and silica gel (5.00 g) were suspended in ethyl acetate (40 mL),
and the solution was stirred for 6.5 hours at room temperature. The
reaction solution was filtered, then, the filtrate was evaporated
in vacuo, and (5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57
g) was obtained as a yellow oil.
[0882] Next, the resulting
(5-[1,3]dioxolan-2-yl-furan-2-yl)-acetaldehyde (1.57 g), aniline
(0.94 mL, 10.3 mmol) and triacetoxy sodium borohydride (3.76 g,
17.2 mmol) were suspended in a mixture solution of tetrahydrofuran
(30 mL) and acetic acid (1 mL) at 0.degree. C., and the mixture was
stirred at room temperature for 19 hours. An aqueous solution of
saturated sodium bicarbonate was added to the reaction mixture at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=5:1), and the title compound (453 mg, 1.75 mmol, 14%) was
obtained as a brown oil.
[0883] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.95 (2H, t,
J=6.8 Hz), 3.43 (2H, t, J=6.8 Hz), 3.99-4.06 (2H, m), 4.10-4.15
(2H, m), 5.88 (1H, s), 6.06 (1H, d, J=3.3 Hz), 6.37 (1H, d, J=3.1
Hz), 6.62 (2H, dd, J=1.1, 8.6 Hz), 6.71 (1H, tt, J=1.1, 7.3 Hz),
7.18 (2H, dd, J=7.3, 8.6 Hz).
Preparation Example 106
5-(2-Phenylamino-ethyl)-furan-2-carbaldehyde
[0884] The title compound (314 mg, 1.46 mmol) was obtained as a
light brown oil from
(2-(5-[1,3]dioxolan-2-yl-furan-2-yl)-ethyl)-phenylamine described
in Preparation Example 105 (453 mg, 1.75 mmol) according to an
analogous method to Preparation Example 44.
[0885] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.05 (2H, t,
J=6.8 Hz), 3.53 (2H, t, J=6.8 Hz), 6.33 (1H, d, J=3.5 Hz), 6.62
(2H, dd, J=1.1, 8.6 Hz), 6.73 (1H, t, J=7.3 Hz), 7.17-7.21 (3H, m),
9.55 (1H, s).
Preparation Example 107
(2-(5-Aminomethyl-furan-2-yl)-ethyl)-phenylamine
[0886] The title compound (117 mg, 0.541 mmol, 78%) was obtained as
a pale yellow oil from 5-(2-phenylamino-ethyl)-furan-2-carbaldehyde
described in Preparation Example 106 (150 mg, 0.697 mmol) according
to an analogous method to Preparation Example 45.
[0887] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.92 (2H, t,
J=6.8 Hz), 3.41 (2H, t, J=6.8 Hz), 3.78 (2H, s), 6.00 (1H, d, J=3.1
Hz), 6.04 (1H, d, J=2.9 Hz), 6.62 (2H, dd, J=1.1, 8.6 Hz), 6.71
(1H, t, J=7.3 Hz), 7.18 (2H, dd, J=7.3, 8.6 Hz).
Preparation Example 108
2-(4-Bromo-thiophen-2-yl)-[1,3]dioxolane
[0888] 4-Bromo-thiophene-2-carbaldehyde (9.24 g, 48.4 mmol),
ethane-1,2-diol (13.5 mL, 242 mmol), toluene-4-sulfonic acid
monohydrate (416 mg, 2.42 mmol) were dissolved in toluene (100 mL),
and the solution was stirred for 1.5 hours under reflux. An aqueous
solution of saturated sodium bicarbonate was added to the reaction
solution at 0.degree. C., which was then extracted with ethyl
acetate, the organic layer was washed with brine and dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was purified by NH silica gel column chromatography
(hexane:ethyl acetate=20:1), and the title compound (11.8 g,
quantitatively) was obtained as a white solid.
[0889] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.02-4.04
(2H, m), 4.09-4.11 (2H, m), 6.07 (1H, s), 7.08 (1H, dd, J=0.73, 1.5
Hz), 7.22 (1H, d, J=1.5 Hz).
Preparation Method 109
2-(4-Phenoxy-thiophen-2-yl)-[1,3]dioxolane
[0890] The title compound (5.40 g, 21.7 mmol, 73%) was obtained as
a pale yellow oil from 2-(4-bromo-thiophen-2-yl)-[1,3]dioxolane
described in Preparation Example 108 (6.96 g, 29.6 mmol) and phenol
(6.60 g, 71.0 mmol) according to an analogous method to Preparation
Example 33.
[0891] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.00-4.04
(2H, m), 4.12-4.17 (2H, m), 6.04 (1H, s), 6.60 (1H, d, J=1.7 Hz),
6.94 (1H, d, J=1.7 Hz), 7.04 (2H, dd, J=1.1, 8.6 Hz), 7.09 (1H, tt,
J=1.1, 7.3 Hz), 7.32 (2H, dd, J=7.3, 8.6 Hz).
Preparation Example 110
4-Phenoxy-thiophene-2-carbaldehyde
[0892] The title compound (183 mg, 0.896 mmol, 44%) was obtained as
a colorless oil from 2-(4-phenoxy-thiophen-2-yl)-[1,3]dioxolane
described in Preparation Example 109 (500 mg, 2.01 mmol) according
to an analogous method to Preparation Example 34.
[0893] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 7.04 (1H,
dd, J=1.3, 1.6 Hz), 7.07 (2H, dd, J=1.1, 8.8 Hz), 7.16 (1H, tt,
J=1.1, 7.3 Hz), 7.35 (2H, dd, J=7.3, 8.6 Hz), 7.51 (1H, d, J=1.7
Hz), 9.84 (1H, s).
Preparation Example 111
C-(4-Phenoxy-thiophen-2-yl)-methylamine
[0894] The title compound (94 mg, 0.458 mmol, 51%) was obtained as
a pale yellow oil from 4-phenoxy-thiophene-2-carbaldehyde described
in Preparation Example 110 (183 mg, 0.896 mmol) according to an
analogous method to Preparation Example 35.
[0895] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.99 (2H,
s), 6.46 (1H, d, J=1.7 Hz), 6.69-6.70 (1H, m), 7.05 (2H, dd, J=1.1,
7.7 Hz), 7.09 (1H, t, J=7.5 Hz), 7.33 (2H, dd, J=7.5, 8.6 Hz).
Preparation Example 112
5-Oxo-2,5-dihydro-isoxazole-4-carboxylic acid ethyl ester
[0896] 2-Ethoxymethylene-malonic acid diethyl ester (5.00 g, 23.1
mmol), hydroxylamine hydrochloride (4.01 g, 57.8 mmol) and
triethylamine (8.06 mL, 57.8 mmol) were dissolved in ethanol (100
mL), the solution was stirred at room temperature for 17 hours,
then, the solution was stirred for 4.5 hours under reflux. The
reaction solution was cooled to room temperature, water was added,
and 1N hydrochloric acid was added until a salt precipitated. The
precipitated salt was collected by filtration, and a hydrochloride
salt of the title compound (2.39 g, 15.2 mmol, 66%) was obtained as
a white solid.
[0897] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.19 (3H, t,
J=7.1 Hz), 4.08 (2H, q, J=7.1 Hz), 4.90 (1H, brs), 8.51 (1H, d,
J=6.8 Hz).
Preparation Example 113
5-Oxo-2-phenoxy thiocarbonyl-2,5-dihydro-isoxazole-4-carboxylic
acid ethyl ester
[0898] 5-Oxo-2,5-dihydro-isoxazole-4-carboxylic acid ethyl ester
described in Preparation Example 112 (1.00 g, 5.17 mmol), phenyl
chlorothionoformate (786 .mu.l, 5.69 mmol) and pyridine (919 .mu.l,
11.4 mmol) were dissolved at 0.degree. C. in toluene (20 mL), and
the solution was stirred at room temperature for 17 hours under
nitrogen atmosphere. Water was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, and the
organic layer was washed with brine. The solvent was evaporated in
vacuo, the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1), and the title compound (1.66 g, 5.66
mmol, quantitatively) was obtained as a pale yellow solid.
[0899] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.39 (3H, t,
J=7.1 Hz), 4.39 (2H, q, J=7.1 Hz), 7.16 (2H, dd, J=1.3, 8.6 Hz),
7.38 (1H, t, J=7.1 Hz), 7.49 (2H, dd, J=7.1, 8.8 Hz), 9.30 (1H,
s).
Preparation Example 114
2-Phenoxy-thiazole-5-carboxylic acid ethyl ester
[0900]
5-Oxo-2-phenoxythiocarbonyl-2,5-dihydro-isoxazole-4-carboxylic acid
ethyl ester described in Preparation Example 113 (500 mg, 2.01
mmol) was dissolved in acetone (500 mL), and the solution was
irradiated with light (300 nm) for 30 minutes at room temperature.
The reaction solution was evaporated in vacuo, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=2:1), and the title compound (384 mg, 1.54 mmol, 90%) was
obtained as a pale yellow oil.
[0901] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.35 (3H, t,
J=7.1 Hz), 4.33 (2H, q, J=7.1 Hz), 7.26-7.35 (3H, m), 7.47 (2H, dd,
J=7.5, 8.4 Hz), 7.90 (1H, s).
Preparation Example 115
(2-Phenoxy-thiazol-5-yl)-methanol
[0902] 2-Phenoxy-thiazole-5-carboxylic acid ethyl ester described
in Preparation Example 114 (384 mg, 1.54 mmol) was dissolved in
tetrahydrofuran (5 mL), and lithium aluminum hydride (292 mg, 7.70
mmol) was added at 0.degree. C. The solution was stirred at room
temperature for 1 hour, then, at 0.degree. C., water (292 .mu.l),
an aqueous solution of 5N sodium hydroxide (292 .mu.l) and water
(876 .mu.l) were sequentially added thereto. The reaction solution
was filtered through Celite pad, then, the filtrate was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:4), and the title compound
(270 mg, 1.30 mmol, 85%) was obtained as a white solid.
[0903] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.73 (2H, d,
J=5.9 Hz), 7.13 (1H, s), 7.25-7.29 (3H, m), 7.41-7.45 (2H, m).
Preparation Example 116
2-(2-Phenoxy-thiazol-5-ylmethyl)-isoindol-1,3-dione
[0904] The title compound (131 mg, 0.389 mmol, 30%) was obtained as
a colorless oil from (2-phenoxy-thiazole-5-yl)-methanol described
in Preparation Example 115 (270 mg, 1.30 mmol) according to an
analogous method to Preparation Example 94.
[0905] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.89 (2H,
s), 7.21-7.28 (4H, m), 7.40 (2H, t, J=8.0 Hz), 7.73 (2H, dd, J=3.1,
5.3 Hz), 7.86 (2H, dd, J=2.9, 5.5 Hz).
Preparation Example 117
C-(2-Phenoxy-thiazol-5-yl)-methylamine
[0906] The title compound (63 mg, 0.3 .mu.mol, 78%) was obtained as
a colorless oil from
2-(2-phenoxy-thiazol-5-ylmethyl)-isoindol-1,3-dione described in
Preparation Example 116 (131 mg, 0.389 mmol) according to an
analogous method to Preparation Example 95.
[0907] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.95 (2H,
s), 7.03 (1H, t, J=1.1 Hz), 7.25-7.28 (3H, m), 7.39-7.43 (2H,
m).
Preparation Example 118
4-Benzyloxy-2-fluoro-benzonitrile
[0908] To a solution of 4-hydroxy-2-fluoro-benzonitrile (1.0 g, 7.3
mmol) in N,N-dimethylformamide (15 mL) was added potassium
carbonate (2.0 g, 15 mmol) and benzyl bromide (0.87 mL, 7.3 mmol),
and the solution was stirred at room temperature for 5 hours. Water
and ethyl acetate were added to the reaction solution, which was
then extracted, washed with brine, then, the solvent was evaporated
in vacuo. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=5:1), and the title compound
(1.5 g, 6.7 mmol, 92%) was obtained as a white solid.
[0909] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.11 (2H,
s), 6.78 (1H, dd, J=2.4, 11.0 Hz), 6.83 (1H, ddd, J=0.6, 2.4, 8.8
Hz), 7.37-7.43 (5H, m), 7.52 (1H, dd, J=7.5, 8.6 Hz).
Preparation Example 119
4-[1,3]-Dioxolane-2-yl-benzonitrile
[0910] 4-Formyl-benzonitrile (3.00 g, 22.9 mmol), ethane-1,2-diol
(6.38 mL, 115 mmol) and toluene-4-sulfonic acid monohydrate (197
mg, 1.15 mmol) were dissolved in toluene (60 mL), and the solution
was stirred under reflux for 10 hours. An aqueous solution of
saturated sodium bicarbonate was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine, and the organic layer was
dried over anhydrous magnesium sulfate. The solvent was evaporated
in vacuo, the residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=10:1), and the title compound
(3.78 g, 21.6 mmol, 94%) was obtained as a white solid.
[0911] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.04-4.13
(4H, m), 5.85 (1H, s), 7.59 (2H, d, J=8.1 Hz), 7.68 (2H, d, J=8.4
Hz).
Preparation Example 120
4-[1,3]-Dioxolan-2-yl-benzylamine
[0912] 4-[1,3]Dioxolan-2-yl-benzonitrile described in Preparation
Example 119 (3.78 g, 21.6 mmol) was dissolved in tetrahydrofuran
(76 mL), lithium aluminum hydride (4.09 g, 108 mmol) was added at
0.degree. C., and the solution was stirred overnight at room
temperature. Water (4.09 mL), an aqueous solution of 5N sodium
hydroxide (4.09 mL) and water (12.3 mL) were sequentially added to
the reaction solution. The reaction solution was filtered through
Celite pad, then, the filtrate was evaporated in vacuo, and the
title compound (3.92 g, quantitatively) was obtained as a pale
yellow oil.
[0913] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.89 (2H,
s), 4.03-4.16 (4H, m), 5.81 (1H, s), 7.34 (2H, d, J=7.9 Hz), 7.46
(2H, d, J=8.1 Hz).
Preparation Example 121
5-(3-Chloro-phenoxy)-thiophene-2-carbonitrile
[0914] 5-Nitro-thiophene-2-carbonitrile (5.00 g, 32.5 mmol),
3-chloro-phenol (6.90 mL, 65.0 mmol) and potassium carbonate (13.4
g, 97.5 mmol) were suspended in dimethylsulfoxide (50 mL), and the
mixture was stirred at 60.degree. C. for 4 hours. Water was added
to the reaction mixture at 0.degree. C., which was then extracted
with ethyl acetate, the organic layer was washed with water twice,
and further washed with brine. The organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was purified by NH silica gel silica gel column
chromatography (hexane:ethyl acetate=20:1), and the title compound
(5.56 g, 23.6 mmol, 73%) was obtained as a pale yellow oil.
[0915] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 6.49 (1H, d,
J=4.2 Hz), 7.04 (1H, ddd, J=0.92, 2.4, 8.2 Hz), 7.15 (1H, t, J=2.2
Hz), 7.22 (1H, ddd, J=0.92, 2.0, 8.1 Hz), 7.33 (1H, t, J=8.2 Hz),
7.4 (1H, d, J=4.2 Hz).
Preparation Example 122
2-(5-(2-Fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane
[0916] The title compound (4.33 g, 16.4 mmol, 54%) was obtained as
a pale yellow oil from 2-(5-bromo-thiophen-2-yl)-[1,3]dioxolane
(8.00 g, 30.4 mmol) and 1-bromo methyl-2-fluoro-benzene (4.48 mL,
36.5 mmol) according to an analogous method to Preparation Example
36
[0917] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.97-4.03
(2H, m), 4.06-4.13 (2H, m), 4.14 (2H, s), 6.01 (1H, s), 6.71 (1H,
d, J=3.7 Hz), 6.98 (1H, d, J=3.9 Hz), 7.01-7.08 (2H, m), 7.19-7.23
(2H, m).
Preparation Example 123
5-(2-Fluoro-benzyl)-thiophene-2-carbaldehyde
[0918] 2-(5-(2-Fluoro-benzyl)-thiophen-2-yl)-[1,3]dioxolane
described in Preparation Example 122 (4.33 g, 16.4 mmol) was
dissolved in a mixture solvent of methanol (40 mL) and water (10
mL), 1N hydrochloric acid (20 mL) was added thereto, followed by
stirring at room temperature for 1 hour. An aqueous solution of
saturated sodium bicarbonate was added to the reaction solution at
0.degree. C., which was then extracted with ethyl acetate, the
organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by silica gel column chromatography (hexane:ethyl
acetate=10:1), and the title compound (3.54 g, 16.1 mmol, 98%) was
obtained as a light yellow oil.
[0919] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.22 (2H,
s), 6.94 (1H, d, J=3.8 Hz), 7.05-7.13 (2H, m), 7.21-7.28 (2H, m),
7.60 (1H, d, J=3.8 Hz), 9.81 (1H, s).
Preparation Example 124
(5-(2-fluoro-benzyl)-thiophene-2-yl)-methanol
[0920] 5-(2-Fluoro-benzyl)-thiophene-2-carbaldehyde described in
Preparation Example 123 (2.81 g, 12.7 mmol) was dissolved in
ethanol (40 mL), sodium borohydride (964 mg, 25.4 mmol) was added
at 0.degree. C., and the solution was stirred at room temperature
for 1 hour. Water was added to the reaction solution at 0.degree.
C., which was then extracted with ethyl acetate, the organic layer
was washed with brine and dried over anhydrous magnesium sulfate.
The solvent was evaporated in vacuo, the residue was purified by
silica gel column chromatography (hexane:ethyl acetate=5:1), and
the title compound (2.10 g, 9.45 mmol, 74%) was obtained as a
colorless oil.
[0921] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.14 (2H,
s), 4.73 (2H, s), 6.69 (1H, d, J=3.5 Hz), 6.82 (1H, d, J=3.7 Hz),
7.02-7.10 (2H, m), 7.19-7.26 (2H, m).
Preparation Example 125
2-(5-(2-fluoro-benzyl)-thiophen-2-ylmethyl)-isoindol-1,3-dione
[0922] The title compound (1.49 g, 4.24 mmol, 45%) was obtained as
a pale yellow solid from
(5-(2-fluoro-benzyl)-thiophen-2-yl)-methanol described in
Preparation Example 124 (2.10 g, 9.44 mmol) according to an
analogous method to Preparation Example 94.
[0923] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.08 (2H,
s), 4.92 (2H, s), 6.63 (1H, d, J=3.5 Hz), 6.94 (1H, d, J=3.5 Hz),
6.99-7.08 (2H, m), 7.12-7.23 (2H, m), 7.70 (2H, dd, J=3.1, 5.5 Hz),
7.84 (2H, dd, J=3.1, 5.5 Hz).
Preparation Example 126
C-(5-(2-Fluoro-benzyl)thiophen-2-yl)-methylamine
[0924] The title compound (901 mg, 4.07 mmol, 96%) was obtained as
a pale yellow oil from
2-(5-(2-fluoro-benzyl)-thiophen-2-ylmethyl)-isoindol-1,3-dione
described in Preparation Example 125 (1.49 g, 4.24 mmol) according
to an analogous method to Preparation Example 95.
[0925] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.95 (2H,
s), 4.12 (2H, s), 6.65 (1H, d, J=3.5 Hz), 6.71 (1H, d, J=3.5 Hz),
7.01-7.09 (2H, m), 7.18-7.25 (2H, m).
Preparation Example 127
(5-Bromo-4-phenoxy-thiophen-2-yl)-methanol
[0926] 2-(4-Phenoxy-thiophen-2-yl)-[1,3]dioxolane described in
Preparation Example 109 (4.88 g, 19.7 mmol) and N-bromosuccinimide
(3.85 g, 21.7 mmol) were dissolved in tetrahydrofuran (100 mL), and
the solution was stirred for 4.5 hours at room temperature. An
aqueous solution of saturated sodium bicarbonate was added to the
reaction solution at 0.degree. C., which was then extracted with
ethyl acetate, the organic layer was washed with brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated in
vacuo, and the residue was silica gel-filtered to obtain
2-(5-bromo-4-phenoxy-thiophen-2-yl)-[1,3]dioxolane (5.48 g) as a
pale yellow oil.
[0927] Then, 5-bromo-4-phenoxy-thiophene-2-carbaldehyde (3.11 g)
was obtained as a colorless oil from
2-(5-bromo-4-phenoxy-thiophen-2-yl)-[1,3]dioxolane (5.48 g)
according to an analogous method to Preparation Example 34.
[0928] Then, the title compound (2.76 g, 9.68 mmol, 88%) was
obtained as a colorless oil from
5-bromo-4-phenoxy-thiophene-2-carbaldehyde (3.11 g, 11.0 mmol)
according to an analogous method to Preparation Example 93.
[0929] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.70 (2H,
s), 6.62 (1H, s), 6.98 (2H, dd, J=1.1, 8.8 Hz), 7.09 (1H, tt,
J=1.1, 7.5 Hz), 7.29-7.34 (2H, m).
Preparation Example 128
2-(5-Bromo-4-phenoxy-thiophen-2-ylmethyl)-isoindol-1,3-dione
[0930] The title compound (2.66 g, 6.42 mmol, 68%) was obtained as
a white solid from (5-bromo-4-phenoxy-thiophen-2-yl)-methanol
described in Preparation Example 127 (2.71 g, 9.50 mmol) according
to an analogous method to Preparation Example 94.
[0931] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.86 (2H,
s), 6.76 (1H, s), 6.95 (2H, dd, J=1.1, 8.8 Hz), 7.08 (1H, t, J=7.5
Hz), 7.30 (2H, dd, J=7.3, 8.8 Hz), 7.70-7.76 (2H, m), 7.83-7.88
(2H, m).
Preparation Example 129
C-(5-Bromo-4-phenoxy-thiophen-2-yl)-methylamine
[0932] The title compound (1.62 g, 5.70 mmol, 89%) was obtained as
a colorless oil from
2-(5-bromo-4-phenoxy-thiophen-2-ylmethyl)-isoindole-1,3-diene
described in Preparation Example 128 (2.66 g, 6.42 mmol) according
to an analogous method to Preparation Example 95.
[0933] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.94 (2H,
s), 6.53 (1H, t, J=1.1 Hz), 6.97 (2H, dd, J=1.1, 8.6 Hz), 7.08 (1H,
tt, J=1.1, 7.5 Hz), 7.31 (2H, dd, J=7.5, 8.8 Hz).
Preparation Example 130
3-Aminomethylphenol
[0934] The title compound (2.9 g, 24 mmol, 97%) was obtained as a
white solid from 3-hydroxybenzaldehyde (3.0 g, 24 mmol) according
to an analogous method to Preparation Example 38.
[0935] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.60 (2H,
s), 6.55 (1H, d, J=7.5 Hz), 6.68-6.70 (2H, m), 7.03-7.07 (1H,
m).
Preparation Example 131
1-Quinolin-6-yl-ethanone
[0936] 6-Bromoquinoline (4.4 g, 21.3 mmol), 1-ethoxyvinyl
(tri-n-butyl)tin (10 g, 27.69 mmol) and
dichlorobis(triphenylphosphine)palladium(II) (1.2 g, 1.7 mmol) were
dissolved in toluene (120 mL) under nitrogen atmosphere, and the
solution was stirred at 80.degree. C. for 7 hours. At room
temperature, 5M hydrochloric acid (30 mL) and tetrahydrofuran (150
mL) were added to the reaction solution, which was then stirred for
15 hours. The reaction solution was poured into an aqueous solution
of saturated sodium bicarbonate containing finely ground ice (200
mL), the solution was adjusted to pH 8-9, and filtered through
Celite pad. The filtrate was extracted with ethyl acetate twice,
washed with brine twice, dried over anhydrous magnesium sulfate,
and then, filtered. The organic layer was evaporated in vacuo,
then, residue of reddish brown oil (16.8 g) was obtained. Ethyl
acetate (20 mL) was added thereto, which was dissolved, then,
silica gel (80 mL) was added, the solvent was evaporated in vacuo
for adsorption, purification was carried out by silica gel column
chromatography (hexane:ethyl acetate=95:5, then hexane:ethyl
acetate=60:40), and a yellow solid (4.16 g) was obtained. This
yellow solid was dissolved in ethyl acetate (100 mL), then, the
solution was extracted with 1M hydrochloric acid (70, 50 mL) twice,
the aqueous layer was adjusted to pH 8 with sodium bicarbonate,
then, the solution was extracted with ethyl acetate twice. The
organic layer was washed with brine, dried over anhydrous magnesium
sulfate, then, filtered, organic layer was evaporated in vacuo,
then, the title compound (2.98 g, 17.4 mmol, 77%) was obtained as a
yellow solid.
[0937] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 2.73
(3H, s), 7.07 (1H, dd, J=8.4, 4.4 Hz), 8.11 (1H, d, J=9.2 Hz), 8.27
(1H, dd, J=8.8, 2.0 Hz), 8.50-8.53 (1H, m), 8.70 (1H, m), 9.02 (1H,
m).
Preparation Example 132
4-Benzyloxy-3-methoxymethoxy-benzonitrile
[0938] To a solution of 3,4-dihydroxy-benzonitrile (1.36 g, 1.0
mmol) and potassium tert-butoxide (1.5 g, 13 mmol) in
dimethylsulfoxide (15 mL) was added benzyl chloride (1.5 mL, 13
mmol) under nitrogen atmosphere at room temperature, and the
solution was stirred for 24 hours. Silica gel (100 mL) was added
portionwise to the reaction solution for adsorption, a pale yellow
oil of 4-benzyloxy-3-hydroxy-benzonitrile (2.38 g) was obtained by
silica gel column chromatography (hexane:ethyl acetate=7:3), in
addition, this was purified by NH silica gel column chromatography
(hexane:ethyl acetate=1:1, then ethyl acetate, then ethyl
acetate:methanol=90:10, then 85:15), and
4-benzyloxy-3-hydroxy-benzonitrile (0.588 g, 2.61 mmol, 24.8%) was
obtained as a pale yellow solid.
[0939] To a solution of the resulting
4-benzyloxy-3-hydroxy-benzonitrile (300 mg, 1.33 mmol) and
potassium tert-butoxide (300 mg, 2.66 mmol) in dimethylsulfoxide (4
mL) was added chloromethyl methyl ether (0.204 mL, 2.66 mmol)
portionwise under nitrogen atmosphere stirring on an ice bath, and
the solution was stirred for 2 days. NH silica gel (25 mL) was
added to the reaction solution, purification was carried out by NH
silica gel column chromatography (hexane:ethyl acetate=7:3) then
silica gel column chromatography (hexane:ethyl acetate=7:3), and
the title compound (306 mg, 0.829 mmol, 85.3%) was obtained as a
pale yellow solid.
[0940] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 3.46
(3H, s), 5.26 (2H, s), 5.27 (2H,$), 7.26 (1H, d, J=8.4 Hz),
7.36-7.44 (4H, m), 7.45 (1H, d, J=2.4 Hz), 7.50-7.53 (2H, m).
Preparation Example 133
3-(3-Methyl-2-butenyloxy)-benzonitrile
[0941] 3-Hydroxybenzonitrile (1.19 g, 10 mmol) and
4-bromo-2-methyl-2-butene (1.66 g, 10 mmol) were dissolved in
N,N-dimethylformamide (5 mL), potassium carbonate (1.66 g, 12 mmol)
was added, and the solution was stirred at room temperature for 2
hours. Water (50 mL) was added to the reaction solution, which was
then extracted with ethyl acetate (50 mL). The extract was washed,
then, dried over anhydrous magnesium sulfate, and the solvent was
evaporated in vacuo. The residue was purified by silica gel column
chromatography (hexane:ethyl acetate=95:5), and the title compound
(1.71 g, 10 mmol, 99.4%) was obtained as a colorless oil.
[0942] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.73 (3H,
s), 1.78 (3H, s), 4.51 (2H, d, J=6.8 Hz), 5.48 (1H, t, J=6.8 Hz),
7.13 (1H, dd, J=2.4, 8.4 Hz), 7.15 (1H, d, J=2.4 Hz), 7.23 (1H, d,
J=8.4 Hz), 7.28 (1H, t, J=8.4 Hz).
Preparation Example 134
3-(3-Methyl-2-butenyloxy)-benzylamine
[0943] 3-(3-Methyl-2-butenyloxy)-benzonitrile described in
Preparation Example 133 (1.71 g, 10 mmol) was dissolved in
tetrahydrofuran (20 mL), lithium aluminum hydride (0.57 g, 15 mmol)
was added under stirring at room temperature, the solution was
heated to 70.degree. C., then stirring continued for 2 hours. The
reaction solution was cooled on an ice bath, then, water (0.6 mL),
an aqueous solution of 15% sodium hydroxide (0.6 mL) and water (1.8
mL) were added in this order, then, the solid was filtered, and
washed with tetrahydrofuran (20 mL). The filtrate and the washings
were combined, and dried over anhydrous sodium sulfate. The solvent
was evaporated in vacuo, and the title compound (1.50 g, 8.52 mmol,
85.2%) was obtained as a colorless oil.
[0944] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.73 (3H,
s), 1.78 (3H, s), 4.51 (2H, d, J=6.8 Hz), 4.68 (2H, d, J=5.6 Hz),
5.48 (1H, t, J=6.8 Hz), 6.77 (1H, dd, J=2.4, 8.4 Hz), 6.83 (1H, d,
J=2.4 Hz), 6.87 (1H, s), 7.23 (1H, t, J=8.4 Hz).
Preparation Example 135
(3-Cyanobenzyl)phosphonic acid diethyl ester
[0945] 3-Cyanobenzyl bromide (9.8 g, 50 mmol) and triethylphosphite
(9.97 g, 60 mmol) were stirred at 140.degree. C. for 3 hours. The
resulting residue was evaporated, the distillate which has
145.degree. C./1 mmHg was collected, and the title compound (10 g,
39.5 mmol, 79.1%) was obtained as a colorless oil.
Preparation Example 136
3-(2-Methylpropenyl)benzonitrile
[0946] Sodium hydride (0.40 g, 1.0 mmol, 60% in oil) was suspended
in tetrahydrofuran (5 mL), (3-cyanobenzyl)phosphonic acid diethyl
ester obtained in Preparation Example 135 (2.53 g, 10 mmol) was
added dropwise under stirring at room temperature. After stirring
for 1 hour at 60.degree. C., the solution was allowed to room
temperature, acetone (0.92 g, 20 mmol) was added dropwise, and the
solution was further stirred for 30 minutes at room temperature.
Water (100 mL) was added to the reaction solution, which was then
extracted with ethyl acetate (50 mL). The organic layer was washed
with water, then, dried over anhydrous magnesium sulfate, and the
solvent was evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane:ethyl acetate=97:3), and the
title compound (0.44 g, 2.80 mmol, 28%) was obtained as a colorless
oil.
[0947] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.85 (3H,
s), 1.93 (3H, s), 6.23 (1H, s), 7.40-7.50 (4H, m).
Preparation Example 137
(3-(2-Methylpropenyl)-benzylamine)
[0948] 3-(2-Methylpropenyl)benzonitrile described in Preparation
Example 136 (0.44 g, 2.8 mmol) was dissolved in tetrahydrofuran (5
mL), lithium aluminum hydride (0.16 g, 4.2 mmol) was added under
stirring at room temperature, the solution was heated to 70.degree.
C., followed by stirring for 2 hours. The reaction solution was
cooled on an ice bath, then, water (0.16 mL), an aqueous solution
of 15% sodium hydroxide (0.16 mL) and water (0.48 mL) were
sequentially added, then, the solid was filtered, and washed with
tetrahydrofuran (10 mL). The filtrate and the washings were
combined, and dried over anhydrous sodium sulfate. The solvent was
evaporated in vacuo, and the title compound (0.40 g, 2.48 mmol,
88.7%) was obtained as a colorless oil.
[0949] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.87 (3H,
s), 1.90 (3H, s), 3.85 (2H, s), 6.27 (1H, s), 7.11-7.28 (4H,
m).
Preparation Example 138
3-Cyclopentylydenemethylbenzonitrile
[0950] Potassium tert-butoxide (1.12 g, 10 mmol) was suspended in
N,N-dimethylformamide (10 mL), and (3-cyanobenzyl)phosphonic acid
diethyl ester (2.53 g, 10 mmol) was added dropwise under stirring
at room temperature. The solution was stirred at room temperature
for 1 hour, then, cyclopentanone (0.84 g, 10 mmol) was added, and
the solution was stirred at room temperature for 2 hours. Water
(100 mL) was added to the reaction solution, which was then
extracted with ethyl acetate (50 mL). The organic layer was washed
with water, then, dried over anhydrous magnesium sulfate, and the
solvent was evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane:ethyl acetate=97:3), and the
title compound (1.32 g, 7.21 mol, 72.3%) was obtained as a
colorless oil.
[0951] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.65-1.79
(4H, m), 2.47-2.58 (4H, m), 6.33 (1H, s), 7.40-7.57 (4H, m).
Preparation Example 139
3-Cyclopentylydenemethyl-benzylamine
[0952] 3-Cyclopentylydenemethylbenzonitrile described in
Preparation Example 138 (1.32 g, 7.21 mmol) was dissolved in
tetrahydrofuran (10 mL), lithium aluminum hydride (0.41 g, 10.8
mmol) was added under stirring at room temperature, the solution
was heated to 70.degree. C., followed by stirring for 2 hours. The
reaction solution was cooled on an ice bath, then, water (0.41 mL),
an aqueous solution of 15% sodium hydroxide (0.41 mL) and water
(1.23 mL) were sequentially added, then, the solid was filtered,
and washed with tetrahydrofuran (20 mL). The filtrate and the
washings were combined, and dried over anhydrous sodium sulfate.
The solvent was evaporated in vacuo, and the title compound (1.30
g, 6.95 mmol, 96.4%) was obtained as a colorless oil.
Preparation Example 140
(5-Bromothiophen-2-yl)methanol
[0953] 5-Bromo-2-thiophene carboxy aldehyde (25 g, 131 mmol) was
dissolved in a mixture solvent of ethanol-tetrahydrofuran (1:1)
(200 mL), sodium borohydride (1.86 g, 49 mmol) was added in small
amounts under ice-cold stirring, and stirring continued for 30
minutes. An aqueous solution of saturated ammonium chloride (20 mL)
was added to the reaction solution, which was then stirred for 30
minutes. The reaction solution was extracted with ethyl acetate
(100 mL), washed with water, dried over anhydrous magnesium
sulfate, then, the solvent was evaporated in vacuo. The residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=90:10), and the title compound (6.7 g, 34.7 mmol, 26.5%)
was obtained as a colorless oil.
Preparation Example 141
2-Bromo-5-chloromethylthiophene
[0954] (5-Bromothiophen-2-yl)methanol described in Preparation
Example 140 (6.7 g, 34.7 mmol) was dissolved in diethyl ether (40
mL), 10 mL of concentrated hydrochloric acid was added thereto, and
the solution was vigorously stirred at room temperature for 8
hours. An ice water (200 mL) was added to the reaction solution, an
aqueous solution of sodium bicarbonate was further added for
neutralization, then, the solution was extracted with ethyl acetate
(100 mL). The organic layer was washed with water, dried over
anhydrous magnesium sulfate, then, the solvent was evaporated in
vacuo, and the title compound (7.3 g, 34.5 mmol, 99.4%) was
obtained as a colorless oil.
Preparation Example 142
(5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester
[0955] 2-Bromo-5-chloromethylthiophene described in Preparation
Example 141 (7.3 g, 34.5 mmol) and triethylphosphite (6.35 g, 38.2
mmol) were stirred at 140.degree. C. for 3 hours. The resulting
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=50:50), and the title compound (8.82 g, 31.2
mmol, 90.3%) was obtained as a reddish brown oil.
[0956] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.27-1.36
(6H, m), 3.25 (2H, d, J=24 Hz), 4.05-4.16 (4H, m), 6.72 (1H, d,
J=3.6 Hz), 6.92 (1H, d, J=3.6 Hz).
Preparation Example 143
2-Bromo-5-(2-methylpropenyl)-thiophene
[0957] (5-Bromothiophen-2-ylmethyl)phosphonic acid diethyl ester
described in Preparation Example 142 (3.13 g, 10 mmol) was
dissolved in tetrahydrofuran (20 mL), sodium hydride (0.40 g, 10
mmol, 60% in oil) was added to this solution under stirring at room
temperature. The solution was stirred for 30 minutes at 60.degree.
C., then, acetone (1 g, 17.2 mmol) was added, and the solution was
further stirred for 30 minutes. Water (100 mL) was added to the
reaction solution, which was then extracted with hexane (50 mL),
the organic layer was washed with water, dried over anhydrous
magnesium sulfate, then, the solvent was evaporated in vacuo. The
residue was purified by silica gel column chromatography (hexane),
and the title compound (60 mg, 0.27 mmol, 2.7%) was obtained as a
colorless oil.
[0958] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.90 (3H,
s), 1.93 (3H, s), 6.27 (1H, s), 6.62 (1H, d, J=3.6 Hz), 6.93 (1H,
d, J=3.6 Hz).
Preparation Example 144
5-(2-Methylpropenyl)-thiophene-2-carbonitrile
[0959] 2-Bromo-5-(2-methylpropenyl)-thiophene described in
Preparation Example 143 (60 mg, 0.27 mmol) was dissolved in
N,N-dimethylformamide (1 mL), copper cyanide (62 mg, 0.69 mmol) was
added at 160.degree. C., and the solution was stirred for 2 hours.
The reaction solution was cooled, then, concentrated aqueous
ammonia (5 mL) was added, and the solution was extracted with
diethyl ether (10 mL). The organic layer was washed, dried over
anhydrous magnesium sulfate, then, the solvent was evaporated in
vacuo. The residue was purified by silica gel column chromatography
(hexane:ethyl acetate=95:5), and the title compound (15 mg, 0.092
mmol, 34%) was obtained as a colorless oil.
[0960] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.97 (3H,
s), 2.00 (3H, s), 6.39 (1H, s), 6.85 (1H, d, J=4.0 Hz), 7.50 (1H,
d, J=4.0 Hz).
Preparation Example 145
C-(5-(2-Methylpropenyl)-thiophen-2-yl)-methylamine
[0961] 5-(2-Methylpropenyl)-thiophene-2-carbonitrile described in
Preparation Example 144 (15 mg, 0.092 mmol) was dissolved in
tetrahydrofuran (2 mL), lithium aluminum hydride (10 mg, 0.26 mmol)
was added under stirring at room temperature, the solution was
heated to 70.degree. C., followed by stirring for 2 hours. The
reaction solution was cooled on an ice bath, then, water (0.01 mL),
an aqueous solution of 15% sodium hydroxide (0.01 mL) and water
(0.03 mL) were sequentially added, then, the solid was filtered,
and washed with tetrahydrofuran (5 mL). The filtrate and the
washings were combined, and dried over anhydrous sodium sulfate.
The solvent was evaporated in vacuo, and the title compound (14 mg,
0.083 mmol, 91.1%) was obtained as a colorless oil.
[0962] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.91 (3H,
s), 1.96 (3H, s), 4.09 (2H, s), 6.33 (1H, s), 6.75 (1H, d, J=3.6
Hz), 6.95 (1H, d, J=3.6 Hz).
Preparation Example 146
3-Isobutylbenzylamine
[0963] 3-(2-Methylpropenyl)-benzylamine described in Preparation
Example 137 (100 mg, 0.621 mmol) was dissolved in ethanol (5 mL),
10% palladium-carbon (50% water wet, 20 mg) was added thereto, and
the mixture was stirred for 2 hours at room temperature under
hydrogen atmosphere. The catalyst was filtered, then, the solvent
was evaporated, and the title compound (58 mg, 56.6%) was obtained
as a colorless oil.
[0964] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.90 (6H, d,
J=6.8 Hz), 1.87 (1H, dq, J=7.6, 6.8 Hz), 2.48 (2H, d, J=7.6 Hz),
3.84 (2H, s), 7.02-7.28 (4H, m).
Preparation Example 147
2-(2-cyclopropyl vinyl)thiophene
[0965] Potassium tert-butoxide (1.81 g, 16.2 mmol) was suspended in
N,N-dimethylformamide (50 mL), thiophen-2-ylmethyl
triphenylphosphonium chloride (6.38 g, 16.2 mmol) was added while
stirring at room temperature under a nitrogen stream, and the
mixture was stirred at room temperature for 30 minutes. Then,
cyclopropanecarboxyaldehyde (1.13 g, 16.2 mmol) was added dropwise
to the reaction solution, and the solution was stirred for 1 hour.
Water (100 mL) was added to the reaction solution, which was then
extracted with hexane (50 mL). The organic layer was passed through
silica gel (10 g) for filtration, the filtrate was evaporated in
vacuo, and the title compound (1.27 g, 8.47 mmol, 52.3%) was
obtained as a colorless oil.
[0966] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.44-0.52
(2H, m), 0.76-0.84 (2H, m), 1.451.55 (1H, m), 5.60 (1H, dd, J=8.8,
15.6 Hz), 6.83 (1H, d, J=3.2 Hz), 6.92 (1H, dd, J=3.2, 5.2 Hz),
7.00 (1H, dd, J=3.2, 5.2 Hz), 7.05 (1H, J=5.2 Hz).
Preparation Example 148
5-(2-Cyclopropylvinyl)thiophene-2-carboxy aldehyde
[0967] 2-(2-Cyclopropylvinyl)thiophene described in Preparation
Example 147 (1.27 g, 8.47 mmol) was dissolved in anhydrous diethyl
ether (20 mL), n-butyl lithium (2.47M hexane solution, 4.1 mL, 10.2
mmol) was added dropwise under stirring on an ice bath, and the
solution was stirred for 30 minutes. The reaction solution was
cooled on a dry ice-acetone bath, N,N-dimethylformamide (2 g, 27.4
mmol) was added thereto, and the solution was stirred as is for 30
minutes. Acetic acid (1 mL) and water (10 mL) were sequentially
added to the reaction solution, which was then allowed to room
temperature. The reaction solution was extracted with ethyl acetate
(50 mL), then, the organic layer was washed with brine and dried
over anhydrous magnesium sulfate. The solvent was evaporated in
vacuo, the residue was purified by silica gel column chromatography
(hexane:ethyl acetate=95:5), and the title compound (960 mg, 5.39
mmol, 63.7%) was obtained as a colorless oil.
[0968] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.57-0.63
(2H, m), 0.88-0.94 (2H, m), 1.53-1.60 (1H, m), 5.84 (1H, dd, J=9.2,
15.6 Hz), 6.59 (1H, d, J=15.6 Hz), 6.91 (1H, d, J=3.6 Hz), 7.59
(1H, d, J=3.6 Hz), 9.80 (1H, s).
Preparation Example 149
(5-(2-Cyclopropylvinyl)thiophen-2-yl)methanol
[0969] 5-(2-Cyclopropylvinyl)thiophen-2-aldehyde described in
Preparation Example 148 (960 mg, 5.39 mmol) was dissolved in a
mixture solvent of tetrahydrofuran-ethanol (2:1) (30 mL), sodium
borohydride (100 mg, 2.64 mmol) was added under stirring on an ice
bath, and the solution was stirred for 30 minutes. Acetic acid (0.5
mL) and water (10 mL) were added sequentially to the reaction
solution, which was then extracted with ethyl acetate (50 mL). The
organic layer was washed with an aqueous solution of saturated
sodium bicarbonate and brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, and the title
compound (930 mg, 5.19 mmol, 96.2%) was obtained as a colorless
oil.
Preparation Example 150
2-(5-(2-cyclopropylvinyl)thiophen-2-ylmethyl)
isoindol-1,3-dione
[0970] (5-(2-Cyclopropylvinyl)thiophen-2-yl)methanol described in
Preparation Example 149 (930 mg, 5.19 mmol), triphenylphosphine
(2040 mg, 7.78 mmol) and phthalimide (1140 mg, 7.78 mmol) were
dissolved in tetrahydrofuran (50 mL), azodicarboxylic acid dimethyl
ester (1140 mg, 7.78 mmol) was added under stirring at room
temperature, and the solution was stirred for 1 hour. Water (50 mL)
was added to the reaction solution, which was then extracted with
ethyl acetate (50 mL). The organic layer was washed with water,
dried over anhydrous magnesium sulfate, and the solvent was
evaporated in vacuo. The residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate=9:1), and the title
compound (330 mg, 1.07 mmol, 20.6%) was obtained as a white
solid.
[0971] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.44-0.48
(2H, m), 0.76-0.80 (2H, m), 1.42-1.50 (1H, m), 4.92 (2H, s), 5.52
(1H, dd, J=8.8, 15.6 Hz), 6.47 (1H, d, J=15.6 Hz), 6.62 (1H, d,
J=3.6 Hz), 6.93 (1H, d, J=3.6 Hz), 7.67-7.73 (2H, m), 7.82-7.86
(2H, m).
Preparation Example 151
C-(5-(2-Cyclopropylvinyl)thiophen-2-yl)methylamine
[0972]
2-(5-(2-Cyclopropylvinyl)thiophen-2-ylmethyl)isoindol-1,3-dione
described in Preparation Example 150 (330 mg, 1.02 mmol) was
dissolved in ethanol (50 mL), hydrazine monohydrate (500 mg, 10
mmol) was added thereto, and the solution was stirred under reflux
for 2 hours. After cooling to room temperature, 2N sodium hydroxide
solution (10 mL) and water (100 mL) were added to the reaction
solution, which was then washed twice with hexane (50 mL). The
organic layer was dried over anhydrous sodium sulfate, then, the
solvent was evaporated in vacuo, and the title compound (180 mg,
1.01 mmol, 98.6%) was obtained as a colorless oil.
[0973] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.44-0.48
(2H, m), 0.76-0.80 (2H, m), 1.42-1.50 (1H, m), 3.96 (2H, s), 5.52
(1H, dd, J=8.8, 15.6 Hz), 6.52 (1H, d, J=15.6 Hz), 6.65 (1H, d,
J=3.6 Hz), 6.71 (1H, d, J=3.6 Hz).
Preparation Example 152
C-(5-(2,2-Dicyclopropylvinyl)thiophen-2-yl)methylamine
[0974] The title compound was synthesized according to an analogous
method to Preparation Example 147 to 151.
[0975] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.42-0.46
(2H, m), 0.61-0.66 (2H, m), 0.83-0.88 (4H, m), 1.16-1.23 (1H, m),
1.96-2.03 (1H, m), 3.96 (2H, s), 6.30 (1H, s), 6.85 (1H, d, J=3.2
Hz), 6.90 (1H, d, J=3.2 Hz).
Preparation Example 153
Methanesulfonic acid 2-fluoro-benzyl ester
[0976] To a solution of 2-fluorobenzyl alcohol (4.40 g, 34.9 mmol)
in dichloromethane (40 mL) was added methanesulfonyl chloride (3.24
mL, 41.9 mmol) and triethylamine (5.84 mL, 41.9 mmol) on an ice
bath, the solution was warmed to room temperature and stirred
overnight. The reaction solution was diluted with dichloromethane,
washed with an aqueous solution of 5% sodium bicarbonate, then,
dried over anhydrous magnesium sulfate, the solvent was evaporated,
and the title compound (4.62 g, 65%) was obtained as a brown oil.
This was used in the next reaction without purification.
Preparation Example 154
4-(2-Fluorobenzyloxy)-benzylamine
[0977] The title compound (710 mg, 14%) was obtained as a yellow
oil from p-cyanophenol (2.70 g, 22.7 mmol) and methanesulfonic acid
2-fluoro-benzyl ester described in Preparation Example 153 (4.63 g,
22.7 mmol) according to an analogous method to Preparation Example
6.
Preparation Example 155
4-(4-Fluorobenzyloxy)-benzylamine
[0978] 4-(4-Fluorobenzyloxy)-benzonitrile (5.89 g, quantitatively)
was obtained from p-cyanophenol (3.00 g, 25.2 mmol) and
4-fluorobenzyl bromide (4.76 g, 25.2 mmol) according to an
analogous method to Preparation Example 6.
[0979] Next, the title compound (1.02 g, 67%) was obtained as a
yellow solid from the resulting 4-(4-fluorobenzyloxy)-benzonitrile
(1.5 g, 6.6 mmol) according to an analogous method to Preparation
Example 6.
Preparation Example 156
5-(4-chloro-phenoxy)-thiophene-2-carbonitrile
[0980] The title compound (770 mg, 3.27 mmol, 65%) was obtained as
a pale yellow oil from 5-nitrothiophene-2-carbonitrile (771 mg, 5
mmol) and 4-chlorophenol (643 mg, 5 mmol) according to an analogous
method to Preparation Example 22.
[0981] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 6.72
(1H, d, J=4.4 Hz), 7.30-7.32 (2H, m), 7.50-7.52 (2H, m), 7.67 (1H,
d, J=4.4 Hz)
Preparation Example 157
C-(5-(4-Chloro-phenoxy)-thiophen-2-yl)-methylamine
[0982] The title compound (307 mg, 1.28 mmol, 86%) was obtained as
an orange oil from 5-(4-chloro-phenoxy)-thiophene-2-carbonitrile
described in Preparation Example 156 (350 mg, 1.49 mmol) according
to an analogous method to Preparation Example 23.
[0983] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.19 (2H,
brs), 3.81-3.82 (2H, m), 6.53-6.54 (1H, m), 6.69-6.70 (1H, m),
7.10-7.13 (2H, m), 7.42-7.45 (2H, m).
Preparation Example 158
5-(2-Chloro-phenoxy)-thiophene-2-carbonitrile
[0984] The title compound (516 mg, 2.19 mmol, 44%) was obtained as
a white solid from 5-nitrothiophene-2-carbonitrile (771 mg, 5 mmol)
and 2-chlorophenol (643 mg, 5 mmol) according to an analogous
method to Preparation Example 22.
[0985] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 6.63
(1H, d, J=4.0 Hz), 7.35-7.40 (1H, m), 7.42-7.50 (2H, m), 7.61-7.65
(2H, m).
Preparation Example 159
C-(5-(2-Chloro-phenoxy)-thiophen-2-yl)-methylamine
[0986] The title compound (305 mg, 1.27 mmol, 72%) was obtained as
an orange oil from 5-(2-chloro-phenoxy)-thiophene-2-carbonitrile
described in Preparation Example 158 (356 mg, 1.51 mmol) according
to an analogous method to Preparation Example 23.
[0987] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.10 (2H,
brs), 3.80 (2H, s), 6.48-6.50 (1H, m), 6.66-6.72 (1H, m), 7.15-7.23
(2H, m), 7.34-7.38 (1H, m), 7.56-7.59 (1H, m).
Preparation Example 160
5-(2-Fluoro-phenoxy)-thiophene-2-carbonitrile
[0988] The title compound (684 mg, 3.12 mmol, 77%) was obtained as
a colorless oil from 5-nitrothiophene-2-carbonitrile (771 mg, 5
mmol) and 2-fluorophenol (673 mg, 6 mmol) according to an analogous
method to Preparation Example 22.
[0989] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 6.76 (1H,
d, J=4.4 Hz), 7.29-7.33 (1H, m), 7.35-7.41 (1H, m), 7.43-7.53 (2H,
m), 7.79 (1H, d, J=4.4 Hz).
Preparation Example 161
C-(5-(2-Fluoro-phenoxy)-thiophen-2-yl)-methylamine
[0990] The title compound (298 mg, 1.33 mmol, 84%) was obtained as
a brown oil from 5-(2-fluoro-phenoxy)-thiophene-2-carbonitrile
described in Preparation Example 160 (350 mg, 1.60 mmol) according
to an analogous method to Preparation Example 23.
[0991] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.79 (2H,
s), 6.45-6.47 (1H, m), 6.64-6.70 (1H, m), 7.15-7.27 (3H, m),
7.34-7.41 (1H, m).
Preparation Example 162
3-Bromo-quinoline-6-carboxylic acid methyl ester
[0992] To a mixture of quinoline-6-carboxylic acid methyl ester
(0.50 g, 2.7 mmol) and tetrahydrofuran (10 mL) was added
1,3-dibromo-5,5-dimethyl hydantoin (0.76 g, 2.7 mmol) on an ice
bath, and the solution was stirred at 50.degree. C. for 4 hours.
Water, an aqueous solution of saturated sodium bicarbonate and
ethyl acetate were added to the reaction solution, which was then
partitioned, the organic layer was washed with brine, the solvent
was then evaporated in vacuo. The residue was purified by silica
gel column chromatography (hexane:ethyl acetate=4:1), and the title
compound (69 mg, 0.26 mmol, 10%) was obtained as a white solid.
[0993] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.01 (3H,
s), 8.13 (1H, d, J=8.8 Hz), 8.32 (1H, dd, J=2.0, 8.8 Hz), 8.42 (1H,
d, J=2.4 Hz), 8.52 (1H, d, J=1.8 Hz), 9.00 (1H, d, J=2.4 Hz).
Preparation Example 163
3-Bromo-quinoline-6-carboxylic acid lithium salt
[0994] To a mixture of 3-bromo-quinoline-6-carboxylic acid methyl
ester described in Preparation Example 162 (26 mg, 0.098 mmol) and
tetrahydrofuran (2 mL) were added methanol (0.2 mL), lithium
hydroxide monohydrate (4.1 mg, 0.098 mmol) and water (0.2 mL), and
the solution was stirred overnight at room temperature. The solvent
was evaporated in vacuo, and the title compound (27 mg) was
obtained.
Preparation Example 164
Quinoline-6-carboxylic acid methyl ester N-oxide
[0995] To a mixture of quinoline-6-carboxylic acid methyl ester
(4.7 g, 25 mmol) and chloroform (80 mL) was added 3-chloro-peroxyl
benzoic acid (purity 65%, 8.6 g, 33 mmol) on an ice bath, and the
solution was stirred at room temperature for 75 minutes. Water and
an aqueous solution of 1N sodium hydroxide were added to the
reaction solution, which was then partitioned, the organic layer
was sequentially washed with an aqueous solution of saturated
sodium thiosulfate and brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo, and the title
compound (3.8 g, 19 mmol, 75%) was obtained as a pale yellow
solid.
[0996] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.03 (3H,
s), 7.38 (1H, dd, J=6.0, 8.4 Hz), 7.84 (1H, d, J=8.4 Hz), 8.34 (1H,
dd, J=1.8, 9.2 Hz), 8.60 (1H, dd, J=0.9, 6.0 Hz), 8.63 (1H, d,
J=1.8 Hz), 8.81 (1H, d, J=9.2 Hz).
Preparation Example 165
2-Chloro-quinoline-6-carboxylic acid methyl ester
[0997] Phosphorus oxychloride (10 mL) was added to
quinoline-6-carboxylic acid methyl ester N-oxide (1.5 g, 7.6 mmol),
and the solution was refluxed for 2 hours. The reaction solution
was poured onto an ice, and warmed gradually to room temperature.
Ethyl acetate was added to the reaction solution, which was then
extracted, and sequentially washed with an aqueous solution of
saturated sodium bicarbonate and brine. The solvent was evaporated
in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=2:1), and the title compound
(0.47 g, 2.1 mmol, 28%) was obtained as a white solid.
[0998] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.01 (3H,
s), 7.47 (1H, dd, J=0.6, 8.6 Hz), 8.07 (1H, d, J=8.8 Hz), 8.22 (1H,
d, J=8.6 Hz), 8.32-8.35 (1H, m), 8.59 (1H, s).
Preparation Example 166
2-Chloro-quinoline-6-carboxylic acid lithium salt
[0999] The title compound (54 mg) was obtained as a crude compound
from 2-chloro-quinoline-6-carboxylic acid methyl ester described in
Preparation Example 165 (40 mg, 0.18 mmol) according to an
analogous method to Preparation Example 163.
Preparation Example 167
C-(5-(2-Chloro-phenoxy)-thiophen-2-yl)-methylamine
[1000] To a solution of lithium aluminum hydride (1.79 g, 47.1
mmol) in tetrahydrofuran was added aluminum chloride (7.54 g, 56.5
mmol) on an ice bath, which was then stirred for 10 minutes. To the
suspension was 5-(2-chloro-phenoxy)-thiophene-2-carbonitrile
described in Preparation Example 158 (2.22 g, 9.42 mmol) was added
on an ice bath, and the solution was stirred for 1 hour. An aqueous
ammonia was added to the reaction solution, then, anhydrous
magnesium sulfate was added for drying, and the solution was
filtered through Celite pad. The filtrate was concentrated in
vacuo, the residue was purified by NH silica gel column
chromatography (heptane/ethyl acetate=1/2), and the title compound
(2.26 g, 9.42 mmol, 100%) was obtained as a light brown oil.
[1001] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.81 (2H,
s), 6.56 (1H, d, J=3.6 Hz), 6.69 (1H, dd, J=1.2, 3.6 Hz), 7.05 (1H,
dd, J=2.4, 8.4 Hz), 7.11 (1H, t, J=2.0 Hz), 7.19 (1H, dt, J=1.2,
8.0 Hz), 7.40 (1H, t, J=8.0 Hz).
Preparation Example 168
5-(4-Fluoro-phenoxy)-furan-2-carbaldehyde
[1002] To a solution of 4-fluorophenol (2.39 g, 21.3 mmol) in
dimethylsulfoxide (20 mL) was added sodium hydride (785 mg,
19.6-23.6 mmol, 60-72% in oil), and the solution was stirred at
room temperature for 20 minutes. Next, a solution of
5-nitro-furan-2-carbaldehyde (3 g, 21.3 mmol) in dimethylsulfoxide
(10 mL) was added dropwise, the solution was then stirred for 2
hours at room temperature. The reaction mixture was poured into
brine, and the mixture was extracted with ethyl acetate. The
fractionated organic layer was dried over anhydrous magnesium
sulfate, then concentrated, and the title compound (4.3 g, 20.8
mmol, 98%) was obtained.
[1003] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.23 (1H, d,
J=4.0 Hz), 7.07-7.24 (5H, m), 9.40 (1H, s).
Preparation Example 169
C-(5-(4-Fluoro-phenoxy)-furan-2-yl)methylamine
[1004] A suspension of 5-(4-fluoro-phenoxy)-furan-2-carbaldehyde
described in Preparation Example 168 (4.3 g, 20.9 mmol), Raney
nickel (1.5 g) and 7N ammonia-methanol solution (40 mL) was stirred
at room temperature for 15 hours under hydrogen atmosphere (1 atm).
The reaction solution was filtered through Celite pad to remove the
catalyst, and the filtrate was concentrated. The residue was
dissolved in ethyl acetate, filtered by NH silica gel lined over a
glass filter, and then, this filtrate was concentrated to obtain
the title compound (3.5 g, 16.9 mmol, 81%).
[1005] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.55 (2H,
s), 5.64 (1H, d, J=3.2 Hz), 6.13-6.16 (1H, m), 7.04-7.10 (2H, m),
7.17-7.24 (2H, m).
Preparation Example 170
4-(Pyridin-2-ylmethoxy)-benzonitrile
[1006] To a solution of 4-cyanophenol (5 g, 42 mmol) in
N,N-dimethyl formamide (40 mL) were added potassium carbonate (17.4
g, 126 mmol) and 2-picolyl bromide hydrobromide (10.6 g, 42 mmol),
and the solution was stirred at room temperature for 15 hours. The
reaction solution was poured into brine, and the solution was
extracted with ethyl acetate. The fractionated organic layer was
dried over anhydrous magnesium sulfate, then, filtered by NH silica
gel lined over a glass filter, and the filtrate was concentrated to
obtain the title compound (4.7 g, 22.4 mmol, 53%).
[1007] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.25 (2H,
s), 7.03-7.07 (2H, m), 7.25-7.29 (1H, m), 7.48 (1H, d, J=8.0 Hz),
7.57-7.61 (2H, m), 7.74 (1H, dt, J=1.6 Hz, 8.0 Hz), 8.61-8.63 (1H,
m).
Preparation Example 171
4-(Pyridin-2-ylmethoxy)-benzylamine
[1008] To a solution of 4-(pyridine-2-ylmethoxy)-benzonitrile
described in Preparation Example 170 (1.2 g, 5.70 mmol) in
tetrahydrofuran (30 mL) was added lithium aluminum hydride (0.22 g,
5.80 mmol), and the solution was stirred for 2 hours 30 minutes at
room temperature. Ice water was added to the reaction solution,
which was then stirred for 30 minutes. This mixture was filtered
through Celite pad, and washed with ethyl acetate. The filtrate was
partitioned, this organic layer was dried over anhydrous magnesium
sulfate, then, concentrated, and the title compound (1.1 g, 5.13
mmol, 90%) was obtained.
[1009] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.81 (2H,
s), 5.21 (2H, s), 6.94-6.98 (2H, m), 7.20-7.26 (3H, m), 7.52 (1H,
d, J=7.8 Hz), 7.74 (1H, dt, J=1.6 Hz, 7.8 Hz), 8.59-8.62 (1H,
m).
Preparation Example 172
4-(Pyridin-2-yloxymethyl)-benzylamine
[1010] To a solution of 2-bromopyridine (2.35 g, 15.0 mmol) and
4-(hydroxymethyl)benzonitrile (3.00 g, 22.5 mmol) in
N,N-dimethylformamide (20 mL) was added sodium hydride (0.90 g,
22.5 mmol; 60% in oil), and the solution was stirred at 70.degree.
C. for 30 minutes. The reaction solution was allowed to room
temperature, then, partitioned in ethyl acetate and water, the
organic layer was washed with water, and then, dried over anhydrous
magnesium sulfate. The solvent was evaporated, the residue was
purified by NH silica gel column chromatography (hexane/ethyl
acetate), and a white solid (581 mg, 18%) was obtained.
[1011] To a solution of the obtained white solid (100 mg, 0.476
mmol) in tetrahydrofuran (3 mL) was added lithium aluminum hydride
(45 mg, 1.19 mmol), and the solution was stirred at room
temperature for 1 hour. The reaction solution was partitioned in
ethyl acetate and water, and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
title compound (71 mg, 70%) was obtained as a colorless solid,
which is a crudely purified product.
[1012] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.70 (2H,
s), 5.31 (2H, s), 6.84-6.87 (1H, m), 6.97-7.00 (1H, m), 7.32 (2H,
d, J=8.0 Hz), 7.37 (2H, d, J=8.0 Hz), 7.69-7.74 (1H, m), 8.16-8.18
(1H, m).
Preparation Example 173
5-Bromo-2,3-dihydro-benzofuran
[1013] To a solution of 2,3-dihydrobenzofuran (15.0 g, 125 mmol) in
tetrahydrofuran (300 mL) was added N-bromosuccinimide (24.5 g, 138
mmol) at 0.degree. C. The reaction solution was stirred at room
temperature for 50 minutes, then, water was added, the solution was
extracted with ethyl acetate, and the organic layer was washed with
brine. Anhydrous magnesium sulfate was added to the organic layer
for drying, which was then filtered, the filtrate was concentrated
in vacuo, the residue was purified by NH silica gel column
chromatography (hexane), and the title compound (24.0 g, 97%) was
obtained as a colorless oily substance.
[1014] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.19 (2H,
t, J=8.6 Hz), 4.54 (2H, t, J=8.6 Hz), 6.72 (1H, d, J=8.2 Hz), 7.22
(1H, dd, J=2.2. 8.4 Hz), 7.40 (1H, s).
Preparation Example 174
2,3-Dihydro-benzofuran-5-carbaldehyde
[1015] To a solution of 5-bromo-2,3-dihydro-benzofuran described in
Preparation Example 173 (15.0 g, 75.4 mmol) in tetrahydrofuran (300
mL) was added n-butyl lithium (31.2 mL, 82.9 mmol) at -78.degree.
C. The reaction solution was stirred for 85 minutes at -78.degree.
C., then, N,N-dimethylformamide (6.42 mL, 82.9 mmol) was added
thereto, followed by stirring at room temperature for 1 hour. 1N
Hydrochloric acid was added to the reaction solution, which was
then extracted with ethyl acetate, and the organic layer was washed
with brine. Anhydrous magnesium sulfate was added to the organic
layer for drying, which was then filtered, the filtrate was
concentrated in vacuo, the residue was purified by silica gel
column chromatography (hexane/ethyl acetate=5/1), and the title
compound (10.1 g, 90%) was obtained as a pale yellow oil.
[1016] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.26 (2H,
t, J=8.6 Hz), 4.67 (2H, t, J=8.6 Hz), 6.96 (1H, d, J=7.9 Hz), 7.72
(1H, d, J=8.2 Hz), 7.77 (1H, s), 9.82 (1H, s).
Preparation Example 175
Benzofuran-5-carbaldehyde
[1017] To a solution of 2,3-dihydro-benzofuran-5-carbaldehyde
described in Preparation Example 174 (6.00 g, 40.5 mmol) in toluene
(120 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (18.3
g, 81 mmol), and the solution was refluxed for 4 hours 30 minutes.
The reaction solution was cooled to room temperature, water was
added, the solution was extracted with ethyl acetate and
tetrahydrofuran, and the organic layer was washed with brine.
Anhydrous magnesium sulfate was added to the organic layer for
drying, which was then filtered, the filtrate was concentrated in
vacuo, the residue was purified by silica gel column chromatography
(hexane/ethyl acetate=5/1), and the title compound (1.24 g, 21%)
was obtained as a pale yellow oil.
[1018] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 6.91 (1H,
dd, J=0.92, 2.2 Hz), 7.63 (1H, d, J=8.6 Hz), 7.74 (1H, d, J=2.4
Hz), 7.89 (1H, dd, J=1.7, 8.6 Hz), 8.16 (1H, s), 10.08 (1H, s).
Preparation Example 176
Benzofuran-5-yl-(5-bromo-thiophen-2-yl)-methanol
[1019] To a solution of 2,5-dibromothiophene (2.05 g, 8.48 mmol) in
tetrahydrofuran (25 mL) was added n-butyl lithium (3.48 mL, 8.48
mmol) at -78.degree. C., and the solution was stirred for 40
minutes. Then, benzofuran-5-carbaldehyde described in Preparation
Example 175 (1.24 g, 8.48 mmol) was added to this reaction solution
at -78.degree. C., and the solution was stirred at room temperature
for 75 minutes. Water was added to the reaction solution, which was
then extracted with ethyl acetate, and the organic layer was washed
with brine. Anhydrous magnesium sulfate was added to the organic
layer for drying, which was then filtered, the filtrate was
concentrated in vacuo, the residue was purified by NH silica gel
column chromatography (heptane/ethyl acetate=3/1), and the title
compound (2.11 g, 81%) was obtained as a light brown oil.
[1020] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 5.98 (1H,
s), 6.40 (1H, d, J=2.9 Hz), 6.68 (1H, dd, J=0.92, 3.8 Hz), 6.96
(1H, dd, J=0.92, 2.2 Hz), 7.01 (1H, d, J=3.8 Hz), 7.34 (1H, dd,
J=1.5, 8.4 Hz), 7.55 (1H, d, J=8.4 Hz), 7.68 (1H, s), 7.99 (1H, d,
J=2.2 Hz).
Preparation Example 177
5-(Benzofuran-5-yl-hydroxy-methyl)-thiophene-2-carbonitrile
[1021] To a solution of
benzofuran-5-yl-(5-bromo-thiophen-2-yl)-methanol described in
Preparation Example 176 (755 mg, 2.44 mmol) in
1-methyl-2-pyrrolidinone (15 mL) were added zinc cyanide (344 mg,
2.93 mmol) and tetrakis(triphenylphosphine)palladium (282 mg, 0.244
mmol), and the mixture was stirred at 120.degree. C. for 3 hours.
The reaction mixture was cooled to room temperature, then, aqueous
ammonia was added, and the solution was filtered through Celite
pad. The mother liquor was extracted with ethyl acetate, and the
organic layer was washed with brine. Anhydrous magnesium sulfate
was added to the organic layer for drying, which was then filtered,
the filtrate was concentrated in vacuo, the residue was purified by
silica gel column chromatography (heptane/ethyl acetate=3/1), and
the title compound (364 mg, 58%) was obtained as a pale yellow
oil.
[1022] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta. (ppm): 6.13 (1H,
s), 6.73 (1H, s), 6.97 (1H, d, J=2.2 Hz), 6.99 (1H, d, J=3.8 Hz),
7.37 (1H, dd, J=1.5, 8.4 Hz), 7.58 (1H, d, J=8.6 Hz), 7.72 (1H, s),
7.78 (1H, d, J=3.8 Hz), 8.01 (1H, d, J=2.2 Hz).
Preparation Example 178
C-(5-Benzofuran-5-ylmethyl-thiophen-2-yl)-methylamine
[1023] To a solution of lithium aluminum hydride (488 mg, 12.9
mmol) in tetrahydrofuran (10 mL) was added aluminum chloride (1.72
g, 12.9 mmol) on an ice bath, and the solution was stirred for 10
minutes.
5-(Benzofuran-5-yl-hydroxy-methyl)-thiophene-2-carbonitrile
described in Preparation Example 177 (364 mg, 1.43 mmol) was added
to this suspension on an ice bath, and the solution was stirred for
3 hours. Aqueous ammonia was added to the reaction solution, then,
anhydrous magnesium sulfate was added for drying, and the solution
was filtered through Celite pad. The filtrate was concentrated in
vacuo, the residue was purified by NH silica gel column
chromatography (heptane/ethyl acetate=1/1), and the title compound
(285 mg, 82%) was obtained as a light brown oil.
[1024] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.77 (2H,
s), 4.15 (2H, s), 6.70 (2H, s), 6.91 (1H, d, J=2.2 Hz), 7.19 (1H,
dd, J=1.7, 8.4 Hz), 7.50-7.52 (2H, m), 7.96 (1H, d, J=2.2 Hz).
Preparation Example 179
C-(6-Benzyloxypyridin-3-yl)-methylamine
[1025] To a solution of 2,5-dibromopyridine (5.0 g, 21.1 mmol) and
benzyl alcohol (3.28 mL, 31.7 mmol) in N,N-dimethylformamide (50
mL) was added sodium hydride (1.27 g, 31.7 mmol; 60% in oil), and
the solution was stirred at 70.degree. C. for 2 hours. The reaction
solution was allowed to room temperature, then, partitioned in
ethyl acetate and water, the organic layer was washed with water,
and then, dried over anhydrous magnesium sulfate. The solvent was
evaporated, the residue was purified by silica gel column
chromatography (hexane/ethyl acetate), and a colorless oil (4.60 g,
83%) was obtained.
[1026] To a solution of the resulting colorless oil (2.0 g, 7.60
mmol) in N,N-dimethylformamide (20 mL) were added zinc cyanide
(1.78 g, 15.2 mmol) and tetrakis(triphenylphosphine)palladium (0)
(878 mg, 0.760 mmol) under nitrogen atmosphere, and the solution
was stirred at 140.degree. C. for 4 hours. The reaction solution
was allowed to room temperature, then, partitioned in ethyl acetate
and water, the organic layer was washed with water, and then, dried
over anhydrous magnesium sulfate. The solvent was evaporated, the
residue was purified by silica gel column chromatography
(hexane/ethyl acetate), and a pale yellow solid (1.15 g, 72%) was
obtained.
[1027] To a solution of the pale yellow solid (100 mg, 0.476 mmol)
in tetrahydrofuran (3 mL) was added lithium aluminum hydride (45
mg, 0.120 mmol), and the solution was stirred at room temperature
for 1 hour. The reaction solution was partitioned in ethyl acetate
and water, and the organic layer was dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the title compound (75 mg,
74%) was obtained as a yellow oil, which was a crudely purified
product.
[1028] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.37-4.38
(2H, br d), 5.36 (2H, s), 6.83-6.87 (1H, m), 7.30-7.46 (4H, m),
7.74-7.76 (1H, m), 8.17 (1H, s), 8.80-8.83 (1H, m).
Preparation Example 180
C-(6-Benzyl-pyridin-3-yl)-methylamine
[1029] A solution of 2,5-dibromopyridine (10 g, 42.2 mmol) in
diethyl ether (260 mL) was cooled to -78.degree. C. under nitrogen
atmosphere, and n-butyl lithium (17.8 mL, 46.4 mmol; 2.6M hexane
solution) was added dropwise. This solution was stirred at
-78.degree. C. for 15 minutes, then, a solution of
N,N-dimethylformamide (4.94 mL) in diethyl ether solution (10 mL)
was added dropwise at -78.degree. C. This solution was warmed to
0.degree. C., and further stirred for 2 hours at this temperature.
After the reaction was completed, this solution was partitioned in
diethyl ether and water. The organic layer was separated, washed
with water and dried over anhydrous magnesium sulfate. The solvent
was evaporated, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and an aldehyde derivative
(5.82 g, 74%) was obtained.
[1030] To a solution of the resulting aldehyde derivative (5.82 g,
31.3 mmol) in toluene (120 mL) were added ethyleneglycol (17.5 mL,
0.313 mol) and D-10-camphor-sulfonic acid (73 mg, 0.313 mmol), and
the solution was refluxed for 7 hours. The reaction mixture was
cooled to room temperature, then, washed with an aqueous solution
of saturated sodium hydrogen carbonate and brine, and the organic
layer was separated. The organic layer was dried over anhydrous
magnesium sulfate, then, solvent was evaporated, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate), and an acetal (6.65 g, 93%) was obtained.
[1031] Next, to a suspension of zinc (1.53 g, 23.4 mmol) in
tetrahydrofuran (120 mL) was added benzyl bromide (2.1 mL, 17.6
mmol) dropwise over 15 minutes, at 0.degree. C., and the solution
was stirred at this temperature for 4 hours. After 4 hours,
bis(triphenylphosphine)nickel(II) chloride (1.58 g, 2.42 mmol) and
a solution of the acetal (3.0 g, 13.1 mmol) in tetrahydrofuran (90
mL) were added to this suspension, and the solution was stirred at
room temperature for 12 hours. After the reaction was completed,
this suspension was partitioned in ethyl acetate and an aqueous
solution of saturated ammonium chloride. The organic layer was
separated, washed with water and brine, and then, dried over
anhydrous magnesium sulfate. The solvent was evaporated, the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate), and a 2-benzyl pyridine derivative (1.08 g,
34%) was obtained.
[1032] To a mixture solution of the resulting 2-benzyl pyridine
derivative (1.08 g, 4.48 mmol) in methanol and tetrahydrofuran (5
mL:4 mL) was added 2N hydrochloric acid (5 mL), and the solution
was stirred at room temperature for 2 hours. Furthermore, to this
solution was added 5N hydrochloric acid (8 mL) was added in three
times, the solution was stirred at room temperature for 24 hours,
then, refluxed for 30 minutes. The reaction solution was cooled to
room temperature, then, partitioned in ethyl acetate and an aqueous
solution of saturated sodium bicarbonate. The organic layer was
separated, washed with water, and then, dried over anhydrous
magnesium sulfate. The solvent was evaporated, and a formyl
derivative (950 mg, quantitatively) was obtained.
[1033] To a solution of the resulting formyl derivative (950 mg,
4.48 mmol) in methanol (25 mL) was added sodium borohydride (176
mg, 4.66 mmol), and the solution was stirred at room temperature
for 1 hour. The reaction solution was partitioned in ethyl acetate
and water. This organic layer was separated, washed with water and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
and a benzyl alcohol derivative (810 mg, 91%) was obtained.
[1034] Methanesulfonyl chloride (0.37 mL, 4.83 mmol) and
triethylamine (0.67 mL, 4.84 mL) were added to a solution of the
resulting benzyl alcohol derivative (810 mg, 4.07 mmol) in
dichloromethane (8 mL) that had been cooled to 0.degree. C., and
the solution was stirred at room temperature for 14 hours. The
reaction mixture was partitioned in dichloromethane and an aqueous
solution of saturated sodium bicarbonate. The organic layer was
separated, washed with brine, and then, dried over anhydrous
magnesium sulfate. The solvent was evaporated, and a
methanesulfonate ester derivative (1.09 g, 97%) was obtained.
[1035] To a solution of the resulting methanesulfonate ester
derivative (1.09 g, 3.93 mmol) in N,N-dimethylformamide (10 mL) was
added phthalimide potassium salt (757 mg, 4.09 mmol), and the
solution was stirred for 2 hours under reflux. This reaction
mixture was cooled to room temperature, and partitioned in ethyl
acetate and water. This organic layer was separated, washed with
water and brine, and then, dried over anhydrous magnesium sulfate.
The solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and a phthalimide
derivative (910 mg, 71%) was obtained.
[1036] Then, to a solution of the resulting phthalimide derivative
(910 mg, 2.77 mmol) in ethanol (23 mL) was added hydrazine
monohydrate (144 mg, 2.88 mmol), and the solution was stirred for 2
hours under reflux. The reaction mixture was cooled to room
temperature, then, water was added to this mixture. This mixture
was concentrated in vacuo until the liquid volume of this mixture
became half. This concentrated solution was partitioned in ethyl
acetate and water. This organic layer was separated, washed with 2N
sodium hydroxide and water, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the title compound (360
mg, 66%) was obtained. This was used in the next reaction without
further purification.
Preparation Example 181
2-Amino-methyl-5-phenoxy-pyridine
[1037] 2-Cyano-5-phenoxy-pyridine (150 mg, 0.76 mmol) and lithium
aluminum hydride (58 mg, 1.53 mmol) were suspended in
tetrahydrofuran (5 mL) and diethyl ether (5 mL), and the solution
was stirred for 10 minutes under reflux. The reaction solution was
partitioned in water and ethyl acetate. The organic layer was
separated, the solvent was evaporated, and the title compound (140
mg, brown oil) was obtained as a crude product.
[1038] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.80 (2H,
s), 6.70-6.80 (2H, m), 7.00-7.12 (1H, m), 7.12-7.22 (2H, m),
7.40-7.50 (2H, m), 8.30 (1H, s).
Preparation Example 182
5-Benzyloxy-2-methyl-pyridine
[1039] To a solution of 3-hydroxy-6-methylpyridine (5.00 g, 45.8
mmol) in N,N-dimethylformamide (50 mL) was added sodium hydride
(2.02 g, 50.4 mmol, 60% in oil) at 0.degree. C., and the solution
was stirred for 15 minutes at 0.degree. C. Then, benzyl bromide
(5.99 mL, 50.4 mmol) was added at 0.degree. C., and the solution
was stirred for 3.5 hours at room temperature. The reaction
solution was partitioned in water and ethyl acetate. This organic
layer was separated, washed with water and brine and dried over
anhydrous magnesium sulfate. The organic layer was filtered, then,
the solvent was evaporated in vacuo, the residue was purified by
silica gel column chromatography (heptane/ethyl acetate=2/1), and
the title compound (5.99 g, 66%) was obtained as a colorless
oil.
[1040] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.49 (3H,
s), 5.08 (2H, s), 7.05 (1H, d, J=8.6 Hz), 7.17 (1H, dd, J=2.9 Hz,
8.4 Hz), 7.31-7.44 (5H, m), 8.27 (1H, d, J=2.9 Hz).
Preparation Example 183
(5-Benzyloxy-pyridin-2-yl)-methanol
[1041] To a solution of 5-benzyloxy-2-methylpyridine described in
Preparation Example 182 (5.99 g, 30.1 mmol) in methylene chloride
(100 mL) was added 3-chloroperoxylbenzoic acid (8.79 g, 33.1 mmol,
65%) at 0.degree. C., and the solution was stirred at room
temperature for 2 hours. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C.,
which was partitioned with methylene chloride. This organic layer
was separated, washed with an aqueous solution of saturated sodium
bicarbonate and brine, and dried over anhydrous magnesium sulfate.
The organic layer was filtered, then, the solvent was evaporated in
vacuo, and 5-benzyloxy-2-methyl-pyridine-1-oxide (7.71 g) was
obtained as a crude product of a white solid. Next, acetic
anhydride (77 mL) was added to 5-benzyloxy-2-methyl-pyridin-1-oxide
(7.71 g), and the solution was stirred for 80 minutes at
120.degree. C. This reaction mixture was cooled to room
temperature, then, the solvent was evaporated in vacuo. Ethanol (50
mL) and an aqueous solution of 5N sodium hydroxide (7 mL) were
added to the resulting residue, and the solution was stirred at
room temperature for 50 minutes. The solvent was evaporated in
vacuo, this residue was partitioned in brine and ethyl acetate. The
organic layer was separated, washed with brine and dried over
anhydrous magnesium sulfate. The organic layer was filtered, then,
the solvent was evaporated in vacuo, the residue was purified by NH
silica gel column chromatography (heptane/ethyl acetate=1/1), and
the title compound (4.17 g, 54%) was obtained as a white solid.
[1042] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.46 (2H,
d, J=5.9 Hz), 5.15 (2H, s), 5.26 (1H, t, J=5.9 Hz), 7.29-7.40 (4H,
m), 7.42-7.45 (3H, m), 8.22 (1H, d, J=2.9 Hz).
Preparation Example 184
2-(5-Benzyloxy-pyridin-2-ylmethyl)-isoindol-1,3-dione
[1043] To a solution of (5-benzyloxy-pyridin-2-yl)-methanol
described in Preparation Example 183 (2.00 g, 9.29 mmol) in
tetrahydrofuran (40 mL) were added phthalimide (1.50 g, 10.2 mmol),
triphenylphosphine (2.92 g, 11.1 mmol) and diethyl azodicarboxylate
(5.08 mL, 11.1 mmol, 40% toluene solution) at 0.degree. C., and the
solution was stirred at room temperature for 2 hours. The reaction
solution was partitioned in water and ethyl acetate. The organic
layer was separated, washed with brine and dried over anhydrous
magnesium sulfate. The organic layer was filtered, then, the
solvent was evaporated in vacuo, the residue was purified by silica
gel column chromatography (heptane/ethyl acetate=2/1), and the
title compound (4.1 g, quantitatively) was obtained as a white
solid.
[1044] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.84 (2H,
s), 5.15 (2H, s), 7.31-7.45 (7H, m), 7.86-7.92 (4H, m), 8.20 (1H,
d, J=2.9 Hz).
Preparation Example 185
C-(5-Benzyloxy-pyridin-2-yl)-methylamine
[1045] 2-(5-Benzyloxy-pyridin-2-ylmethyl)-isoindol-1,3-dione
described in Preparation Example 184 (4.10 g, 11.9 mmol) was
dissolved in ethanol (40 mL) and tetrahydrofuran (40 mL). Hydrazine
monohydrate (5.77 mL, 119 mmol) was added to this solution at room
temperature, and the solution was stirred under reflux for 50
minutes. The reaction solution was partitioned in water and ethyl
acetate. This organic layer was separated, washed with brine and
dried over anhydrous magnesium sulfate. The organic layer was
filtered, then, the solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (ethyl
acetate), and the title compound (2.8 g, quantitatively) was
obtained as a pale yellow solid.
[1046] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.70 (2H,
s), 5.15 (2H, s), 7.30-7.45 (7H, m), 8.23 (1H, d, J=3.2 Hz).
Preparation Example 186
2-Methyl-5-phenoxymethyl-pyridine
[1047] Thionyl chloride (1 mL) was added to
(6-methyl-pyridin-3-yl)-methanol (300 mg, 2.44 mmol) at 0.degree.
C., and the solution was stirred at room temperature for 20
minutes. The reaction solution was partitioned in an aqueous
solution of saturated sodium bicarbonate and ethyl acetate. This
organic layer was separated, washed with brine, and then, dried
over anhydrous magnesium sulfate. The organic layer was filtered,
then, the solvent was evaporated in vacuo. N,N-dimethylformamide (5
mL), phenol (230 mg, 2.44 mmol) and potassium carbonate (674 mg,
4.88 mmol) were added to this residue at room temperature. This
reaction mixture was stirred at room temperature for 40 minutes,
then, further stirred for at 60.degree. C. 40 minutes. The reaction
solution was partitioned in water and ethyl acetate. The organic
layer was separated, washed with water and brine, and then, dried
over anhydrous magnesium sulfate. The organic layer was filtered,
then, the solvent was evaporated in vacuo, the residue was purified
by silica gel column chromatography (heptane/ethyl acetate=2/1),
and the title compound (323 mg, 66%) was obtained as a white
solid.
[1048] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.58 (3H,
s), 5.04 (2H, s), 6.96-7.00 (3H, m), 7.18 (1H, d, J=8.2 Hz), 7.30
(2H, t, J=8.8 Hz), 7.67 (1H, dd, J=2.0 Hz, 8.0 Hz), 8.56 (1H,
s).
Preparation Example 187
(5-Phenoxymethyl-pyridin-2-yl)-methanol
[1049] To a solution of 2-methyl-5-phenoxymethyl-pyridine described
in Preparation Example 186 (323 mg, 1.62 mmol) in methylene
chloride was added 3-chloroperoxylbenzoic acid (473 mg, 1.78 mmol,
65%) at 0.degree. C., and the solution was stirred at room
temperature for 7 hours. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C.,
which was then partitioned with ethyl acetate. The organic layer
was separated, washed with an aqueous solution of saturated sodium
bicarbonate and brine, and then, dried over anhydrous magnesium
sulfate. The organic layer was filtered, then, the solvent was
evaporated in vacuo. Acetic anhydride (4 mL) was added to this
residue, which was then stirred for 30 minutes at 120.degree. C.
This reaction solution was cooled to room temperature, then, the
solvent was evaporated in vacuo. Ethanol (5 mL), and an aqueous
solution of 5N sodium hydroxide (2 mL) were added to this residue,
and the solution was stirred at room temperature for 45 minutes.
This reaction solution was concentrated in vacuo, the residue was
partitioned in water and ethyl acetate. The organic layer was
separated, washed with brine, and then, dried over anhydrous
magnesium sulfate. The organic layer was filtered, then, the
solvent was evaporated in vacuo, the residue was purified by NH
silica gel column chromatography (heptane/ethyl acetate=1/1), and
the title compound (167 mg, 48%) was obtained as a white solid.
[1050] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.63 (1H, t,
J=5.2 Hz), 4.78 (2H, d, J=4.8 Hz), 5.09 (2H, s), 6.97-7.02 (3H, m),
7.27-7.33 (3H, m), 7.78 (1H, dd, J=2.2 Hz, 8.0 Hz), 8.63 (1H, d,
J=1.7 Hz).
Preparation Example 188
2-(5-Phenoxymethyl-pyridin-2-ylmethyl)-isoindol-1,3-dione
[1051] To a solution of (5-phenoxymethyl-pyridin-2-yl)-methanol
described in Preparation Example 187 (167 mg, 0.776 mmol) in
tetrahydrofuran (4 mL) were added phthalimide (126 mg, 0.856 mmol),
triphenylphosphine (244 mg, 0.930 mmol) and diethyl
azodicarboxylate (424 .mu.L, 0.93 .mu.mol, 40% toluene solution) at
0.degree. C., and the solution was stirred at room temperature for
30 minutes. The reaction solution was partitioned with water and
ethyl acetate. The organic layer was separated, washed with brine,
and then, dried over anhydrous magnesium sulfate. The organic layer
was filtered, then, the solvent was evaporated in vacuo, the
residue was purified by silica gel column chromatography
(heptane/ethyl acetate=1/1), and the title compound (383 mg,
quantitatively) was obtained as a white solid.
[1052] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.92 (2H,
s), 5.10 (2H, s), 6.94 (1H, t, J=7.3 Hz), 7.00 (2H, dd, J=0.92 Hz,
8.8 Hz), 7.29 (2H, dd, J=7.2 Hz, 8.8 Hz), 7.44 (1H, d, J=7.9 Hz),
7.85 (1H, dd, J=2.0 Hz, 8.0 Hz), 7.87-7.94 (4H, m), 8.52 (1H, d,
J=1.8 Hz).
Preparation Example 189
C-(5-Phenoxymethyl-pyridin-2-yl)-methylamine
[1053] 2-(5-Phenoxymethyl-pyridin-2-ylmethyl)-isoindol-1,3-dione
described in Preparation Example 188 (383 mg, 1.11 mmol) was
dissolved in ethanol (3 mL) and tetrahydrofuran (3 mL). Hydrazine
monohydrate (538 .mu.L, 11.1 mmol) was added to this solution at
room temperature, and the solution was stirred under reflux for 1
hour. The reaction solution was partitioned in water and ethyl
acetate. The organic layer was separated, washed with brine, and
then, dried over anhydrous magnesium sulfate. The organic layer was
filtered, then, the solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (ethyl
acetate/methanol=10/1), and the title compound (122 mg, 51%) was
obtained as a colorless oil.
[1054] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.00 (2H,
s), 5.07 (2H, s), 6.67-7.01 (3H, m), 7.29-7.33 (3H, m), 7.75 (1H,
dd, J=2.4 Hz, 8.0 Hz), 8.63 (1H, d, J=1.6 Hz).
Preparation Example 190
4-(6-Fluoro-pyridin-2-yloxymethyl)-benzylamine
[1055] To a solution of 2,6-difluoropyridine (500 mg, 4.34 mmol)
and 4-(hydroxymethyl)benzonitrile (867 mg, 6.51 mmol) in
N,N-dimethylformamide (3 mL) was added sodium hydride (0.26 g, 6.5
.mu.mol; 60% in oil), and the solution was stirred at 70.degree. C.
for 7 hours. The reaction solution was allowed to room temperature,
then, partitioned in ethyl acetate and water, the organic layer was
washed with water, and then, dried over anhydrous magnesium
sulfate. The solvent was evaporated, the residue was purified by
silica gel column chromatography (hexane/ethyl acetate), and a
white solid (734 mg, 74%) was obtained.
[1056] To a solution of the resulting white solid (734 mg, 3.22
mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride
(244 mg, 6.44 mmol), and the solution was stirred at room
temperature for 30 minutes. The reaction solution was partitioned
in ethyl acetate and water, and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
title compound (662 mg, 89%) was obtained as a crude product.
[1057] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.71 (2H,
s), 5.27 (2H, s), 6.71-6.73 (1H, m), 6.79-6.81 (1H, m), 7.33-7.39
(4H, m), 7.86-7.90 (1H, m).
Preparation Example 191
4-(3-Chloro-benzyloxy)-benzylamine
[1058] To a solution of 4-cyanophenol (2.28 g, 19.1 mmol) and
3-chlorobenzyl bromide (2.2 mL, 16.8 mmol) in N,N-dimethylformamide
(100 mL) was added potassium carbonate (5.88 g, 42.5 mmol), and the
solution was stirred at 50.degree. C. for 9 hours. The reaction
mixture was partitioned in ethyl acetate and water. This organic
layer was separated, washed with 2N sodium hydroxide, water and
then brine, and dried over anhydrous magnesium sulfate. The solvent
was evaporated, and a crude product (4.20 g, quantitatively) was
obtained.
[1059] To a suspension of aluminum chloride in tetrahydrofuran (40
mL) was added lithium aluminum hydride (4.70 g, 35.2 mmol) while
cooling on a water bath. A solution of the crude product (1.15 g,
4.71 mmol) in tetrahydrofuran (10 mL) was added to this suspension,
which was then stirred at 0-1.degree. C. for 50 minutes.
Concentrated aqueous ammonia (8 mL) was added to the reaction
mixture, ultrasound was applied, concentrated aqueous ammonia (8
mL) was further added, and the solution was stirred for 1 hour at
room temperature. This mixture was filtered through Celite pad, and
this filtrate was separated. This filtrate was partitioned in
tetrahydrofuran, ethyl acetate and water. This organic layer was
separated, washed with water and brine, and dried over anhydrous
sodium sulfate and anhydrous magnesium sulfate. The solvent was
evaporated, and the title compound (1.15 g, 99%) was obtained.
[1060] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.03 (2H,
brs), 3.64 (2H, s), 5.11 (2H, s), 6.94 (2H, d, J=8.0 Hz), 7.24 (2H,
d, J=8.0 Hz), 7.37-7.45 (3H, m), 7.50 (1H, s).
Preparation Example 192
4-(3-Methoxy-benzyloxy)-benzylamine
[1061] To a solution of 4-cyanophenol (3.31 g, 27.8 mmol) and
3-methoxybenzyl bromide (3.7 mL, 26.4 mmol) in
N,N-dimethylformamide (100 mL) was added potassium carbonate (8.50
g, 61.5 mmol), and the solution was stirred at 50.degree. C. for 5
hours. The reaction mixture was partitioned in diethyl ether and
water. This organic layer was separated, washed with 2N sodium
hydroxide, water and brine, and dried over anhydrous magnesium
sulfate. The solvent was evaporated, and a crude product (6.52 g,
98%) was obtained.
[1062] To a solution of the resulting crude product (3.75 g, 15.7
mmol) in tetrahydrofuran (80 mL) was added lithium aluminum hydride
(596 mg, 15.7 mmol), and the solution was stirred at room
temperature for 23 hours. Sodium fluoride (6.6 g) was added to the
reaction mixture solution at room temperature, which was then
cooled with an ice water bath, then, a mixture solution of water (2
mL) and tetrahydrofuran (18 mL) was added, followed by stirring.
This mixture solution was filtered through Celite pad, and what was
on Celite was washed with tetrahydrofuran and ethyl acetate. This
filtrate was separated, the solvent was evaporated to obtain the
title compound (3.84 g, quantitatively) as a crude product.
[1063] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.33 (2H,
brs), 3.63 (2H, s), 3.76 (3H, s), 5.06 (2H, s), 6.87-6.90 (2H, d,
J=8.4 Hz), 6.93 (2H, d, J=8.4 Hz), 7.00-7.01 (2H, m), 7.23 (2H, d,
J=8.4 Hz), 7.28-7.32 (1H, m).
Preparation Example 193
4-(4-Methyl-pyridin-2-yloxymethyl)-benzylamine
[1064] To a solution of 2-fluoro-4-methylpyridine (500 mg, 4.50
mmol) and 4-(hydroxymethyl)benzonitrile (899 mg, 6.75 mmol) in
N,N-dimethylformamide (3 mL) was added sodium hydride (0.27 g, 6.75
mmol; 60% in oil), and the solution was stirred at 70.degree. C.
for 1 hour. The reaction solution was allowed to room temperature,
then, partitioned in ethyl acetate and water, the organic layer was
washed with water, and then, dried over anhydrous magnesium
sulfate. The solvent was evaporated, the residue was purified by
silica gel column chromatography (hexane/ethyl acetate), and a
white solid (833 mg, 83%) was obtained.
[1065] To a solution of the resulting white solid (200 mg, 0.89
.mu.mol) in tetrahydrofuran (3 mL) was lithium aluminum hydride (68
mg, 1.78 mmol), and the solution was stirred at room temperature
for 1 hour. The reaction solution was partitioned in ethyl acetate
and water, and the organic layer was dried over anhydrous magnesium
sulfate. The solvent was evaporated, and the title compound (181
mg, 89%) was obtained as a crude product.
[1066] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.77 (3H,
s), 3.69 (2H, s), 5.29 (2H, s), 6.68 (1H, s), 6.82 (1H, d, J=4.4
Hz), 7.30-7.39 (4H, m), 8.02 (1H, d, J=5.6 Hz).
Preparation Example 194
4-(5-Methyl-pyridin-2-yloxymethyl)-benzylamine
[1067] To a solution of 2-fluoro-5-methylpyridine (1.0 g, 9.0 mmol)
and 4-(hydroxymethyl)benzonitrile (1.8 g, 13.5 mmol) in
N,N-dimethylformamide (5 mL) was added sodium hydride (0.54 mg,
13.5 mmol; 60% in oil), and the solution was stirred for 30 minutes
at 70.degree. C. The reaction solution was allowed to room
temperature, then, partitioned in ethyl acetate and water, the
organic layer was washed with water, and then, dried over anhydrous
magnesium sulfate. The solvent was evaporated, the residue was
purified by silica gel column chromatography (hexane/ethyl
acetate), and a white solid (1.46 g, 72%) was obtained.
[1068] To a solution of the resulting white solid (500 mg, 2.23
mmol) in tetrahydrofuran (5 mL) was added lithium aluminum hydride
(169 mg, 4.46 mmol), and the solution was stirred at room
temperature for 30 minutes. The reaction solution was partitioned
in ethyl acetate and water, and the organic layer was dried over
anhydrous magnesium sulfate. The solvent was evaporated, and the
title compound (457 mg, 90%) was obtained as a crude product.
[1069] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.20 (3H,
s), 3.69 (2H, s), 5.27 (2H, s), 6.76 (1H, d, J=8.4 Hz), 7.30-7.39
(4H, m), 7.54 (1H, d, J=7.2 Hz), 7.97 (1H, s).
Preparation Example 195
1-Bromo-4-(2-propoxy-ethyl)-benzene
[1070] To a mixture of sodium hydride (66%, 360 mg, 15 mmol) and
tetrahydrofuran (10 mL) was added 2-(4-bromophenyl)ethanol (1.5 g,
7.5 mmol) on an ice bath, the solution was stirred at room
temperature for 1 hour. 1-Iodopropane (1.5 mL, 15 mmol) and
N,N-dimethylformamide (10 mL) were added to the reaction solution
on an ice bath, and the solution was stirred overnight at
45.degree. C. The reaction solution was partitioned with water (100
mL) and heptane (200 mL). The organic layer was separated, and
washed with brine. this solvent was evaporated in vacuo, the
residue was purified by silica gel column chromatography
(heptane:ethyl acetate=30:1), and the title compound (0.80 g, 3.3
mmol, 44%) was obtained as a colorless oil.
[1071] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.88-0.92
(3H, m), 1.55-1.61 (2H, m), 2.83 (2H, t, J=7.0 Hz), 3.36-3.40 (2H,
m), 3.60 (2H, dt, J=1.5, 7.0 Hz), 7.10 (2H, d, J=8.1 Hz), 7.40 (2H,
d, J=8.2 Hz).
Preparation Example 196
4-(2-Propoxy-ethyl)-benzonitrile
[1072] 1-Bromo-4-(2-propoxy-ethyl)-benzene described in Preparation
Example 195 (790 mg, 3.2 mmol), zinc cyanide (380 mg, 3.2 mmol) and
tetrakis(triphenylphosphine)palladium (190 mg, 0.16 mmol) were
added to N-methylpyrrolidinone (10 mL), and this mixture was
stirred at 125.degree. C. for 4 hours. This reaction mixture was
allowed to cool, and water (50 mL) and ethyl acetate (50 mL) were
added thereto. This mixture solution was filtered through Celite
pad. The organic layer was separated, then, washed with water (3
times) and brine, and then, concentrated in vacuo. The residue was
purified by silica gel column chromatography (heptane:ethyl
acetate=8:1), and the title compound (120 mg, 0.62 mmol, 19%) was
obtained as a colorless oil.
[1073] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.89 (3H, t,
J=7.3 Hz), 1.57 (2H, tq, J=7.3, 7.3 Hz), 2.93 (2H, t, J=6.6 Hz),
3.38 (2H, t, J=6.7 Hz), 3.64 (2H, t, J=6.6 Hz), 7.34 (2H, d, J=8.1
Hz), 7.58 (2H, d, J=8.2 Hz).
Preparation Example 197
4-(2-Propoxy-ethyl)-benzylamine
[1074] To a mixture of lithium aluminum hydride (120 mg, 2.5 mmol)
and tetrahydrofuran (3 mL) was added
4-(2-propoxy-ethyl)-benzonitrile described in Preparation Example
196 (120 mg, 0.62 mmol), the solution was stirred overnight at room
temperature. The reaction solution was cooled to 0.degree. C.,
tetrahydrofuran (30 mL), water (0.12 mL), an aqueous solution of 5N
sodium hydroxide (0.12 mL) and water (0.36 mL) were sequentially
added dropwise. After stirring for 1 hour at room temperature, this
reaction mixture was filtered through a filter paper. This filtrate
was concentrated in vacuo, the residue was filtered using NH-silica
gel, and the title compound (123 mg, 0.64 mmol, 103%) was obtained
as a colorless oil.
[1075] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.91 (3H, t,
J=7.4 Hz), 1.55-1.62 (2H, m), 2.88 (2H, t, J=7.3 Hz), 3.40 (2H, t,
J=6.7 Hz), 3.63 (2H, t, J=7.2 Hz), 3.84 (2H, s), 7.20 (2H, d, J=8.1
Hz), 7.23 (2H, d, J=8.2 Hz).
Example A-1
2,6-Diamino-N-(5-(4-fluoro-phenoxy)-furan-2-ylmethyl)-nicotinamide
[1076] 2,6-Diamino-nicotinic acid described in Preparation Example
A-15 (0.15 g, 0.98 mmol), triethylamine (0.41 mL, 2.94 mmol) and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (0.65 g, 1.47 mmol) were dissolved in
N,N-dimethylformamide (5 mL), and the solution was stirred at room
temperature for 10 minutes. Then, a solution of
C-(5-(4-fluoro-phenoxy)-furan-2-yl)methylamine described in
Preparation Example 169 (304 mg, 1.47 mmol) in
N,N-dimethylformamide (1 mL) was added thereto, followed by
stirring at room temperature for 14 hours 50 minutes. After the
reaction was completed, reaction solution was poured into brine,
the solution was extracted with ethyl acetate, the fractionated
organic layer was dried over anhydrous magnesium sulfate and then
concentrated. The obtained residue was subjected to silica gel
column chromatography, eluted with solvent (ethyl acetate), and the
title compound (0.12 g, 0.35 mmol, 36%) was obtained.
[1077] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.28 (2H,
d, J=5.2 Hz), 5.64-5.69 (2H, m), 6.10 (2H, br s), 6.22 (1H, d,
J=3.2 Hz), 6.96 (2H, br s), 7.08-7.14 (2H, m), 7.19-7.26 (2H, m),
7.63 (1H, d, J=8.8 Hz), 8.22 (1H, t, J=5.2 Hz)
Example A-2
2,6-Diamino-N-(5-benzofuran-2-ylmethyl-furan-2-ylmethyl)-nicotinamide
[1078] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.18 (2H,
s), 4.31 (2H, d, J=5.6 Hz), 5.65 (1H, dd, J=1.2, J=8.4 Hz), 6.08
(2H, brs), 6.13-6.20 (2H, m), 6.65 (1H, s), 6.95 (2H, brs),
7.18-7.28 (2H, m), 7.48-7.53 (1H, m), 7.55 (1H, dd, J=0.8, J=5.6
Hz), 7.63 (1H, d, J=8.4 Hz), 8.23 (1H, t, J=5.6 Hz).
Example A-3
2-Amino-N-(5-(4-chloro-phenoxy)-furan-2-ylmethyl)nicotinamide
[1079] The title compound (55 mg, 0.160 mmol, 72.9%) was obtained
as a brown oil from 2-aminonicotinic acid (34 mg, 0.24 mmol) and
C-(5-(4-chlorophenoxy)furan-2-yl)methylamine described in
Preparation Example 47 (50 mg, 0.22 mmol) according to an analogous
method to Example Q-6.
[1080] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.33 (2H,
d, J=5.6 Hz), 5.73-5.77 (1H, m), 6.29 (1H, d, J=3.2 Hz), 6.54-6.58
(1H, m), 7.00-7.10 (4H, m), 7.38-7.45 (2H, m), 7.88 (1H, d, J=7.6
Hz), 8.03-8.07 (1H, m), 8.85 (1H, t, J=5.6 Hz).
Example A-4
2-Amino-N-(5-(3-chloro-benzyl)-furan-2-ylmethyl)-nicotinamide
[1081] The title compound (110 mg, 0.322 mmol, 89.4%) was obtained
as a white solid from 2-aminonicotinic acid (55 mg, 0.39 mmol) and
C-(5-(3-chloro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 56 (80 mg, 0.36 mmol) according to an analogous
method to Example Q-6.
[1082] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.94 (2H,
s), 4.34 (2H, d, J=5.6 Hz), 6.05 (1H, d, J=3.2 Hz), 6.15 (1H, d,
J=3.2 Hz), 6.54 (1H, dd, J=4.0, 8.0 Hz), 7.03 (2H, brs), 7.16-7.20
(1H, m), 7.24-7.35 (3H, m), 7.87 (1H, dd, J=1.6, 8.0 Hz), 8.05 (1H,
dd, J=1.6, 4.0 Hz), 8.48 (1H, t, J=5.6 Hz).
Example A-5
2-Amino-N-(5-benzyl-furan-2-ylmethyl)-nicotinamide
[1083] The title compound (118 mg, 0.384 mmol, 24%) was obtained
from C-(5-benzyl-furan-2-yl)-methylamine (360 mg, 1.92 mmol)
prepared from 5-benzyl-furan-2-carbaldehyde according to an
analogous method to Example Q-1, and 2-aminonicotinic acid (221 mg,
1.60 mmol) according to an analogous method to Example H-1.
[1084] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.91 (2H,
s), 4.34 (2H, d, J=6.0 Hz), 6.00 (1H, d, J=2.8 Hz), 6.14 (1H, d,
J=2.8 Hz), 6.54 (1H, dd, J=4.8, 7.6 Hz), 7.04 (2H, brs), 7.13-7.32
(5H, m), 7.87 (1H, dd, J=1.6, 7.6 Hz), 8.05 (1H, d, J=1.6, 4.8 Hz),
8.84 (1H, t, J=6.0 Hz).
Example A-6
2-Amino-N-(5-(3-fluoro-benzyl)-furan-2-ylmethyl)-nicotinamide
[1085] The title compound (252 mg, 0.775 mmol, 65%) was obtained
from 2-aminonicotinic acid (164 mg, 1.19 mmol) and
C-(5-(3-fluoro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 84 (269 mg, 1.3 .mu.mol) according to an
analogous method to Example H-1.
[1086] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.95 (2H,
s), 4.34 (2H, d, J=5.6 Hz), 6.04 (1H, d, J=3.2 Hz), 6.15 (1H, d,
J=3.2 Hz), 6.54 (1H, dd, J=4.8, 7.6 Hz), 6.97-7.12 (5H, m),
7.28-7.36 (1H, m), 7.87 (1H, dd, J=2.0, 7.6 Hz), 8.04 (1H, dd,
J=2.0, 4.8 Hz), 8.84 (1H, t, J=5.6 Hz).
Example A-7
2-Amino-N-(5-phenylaminomethyl-furan-2-ylmethyl)-nicotinamide
[1087] The title compound (49 mg, 0.15 mmol, 90%) was obtained as a
white solid from (5-aminomethyl-furan-2-ylmethyl)-phenyl-amine
described in Preparation Example 104 (34 mg, 0.17 mmol) and
2-amino-nicotinic acid (26 mg, 0.19 mmol) according to an analogous
method to Example A-26.
[1088] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.19 (2H,
d, J=6.0 Hz), 4.39 (2H, d, J=5.5 Hz), 6.02 (1H, t, J=6.0 Hz), 6.19
(2H, dd, J=3.1, 11 Hz), 6.52 (1H, t, J=7.3 Hz), 6.57 (1H, dd,
J=4.8, 7.7 Hz), 6.62 (2H, d, J=7.7 Hz), 7.03-7.07 (4H, m), 7.91
(1H, dd, J=1.7, 7.7 Hz), 8.07 (1H, dd, J=1.7, 4.8 Hz), 8.88 (1H, t,
J=5.5 Hz).
Example A-8
2-Amino-N-(5-(2-phenylamino-ethyl)-furan-2-ylmethyl)-nicotinamide
[1089] The title compound (29 mg, 86 .mu.mol, 89%) was obtained as
a white solid from 2-(5-aminomethyl-furan-2-yl)-ethyl)-phenylamine
described in Preparation Example 107 (21 mg, 97 mmol) and
2-amino-nicotinic acid (16 mg, 0.12 mmol) according to an analogous
method to Example A-26.
[1090] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.83 (2H,
t, J=7.3 Hz), 3.26 (2H, m), 4.38 (2H, d, J=5.5 Hz), 5.61 (1H, t,
J=5.7 Hz), 6.12 (1H, d, J=3.1 Hz), 6.17 (1H, d, J=3.1 Hz), 6.52
(1H, t, J=7.3 Hz), 6.54-6.59 (3H, m), 7.04-7.08 (4H, m), 7.92 (1H,
dd, J=1.8, 7.7 Hz), 8.07 (1H, dd, J=1.8, 4.8 Hz), 8.87 (1H, t,
J=5.7 Hz).
Example A-9
6-Amino-N-(5-(3-fluoro-benzyl)-furan-2-ylmethyl)-nicotinamide
[1091] The title compound (265 mg, 0.814 mmol, 63%) was obtained
from 6-aminonicotinic acid (180 mg, 1.30 mmol) and
C-(5-(3-fluoro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 84 (293 mg, 1.43 mmol) according to an
analogous method to Example H-1.
[1092] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.95 (2H,
s), 4.33 (2H, d, J=5.6 Hz), 6.03 (1H, d, J=3.2 Hz), 6.12 (1H, d,
J=3.2 Hz), 6.38 (1H, d, J=8.8 Hz), 6.45 (2H, brs), 7.00-7.09 (3H,
m), 7.28-7.36 (1H, m), 7.78 (1H, dd, J=2.4, 8.4 Hz), 8.43 (1H, d,
J=2.4 Hz), 8.56 (1H, t, J=5.6 Hz).
Example A-10
2,6-Diamino-N-(4-benzyloxy-benzyl)-nicotinamide
[1093] 2,6-Diamino-nicotinic acid described in Preparation Example
A-15 (0.6 g, 3.92 mmol), triethylamine (1.64 mL, 11.8 mmol) and
benzotriazole-1-yloxy tris(dimethylamino)phosphonium
hexafluorophosphate (2.6 g, 5.9 mmol) were dissolved in
N,N-dimethylformamide (200 mL), 4-benzyloxy-benzylamine described
in Preparation Example 1 (1.25 g, 5.9 mmol) was added thereto, and
the solution was stirred at room temperature for 16 hours. After
the reaction was completed, the reaction solution was poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1, then ethyl
acetate), the resulting solid was washed with solvent
(chloroform:ethyl acetate=2:1), and the title compound (0.37 g, 1.1
mmol, 27%) was obtained.
[1094] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.29 (2H,
d, J=6.0 Hz), 5.07 (2H, s), 5.66 (1H, d, J=8.4 Hz), 6.06 (2H, br
s), 6.91-6.97 (4H, m), 7.19 (2H, d, J=8.8 Hz), 7.29-7.45 (5H, m),
7.65 (1H, d, J=8.4 Hz), 8.27 (1H, t, J=6.0 Hz).
Example A-11
2,6-Diamino-N-(4-(2-fluoro-benzyloxy)-benzyl)-nicotinamide
[1095] 2,6-Diamino-nicotinic acid described in Preparation Example
A-15 (200 mg, 1.3 mmol), triethylamine (0.54 mL, 3.87 mmol) and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (862 mg, 1.95 mmol) were added to
N,N-dimethylformamide (20 mL), and the solution was stirred at room
temperature for 20 minutes. Next,
4-(2-fluoro-benzyloxy)-benzylamine described in Preparation Example
154 (453 mg, 1.96 mmol) was added thereto, and the solution was
stirred at room temperature for 14 hours. After the reaction was
completed, the reaction solution was poured into brine, the
solution was extracted with ethyl acetate, the fractionated organic
layer was dried over anhydrous magnesium sulfate and then
concentrated. The obtained residue was subjected to silica gel
column chromatography, eluted with solvent (ethyl acetate) and the
title compound (147 mg, 0.40 mmol, 31%) was obtained.
[1096] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.30 (2H,
d, J=6.0 Hz), 5.11 (2H, s), 5.67 (1H, d, J=8.8 Hz), 6.06 (2H, br
s), 6.89-7.02 (4H, m), 7.16-7.28 (4H, m), 7.37-7.44 (1H, m),
7.51-7.56 (1H, m), 7.66 (1H, d, J=8.8 Hz), 8.28 (1H, t, J=6.0
Hz).
Example A-12
2,6-Diamino-N-(4-(pyridin-2-ylmethoxy)-benzyl)-nicotinamide
[1097] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.29 (2H,
d, J=6.0 Hz), 5.15 (2H, s), 5.66 (1H, d, J=8.8 Hz), 6.06 (2H, br
s), 6.91-6.98 (4H, m), 7.17-7.23 (2H, m), 7.31-7.35 (1H, m), 7.49
(1H, d, J=7.6 Hz), 7.65 (1H, d, J=8.8 Hz), 7.82 (1H, dt, J=2.0, 7.6
Hz), 8.28 (1H, t, J=6.0 Hz), 8.55-8.58 (1H, m).
Example A-13
2,6-Diamino-N-(4-phenoxymethyl-benzyl)-nicotinamide
[1098] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.51 (2H,
brs), 4.57 (2H, d, J=5.6 Hz), 5.06 (2H, s), 5.77 (1H, d, J=8.4 Hz),
6.04 (1H, brs), 6.45 (2H, brs), 6.96-6.98 (3H, m), 7.28-7.31 (3H,
m), 7.34-7.43 (4H, m).
Example A-14
2,6-Diamino-N-(4-(thiophen-3-ylmethoxy)-benzyl)-nicotinamide
[1099] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.28 (2H,
d, J=6.0 Hz), 5.04 (2H, s), 5.65 (1H, d, J=8.4 Hz), 6.05 (2H, br
s), 6.89-6.99 (4H, m), 7.13-7.21 (3H, m), 7.51-7.55 (2H, m), 7.64
(1H, d, J=8.4 Hz), 8.26 (1H, t, J=6.0 Hz).
Example A-15
2-amino-N-(4-(2-nitro benzyloxy)-benzyl)-nicotinamide
[1100] To a solution of sodium
4-(((2-aminopyridin-3-carbonyl)-amino)-methyl)-phenolate described
in Preparation Example A+-1 (100 mg, 0.377 mmol) in
N,N-dimethylformamide (2.5 mL) was added O-Nitrobenzyl chloride (65
mg, 0.379 mmol), and the solution was stirred at room temperature
for 2 hours. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water and dried over anhydrous magnesium sulfate. The residue
was purified by silica gel column chromatography (hexane:ethyl
acetate), and the title compound (51 mg, 37%) was obtained as a
white solid.
[1101] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.55 (2H, d,
J=5.6 Hz), 5.50 (2H, s), 6.23 (1H, brs), 6.39 (2H, brs), 6.57-6.60
(1H, m), 6.98 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.50-7.52
(1H, m), 7.58-7.60 (1H, m), 7.67-7.71 (1H, m), 7.87-7.89 (1H, m),
8.15-8.18 (2H, m).
Example A-16
2-Amino-N-(4-(2-amino-benzyloxy)-benzyl)-nicotinamide
[1102] 2-Amino-N-(4-(2-nitrobenzyloxy)-benzyl)-nicotinamide
described in Example A-15 was dissolved in a mixture solvent of
ethanol-tetrahydrofuran-water (3:1:1.5), iron powder (4 mg) and
ammonium chloride (85 mg) were added thereto, and the solution was
stirred overnight under reflux. In addition, iron powder (10 mg)
and ammonium chloride (20 mg) were added, and the solution was
stirred under reflux for 2 hours. The reaction solution was allowed
to room temperature, filtered through Celite pad to remove
insoluble matter, and the filtrate was concentrated in vacuo. The
residue was purified by NH silica gel chromatography (hexane:ethyl
acetate), and the title compound (9 mg, 98%) was obtained as a pale
brown solid.
[1103] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.53 (2H, d,
J=5.6 Hz), 5.04 (2H, s), 6.24 (1H, brs), 6.51 (2H, brs), 6.57-6.60
(1H, m), 6.72-6.79 (2H, m), 6.99 (2H, d, J=8.4 Hz), 7.16-7.20 (2H,
m), 7.28 (2H, d, J=8.4 Hz), 7.58-7.60 (1H, m), 8.13-8.14 (1H,
m).
Example A-17
2-Amino-N-(4-benzyloxy-benzyl)-nicotinamide
[1104] The title compound (257 mg, 0.771 mmol, 72%) was obtained
from 2-aminonicotinic acid (148 mg, 1.07 mmol) and
4-benzyloxy-benzylamine described in Preparation Example 1 (251 mg,
1.18 mmol) according to an analogous method to Example H-1.
[1105] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.34 (2H,
d, J=6.0 Hz), 5.06 (2H, s), 6.55 (1H, dd, J=4.8, 7.6 Hz), 6.94 (2H,
d, J=8.0 Hz), 7.03 (2H, brs), 7.20 (2H, d, J=8.0 Hz), 7.29 (1H, t,
J=6.4 Hz), 7.36 (2H, dd, J=6.4, 6.8 Hz), 7.41 (2H, d, J=6.8 Hz),
7.90 (1H, d, J=7.6 Hz), 8.05 (1H, d, J=4.8 Hz), 8.88 (1H, t, J=6.0
Hz).
Example A-18
2-Amino-N-(3-phenoxy-benzyl)-nicotinamide
[1106] The title compound (87 mg, 0.27 mmol, 26%) was obtained from
2-aminonicotinic acid (144 mg, 1.04 mmol) and 3-phenoxy-benzylamine
described in Preparation Example 4 (228 mg, 1.15 mmol) according to
an analogous method to Example H-1.
[1107] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.40 (2H,
d, J=5.6 Hz), 6.56 (1H, dd, J=4.8, 7.6 Hz), 6.85 (1H, dd, J=1.2,
8.0 Hz), 6.92-7.05 (5H, m), 7.06 (1H, d, J=7.6 Hz), 7.11 (1H, dd,
J=7.6, 8.0 Hz), 7.29-7.40 (3H, m), 7.89 (1H, dd, J=2.0, 7.6 Hz),
8.06 (1H, dd, J=2.0, 4.8 Hz), 8.96 (1H, t, J=5.6 Hz).
Example A-19
2-Amino-N-(4-(3-fluoro-benzyloxy)-benzyl)-nicotinamide
[1108] The title compound (172 mg, 0.489 mmol, 40%) was obtained
from 2-aminonicotinic acid (170 mg, 1.23 mmol) and
4-(3-fluoro-benzyloxy)-benzylamine described in Preparation Example
6 (312 mg, 1.35 mmol) according to an analogous method to Example
H-1.
[1109] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.35 (2H,
d, J=6.0 Hz), 5.10 (2H, s), 6.45-6.60 (1H, m), 6.85-7.46 (10H, m),
7.85-7.92 (1H, m), 8.03-8.07 (1H, m), 8.75-8.92 (1H, m).
Example A-20
2-Amino-N-(4-(2-fluoro-benzyloxy)-benzyl)-nicotinamide
[1110] The title compound (67 mg, 0.19 mmol, 45%) was obtained from
2-aminonicotinic acid (58 mg, 0.42 mmol) and
4-(2-fluoro-benzyloxy)-benzylamine described in Preparation Example
154 (117 mg, 0.506 mmol) according to an analogous method to
Example H-1 (with the proviso that only the reaction temperature
was changed to 60.degree. C.).
[1111] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.34 (2H,
d, J=6.0 Hz), 5.10 (2H, s), 6.56 (1H, dd, J=4.8, 7.6 Hz), 6.90-7.00
(2H, m), 7.04 (2H, brs), 7.15-7.28 (4H, m), 7.35-7.44 (1H, m),
7.50-7.58 (1H, m), 7.90 (1H, dd, J=1.2, 7.6 Hz), 8.05 (1H, dd,
J=1.2, 4.8 Hz), 8.86-8.95 (1H, m).
Example A-21
2-Amino-N-(4-(4-fluoro-benzyloxy)-benzyl)-nicotinamide
[1112] The title compound (187 mg, 0.532 mmol, 96%) was obtained
from 2-aminonicotinic acid (77 mg, 0.56 mmol) and
4-(4-fluoro-benzyloxy)-benzylamine described in Preparation Example
155 (155 mg, 0.670 mmol) according to an analogous method to
Example H-1 (with the proviso that only the reaction temperature
was changed to 60.degree. C.).
[1113] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.34 (2H,
d, J=5.6 Hz), 5.04 (2H, s), 6.56 (1H, dd, J=5.2, 8.0 Hz), 6.94 (2H,
d, J=8.4 Hz), 7.03 (2H, brs), 7.12-7.25 (4H, m), 7.46 (2H, dd,
J=6.0, 8.4 Hz), 7.90 (1H, d, J=8.0 Hz), 8.05 (1H, d, J=5.2 Hz),
8.88 (1H, t, J=5.6 Hz).
Example A-22
2-Amino-N-(4-benzyloxy-benzyl)-thionicotinamide
[1114] A mixture of 2-amino-N-(4-benzyloxy-benzyl)-nicotinamide
described in Example
[1115] A-17 (220 mg, 0.67 mmol),
2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulphide
(Lawesson's reagent) (670 mg, 1.7 mmol) and toluene (8 mL) was
stirred at 80.degree. C. for 15 minutes, then, refluxed for 45
minutes. After cooling, the precipitate was filtered, and the
filtrate was evaporated in vacuo. Purification was carried out by
NH silica gel column chromatography (ethyl acetate), and the title
compound (28 mg, 0.080 mmol, 12%) was obtained as a pale yellow
oil.
[1116] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.87 (2H, d,
J=4.9 Hz), 5.08 (2H, s), 5.88 (2H, brs), 6.62 (1H, dd, J=4.9, 7.5
Hz), 6.98 (2H, d, J=8.6 Hz), 7.30 (2H, d, J=8.6 Hz), 7.32-7.44 (6H,
m), 7.71 (1H, brs), 8.07 (1H, dd, J=1.7, 4.9 Hz).
Example A-23
2-Amino-N-(3-(2-butynyloxy)benzyl)-nicotinamide
[1117] Trifluoroacetic acid salt of the title compound (10 mg,
0.024 mmol, 49%) was obtained from
2-amino-N-(3-hydroxybenzyl)-nicotinamide described in Preparation
Example A+-17 (12 mg, 0.050 mmol) and 1-bromo-2-butyne (6.6 mg,
0.050 mmol) according to an analogous method to Example E-43.
[1118] MS m/e (ESI) 296.3 (MH.sup.+)
Example A-24
2-Amino-N-(4-benzylamino-benzyl)-6-chloro-nicotinamide
[1119] To a solution of (4-aminomethylphenyl)-benzylamine described
in Preparation Example 19 (369 mg, 1.74 mmol) and
2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in
N,N-dimethylformamide (10 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL,
3.48 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (310 mg, 49%) was obtained as a pale yellow solid.
[1120] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.32-4.34
(3H, m), 4.45 (2H, d, J=5.6 Hz), 6.07 (1H, brs), 6.54-6.63 (5H, m),
7.03 (1H, dd, J=2.4, J=8.4 Hz), 7.14 (2H, d, J=8.4 Hz), 7.35-7.36
(4H, m), 7.48 (1H, d, J=8.0 Hz).
Example A-25
2-Amino-6-chloro-N-(4-phenylamino-benzyl)-nicotinamide
[1121] To a solution of (4-aminomethyl-phenyl)-phenylamine
described in Preparation Example 20 (345 mg, 1.74 mmol) and
2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in
N,N-dimethylformamide (10 mL) were
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL,
3.48 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (360 mg, 59%) was obtained as a pale yellow solid.
[1122] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.51 (2H, d,
J=5.2 Hz), 5.74 (1H, s), 6.16 (1H, brs), 6.57 (1H, d, J=8.0 Hz),
6.58 (2H, s), 6.94-6.97 (1H, m), 7.04-7.09 (4H, m), 7.21-7.30 (4H,
m), 7.52 (1H, d, J=8.0 Hz).
Example A-26
2-Amino-6-chloro-N-(4-phenylaminomethyl-benzyl)-nicotinamide
[1123] To a solution of (4-aminomethyl-benzyl)-phenylamine
described in Preparation Example 21 (369 mg, 1.74 mmol) and
2-amino-6-chloro-nicotinic acid (300 mg, 1.74 mmol) in
N,N-dimethylformamide (10 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (924 mg, 2.09 mmol) and triethylamine (0.49 mL,
3.48 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (479 mg, 75%) was obtained as a pale yellow solid.
[1124] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.08 (1H,
brs), 4.31 (2H, s), 4.57 (2H, d, J=5.6 Hz), 6.21 (1H, brs), 6.57
(1H, d, J=8.0 Hz), 6.58 (2H, s), 6.61-6.63 (2H, m), 6.70-6.74 (1H,
m), 7.15-7.19 (2H, m), 7.30 (2H, d, J=8.0 Hz), 7.37 (2H, d, J=8.0
Hz), 7.51 (1H, d, J=8.0 Hz).
Example A-27
2-Amino-6-chloro-N-(4-benzyloxy-benzyl)-nicotinamide
[1125] 2-Amino-6-chloro-nicotinic acid described in Preparation
Example A-1 (220 mg, 1.4 mmol), triethylamine (0.47 mL, 3.37 mmol)
and benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (764 mg, 1.73 mmol) were dissolved in
N,N-dimethylformamide (3 mL), 4-benzyloxy-benzylamine described in
Preparation Example 1 (399 mg, 1.87 mmol) was added thereto,
followed by stirring at room temperature for 17 hours 30 minutes.
After the reaction was completed, the reaction solution was poured
into brine, which was then extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1), and the title
compound (115 mg, 0.31 mmol, 22%) was obtained.
[1126] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.35 (2H,
d, J=6.0 Hz), 5.08 (2H, s), 6.63 (1H, d, J=8.0 Hz), 6.94-6.98 (2H,
m), 7.23 (2H, d, J=8.4 Hz), 7.29-7.45 (5H, m), 7.52 (2H, brs), 7.97
(1H, d, J=8.0 Hz), 8.96 (1H, t, J=6.0 Hz).
Example A-28
2-Amino-N-(4-benzyloxy-benzyl)-6-cyclopropylamino-nicotinamide
[1127] 2-Amino-6-chloro-N-(4-benzyloxy-benzyl)-nicotinamide
described in Example A-27 (80 mg, 0.22 mmol) was dissolved in
tetrahydrofuran (3 mL), cyclopropylamine (0.3 mL, 4.3 mmol) was
added thereto, and the solution was heated in a sealed tube for 16
hours (oil bath temperature: 140.degree. C.). The reaction solution
was allowed to room temperature, the solution was concentrated, the
obtained residue was purified by NH silica gel column
chromatography (ethyl acetate:hexane=2:1), and the title compound
(12 mg, 0.03 .mu.mol, 14%) was obtained.
[1128] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.52-0.58
(2H, m), 0.74-0.81 (2H, m), 2.47-2.56 (1H, m), 4.45 (2H, d, J=5.2
Hz), 5.07 (2H, s), 5.02 (1H, brs), 5.96-6.01 (1H, m), 6.04 (1H, d,
J=8.4 Hz), 6.39 (2H, brs), 6.95 (2H, d, J=8.8 Hz), 7.23-7.45 (8H,
m).
Example A-29
2-Amino-N-(4-benzyloxy-benzyl)-6-ethoxy-nicotinamide
[1129] Sodium hydride (70 mg, 1.7 mmol, 60% in oil), catalytic
amount of copper(I) iodide, 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (30 mg, 0.17 mmol) were added
sequentially to ethanol (0.5 mL), the solution was stirred at
110.degree. C. for 3 hours, then, stirred overnight at 80.degree.
C. After cooling to room temperature, water, diethyl ether and an
aqueous solution of 29% ammonia were added to the reaction
solution, which was then partitioned, and the aqueous layer was
neutralized with citric acid. Dichloromethane was added to the
aqueous layer, the organic layer was partitioned, washed with
brine, then, the solvent was evaporated in vacuo. Trifluoroacetic
acid salt of the title compound (3.4 mg, 0.0069 mmol, 14%) was
obtained from a portion (10 mg) of the residue (35 mg) and
4-benzyloxybenzylamine (10 mg, 0.047 mmol) according to an
analogous method to Example Q-6.
[1130] MS m/e (ESI) 378.5 (MH.sup.+)
Example A-30
(6-amino-5-(4-benzyloxy-benzylcarbamoyl)-pyridin-2-ylamino)-acetic
acid
[1131] Glycine (935 mg, 12.5 mmol) and
1,8-diazabicyclo[5,4,0]undec-7-ene (1.86 mL, 12.5 mmol) were added
to 2-amino-N-(4-benzyloxy-benzyl)-6-chloro-nicotinamide described
in Preparation Example A+-18 (454 mg, 1.25 mmol) under nitrogen
atmosphere, and the solution was stirred for 6 hours at 130.degree.
C. Dimethylsulfoxide (35 mL) was added to the reaction mixture,
which was then filtered with polytetrafluoroethylene membrane
filter (Whatman Inc), the filtrate was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), and the
title compound (287 mg, 0.551 mmol, 44%) was obtained.
[1132] MS m/e (ESI) 406.91 (MH.sup.+)
[1133] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.82-4.00
(2H, m), 4.29 (2H, d, J=6.0 Hz), 5.06 (2H, s), 5.77-5.88 (1H, m),
6.93 (2H, d, J=8.8 Hz), 7.18 (2H, d, J=8.8 Hz), 7.28-7.42 (5H, m),
7.68-7.80 (1H, m).
Example A-31
2-Amino-6-methoxymethyl-N-(4-(pyridin-2-ylmethoxy)-benzyl)-nicotinamide
[1134] To a solution of 2-amino-6-methoxymethyl-nicotinic acid
described in Preparation Example A-11 (100 mg, 0.55 mmol) and
4-(pyridin-2-ylmethoxy)-benzylamine described in Preparation
Example 171 (170 mg, 0.82 mmol) in N,N-dimethylformamide (5 mL)
were added benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (290 mg, 0.66 mmol) and triethylamine (0.23 mL,
1.7 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution for extraction, the organic layer was washed with brine,
then, the solvent was evaporated in vacuo. The residue was purified
by silica gel column chromatography (heptane:ethyl acetate=1:2),
and the title compound (150 mg, 0.40 mmol, 73%) was obtained as a
colorless solid.
[1135] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.32 (3H,
s), 4.27 (2H, s), 4.33 (2H, d, J=5.9 Hz), 5.14 (2H, s), 6.58 (1H,
d, J=7.9 Hz), 6.96 (2H, d, J=8.6 Hz), 7.10 (2H, br s), 7.22 (2H, d,
J=8.6 Hz), 7.31 (1H, ddd, J=7.5, 4.8, 1.1 Hz), 7.47 (1H, d, J=7.9
Hz), 7.80 (1H, td, J=7.6, 1.8 Hz), 7.94 (1H, d, J=8.1 Hz),
8.54-8.56 (1H, m), 8.87 (1H, t, J=5.9 Hz).
Example A-32
2-Amino-N-(4-(4-fluoro-benzyloxy)-benzyl)-6-methoxymethyl-nicotinamide
[1136] To a solution of 2-amino-6-methoxymethyl-nicotinic acid
described in Preparation Example A-11 (10 mg, 0.055 mmol) and
4-(4-fluoro-benzyloxy)-benzylamine described in Preparation Example
155 (19 mg, 0.082 mmol) in N,N-dimethylformamide (1 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (29 mg, 0.066 mmol) and triethylamine (0.022
mL, 0.16 mmol), and the solution was stirred overnight at room
temperature. Water was added to the reaction solution, the
precipitated solid was filtered, and the title compound (13 mg,
0.033 mmol, 60%) was obtained as a colorless solid.
[1137] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.32 (3H,
s), 4.27 (2H, s), 4.33 (2H, d, J=5.9 Hz), 5.04 (2H, s), 6.58 (1H,
d, J=7.9 Hz), 6.94 (2H, d, J=8.8 Hz), 7.09 (2H, br s), 7.16-7.22
(4H, m), 7.46 (2H, dd, J=8.7, 5.6 Hz), 7.93 (1H, d, J=8.1 Hz),
8.85-8.88 (1H, m).
Example A-33
2-Amino-N-(4-benzyloxy-benzyl)-6-methoxymethyl-nicotinamide
[1138] MS m/e (ESI) 378 (MH.sup.+)
Example A-34
2-Amino-6-methoxymethyl-N-(4-(pyridin-2-yloxymethyl)-benzyl)-nicotinamide
[1139] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.40 (2H, s), 4.60 (2H, d, J=5.6 Hz), 5.38 (2H, s), 6.25 (1H,
brs), 6.40 (2H, brs), 6.68-6.70 (1H, m), 6.77-6.81 (1H, m),
6.87-6.91 (1H, m), 7.35-7.37 (2H, m), 7.46-7.48 (2H, m), 7.57-7.61
(2H, m), 8.16-8.18 (1H, m).
Example A-35
2-Amino-N-(4-(3-fluoro-benzyloxy)-benzyl)-6-methoxymethyl-nicotinamide
[1140] MS m/e (ESI) 396 (MH.sup.+)
Example A-36
2-Amino-N-(4-benzyloxy-benzyl)-6-(3-methoxypropoxy)-nicotinamide
[1141] Trifluoroacetic acid salt of the title compound (0.65 mg,
0.0012 mmol, 2.4%) was obtained from 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (8.6 mg, 0.050 mmol) and
3-methoxypropanol (0.5 mL) according to an analogous method to
Example A-29.
[1142] MS m/e (ESI) 422.5 (MH.sup.+)
Example A-37
2-Amino-N-(4-benzyloxy-benzyl)-6-methyl-nicotinamide
[1143] Trifluoroacetic acid salt of the title compound (0.38 mg,
0.00082 mmol, 4.6%) was obtained from
2-amino-N-(4-benzyloxy-benzyl)-6-chloro-nicotinamide described in
Preparation Example A+-18 (6.5 mg, 0.018 mmol) and methylmagnesium
bromide (0.93M tetrahydrofuran solution, 0.12 mL, 0.11 mmol)
according to an analogous method to Example E-40.
[1144] MS m/e (ESI) 348.5 (MH.sup.+)
Example A-38
2-Amino-N-(4-benzyloxy-benzyl)-6-propoxy-nicotinamide
[1145] Trifluoroacetic acid salt of the title compound (1.5 mg,
0.0030 mmol, 5.9%) was obtained from 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (8.6 mg, 0.050 mmol) and
propanol (0.5 mL) according to an analogous method to Example
A-29.
[1146] MS m/e (ESI) 406.6 (MH.sup.+)
Example A-39
6-Amino-N-(4-benzyloxybenzyl)-nicotinamide
[1147] Trifluoroacetic acid salt of the title compound (7.1 mg,
0.016 mmol, 32%) was obtained from 4-benzyloxybenzylamine described
in Preparation Example 1 (11 mg, 0.050 mmol) and 6-aminonicotinic
acid (6.9 mg, 0.050 mmol) according to an analogous method to
Example Q-6.
[1148] MS m/e (ESI) 334.3 (MH.sup.+)
Example A-40
6-Amino-N-(3-phenoxybenzyl)-nicotinamide
[1149] Trifluoroacetic acid salt of the title compound (16 mg,
0.037 mmol, 74%) was obtained from 3-phenoxybenzylamine described
in Preparation Example 4 (10 mg, 0.050 mmol) and 6-aminonicotinic
acid (6.9 mg, 0.050 mmol) according to an analogous method to
Example Q-6.
[1150] MS m/e (ESI) 320.2 (MH.sup.+)
Example A-41
6-Chloro-N-(3-phenoxy-benzyl)-nicotinamide
[1151] The title compound (240 mg, 0.71 mmol, 61%) was obtained as
a white solid from 3-phenoxy-benzylamine described in Preparation
Example 4 (230 mg, 1 .mu.mol) and 6-chloronicotinic acid (180 mg,
1.1 mmol) according to an analogous method to Example Q-6.
[1152] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.63 (2H, d,
J=5.7 Hz), 6.42 (1H, brs), 6.94 (1H, dd, J=1.8, 8.1 Hz), 6.98-7.03
(3H, m), 7.08 (1H, d, J=7.5 Hz), 7.11-7.15 (1H, m), 7.30-7.37 (3H,
m), 7.41-7.43 (1H, m), 8.09 (1H, dd, J=2.6, 8.2 Hz), 8.74 (1H, d,
J=2.2 Hz).
Example A-42
N-(4-Benzyloxy-benzyl)-6-methylamino-nicotinamide
[1153] The title compound (71 mg, 0.19 mmol, 88%) was obtained as a
white solid from
N-(4-benzyloxy-benzyl)-6-(ethoxymethyl-amino)-nicotinamide
described in Preparation Example A+-8 (90 mg, 0.22 mmol) according
to an analogous method to Example A-163.
[1154] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.96 (3H,
s), 4.56 (2H, d, J=5.5 Hz), 5.07 (2H, s), 6.12 (1H, brs), 6.38 (1H,
d, J=8.8 Hz), 6.96 (2H, d, J=8.8 Hz), 7.22-7.34 (4H, m), 7.36-7.44
(3H, m), 7.89 (1H, dd, J=2.4, 8.6 Hz), 8.50 (1H, d, J=2.4 Hz).
Example A-43
N-(4-benzyloxybenzyl)-nicotinamide
[1155] The title compound (8.5 mg, 0.027 mmol, 33%) was obtained as
a white solid from 4-benzyloxybenzylamine described in Preparation
Example 1 (26 mg, 0.12 mmol) and nicotinic acid (10 mg, 0.08
.mu.mol) according to an analogous method to Example Q-6.
[1156] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.59 (2H, d,
J=5.5 Hz), 5.07 (2H, s), 6.41 (1H, brs), 6.97 (2H, d, J=8.6 Hz),
7.29 (2H, d, J=8.6 Hz), 7.32-7.44 (6H, m), 8.11-8.14 (1H, m), 8.71
(1H, dd, J=1.5, 4.8 Hz), 8.96 (1H, d, J=1.8 Hz).
Example A-44
2-Amino-N-(4-benzyloxy-3-hydroxy-benzyl)-nicotinamide
[1157] To a solution of 4-benzyloxy-3-methoxymethoxy-benzonitrile
obtained in Preparation Example 132 (100 mg, 0.371 mmol) in
tetrahydrofuran (5 mL) was added lithium aluminum hydride (75 mg,
1.98 mmol) portionwise under nitrogen atmosphere on an ice bath,
the solution was stirred for 24 hours. In addition, lithium
aluminum hydride (75 mg, 1.98 mmol) was added portionwise on an ice
bath, then, the solution was stirred at 50-60.degree. C. for 3
hours. Ethyl acetate (10 mL) and methanol (5 mL) were added little
by little to the reaction solution on an ice bath, then, NH silica
gel (50 mL) was added, and a pale yellow oily residue (73 mg) was
obtained by NH silica gel column chromatography (hexane:ethyl
acetate=7:3). This residue was purified again by NH silica gel
column chromatography (hexane:ethyl acetate=7:3), and
4-benzyloxy-3-methoxymethoxy-benzylamine (30 mg, 0.11 mmol, 30%)
was obtained as a pale yellow oil.
[1158] Next, a solution of 2-amino-nicotinic acid (16 mg, 0.116
mmol), 4-benzyloxy-3-methoxymethoxy-benzylamine (15 mg, 0.0549
mmol), benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (55 mg, 0.124 mmol) and triethylamine (0.08 mL,
0.574 mmol) in dimethylsulfoxide (4 mL) was stirred under nitrogen
atmosphere at room temperature for 24 hours. Water (100 mL) and
brine (50 mL) were added to the reaction solution, which was then
extracted with ethyl acetate (100 mL) twice, and washed with water
twice. The organic layer was dried over anhydrous magnesium
sulfate, which was then filtered, the filtrate was evaporated in
vacuo, and
2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide was
obtained as a pale yellow oil. This was purified by NH silica gel
column chromatography (hexane:ethyl acetate=1:1, then hexane:ethyl
acetate=3:7), and
2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide) (9.4
mg, 0.0239 mmol, 43.5%) was obtained as a pale yellow oil. A
solution of the resulting
2-amino-N-(4-benzyloxy-3-methoxymethoxy-benzyl)-nicotinamide (7.8
mg, 0.0198 mmol) and 2M hydrochloric acid (2 mL) in methanol (3 mL)
was stirred for 21 hour at room temperature. Sodium bicarbonate
(600 mg, 7.14 mmol) was added to the reaction mixture to basify it,
which was then filtered, evaporation in vacuo was carried out,
then, the obtained residue was purified by thin layer NH silica gel
chromatography (methanol:ethyl acetate=5:95), and the title
compound (2.0 mg, 0.0057 mmol, 29%) was obtained as a white
solid.
[1159] MS m/e (ESI) 350 (MH.sup.+)
Example A-45
2-Amino-N-(6-benzyloxypyridin-3-ylmethyl)-6-methoxymethyl-nicotinamide
[1160] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.45 (3H,
s), 4.39 (2H, s), 4.53 (2H, d, J=5.6 Hz), 5.38 (2H, s), 6.23 (1H,
brs), 6.39 (2H, brs), 6.69-6.71 (1H, m), 6.80-6.82 (1H, m),
7.30-7.33 (1H, m), 7.36-7.40 (2H, m), 7.57-7.59 (2H, m), 7.60-7.63
(2H, m), 8.15-8.15 (1H, m).
Example A-46
2,6-Diamino-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-nicotinamide
[1161] The title compound (6.2 mg, 0.018 mmol, 5.5%) was obtained
from 2,6-diamino-nicotinic acid ethyl ester described in
Preparation Example A-14 (60 mg, 0.33 mmol) and
C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)-methylamine described in
Preparation Example 59 (159 mg, 0.78 mmol) according to an
analogous method to Example A-54.
[1162] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.40 (2H, d,
J=4.8 Hz), 4.53 (2H, brs), 5.01 (2H, s), 5.76 (1H, d, J=8.4 Hz),
5.84-5.89 (1H, m), 6.17 (1H, t, J=2.0 Hz), 6.48 (2H, brs),
6.62-6.67 (2H, m), 6.78-6.82 (1H, m), 6.91-6.93 (1H, m), 6.98 (1H,
dt, J=2.4, 8.4 Hz), 7.27-7.33 (1H, m), 7.36 (1H, d, J=8.4 Hz).
Example A-47
2-Amino-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)nicotinamide
[1163] The title compound (106 mg, 0.327 mmol, 66.7%) was obtained
as a white solid from
C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)methylamine described in
Preparation Example 59 (100 mg, 0.49 mmol) and 2-aminonicotinic
acid (68 mg, 0.49 mmol) according to an analogous method to Example
Q-6.
[1164] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.22 (2H,
d, J=5.6 Hz), 5.03 (2H, s), 5.97-6.01 (1H, m), 6.50-6.55 (1H, m),
6.73 (2H, s), 6.95-7.10 (5H, m), 7.32-7.38 (1H, m), 7.83-7.88 (1H,
m), 8.00-8.05 (1H, m), 8.63 (1H, t, J=5.6 Hz).
Example A-48
2-Amino-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-6-methylamino-nicotin-
amide
[1165]
2-Amino-6-chloro-N-(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-nicot-
inamide described in Preparation Example A+-5 (50 mg, 0.14 mmol)
was dissolved in a mixture solution of dimethylsulfoxide (1 mL) and
N,N-diisopropylethylamine (0.5 mL), methylamine (2.0M
tetrahydrofuran solution) (1 mL, 2 mmol) was added thereto, and the
solution was heated in a sealed tube for 15 hours (oil bath
temperature: 135.degree. C.). The reaction mixture was allowed to
room temperature, poured into brine, and the solution was extracted
with ethyl acetate. The organic layer was dried over anhydrous
magnesium sulfate then concentrated, the obtained residue was
purified by NH silica gel column chromatography (ethyl acetate),
and the title compound (7.3 mg, 0.021 mmol, 15%) was obtained.
[1166] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.88 (3H, d,
J=5.2 Hz), 4.40 (2H, d, J=5.2 Hz), 4.58-4.66 (1H, m), 5.01 (2H, s),
5.66 (1H, J=8.8 Hz), 5.81-5.87 (1H, m), 6.17 (1H, t, J=2.4 Hz),
6.45 (2H, brs), 6.63 (1H, t, J=2.4 Hz), 6.66 (1H, brs), 6.78-6.83
(1H, m), 6.92 (1H, br d, J=7.2 Hz), 6.97 (1H, dt, J=2.4, 8.4 Hz),
7.27-7.33 (1H, m), 7.36 (1H, d, J=8.8 Hz).
Example A-49
N-(1-(3-Fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-6-methyl-nicotinamide
[1167] The title compound (61 mg, 0.18 mmol, 65.1%) was obtained as
a colorless oil from
C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)methylamine described in
Preparation Example 59 (60 mg, 0.29 mmol) and 6-methylnicotinic
acid (40 mg, 0.29 mmol) according to an analogous method to Example
Q-6.
[1168] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.48 (3H,
s), 4.27 (2H, d, 5.6 Hz), 5.03 (2H, s), 5.99-6.02 (1H, m),
6.74-6.78 (2H, m), 6.96-7.10 (3H, m), 7.28-7.38 (2H, m), 8.06 (1H,
dd, J=2.4, 8.0 Hz), 8.80 (1H, t, J=5.6 Hz), 8.87 (1H, d, J=2.4
Hz).
Example A-50
2-Amino-N-(2-phenoxy-thiazol-5-ylmethyl)-nicotinamide
[1169] The title compound (13.5 mg, 41 mmol, 87%) was obtained as a
white solid from C-(2-phenoxy-thiazol-5-yl)-methylamine described
in Preparation Example 117 (9.8 mg, 48 mmol) and 2-amino-nicotinic
acid (7.9 mg, 58 mmol) according to an analogous method to Example
A-26.
[1170] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.44 (2H,
d, J=5.7 Hz), 6.55 (1H, dd, J=4.8, 7.7 Hz), 7.05 (2H, s), 7.18 (1H,
s), 7.27-7.31 (3H, m), 7.45 (2H, t, J=8.2 Hz), 7.84 (1H, d, J=7.5
Hz), 8.06 (1H, d, J=4.6 Hz), 9.05 (1H, t, J=6.0 Hz).
Example A-51
2-((furan-2-ylmethyl)-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamid-
e
[1171] The title compound (2.29 mg, 0.0044 mmol, 4.4%) was obtained
as a trifluoroacetic acid salt from
2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described
in Preparation Example A+-7 (35 mg, 0.10 mmol) and furfurylamine
(16 .mu.l, 0.18 mmol) according to an analogous method to Example
A-133.
[1172] MS m/e (ESI) 406.15 (MH.sup.+)
Example A-52
4-((3-((5-Phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-yl)amino)-meth-
yl)benzoic acid
[1173] The title compound (2.75 mg, 0.0048 mmol, 4.8%) was obtained
as a trifluoroacetic acid salt from
2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described
in Preparation Example A+-7 (36 mg, 0.10 mmol) and
4-(aminomethyl)benzoic acid (16 mg, 0.11 mmol) according to an
analogous method to Example A-133.
[1174] MS m/e (ESI) 460.17 (MH.sup.+)
[1175] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.50 (2H,
d, J=6.0 Hz), 4.71 (2H, d, J=4.8 Hz), 6.51 (1H, d, J=3.6 Hz), 6.63
(1H, dd, J=4.8, 8.0 Hz), 6.79 (1H, d, J=3.6 Hz), 7.09 (2H, d, J=8.0
Hz), 7.09-7.19 (1H, m), 7.32-7.47 (4H, m), 7.87 (2H, d, J=7.6 Hz),
7.98 (1H, dd, J=0.8, 8.0 Hz), 8.13 (1H, dd, J=0.8, 4.8 Hz), 8.87
(1H, brs), 9.16-9.24 (1H, m).
Example A-53
2,6-Diamino-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1176] The title compound (180 mg, 0.50 mmol, 38.6%) was obtained
as a white solid from
C-(5-(4-fluoro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 28 (290 mg, 1.3 mmol) and 2,6-diaminonicotinic
acid described in Preparation Example A-15 (200 mg, 1.3 mmol)
according to an analogous method to Example Q-6.
[1177] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.40 (2H,
d, J=5.6 Hz), 5.64-5.68 (1H, m), 6.10 (2H, s), 6.45-6.49 (1H, m),
6.70-6.74 (1H, m), 6.95 (2H, s), 7.10-7.18 (2H, m), 7.18-7.26 (2H,
m), 7.60 (1H, d, J=8.0 Hz), 8.40 (1H, t, J=5.6 Hz).
Example A-54
2,6-diamino-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide
[1178] To a solution of 2,6-diamino-nicotinic acid ethyl ester
described in Preparation Example A-14 (18 mg, 0.1 mmol) in ethanol
(10 mL) was added 1N sodium hydroxide aqueous solution (5 mL), and
the solution was stirred for 1 hour 10 minutes under reflux. After
cooling the reaction solution, the solution was neutralized with 1N
hydrochloric acid and concentrated. The resulting crude product was
suspended in N,N-dimethylformamide (3 mL), triethylamine (0.02 mL,
0.15 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (65 mg, 0.15 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (30 mg, 0.15 mmol) were added thereto, followed by
stirring at room temperature for 19 hours 40 minutes. After the
reaction was completed, reaction solution was poured into brine,
and the solution was extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate then concentrated,
the obtained residue was purified by NH silica gel column
chromatography (ethyl acetate), and the title compound (8.7 mg,
0.025 mol, 25%) was obtained.
[1179] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.58-4.61
(2H, m), 4.62 (2H, brs), 5.75 (1H, d, J=8.4 Hz), 6.21-6.27 (1H, m),
6.36-6.38 (1H, m), 6.45 (2H, brs), 6.69-6.72 (1H, m), 7.06-7.12
(3H, m), 7.28-7.34 (2H, m), 7.39 (1H, d, J=8.4 Hz).
Example A-55
2,6-Diamino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide
[1180] To a solution of 2,6-diaminonicotinic acid described in
Preparation Example A-15 (173 mg, 1.13 mmol) in dimethylsulfoxide
(15 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (433 mg, 2.26 mmol), 1-hydroxybenzotriazole (346 mg,
2.26 mmol) and C-(5-benzyl-thiophen-2-yl)-methylamine described in
Preparation Example 42 (230 mg, 1.13 mmol), and the solution was
stirred at room temperature for 16 hours 30 minutes. The reaction
solution was poured into brine, the solution was extracted with
ethyl acetate, the organic layer was dried over anhydrous magnesium
sulfate and then concentrated. The obtained residue was subjected
to NH silica gel column chromatography, eluted with solvent (ethyl
acetate) and the title compound (114 mg, 0.34 mmol, 30%) was
obtained.
[1181] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.00 (2H,
s), 4.53 (2H, d, J=5.6 Hz), 4.70 (2H, br s), 5.69 (1H, d, J=8.4
Hz), 6.39 (2H, br s), 6.55 (1H, d, J=3.2 Hz), 6.67-6.95 (2H, m),
7.09-7.25 (5H, m), 7.38 (1H, d, J=8.4 Hz).
Example A-56
2,6-Diamino-N-(5-benzyloxy-thiophen-2-ylmethyl)-nicotinamide
[1182] To a solution of 2,6-diaminonicotinic acid described in
Preparation Example A-15 (109 mg, 0.71 mmol) in dimethylsulfoxide
(10 mL) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
hydrochloride (272 mg, 1.42 mmol), 1-hydroxybenzotriazole (217 mg,
1.42 mmol) and C-(5-benzyloxy-thiophen-2-yl)methylamine described
in Example E-76 (156 mg, 0.71 mmol), and the solution was stirred
at room temperature for 14 hours. The reaction solution was poured
into brine, extracted with ethyl acetate, the fractionated organic
layer was dried over anhydrous magnesium sulfate and then
concentrated. The obtained residue was subjected to NH silica gel
column chromatography, eluted with solvent (ethyl acetate) and the
title compound (157 mg, 0.44 mmol, 62%) was obtained.
[1183] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.53 (2H, d,
J=5.2 Hz), 4.69 (2H, br s), 5.03 (2H, s), 5.76 (1H, d, J=8.8 Hz),
6.08 (1H, d, J=4.0 Hz), 6.46 (3H, br), 6.59 (1H, d, J=4.0 Hz),
7.31-7.44 (6H, m).
Example A-57
2,6-Diamino-N-(5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1184] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 4.42 (2H,
d, J=6.0 Hz), 5.66 (1H, d, J=8.4 Hz), 6.11 (2H, brs), 6.55-6.59
(1H, m), 6.75 (1H, d, J=4.0 Hz), 6.90-7.02 (5H, m), 7.38-7.45 (1H,
m), 7.60 (1H, d, J=8.4 Hz), 8.42 (1H, t, J=6.0 Hz).
Example A-58
2,6-Diamino-N-(5-benzofuran-2-ylmethyl-thiophen-2-ylmethyl)-nicotinamide
[1185] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.29 (2H,
s), 4.43 (2H, d, J=6.0 Hz), 5.64 (1H, d, J=8.4 Hz), 6.09 (2H, brs),
6.66 (1H, d, J=0.8 Hz), 6.92 (2H, s), 6.94 (2H, brs), 7.17-7.26
(2H, m), 7.47-7.64 (3H, m), 8.37 (1H, t, J=6.0 Hz).
Example A-59
2,6-Diamino-N-(5-benzo[b]thiophen-2-ylmethyl-thiophen-2-ylmethyl)-nicotina-
mide
[1186] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.39 (2H,
s), 4.44 (2H, d, J=5.6 Hz), 5.64 (1H, d, J=8.4 Hz), 6.09 (2H, brs),
6.78-6.84 (2H, m), 6.95 (2H, brs), 7.23-7.36 (3H, m), 7.59 (1H, d,
J=8.4 Hz), 7.74 (1H, dd, J=0.8, J=6.0 Hz), 7.85 (1H, dd, J=0.8,
J=6.0 Hz), 8.38 (1H, t, J=5.6 Hz).
Example A-60
N-(5-(3-Fluorophenoxy)thiophen-2-ylmethyl)-2,6-dimethylnicotinamide
[1187] The title compound (56 mg, 0.157 mmol, 47.6%) was obtained
as a light brown solid from 2,6-dimethylnicotinic acid (50 mg, 0.33
mmol) and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described
in Preparation Example 23 (66 mg, 0.297 mmol) according to an
analogous method to Example Q-6.
[1188] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.44 (3H,
s), 2.46 (3H, s), 4.51 (2H, d, J=5.6 Hz, 6.59-6.62 (1H, m),
6.80-6.84 (1H, m), 6.90-7.03 (3H, m), 7.12 (1H, d, J=8.0 Hz),
7.40-7.47 (1H, m), 7.60 (1H, d, J=8.0 Hz), 9.00 (1H, t, J=5.6
Hz).
Example A-61
2-Acetylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1189] To a mixture of
2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in
Example A-67 (50 mg, 0.15 mmol), acetonitrile (5 mL) and
tetrahydrofuran (2 mL) was added nitronium tetrafluoroborate (0.50M
sulfolane solution, 0.46 mL, 0.23 mmol) on an ice bath, and the
solution was stirred overnight at room temperature. Water, ethyl
acetate, tetrahydrofuran and an aqueous solution of saturated
sodium bicarbonate were added to the reaction solution for
extraction, washed with brine, then, the solvent was evaporated in
vacuo. The residue was purified by silica gel column chromatography
(methanol:ethyl acetate=1:30), and the title compound (1.3 mg,
0.0035 mmol, 2.3%) was obtained as a white solid.
[1190] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.31 (3H,
s), 4.67 (2H, d, J=5.5 Hz), 6.40 (1H, d, J=3.9 Hz), 6.60 (1H, brs),
6.77 (1H, d, J=3.7 Hz), 7.05 (1H, dd, J=4.9, 7.8 Hz), 7.08-7.14
(3H, m), 7.32-7.36 (2H, m), 7.84 (1H, brs), 8.51 (1H, brs).
Example A-62
2-Amino-N-(5-(3-cyano-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1191] To a solution of
C-(5-(3-bromophenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 17 (366 mg, 1.29 mmol) and
2-aminopyridine-3-carboxylic acid (178 mg, 1.29 mmol) in
tetrahydrofuran (5 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (685 mg, 1.55 mmol) and triethylamine (0.36 mL,
2.58 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and a mixture of
2-amino-N-(5-(3-bromophenoxy)-thiophen-2-ylmethyl)-nicotinamide and
debrominated compound (344 mg, 66%) was obtained as a yellow
solid.
[1192] Next, to a solution of a mixture of
2-amino-N-(5-(3-bromophenoxy)-thiophen-2-ylmethyl)-nicotinamide and
debrominated compound (100 mg, 0.247 mmol) in N,N-dimethylformamide
(3.0 mL) were added zinc cyanide (58 mg, 0.495 mmol) and
tetrakis(triphenylphosphine)palladium(0) (285 mg, 0.247 mmol) under
nitrogen atmosphere, and the solution was stirred at 140.degree. C.
for 3 hours and a half. The reaction solution was allowed to room
temperature, ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water and dried over anhydrous magnesium sulfate. The solvent
was evaporated, then, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (9 mg, 10%) was obtained as a pale yellow oil.
[1193] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.69 (2H, d,
J=6.0 Hz), 6.36 (2H, brs), 6.41 (1H, brs), 6.47-6.48 (1H, m),
6.59-6.62 (1H, m), 6.79-6.80 (1H, m), 7.31-7.34 (2H, m), 7.37-7.44
(2H, m), 7.61-7.63 (1H, m), 8.17-8.19 (1H, m).
Example A-64
2-Amino-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide
[1194] The title compound (126 mg, 0.37 mmol, 80.8%) was obtained
as a brown oil from 2-aminonicotinic acid (69 mg, 0.51 mmol) and
C-(5-m-tolyloxy-thiophen-2-yl)-methylamine described in Preparation
Example 30 (100 mg, 0.46 mmol) according to an analogous method to
Example Q-6.
[1195] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.26 (3H,
s), 4.46 (2H, d, J=5.6 Hz), 6.46 (1H, d, J=3.6 Hz), 6.55 (1H, dd,
J=4.8, 8.0 Hz), 6.74 (1H, d, J=3.6 Hz), 6.84-6.96 (3H, m), 7.04
(2H, s), 7.22 (1H, dd, J=8.0, 8.0 Hz), 7.86 (1H, dd, J=1.6, 8.0
Hz), 8.05 (1H, dd, J=1.6, 4.8 Hz), 9.02 (1H, t, J=5.6 Hz).
Example A-65
2-Amino-N-(5-p-tolyloxy-thiophen-2-ylmethyl)nicotinamide
[1196] The title compound (72 mg, 0.212 mmol, 57.4%) was obtained
as a light brown solid from 2-aminonicotinic acid (55 mg, 0.41
mmol) and C-(5-p-tolyloxythiophen-2-yl)methylamine described in
Preparation Example 32 (80 mg, 0.37 mmol) according to an analogous
method to Example Q-6.
[1197] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.24 (3H,
s), 4.44 (2H, d, J=5.6 Hz), 6.40-6.44 (1H, m), 6.53-6.58 (1H, m),
6.72 (1H, d, J=3.6 Hz), 6.95-7.00 (2H, m), 7.04 (2H, s), 7.12-7.18
(2H, m), 7.85 (1H, d, J=7.6 Hz), 8.03-8.08 (1H, m), 9.01 (1H, t,
J=5.6 Hz).
Example A-66
2-amino-4-(5-(3-chloro-benzyl)thiophene-2-ylmethyl)-nicotinamide
[1198] The title compound (63 mg, 0.176 mmol, 51.9%) was obtained
as a white solid from 2-aminonicotinic acid (51 mg, 0.37 mmol) and
C-(5-(3-chloro-benzyl)thiophen-2-yl)-methylamine described in
Preparation Example 45 (80 mg, 0.34 mmol) according to an analogous
method to Example Q-6.
[1199] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.06 (2H,
s), 4.47 (2H, d, J=5.6 Hz), 6.54 (1H, dd, J=4.8, 7.6 Hz), 6.72 (1H,
d, J=3.6 Hz), 6.80 (1H, d, J=3.6 Hz), 7.05 (2H, brs), 7.18-7.34
(4H, m), 7.84 (1H, dd, J=1.6, 7.6 Hz), 8.04 (1H, dd, J=1.6, 4.8
Hz), 8.98 (1H, t, J=5.6 Hz).
Example A-67
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1200] The title compound (148 mg, 0.455 mmol, 73%) was obtained
from 2-aminonicotinic acid (87 mg, 0.63 mmol) and
C-(5-phenoxy-thiophen-2-yl)methylamine described in Preparation
Example 24 (143 mg, 0.697 mmol) according to an analogous method to
Example H-1.
[1201] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta. (ppm): 4.46 (2H,
d, J=5.6 Hz), 6.49 (1H, d, J=4.0 Hz), 6.55 (1H, dd, J=4.8, 7.6 Hz),
6.76 (1H, d, J=4.0 Hz), 7.00-7.17 (5H, m), 7.32-7.40 (2H, m), 7.87
(1H, dd, J=1.6, 7.6 Hz), 8.06 (1H, dd, J=1.6, 4.8 Hz), 9.00-9.09
(1H, m).
Example A-68
2-Amino-N-(5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1202] The title compound (112 mg, 0.326 mmol, 75%) was obtained
from 2-aminonicotinic acid (60 mg, 0.43 mmol) and
C-(5-(3-fluoro-phenoxy)-thiophen-2-yl)methylamine described in
Preparation Example 23 (106 mg, 0.475 mmol) according to an
analogous method to Example H-1.
[1203] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.48 (2H,
d, J=5.2 Hz), 6.52-6.59 (2H, m), 6.79 (1H, d, J=2.8 Hz), 6.87-7.00
(3H, m), 7.06 (2H, brs), 7.34-7.45 (1H, m), 7.87 (1H, dd, J=2.0,
7.6 Hz), 8.06 (1H, dd, J=2.0, 4.8 Hz), 9.05 (1H, t, J=5.2 Hz).
Example A-69
2-Amino-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1204] The title compound (174 mg, 0.507 mmol, 65%) was obtained
from 2-aminonicotinic acid (107 mg, 0.777 mmol) and
C-(5-(4-fluoro-phenoxy)-thiophen-2-yl)methylamine described in
Preparation Example 28 (191 mg, 0.856 mmol) according to an
analogous method to Example H-1.
[1205] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, J=6.0 Hz), 6.46 (1H, d, J=4.0 Hz), 6.55 (1H, dd, J=4.8, 7.6 Hz),
6.74 (1H, d, J=4.0 Hz), 6.85-7.25 (6H, m), 7.86 (1H, d, J=7.6 Hz),
8.05 (1H, d, J=4.8 Hz), 8.96-9.08 (1H, m).
Example A-70
2-Amino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide
[1206] The title compound (67 mg, 0.21 mmol, 92%) was obtained from
2-aminonicotinic acid (31 mg, 0.224 mmol) and
C-(5-benzyl-thiophen-2-yl)-methylamine described in Preparation
Example 42 (50 mg, 0.245 mmol) according to an analogous method to
Example H-1.
[1207] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.04 (2H,
s), 4.46 (2H, d, J=5.2 Hz), 6.54 (1H, dd, J=4.8, 8.0 Hz), 6.69 (1H,
d, J=3.6 Hz), 6.78 (1H, d, J=3.6 Hz), 7.05 (2H, brs), 7.15-7.30
(5H, m), 7.85 (1H, dd, J=2.0, 8.0 Hz), 8.04 (1H, d, J=2.0, 4.8 Hz),
8.98 (1H, t, J=5.2 Hz).
Example A-71
2-Amino-N-(5-(3-fluoro-benzyl)-thiophen-2-ylmethyl)-nicotinamide
[1208] The title compound (13 mg, 0.038 mmol, 19%) was obtained
from 2-aminonicotinic acid (28 mg, 0.205 mmol) and
C-(5-(3-fluoro-benzyl)-thiophen-2-yl)-methylamine obtained by the
method described in Example A-146 (50 mg, 0.226 mmol) according to
an analogous method to Example H-1.
[1209] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.07 (2H,
s), 4.40-4.53 (2H, m), 6.50-6.58 (1H, m), 6.71 (1H, d, J=3.2 Hz),
6.79 (1H, d, J=3.2 Hz), 6.94-7.09 (5H, m), 7.22-7.37 (1H, m), 7.84
(1H, dd, J=1.6, 8.0 Hz), 8.03-8.06 (1H, m), 8.92-9.03 (1H, m).
Example A-72
2-Amino-N-(4-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1210] The title compound (108 mg, 0.33 .mu.mol, 74%) was obtained
as a white solid from C-(4-phenoxy-thiophen-2-yl)-methylamine
described in Preparation Example 111 (92 mg, 0.45 mmol) and
2-amino-nicotinic acid (68 mg, 0.49 mmol) according to an analogous
method to Example A-26.
[1211] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.70 (2H, d,
J=5.7 Hz), 6.35 (3H, brs), 6.48 (1H, d, J=1.7 Hz), 6.60 (1H, dd,
J=4.9, 7.7 Hz), 6.82 (1H, d, J=1.6 Hz), 7.05 (2H, dd, J=1.1, 8.6
Hz), 7.11 (1H, tt, J=1.1, 7.7 Hz), 7.34 (2H, t, J=8.6 Hz), 7.61
(1H, dd, J=1.7, 7.7 Hz), 8.18 (1H, dd, J=1.8, 4.8 Hz).
Example A-73
2-Amino-N-(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1212] C-(5-(3-Chloro-phenoxy)-thiophen-2-yl)-methylamine (1.02 g,
4.25 mmol, 98%) was obtained as an oil from
5-(3-chloro-phenoxy)-thiophene-2-carbonitrile described in
Preparation Example 121 (1.02 g, 4.32 mmol) according to an
analogous method to Example E-24. Then, title compound (12.1 mg)
was obtained from the resulting
C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine (30 mg, 0.13
mmol) and 2-amino-nicotinic acid (17 mg, 0.13 mmol).
Trifluoroacetic acid salt of the title compound (12.1 mg) was
obtained by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1213] MS m/e (ESI): 360.3 (MH.sup.+)
Example A-74
2-Amino-N-(5-(2-fluoro-benzyl)-thiophen-2-ylmethyl)nicotinamide
[1214] The title compound was obtained from
C-(5-(2-fluoro-benzyl)thiophen-2-yl)-methylamine described in
Preparation Example 126 (30 mg, 0.14 mmol) and 2-amino-nicotinic
acid (21 mg, 0.15 mmol) according to an analogous method to Example
A-26. Trifluoroacetic acid salt of the title compound (16.2 mg) was
obtained by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1215] MS m/e (ESI) 342.34 (MH.sup.+)
Example A-75
2-Amino-N-(5-(4-chloro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1216] A solution of 2-amino-nicotinic acid (21 mg, 0.15 mmol),
C-(5-(4-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 157 (36 mg, 0.15 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (86 mg, 0.195 mmol) and triethylamine (0.065
mL, 0.45 mmol) in dimethylsulfoxide (1 mL) was stirred under
nitrogen atmosphere for 17 hours at room temperature. This reaction
solution was purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and trifluoroacetic acid salt of
the title compound (17.7 mg, 0.037 mmol, 24.9%) was obtained as a
pale yellow solid.
[1217] MS m/e (ESI) 360 (MH.sup.+)
Example A-76
2-Amino(5-(2-chloro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1218] Trifluoroacetic acid salt of the title compound (31.1 mg,
0.07 mmol, 43.7%) was obtained as a light brown oil from
2-amino-nicotinic acid (21 mg, 0.15 mmol) and
C-(5-(2-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 159 (36 mg, 0.15 mmol) according to an
analogous method to Example A-75.
[1219] MS m/e (ESI) 360 (MH.sup.+)
Example A-77
2-Amino-N-(5-(2,2-dicyclopropylvinyl)thiophen-2-ylmethyl)nicotinamide
[1220] The title compound (25 mg, 0.0742 mol, 53.8%) was obtained
as a white solid from 2-aminonicotinic acid (19 mg, 0.138 mmol) and
C-(5-(2,2-dicyclopropylvinyl)thiophen-2-yl)methylamine described in
Preparation Example 152 (30 mg, 0.138 mmol) according to an
analogous method to Example A-149.
[1221] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.42-0.46
(2H, m), 0.61-0.66 (2H, m), 0.83-0.88 (4H, m), 1.16-1.23 (1H, m),
1.96-2.03 (1H, m), 4.73 (2H, d, J=5.6 Hz), 6.27 (1H, s), 6.34 (3H,
s), 6.58 (1H, dd, J=4.8, 7.6 Hz), 6.84 (1H, d, J=3.2 Hz), 6.92 (1H,
d, J=3.2 Hz), 7.57 (1H, dd, J=1.6, 7.6 Hz), 8.16 (1H, dd, J=1.6,
4.8 Hz).
Example A-78
2-Amino-5-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1222] Trifluoroacetic acid salt of the title compound (1.7 mg,
0.0036 mmol, 5.6%) was obtained as a by-product from Example
A-171.
[1223] MS m/e (ESI) 360.1 (MH.sup.+)
Example A-79
2-Amino-5-methyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1224] The title compound was obtained from
2-amino-5-iodine-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Preparation Example A+-16 (10 mg, 22 .mu.mol)
according to an analogous method to Example A-170. Trifluoroacetic
acid salt of the title compound was obtained by reverse phase high
performance liquid chromatography (acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid) was used).
[1225] MS m/e (ESI) 340.12 (MH.sup.+)
Example A-80
2-Amino-6-(1-pentynyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1226] Trifluoroacetic acid salt of the title compound (0.70 mg,
0.00014 mmol, 3.3%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (15 mg, 0.042 mmol) and 1-pentyne (3.4
mg, 0.050 mmol) according to an analogous method to Example
A-91.
[1227] MS m/e (ESI) 392.2 (MH.sup.+)
Example A-81
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(3-[1,2,3]-triazol-2-yl-propyl-
amino)-nicotinamide
[1228] The title compound (14.96 mg, 0.027 mmol, 9.2%) was obtained
from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (105 mg, 0.292 mmol) and
3-[1,2,3]triazol-2-yl-propylamine (279 mg, 2.21 mmol) according to
an analogous method to Example A-126.
[1229] MS m/e (ESI) 450.38 (MH.sup.+)
Example A-82
2-Amino-6-(furfurylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1230]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (180 mg, 0.5 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (2 mL) and
diisopropylethylamine (1 mL), furfurylamine (0.663 mL, 7.5 mmol)
was added, and the solution was heated in a sealed tube for 13
hours 30 minutes (oil bath temperature: 135.degree. C.). The
reaction mixture was allowed to room temperature, poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1), and the title
compound (144 mg, 0.34 mmol, 68%) was obtained.
[1231] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.50 (2H, d,
J=5.6 Hz), 4.61 (2H, dd, J=0.8, 5.6 Hz), 4.87-4.94 (1H, m), 5.74
(1H, d, J=8.8 Hz), 6.04 (1H, t, J=5.2 Hz), 6.22 (1H, dd, J=0.8, 3.2
Hz), 6.31 (1H, dd, J=2.0, 3.2 Hz), 6.38 (1H, d, J=3.6 Hz), 6.45
(2H, brs), 6.69-6.72 (1H, m), 7.06-7.12 (3H, m), 7.29-7.38 (4H,
m).
Example A-83
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(2-pyridin-2-yl-ethylamino)-ni-
cotinamide
[1232]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (20 mg, 37 .mu.mol) and
2-pyridin-2-yl-ethyl amine (66 .mu.l, 0.56 mmol) were dissolved in
a mixture solvent of dimethylsulfoxide (1 mL) and
N,N-diisopropylethylamine (0.5 mL), and the solution was stirred at
130.degree. C. for 17 hours. The reaction solution was cooled to
room temperature, water and ethyl acetate were added, the organic
layer was partitioned, washed with water and brine, and dried over
anhydrous magnesium sulfate. The solvent was evaporated in vacuo,
the residue was purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and the title compound (17.7 mg)
was obtained as a trifluoroacetic acid salt.
[1233] MS m/e (ESI) 446.05 (MH.sup.+)
Example A-84
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(tetrahydrofuran-2-ylmethoxy)--
nicotinamide
[1234] Trifluoroacetic acid salt of the title compound (16 mg,
0.030 mmol, 31%) was obtained from 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (17 mg, 0.096 mmol),
tetrahydrofuran-2-ylmethanol (0.5 mL) and
C-(5-phenoxy-thiophen-2-yl)-methylamine (20 mg, 0.097 mmol)
according to an analogous method to Example A-29.
[1235] MS m/e (ESI) 426.2 (MH.sup.+)
Example A-85
2-Amino-6-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(2-(R)-(-)-tetrahydrofurfury-
lamino)-nicotinamide
[1236]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (1 mL) and
diisopropylethylamine (0.5 mL), (R)-(-)-tetrahydrofurfuryl amine
(0.086 mL, 0.83 mmol) was added thereto, followed by heating in a
sealed tube for 22 hours 30 minutes (oil bath temperature:
130.degree. C.). The reaction mixture was allowed to room
temperature, poured into brine, and the solution was extracted with
ethyl acetate. The organic layer was dried over anhydrous magnesium
sulfate, then concentrated, the obtained residue was purified by
silica gel column chromatography (ethyl acetate:hexane=1:1), and
the title compound (22 mg, 0.052 mmol, 62%) was obtained.
[1237] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.56-1.67
(1H, m), 1.86-2.04 (3H, m), 3.23-3.31 (1H, m), 3.54-3.62 (1H, m),
3.73-3.80 (1H, m), 3.84-3.91 (1H, m), 4.02-4.09 (1H, m), 4.61 (2H,
d, J=5.6 Hz), 4.91-5.02 (1H, m), 5.71 (1H, d, J=8.8 Hz), 5.98-6.04
(1H, m), 6.38 (1H, d, J=3.6 Hz), 6.46 (2H, brs), 6.71 (1H, d, J=3.6
Hz), 7.06-7.12 (3H, m), 7.29-7.37 (3H, m).
Example A-86
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-thiazol-2-yl-nicotinamide
[1238] To a solution of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (101 mg, 0.281 mmol) in xylene (7 mL)
were added 2-tributylstanyl thiazole (137 mg, 0.365 mmol) and
tetrakis(triphenylphosphine)palladium(0) (81 mg, 0.070 mmol) under
nitrogen atmosphere, and the solution was stirred for 12 hours at
120.degree. C. The reaction mixture was concentrated, the obtained
residue was purified by silica gel chromatography (toluene-ethyl
acetate), then, the obtained residue was washed by hexane-ethyl
acetate (20:1), and the title compound (22 mg, 0.054 mmol, 19%) was
obtained.
[1239] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.50 (2H,
d, J=6.0 Hz), 6.50 (1H, d, J=3.6 Hz), 6.78 (1H, d, J=3.6 Hz),
7.00-7.18 (3H, m), 7.22-7.50 (5H, m), 7.85 (1H, d, J=2.8 Hz), 7.97
(1H, d, J=2.8 Hz), 8.05 (1H, d, J=8.4 Hz), 9.12-9.22 (1H, m).
Example A-87
2-Amino-6-(3-methyl-2-butenyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinam-
ide
[1240] Trifluoroacetic acid salt of the title compound (0.71 mg,
0.0014 mmol, 1.7%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and
tributyl(3-methyl-2-butenyl)tin (0.084 mL, 0.25 mmol) according to
an analogous method to Example A-29, followed by purifying by
reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1241] MS m/e (ESI) 394.2 (MH.sup.+)
Example A-88
2-Amino-6-(3-dimethylamino-1-propynyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-n-
icotinamide
[1242] Trifluoroacetic acid salt of the title compound (1.00 mg,
0.00019 mmol, 4.6%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (15 mg, 0.042 mmol) and
1-dimethylamino-2-propyn (4.2 mg, 0.050 mmol) according to an
analogous method to Example A-91.
[1243] MS m/e (ESI) 407.2 (MH.sup.+)
Example A-89
2-Amino-6-(3-fluoro-benzylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotin-
amide
[1244] The title compound (20.6 mg, 0.0365 mmol, 43%) was obtained
from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.085 mmol) and
3-fluorobenzylamine (146 .mu.l, 1.28 mmol) according to an
analogous method to Example A-94.
[1245] MS m/e (ESI) 449.50 (MH.sup.+)
Example A-90
2-Amino-6-(3-methoxy-1-(Z)-propenyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nic-
otinamide
[1246] To a mixture of
2-amino-6-(3-methoxy-1-propynyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicoti-
namide described in Example A-91 (11 mg, 0.028 mmol) and
tetrahydrofuran (1 mL) were added quinoline (5.4 mg, 0.042 mmol)
and Lindlar catalyst (5.0 mg), and the mixture was stirred under
hydrogen atmosphere at room temperature for 15 minutes. The
interior of the reaction system was exchanged with nitrogen, then,
filtration was carried out through Celite pad, and the solvent was
evaporated in vacuo. The residue was filtered by NH silica gel,
then, purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and trifluoroacetic acid salt of
the title compound (4.4 mg, 0.0086 mmol, 31%) was obtained.
[1247] MS m/e (ESI) 396.5 (MH.sup.+)
Example A-91
2-Amino-6-(3-methoxy-1-propynyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotin-
amide
[1248] A mixture of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (15 mg, 0.042 mmol), methylpropargyl
ether (3.5 mg, 0.050 mmol), diisopropylethylamine (0.023 mL, 0.13
mmol), pyridine (0.011 mL, 0.13 mmol), catalytic amount of
copper(I) iodide, tetrakis(triphenylphosphine)palladium(0) (9.6 mg,
0.0083 mmol) and N-methylpyrrolidinone (1 mL) was stirred for 4
hours at 120.degree. C. After cooling, water and dichloromethane
were added to the reaction solution for extraction, and the organic
layer was filtered through a membrane filter. The solvent was
evaporated in vacuo, then, the residue was purified by reverse
phase high performance liquid chromatography (acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid) was used),
trifluoroacetic acid salt of the title compound (1.5 mg, 0.00030
mmol, 7.2%) was obtained.
[1249] MS m/e (ESI) 394.2 (MH.sup.+)
Example A-92
2-Amino-6-(2-(4-amino-phenylamine)-ethylamino)-N-(5-phenoxy-thiophen-2-ylm-
ethyl)-nicotinamide
[1250]
2-Amino-6-(2-(4-nitro-phenylamino)-ethylamino)-N-(5-phenoxy-thiophe-
n-2-ylmeth yl)-nicotinamide described in Preparation Example A+-13
(17 mg, 28 mmol), iron powder (7.7 mg, 138 mmol) and ammonium
chloride (4.41 mg, 83 mmol) were suspended in a mixture solvent of
ethanol (1 mL) and water (250 .mu.l), and the solution was stirred
at 90.degree. C. for 8 hours. The reaction suspension was cooled to
room temperature, then, filtered through Celite pad, water was
added to the filtrate, which was then extracted with ethyl acetate,
the organic layer was washed with brine and dried over anhydrous
magnesium sulfate. The solvent was evaporated in vacuo, the residue
was purified by NH silica gel column chromatography (ethyl
acetate:methanol=10:1), and the title compound (10 mg, 21 .mu.mol,
77%) was obtained as a white solid.
[1251] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.80 (3H,
brs), 3.28 (2H, t, J=5.7 Hz), 3.53 (2H, q, J=5.7 Hz), 4.60 (2H, d,
J=4.9 Hz), 4.91 (1H, t, J=5.7 Hz), 5.68 (1H, d, J=8.6 Hz), 6.07
(1H, t, J=5.3 Hz), 6.38 (1H, d, J=3.7 Hz), 6.46 (2H, s), 6.52 (2H,
d, J=8.8 Hz), 6.60 (2H, d, J=8.8 Hz), 6.71 (1H, d, J=3.7 Hz),
7.08-7.12 (3H, m), 7.29-7.34 (3H, m).
Example A-93
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(2-(4-sulfamoyl-phenylamino)-e-
thylamino)-nicotinamide
[1252] MS m/e (ESI) 539.47 (MH.sup.+)
Example A-94
2-Amino-6-(4-chloro-benzylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotin-
amide
[1253] To a solution of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (35 mg, 0.10 mmol) in dimethylsulfoxide
(1 mL) were added 4-chlorobenzylamine (234 .mu.l, 1.92 mmol) and
N,N-diisopropylethylamine (1.0 mL, 5.74 mmol), and the solution was
stirred at 140.degree. C. for 2.5 days. Ethanolamine (116 .mu.l,
1.92 mmol) and N,N-diisopropylethylamine (1.0 mL, 5.74 mmol) were
added to the reaction mixture, which was then further stirred at
140.degree. C. for 2.5 days. Water was added to the reaction
mixture, which was then extracted with ethyl acetate, the organic
layer was sequentially washed with water and brine, dried over
anhydrous sodium sulfate, and then, concentrated in vacuo. The
obtained residue was purified by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used), and the title compound (13.8
mg, 0.024 mmol, 24%) was obtained as a trifluoroacetic acid
salt.
[1254] MS m/e (ESI) 465.07 (MH.sup.+)
Example A-95
2-Amino-6-(4-fluoro-benzylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotin-
amide
[1255] The title compound (10.6 mg, 0.0188 mmol, 16%) was obtained
as a trifluoroacetic acid salt from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (41 mg, 0.12 mmol) and
4-fluorobenzylamine (200 .mu.l, 1.75 mmol) according to an
analogous method to Example A-94.
[1256] MS m/e (ESI) 449.56 (MH.sup.+)
Example A-96
2-Amino-6-(4-methoxy-benzylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicoti-
namide
[1257] The title compound (19.4 mg, 0.034 mmol, 37%) was obtained
as a trifluoroacetic acid salt from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (32 mg, 0.091 mmol) and
4-methoxybenzylamine (238 .mu.l, 1.82 mmol) according to an
analogous method to Example A-126.
[1258] MS m/e (ESI) 461.21 (MH.sup.+)
Example A-97
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-(4-trifluoromethyl-benzylamino-
)-nicotinamide
[1259] The title compound (15.0 mg, 0.024 mmol, 16%) was obtained
from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (54 mg, 0.15 mmol) and
4-(trifluoromethyl)benzylamine (330 .mu.l, 2.45 mmol) according to
an analogous method to Example A-126.
[1260] MS m/e (ESI) 499.10 (MH.sup.+)
Example A-98
6-Acetyl-2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1261] To a mixture of 2-amino-6-(1-ethoxy
vinyl)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide described in
Preparation Example A+-14 (2.0 mg, 0.0051 mmol) and acetone (2 mL)
were added water (1 mL) and concentrated sulfuric acid (0.2 mL),
and the solution was stirred at room temperature for 3 hours. The
reaction solution was neutralized with an aqueous solution of
saturated sodium bicarbonate, and ethyl acetate was added for
extraction. The organic layer was washed with brine, the solvent
was then evaporated in vacuo, the residue was purified by silica
gel column chromatography (hexane:ethyl acetate=2:1), and the title
compound (1.0 mg, 0.0027 mmol, 53%) was obtained as a white
solid.
[1262] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.62 (3H,
s), 4.66 (2H, d, J=5.7 Hz), 6.39-6.40 (4H, m), 6.75 (1H, d, J=3.9
Hz), 7.08-7.13 (3H, m), 7.29-7.35 (3H, m), 7.71 (1H, d, J=7.9
Hz).
Example A-99
(6-Amino-5-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-ylamino)--
acetic acid
[1263] Glycine (610 mg, 8.13 mmol) and
1,8-diazabicyclo[5,4,0]undec-7-ene (405 .mu.l, 2.71 mmol) were
added to
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (195 mg, 0.542 mmol) under nitrogen
atmosphere, and the solution was stirred at 190.degree. C. for 4
hours. Dimethylsulfoxide (5 mL) was added to the reaction mixture,
which was then filtered with a polytetrafluoroethylene membrane
filter (Whatman Inc), the filtrate was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), title
compound (55.36 mg, 0.108 mmol, 20%) was obtained.
[1264] MS m/e (ESI) 399.30 (MH.sup.+)
Example A-100
2-amino-6-(1-(Z)-hydroxyimino-ethyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nic-
otinamide
[1265] To a mixture of
6-acetyl-2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-98 (9.0 mg, 0.024 mmol), ethanol (1 mL) and
water (0.5 mL) were added hydroxylamine hydrochloride (2.6 mg,
0.037 mmol) and sodium acetate (3.0 mg, 0.037 mmol), and the
solution was stirred under reflux for 6 hours. After cooling the
reaction solution, water and ethyl acetate were added for
extraction. The solvent was evaporated in vacuo, the residue was
purified by NH silica gel column chromatography (methanol:ethyl
acetate=1:50), and the title compound (8.3 mg, 0.022 mmol, 90%) was
obtained as a white solid.
[1266] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.28 (3H,
s), 4.65 (2H, d, J=5.7 Hz), 6.36 (1H, brs), 6.39 (1H, d, J=3.9 Hz),
6.49 (2H, brs), 6.74 (1H, d, J=3.8 Hz), 7.06-7.13 (4H, m),
7.31-7.34 (2H, m), 7.58 (1H, d, J=8.1 Hz).
Example A-101
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1267] 2-Amino-6-chloro-nicotinic acid described in Preparation
Example A-1 (400 mg, 2.31 mmol) was dissolved in
N,N-dimethylformamide (10 mL), triethylamine (0.78 mL, 5.6 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (1.23 g, 2.8 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (572 mg, 2.8 mmol) were added, and the solution was
stirred for 13 hours 30 minutes at room temperature. After the
reaction was completed, the reaction solution was poured into
brine, which was then extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1), and the title
compound (380 mg, 1.05 mmol, 46%) was obtained.
[1268] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.47 (2H,
d, J=6.0 Hz), 6.50 (1H, d, J=4.0 Hz), 6.64 (1H, d, J=8.0 Hz), 6.78
(1H, d, J=4.0 Hz), 7.07-7.17 (3H, m), 7.36-7.41 (2H, m), 7.53 (2H,
brs), 7.93 (1H, d, J=8.0 Hz), 9.11 (1H, t, J=6.0 Hz).
Example A-102
2-Amino-6-cyclopropyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1269] To a mixture of
2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-vinyl-nicotinamide
described in Example A-168 (6.0 mg, 0.017 mmol) and toluene (0.5
mL) were added diiodine methane (0.0055 mL, 0.068 mmol) and diethyl
zinc (1.1M toluene solution, 0.046 mL, 0.05 .mu.mol) on an ice
bath, and the solution was stirred at room temperature for 30
minutes. Water, ethyl acetate and an aqueous solution of 29%
ammonia were added to the reaction solution for extraction, the
organic layer was then washed with brine. The organic layer was
evaporated in vacuo, then, residue was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), and
trifluoroacetic acid salt of the title compound (0.40 mg, 0.00083
mmol, 4.9%) was obtained.
[1270] MS m/e (ESI) 366.1 (MH.sup.+)
Example A-103
[1271]
2-Amino-6-cyclopropylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicoti-
namide
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (1 mL) and
N,N-diisopropylethylamine (0.5 mL), cyclopropylamine (0.058 mL,
0.84 mmol) was added thereto, followed by heating in a sealed tube
for 15 hours 30 minutes (oil bath temperature: 130.degree. C.). The
reaction mixture was allowed to room temperature, poured into
brine, which was then extracted with ethyl acetate. The organic
layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1), and the title
compound (15 mg, 0.039 mmol, 47.5%) was obtained.
[1272] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.52-0.57
(2H, m), 0.74-0.80 (2H, m), 2.47-2.54 (1H, m), 4.62 (2H, d, J=5.6
Hz), 5.09 (1H, brs), 6.06 (1H, d, J=8.4 Hz), 6.08-6.14 (1H, m),
6.34-6.42 (3H, m), 6.72 (1H, d, J=3.6 Hz), 7.06-7.13 (3H, m),
7.29-7.35 (2H, m), 7.45 (1H, d, J=8.4 Hz).
Example A-104
2-Amino-6-(cyclopropylmethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nico-
tinamide
[1273] MS m/e (ESI) 395.22 (MH.sup.+)
Example A-105
2-Amino-6-(2-ethoxy-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotina-
mide
[1274]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (100 mg, 0.28 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (2 mL) and
N,N-diisopropylethylamine (1 mL), 2-ethoxyethylamine (0.051 mL,
0.49 mmol) was added thereto, followed by heating in a sealed tube
for 32 hours 40 minutes (oil bath temperature: 130.degree. C.). The
reaction mixture was allowed to room temperature, poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1), and the title
compound (37 mg, 0.09 mmol, 32%) was obtained.
[1275] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.11 (3H,
t, J=7.2 Hz), 3.35-3.47 (6H, m), 4.41 (2H, d, J=6.0 Hz), 5.72 (1H,
d, J=8.8 Hz), 6.48 (1H, d, J=3.6 Hz), 6.67-6.77 (2H, m), 7.05 (2H,
brs), 7.05-7.16 (3H, m), 7.35-7.41 (2H, m), 7.59 (1H, d, J=8.8 Hz),
8.39 (1H, t, J=6.0 Hz).
Example A-106
2-Amino-6-ethylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1276]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (1 mL) and
N,N-diisopropylethylamine (0.5 mL), ethylamine (2M tetrahydrofuran
solution) (2 mL, 4 mmol) was added thereto, followed by heating in
a sealed tube for 17 hours (oil bath temperature: 135.degree. C.).
The reaction mixture was allowed to room temperature, poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1), and the title
compound (117 mg, 0.32 mmol, 57%) was obtained.
[1277] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.21 (3H, t,
J=7.2 Hz), 3.24-3.32 (2H, m), 4.56-4.63 (3H, m), 5.67 (1H, d, J=8.8
Hz), 6.06-6.11 (1H, m), 6.37 (1H, d, J=4.0 Hz), 6.42 (2H, brs),
6.71 (1H, d, J=4.0 Hz), 7.06-7.12 (3H, m), 7.29-7.34 (2H, m), 7.37
(1H, J=8.8 Hz).
Example A-107
(.+-.)-2-(6-Amino-5-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2--
ylamino)-(R)-3-hydroxy-butyric acid
[1278] Trifluoroacetic acid salt of the title compound (12 mg,
0.022 mmol, 26%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and (L)-threonine
(99 mg, 0.83 mmol) according to an analogous method to Example
A-99.
[1279] MS m/e (ESI) 443.1 (MH.sup.+)
Example A-108
(.+-.)-2-(6-Amino-5-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2--
ylamino)-3-phenyl-propionic acid
[1280] Trifluoroacetic acid salt of the title compound (11 mg,
0.019 mmol, 23%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and
(.+-.)-phenylalanine (140 mg, 0.83 mmol) according to an analogous
method to Example A-99, trifluoroacetic acid salt of the title
compound (11 mg, 0.019 mmol, 23%) was obtained.
[1281] MS m/e (ESI) 489.1 (MH.sup.+)
Example A-109
(.+-.)-2-(6-Amino-5-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2--
ylamino)-4-methyl-pentanoic acid
[1282] Trifluoroacetic acid salt of the title compound (6.8 mg,
0.012 mmol, 14%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and (D)-leucine (110
mg, 0.83 mmol) according to an analogous method to Example
A-99.
[1283] MS m/e (ESI) 455.2 (MH.sup.+)
Example A-110
(.+-.)-2-(6-Amino-5-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2--
ylamino)-3-methoxy-propionic acid
[1284] Trifluoroacetic acid salt of the title compound (5.5 mg,
0.0099 mmol, 12%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and
(.+-.)--O-methylserine (99 mg, 0.83 mmol) according to an analogous
method to Example A-99.
[1285] MS m/e (ESI) 443.1 (MH.sup.+)
Example A-111
(.+-.)-2-(6-Amino-5-((5-phenoxy-thiophene-2-ylmethyl)-carbamoyl)-pyridin-2-
-ylamino)-pentanedioic acid
[1286] Trifluoroacetic acid salt of the title compound (1.7 mg,
0.0029 mmol, 3.5%) was obtained from
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol) and (.+-.)-glutamic
acid (122 mg, 0.83 mmol) according to an analogous method to
Example A-99.
[1287] MS m/e (ESI) 471.4 (MH.sup.+)
Example A-112
2-Amino-6-(2-hydroxyethoxy)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1288] Sodium hydride (3.1 mg, 0.078 mmol, 60% in oil), catalytic
amount of copper(I) iodide,
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-102 (4.0 mg, 0.011 mmol) were added
sequentially to ethyleneglycol (0.7 mL), and the solution was
stirred at 65.degree. C. for 2 hours. After further stirring at
90.degree. C., the solution was allowed to cool to room
temperature. Water, dichloromethane and an aqueous solution of
saturated ammonium chloride were added to the reaction solution for
extraction, which was then washed with brine, then, the solvent was
evaporated in vacuo. The residue was purified by reverse phase high
performance liquid chromatography (acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid) was used), and
trifluoroacetic acid salt of the title compound (0.26 mg, 0.00052
mmol, 4.7%) was obtained.
[1289] MS m/e (ESI) 386.2 (MH.sup.+)
Example A-113
2-Amino-6-(2-hydroxy-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotin-
amide
[1290]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (170 mg, 0.47 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (2 mL) and
diisopropylethylamine (1 mL), ethanolamine (0.428 mL, 7.1 mmol) was
added thereto, followed by heating in a sealed tube for 15 hours 20
minutes (oil bath temperature: 135.degree. C.). The reaction
mixture was allowed to room temperature, poured into brine, and the
solution was extracted with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, then concentrated, the
obtained residue was purified by NH silica gel column
chromatography (ethyl acetate:hexane=2:1), and the title compound
(138 mg, 0.36 mmol, 76%) was obtained.
[1291] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.24-3.31
(2H, m), 3.44-3.51 (2H, m), 4.39 (2H, d, J=5.6 Hz), 4.68 (1H, t,
J=5.2 Hz), 5.70 (1H, d, J=8.4 Hz), 6.46 (1H, d, J=4.0 Hz), 6.66
(1H, brs), 6.70 (1H, d, J=4.0 Hz), 7.02 (2H, brs), 7.04-7.14 (3H,
m), 7.34-7.39 (2H, m), 7.57 (1H, d, J=8.4 Hz), 8.37 (1H, t, J=5.6
Hz).
Example A-114
2-Amino-6-hydroxymethyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1292] To a mixture of
2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-tributylstanyl-nicotinamide
described in Preparation Example A+-15 (98 mg, 0.16 mmol) in
tetrahydrofuran (1.5 mL) was added n-butyl lithium (2.4M hexane
solution, 0.32 mL, 0.80 mmol) dropwise at -78.degree. C., and the
solution was stirred for 1 hour 40 minutes at the same temperature.
N,N-dimethylformamide (0.037 mL, 0.48 mmol) was added at the same
temperature, the solution was stirred for 35 minutes, then, a
solution of sodium borocyanide (50 mg, 0.80 mmol) in
tetrahydrofuran (1 mL) was added dropwise at the same temperature,
and the solution was stirred at -3.degree. C. for 1 hour. The
reaction solution was cooled to -78.degree. C., acetic acid (0.091
mL, 1.6 mmol) was added, and the solution was warmed gradually to
0.degree. C. Water, ethyl acetate and tetrahydrofuran were added to
the reaction solution for extraction, which was then washed with
brine, then, the solvent was evaporated in vacuo. The residue was
purified by silica gel column chromatography (methanol:ethyl
acetate=1:50), and the title compound (19 mg, 0.053 mmol, 33%) was
obtained as a pale yellow oil.
[1293] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.58 (2H,
s), 4.64 (2H, d, J=5.5 Hz), 6.38 (1H, d, J=3.7 Hz), 6.43 (1H, brs),
6.48-6.50 (3H, m), 6.74 (1H, d, J=3.7 Hz), 7.08-7.13 (3H, m),
7.30-7.34 (2H, m), 7.59 (1H, d, J=7.9 Hz).
Example A-115
2-Amino-6-isopropoxy-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1294] Trifluoroacetic acid salt of the title compound (4.3 mg,
0.0086 mmol, 9.0%) was obtained from 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (17 mg, 0.096 mmol),
isopropanol (0.5 mL) and C-(5-phenoxy-thiophen-2-yl)-methylamine
(20 mg, 0.097 mmol) according to an analogous method to Example
A-29.
[1295] MS m/e (ESI) 384.2 (MH.sup.+)
Example A-116
2-Amino-6-methoxy-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1296] 2,5-Diamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Preparation Example A+-10 (27 mg, 59 mmol), sodium
nitrite (4.1 mg, 59 mmol) and sulfuric acid (several drops) were
dissolved in methanol (5 mL), and the solution was stirred for 30
minutes under reflux. An aqueous solution of saturated sodium
bicarbonate was added to the reaction solution at 0.degree. C.,
which was then extracted with ethyl acetate, and the organic layer
was washed with brine. The solvent was evaporated in vacuo, the
residue was purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), then, further by NH silica gel
column chromatography (hexane:ethyl acetate=5:1), and the title
compound (0.7 mg) was obtained as a white solid.
[1297] MS m/e (ESI) 356.32 (MH.sup.+).
[1298] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.87 (3H,
s), 4.63 (2H, d, J=5.7 Hz), 6.01 (1H, d, J=8.6 Hz), 6.11 (1H, brs),
6.39 (1H, d, J=3.8 Hz), 6.51 (1H, brs), 6.73 (1H, d, J=3.3 Hz),
7.08-7.12 (3H, m), 7.22-7.26 (1H, m), 7.32 (2H, t, J=8.6 Hz), 7.50
(1H, t, J=8.8 Hz).
Example A-117
2-Amino-N-(5-benzofuran-5-ylmethyl-thiophen-2-ylmethyl)-6-methoxymethyl-ni-
cotinamide
[1299] MS m/e (ESI) 407.85 (MH.sup.+)
Example A-118
2-Amino-N-(5-benzo[1,3]dioxol-5-ylmethyl-thiophen-2-ylmethyl)
6-methoxymethyl-nicotinamide
[1300] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.33 (3H,
s), 3.96 (2H, s), 4.28 (2H, s), 4.47 (2H, d, J=6.0 Hz), 5.96 (2H,
d, J=1.2 Hz), 6.59 (1H, d, J=8.0 Hz), 6.68-6.74 (2H, m), 6.77-6.84
(3H, m), 7.12 (2H, brs), 7.90 (1H, d, J=8.0 Hz), 8.97 (1H, t, J=6.0
Hz).
Example A-119
2-Amino-6-methoxymethyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1301] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.41 (2H, s), 4.64-4.66 (2H, m), 6.32 (1H, br s), 6.39 (1H, d,
J=3.8 Hz), 6.47 (2H, br s), 6.71 (1H, d, J=7.9 Hz), 6.74 (1H, d,
J=3.8 Hz), 7.08-7.13 (3H, m), 7.31-7.35 (2H, m), 7.62 (1H, d, J=7.9
Hz).
Example A-120
2-Amino-N-(4-benzylamino-benzyl)-6-methoxymethyl-nicotinamide
[1302] MS m/e (ESI) 377 (MH.sup.+)
Example A-121
2-Amino-N-(5-benzyl-thiophen-2-ylmethyl)-6-methoxymethyl-nicotinamide
[1303] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.44 (3H,
s), 4.09 (2H, s), 4.38 (2H, s), 4.66 (2H, d, J=5.2 Hz), 6.25-6.34
(1H, m), 6.38 (2H, br s), 6.65 (1H, d, J=3.6 Hz), 6.67 (1H, d,
J=8.0 Hz), 6.82 (1H, d, J=3.6 Hz), 7.20-7.27 (3H, m), 7.27-7.34
(2H, m), 7.57 (1H, d, J=8.0 Hz).
Example A-122
2-Amino-N-(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-6-methoxymethyl-nicot-
inamide
[1304] MS m/e (ESI) 404 (MH.sup.+)
Example A-123
2-Amino-N-(5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-6-methoxymethyl-nicot-
inamide
[1305] MS m/e (ESI) 388 (MH.sup.+)
Example A-124
2-Amino-6-(3-methoxy-propyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamid-
e
[1306] To a mixture of
2-amino-6-(3-methoxy-1-(Z)-propenyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-ni-
cotinamide described in Example A-90 (3.0 mg, 0.0059 mmol) and
tetrahydrofuran (1 mL) were added triethylamine (3.6 mg, 0.036
mmol) and 10% palladium-carbon (50% water wet, 5 mg), and the
solution was stirred under hydrogen atmosphere at room temperature
for 15 minutes. The interior of the reaction system was exchanged
with nitrogen, then, filtration was carried out through Celite pad,
the solvent was evaporated in vacuo. The residue was purified by
reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and trifluoroacetic acid salt of the title
compound (0.48 mg, 0.00094 mmol, 16%) was obtained.
[1307] MS m/e (ESI) 398.3 (MH.sup.+)
Example A-125
2-Amino-6-methylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1308]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (1 mL) and
diisopropylethylamine (0.5 mL), methylamine (2M tetrahydrofuran
solution) (2 mL, 4 mmol) was added thereto, followed by heating in
a sealed tube for 14 hours (oil bath temperature: 135.degree. C.).
The reaction mixture was allowed to room temperature, poured into
brine, and the solution was extracted with ethyl acetate. The
organic layer was dried over anhydrous magnesium sulfate, then
concentrated, the obtained residue was purified by NH silica gel
column chromatography (ethyl acetate:hexane=2:1), and the title
compound (144 mg, 0.41 mmol, 73%) was obtained.
[1309] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.89 (3H, d,
J=5.2 Hz), 4.61 (2H, d, J=5.6 Hz), 4.64-4.71 (1H, m), 5.69 (1H, d,
J=8.4 Hz), 6.03-6.09 (1H, m), 6.38 (1H, d, J=4.0 Hz), 6.44 (2H,
brs), 6.71 (1H, d, J=4.0 Hz), 7.06-7.12 (3H, m), 7.29-7.35 (2H, m),
7.39 (1H, d, J=8.4 Hz).
Example A-126
2-Amino-6-benzylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1310] To a solution of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (110 mg, 0.31 mmol) in dimethylsulfoxide
(1 mL) were added benzylamine (1.8 mL, 16.5 mmol) and
N,N-diisopropylethylamine (0.5 mL, 2.94 mmol), and the solution was
stirred for 17 hours at 135.degree. C. Water was added to the
reaction mixture, which was then extracted with ethyl acetate, the
organic layer was sequentially washed with water and brine, dried
over anhydrous sodium sulfate, and then, concentrated in vacuo. The
obtained residue was purified by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used), and the title compound (23.4
mg, 0.0429 mmol, 14%) was obtained as a trifluoroacetic acid
salt.
[1311] MS m/e (ESI) 431.27 (MH.sup.+)
Example A-127
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-propoxy-nicotinamide
[1312] Trifluoroacetic acid salt of the title compound (5.3 mg,
0.011 mmol, 11%) was obtained from 2-amino-6-chloronicotinic acid
described in Preparation Example A-4 (17 mg, 0.096 mmol), propanol
(0.5 mL) and C-(5-phenoxy-thiophen-2-yl)-methylamine (20 mg, 0.097
mmol) according to an analogous method to Example A-29.
[1313] MS m/e (ESI) 384.1 (MH.sup.+)
Example A-128
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-propylamino-nicotinamide
[1314]
2-Amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (200 mg, 0.56 mmol) was dissolved in a
mixture solution of dimethylsulfoxide (2 mL) and
N,N-diisopropylethylamine (1 mL), propylamine (0.685 mL, 8.3 mmol)
was added thereto, followed by heating in a sealed tube for 13
hours (oil bath temperature: 135.degree. C.). The reaction mixture
was allowed to room temperature, poured into brine, which was then
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, then concentrated, the obtained
residue was purified by NH silica gel column chromatography (ethyl
acetate:hexane=2:1), and the title compound (89 mg, 0.23 mmol, 42%)
was obtained.
[1315] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.96 (3H, t,
J=7.6 Hz), 1.54-1.64 (2H, m), 3.16-3.22 (2H, m), 4.59 (2H, d, J=5.6
Hz), 4.69 (1H, t, J=5.2 Hz), 5.67 (1H, d, J=8.8 Hz), 6.16 (1H, t,
J=5.6 Hz), 6.36 (1H, d, J=3.6 Hz), 6.42 (2H, brs), 6.69 (1H, d,
J=3.6 Hz), 7.06-7.12 (3H, m), 7.29-7.35 (2H, m), 7.37 (1H, J=8.8
Hz).
Example A-129
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-((pyrazin-2-ylmethyl)-amino)-n-
icotinamide
[1316] MS m/e (ESI) 433.15 (MH.sup.+)
[1317] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.33 (2H,
d, J=5.6 Hz), 4.68 (2H, s), 5.99 (1H, d, J=8.4 Hz), 6.48 (1H, d,
J=3.6 Hz), 6.73 (1H, d, J=3.6 Hz), 7.06-7.15 (3H, m), 7.34-7.39
(2H, m), 7.82-7.94 (1H, m), 8.55 (1H, d, J=2.4 Hz), 8.60 (1H, dd,
J=2.4, 1.2 Hz), 8.67 (1H, d, J=1.2 Hz), 8.69-8.79 (1H, m).
Example A-130
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-((pyridin-2-ylmethyl)-amino)-n-
icotinamide
[1318] MS m/e (ESI) 432.17 (MH.sup.+)
Example A-131
3-(3-(5-Phenoxy-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-ylamino)-propion-
ic acid
[1319] To a solution of
2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described
in Preparation Example A+-7 (51 mg, 0.15 mmol) in dimethylsulfoxide
(2 mL) were added tert-butyl 3-aminopropanoate hydrochloride (32
mg, 0.178 mmol) and triethylamine (27 .mu.l, 0.192 mmol), and the
solution was stirred for 2.5 hours at 120.degree. C. Potassium
carbonate (49 mg, 0.36 mmol) was added to the reaction mixture,
which was then stirred for 20 hours 120.degree. C. Water was added
to the reaction mixture, which was then extracted with ethyl
acetate and concentrated. To a solution of the resulting residue in
dichloromethane (1 mL) was added trifluoroacetic acid (500 .mu.l,
6.49 mmol), and the solution was stirred for 2.5 hours at room
temperature. The reaction mixture was concentrated, and the
obtained residue was purified by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used), and the title compound (3.44
mg, 0.0067 mmol, 4.5%) was obtained as a trifluoroacetic acid
salt.
[1320] MS m/e (ESI) 398.52 (MH.sup.+)
Example A-132
2-Chloro-N-(5-(3-fluorophenoxy)thiophen-2-ylmethyl)-6-methylnicotinamide
[1321] The title compound (330 mg, 0.877 mmol, 65.0%) was obtained
as a white solid from 2-chloro-6-methylnicotinic acid (230 mg, 1.35
mmol) and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described
in Preparation Example 23 (300 mg, 1.35 mmol) according to an
analogous method to Example Q-6.
[1322] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.47 (3H,
s), 4.52 (2H, d, J=5.6 Hz), 6.60-6.63 (1H, m), 6.84 (1H, d, J=4.0
Hz), 6.92-7.04 (3H, m), 7.32-7.35 (1H, m), 7.40-7.47 (1H, m), 7.77
(1H, d, J=7.2 Hz), 9.15 (1H, t, J=5.6 Hz).
Example A-133
2-(Cyclopropylmethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1323] To a solution of
2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described
in Preparation Example A+-7 (64 mg, 0.186 mmol) in
dimethylsulfoxide (1 mL) was added (aminomethyl)cyclopropane (48
.mu.l, 0.56 mmol), and the solution was stirred for 14 hours at
120.degree. C. The reaction mixture was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), and the
title compound (15.6 mg, 0.0316 mmol, 17%) was obtained as a
trifluoroacetic acid salt.
[1324] MS m/e (ESI) 380.43 (MH.sup.+)
Example A-134
2-(2-Methoxy-ethylamino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1325] To a solution of
2-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described
in Preparation Example A+-7 (16 mg, 0.046 mmol) in
1-methyl-2-pyrrolidone (2 mL) were added 2-methoxyethylamine (6
.mu.l, 0.07 mmol) and sodium hydride (4 mg, 0.092 mmol, 60% in
oil), and the solution was stirred for 8 hours at 110.degree. C. An
aqueous solution of saturated ammonium chloride was added to the
reaction mixture, which was then extracted with ethyl acetate, and
concentrated. The obtained residue was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), and the
title compound (0.67 mg, 0.0013 mmol, 2.8%) was obtained as a
trifluoroacetic acid salt.
[1326] MS m/e (ESI) 384.16 (MH.sup.+)
Example A-135
2-Methyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1327] The title compound (40 mg, 0.123 mmol, 42.4%) was obtained
as a light brown solid from 2-methylnicotinic acid (40 mg, 0.29
mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in
Preparation Example 26 (60 mg, 0.29 mmol) according to an analogous
technique to Example Q-6.
[1328] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.47 (3H,
s), 4.49 (2H, d, J=5.6 Hz), 6.50-6.63 (1H, m), 6.77-6.80 (1H, m),
7.06-7.16 (3H, m), 7.23-7.28 (1H, m), 7.35-7.40 (2H, m), 7.66-7.70
(1H, m), 8.48 (1H, dd, J=1.6, 4.8 Hz), 9.05 (1H, t, J=5.6 Hz).
Example A-136
2-Methylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1329] To a solution of
2-(ethoxymethyl-amino)-N-(5-phenoxy-thiophene-2-ylmethyl)-nicotinamide
described in Preparation Example A+-6 (148 mg, 0.385 mmol) in
dimethylsulfoxide (3 mL) was added sodium borohydride (44 mg, 1.15
mmol), and the solution was stirred for 30 minutes at 100.degree.
C., followed by stirring for 20 minutes at 110.degree. C.
Furthermore, sodium borohydride (35 mg, 0.925 mmol) was added
thereto, followed by stirring for 20 minutes at 110.degree. C.
Water was added to the reaction mixture, which was then extracted
with ethyl acetate, the organic layer was sequentially washed with
water and brine, dried over anhydrous sodium sulfate, and then,
concentrated in vacuo. The obtained residue was purified by silica
gel chromatography (hexane-ethyl acetate), and the title compound
(86 mg, 0.26 mmol, 67%) was obtained.
[1330] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.87 (3H,
d, J=4.8 Hz), 4.46 (2H, d, J=5.6 Hz), 6.48 (1H, d, J=3.6 Hz), 6.53
(1H, dd, J=4.8, 7.6 Hz), 6.76 (1H, d, J=3.6 Hz), 7.00-7.18 (3H, m),
7.30-7.41 (2H, m), 7.88 (1H, dd, J=2.0, 7.6 Hz), 8.10-8.25 (2H, m),
9.07 (1H, t, J=5.6 Hz).
Example A-137
6-Amino-N-(5-(3-fluorophenoxy)thiophen-2-ylmethyl)nicotinamide
[1331] The title compound (20 mg, 0.058 mmol, 21.6%) was obtained
as a white solid from 6-amino-nicotinic acid (37 mg, 0.27 mmol) and
C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 23 (60 mg, 0.27 mmol) according to an analogous
method to Example Q-6.
[1332] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.56 (2H,
d, 6.0 Hz), 6.39 (1H, d, J=8.8 Hz), 6.48 (2H, brs), 6.56 (1H, d,
J=3.6 Hz), 6.76 (1H, d, J=3.6 Hz), 6.88-7.00 (3H, m), 7.39 (1H,
ddd, J=8.0, 8.0, 8.0), 7.79 (1H, dd, J=2.0, 8.8 Hz), 8.43 (1H, d,
J=2.0 Hz), 8.77 (1H, t, J=6.0 Hz).
Example A-138
6-Amino-N-(5-phenoxy thiophen-2-ylmethyl)-nicotinamide
[1333] To a solution of C-(5-phenoxythiophen-2-yl)methylamine
described in Preparation Example 24 (170 mg, 0.83 mmol) and
6-aminonicotinic acid (130 mg, 0.91 mmol) in N,N-dimethylformamide
(10 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (400 mg, 0.91 mmol) and triethylamine (0.3 mL,
2.2 mmol), and the solution was stirred for 35 minutes at
60.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water twice, NH silica gel was added to the organic layer, the
solvent was evaporated in vacuo for adsorption, purification was
carried out by NH silica gel column chromatography (ethyl acetate,
then ethyl acetate:methanol=50:1), and the title compound (130 mg,
0.40 mmol, 48.2%) was obtained as a solid.
[1334] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, 5.2 Hz), 6.39 (1H, d, J=8.8 Hz), 6.43-6.54 (3H, m), 6.70-6.77
(1H, m), 7.20-7.16 (3H, m), 7.31-7.41 (2H, m), 7.78 (1H, d, J=8.8
Hz), 8.43 (1H, s), 8.76 (1H, d, J=5.2 Hz).
Example A-139
6-Amino-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1335] To a solution of
C-(5-(4-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 28 (500 mg, 2.24 mmol) and 6-aminonicotinic
acid (340 mg, 2.46 mmol) in N,N-dimethylformamide (10 mL) were
added benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (1.1 g, 2.46 mmol) and triethylamine (0.6 mL,
4.48 mmol), and the solution was stirred for 30 minutes at
60.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, and the organic layer was
washed with water three times. The organic layer was passed through
a glass filter lined with NH silica gel and silica gel (1:1), and
eluted with a mixture solvent of ethyl acetate and methanol (20:1).
The solvent was evaporated in vacuo, ethyl acetate and hexane were
added to the residue, the generated solid was collected by
filtration, and the title compound (560 mg, 1.63 mmol, 72.8%) was
obtained as a slightly yellow solid.
[1336] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.44 (2H,
d, J=5.2 Hz), 6.39 (1H, d, J=8.8 Hz), 6.44-6.50 (3H, m), 6.72 (1H,
d, J=2.4 Hz), 7.09-7.16 (2H, m), 7.16-7.24 (2H, m), 7.78 (1H, d,
J=8.8 Hz), 8.42 (1H, s), 8.74 (1H, t, J=5.2 Hz).
Example A-140
6-Amino-N-(5-(4-chloro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1337] The title compound (32 mg, 0.089 mmol, 30.7%) was obtained
as a white solid from
C-(5-(4-chlorophenoxy)thiophen-2-yl)methylamine obtained according
to an analogous method to Example E-66 (70 mg, 0.29 mmol) and
6-amino-nicotinic acid (40 mg, 0.29 mmol).
[1338] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, 5.2 Hz), 6.39 (1H, d, J=8.4 Hz), 6.48 (2H, s), 6.51 (1H, d,
J=3.6 Hz), 6.74 (1H, d, J=3.6 Hz), 7.04-7.14 (2H, m), 7.36-7.46
(2H, m), 7.78 (1H, d, J=8.4 Hz), 8.43 (1H, s), 8.76 (1H, t, J=5.2
Hz).
Example A-141
6-Amino-N-(5-m-tolyloxy-thiophen-2-ylmethyl)nicotinamide
[1339] The title compound (243 mg, 0.717 mmol, 52.7%) was obtained
as a light brown solid from
C-(5-m-tolyloxythiophen-2-yl)methylamine described in Preparation
Example 30 (300 mg, 1.36 mmol) and 6-aminonicotinic acid (210 mg,
1.52 mmol) according to an analogous method to Example Q-6.
[1340] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.26 (3H,
s), 4.44 (2H, d, J=5.6 Hz), 6.39 (1H, d, J=8.8 Hz), 6.42-6.52 (3H,
m), 6.70-6.74 (1H, m), 6.84-6.95 (3H, m), 7.22 (1H, dd, J=8.0, 8.0
Hz), 7.78 (1H, dd, J=2.4, 8.8 Hz), 8.43 (1H, d, J=2.4 Hz), 8.74
(1H, t, J=5.6 Hz).
Example A-142
6-Amino-N-(5-p-tolyloxy-thiophene-2-ylmethyl)-nicotinamide
[1341] The title compound (265 mg, 0.78 mmol, 52.1%) was obtained
as a light brown solid from 6-aminonicotinic acid (210 mg, 1.50
mmol) and C-(5-p-tolyloxy-thiophen-2-yl)-methylamine described in
Preparation Example 32 (300 mg, 1.37 mmol) according to an
analogous method to Example Q-6.
[1342] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.24 (3H,
s), 4.43 (2H, d, J=5.6 Hz), 6.38 (1H, d, J=8.8 Hz), 6.41 (1H, d,
J=3.6 Hz), 6.47 (2H, s), 6.70 (1H, d, J=3.6 Hz), 6.94-7.00 (2H, m),
7.13-7.19 (2H, m), 7.78 (1H, dd, J=2.4, 8.8 Hz), 8.42 (1H, d, J=2.4
Hz), 8.73 (1H, t, J=5.6 Hz).
Example A-143
6-Amino-N-(5-(4-fluoro-benzyl)-thiophen-2-ylmethyl)-nicotinamide
[1343] The title compound (46 mg, 0.13 mmol, 81.2%) was obtained as
a white solid from
C-(5-(4-fluoro-benzyl)-thiophen-2-yl)-methylamine described in
Preparation Example 38 (35 mg, 0.16 mmol) and 6-aminonicotinic acid
(24 mg, 0.17 mmol) according to an analogous method to Example
Q-6.
[1344] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.03 (2H,
s), 4.45 (2H, d, J=5.6 Hz), 6.38 (1H, d, J=8.8 Hz), 6.45 (2H, s),
6.67 (1H, d, J=3.6 Hz), 6.76 (1H, d, J=3.6 Hz), 7.04-7.14 (2H, m),
7.20-7.30 (2H, m), 7.77 (1H, dd, J=2.4, 8.8 Hz), 8.41 (1H, d, J=2.4
Hz), 8.69 (1H, t, J=5.6 Hz).
Example A-144
6-Amino-N-(5-benzyl-thiophen-2-ylmethyl)-nicotinamide
[1345] The title compound (27 mg, 0.082 mmol, 31.0%) was obtained
as a white solid from 6-aminonicotinic acid (37 mg, 0.27 mmol) and
C-(5-benzyl-thiophen-2-yl)-methylamine described in Preparation
Example 42 (54 mg, 0.27 mmol) according to an analogous technique
to Example Q-6.
[1346] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta. (ppm): 4.03 (2H,
s), 4.44 (2H, d, J=5.2 Hz), 6.37 (1H, d, J=8.8 Hz), 6.45 (2H, s),
6.67 (1H, d, J=3.2 Hz), 6.75 (1H, d, J=3.2 Hz), 7.15-7.30 (5H, m),
7.76 (1H, dd, J=2.0, 8.8 Hz), 8.41 (1H, d, J=2.0 Hz), 8.68 (1H, t,
J=5.2 Hz).
Example A-145
6-Amino-N-(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-nicotinamide
[1347] The title compound (42 mg, 0.12 mmol, 56.0%) was obtained as
a white solid from C-(5-(3-chloro-benzyl-2-yl)methylamine described
in Preparation Example 45 (50 mg, 0.2 .mu.mol) and 6-aminonicotinic
acid (32 mg, 0.23 mmol) according to an analogous method to Example
Q-6.
[1348] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.05 (2H,
s), 4.45 (2H, d, J=5.6 Hz), 6.38 (1H, d, J=8.8 Hz), 6.45 (2H, s),
6.71 (1H, d, J=3.2 Hz), 6.76 (1H, d, J=3.2 Hz), 7.16-7.34 (4H, m),
7.77 (1H, d, J=8.8 Hz), 8.41 (1H, s), 8.70 (1H, t, J=5.6 Hz).
Example A-146
6-Amino-N-(5-(3-fluoro-benzyl)-thiophen-2-ylmethyl)-nicotinamide
[1349] To a solution of
5-(3-fluoro-benzyl)-thiophene-2-carbaldehyde described in
Preparation Example 53 (485 mg, 2.2 mmol) in 7N ammonia/methanol
(30 mL) was added Raney nickel (1 g), and the solution was stirred
under hydrogen atmosphere at room temperature for 16 hours. The
reaction solution was filtered through Celite pad to remove the
catalyst, then, the organic layer was concentrated in vacuo, the
residue was purified by NH silica gel column chromatography
(hexane, then hexane:ethyl acetate=4:1), and
C-(5-(3-fluoro-benzyl-2-yl)-methylamine (290 mg, 1.3 mmol, 59.6%)
was obtained as a brown oil. Using the resulting
C-(5-(3-fluoro-benzyl-2-yl)-methylamine (50 mg, 0.226 mmol) and
6-aminonicotinic acid (34 mg, 0.248 mmol) according to an analogous
technique to Example Q-6, the title compound (44 mg, 0.129 mmol,
57.1%) was obtained as a white solid.
[1350] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.06 (2H,
s), 4.45 (2H, d, J=5.6 Hz), 6.38 (1H, d, J=8.8 Hz), 6.45 (2H, s),
6.70 (1H, d, J=2.0 Hz), 6.77 (1H, d, J=2.0 Hz), 6.96-7.10 (3H, m),
7.28-7.36 (1H, m), 7.77 (1H, dd, J=2.0, 8.8 Hz), 8.41 (1H, d, J=2.0
Hz), 8.70 (1H, t, J=5.6 Hz).
Example A-147
6-Amino-N-(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1351] The title compound (8.21 mg) was obtained from
C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Example A-73 (30 mg, 0.13 mmol) and 6-amino-nicotinic acid (17 mg,
0.13 mmol) according to an analogous method to Example E-24, the
title compound (8.21 mg) was obtained. Trifluoroacetic acid salt of
the tile compound was obtained by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used).
[1352] MS m/e (ESI) 360.3 (MH.sup.+)
Example A-148
6-Amino-N-(5-(2-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1353] Trifluoroacetic acid salt of the title compound (26.6 mg)
was obtained as a pale yellow oil from 6-amino-nicotinic acid (21
mg, 0.15 mmol) and
C-(5-(2-fluoro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 161 (33.5 mg, 0.15 mmol) according to an
analogous method to Example A-75. Then, the title compound (7.8 mg,
0.023 mmol, 15.1%) was obtained as a pale yellow solid by purifying
again by thin layer NH silica gel chromatography (ethyl
acetate).
[1354] MS m/e (ESI) 344 (MH.sup.+)
Example A-149
6-Amino-N-(5-(2-cyclopropylvinyl)thiophen-2-ylmethyl)nicotinamide
[1355] 6-Aminonicotinic acid (35 mg, 0.251 mmol),
C-(5-(2-cyclopropylvinyl)thiophen-2-yl)methylamine described in
Preparation Example 151 (45 mg, 0.251 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (133 mg, 0.301 mmol) and triethylamine (0.042
mL, 0.301 mmol) were dissolved in N,N-dimethylformamide (3 mL), and
the solution was stirred at room temperature for 3 hours. Water (10
mL) was added to the reaction solution, which was then extracted
with ethyl acetate (30 mL). The organic layer was washed, dried
over anhydrous magnesium sulfate, then, the solvent was evaporated
in vacuo, the obtained residue was purified by NH silica gel column
chromatography (hexane:ethyl acetate=3:1), and the title compound
(50 mg, 0.167 mmol, 66.6%) was obtained as a white solid.
[1356] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.44-0.52
(2H, m), 0.76-0.84 (2H, m), 1.45-1.55 (1H, m), 4.70 (2H, d, J=5.6
Hz), 4.76 (2H, s), 5.53 (1H, dd, J=8.8, 15.6 Hz), 6.21 (1H, d,
J=5.6 Hz), 6.49 (1H, d, J=8.8 Hz), 6.52 (1H, d, J=15.6 Hz), 6.66
(1H, d, J=3.6 Hz), 6.83 (1H, d, J=3.6 Hz), 7.88 (1H, dd, J=2.4, 8.8
Hz), 8.48 (1H, d, J=2.4 Hz).
Example A-150
6-Amino-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1357] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.44 (2H, d,
J=5.2 Hz), 6.39 (1H, d, J=8.8 Hz), 6.43-6.52 (3H, m), 6.72 (1H, d,
J=2.4 Hz), 7.09-7.16 (2H, m), 7.16-7.24 (2H, m), 7.78 (1H, dd,
J=2.4, 8.8 Hz), 8.42 (1H, s), 8.74 (1H, t, J=5.2 Hz).
Example A-151
6-Amino-N-(5-(3-cyano-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
[1358] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.68 (2H, d,
J=5.6 Hz), 4.78 (2H, s), 6.27 (1H, brs), 6.38-6.40 (1H, m),
6.49-6.52 (1H, m), 6.74-6.75 (1H, m), 7.08-7.10 (2H, m), 7.30-7.33
(2H, m), 7.88-7.91 (1H, m), 8.48-8.49 (1H, m).
Example A-152
N-(5-Benzyl-thiophen-2-ylmethyl)-6-(carbamoylmethyl-amino)-nicotinamide
[1359] 5N Hydrochloric acid (1.5 mL) and ethanol (10 mL) were added
to
(5-((5-benzyl-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-yl)-carbamoylmeth-
yl-carbamic acid tert-butyl ester described in Preparation Example
A+-4 (23 mg, 0.047 mmol), and the solution was stirred for 10
minutes at 80.degree. C. An aqueous solution of sodium bicarbonate
and ethyl acetate were added to the reaction solution, which was
then partitioned, the organic layer was washed with water twice and
dried over anhydrous magnesium sulfate. The solvent was evaporated,
and the title compound (12 mg, 0.031 mmol, 67.1%) was obtained as a
brown oily substance.
[1360] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.00-4.07
(4H, m), 4.46 (2H, d, J=5.6 Hz), 6.55 (1H, d, J=8.8 Hz), 6.66-6.69
(1H, m), 6.76 (1H, d, J=3.6 Hz), 7.15-7.30 (5H, m), 7.46 (1H, t,
J=6.0 Hz), 7.80 (1H, dd, J=2.4, 8.8 Hz), 8.44 (1H, d, J=2.4 Hz),
8.74 (1H, t, J=5.6 Hz).
Example A-153
6-(Ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1361] To a solution of
6-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in
Example A-138 (600 mg, 1.8 mmol) in ethanol (40 mL) were added
5,5-dimethylimidazo phospho-2,4-dione (260 mg, 2.0 mmol) and 37%
formaldehyde aqueous solution (3 mL), and the solution was stirred
under reflux for 30 minutes. Water and ethyl acetate were added to
the reaction solution, which was then partitioned, and the organic
layer was washed with water twice. NH silica gel was added to the
organic layer, the solvent was evaporated in vacuo for adsorption,
purification was carried out by NH silica gel column chromatography
(ethyl acetate), and the title compound (457 mg, 1.19 mmol, 66.1%)
was obtained as a white solid.
[1362] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.05 (3H,
t, J=7.2 Hz), 3.42 (2H, q, J=7.2 Hz), 4.47 (2H, d, J=5.6 Hz), 4.73
(2H, d, J=6.8 Hz), 6.44-6.50 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.74
(1H, d, J=3.6 Hz), 7.03-7.15 (3H, m), 7.30-7.40 (2H, m), 7.83-7.92
(2H, m), 8.53 (1H, d, J=2.0 Hz), 8.85 (1H, t, J=5.6 Hz).
Example A-154
6-(Ethoxymethyl-amino)-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicoti-
namide
[1363] The title compound (120 mg, 0.30 mmol, 51.7%) was obtained
as a white solid from
(6-amino-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicotinamide
described in Example A-139 (200 mg, 0.58 mmol) according to an
analogous method to Example A-153.
[1364] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.03-1.10
(3H, m), 3.40-3.46 (2H, m), 4.46 (2H, d, J=5.6 Hz), 4.73 (2H, d,
J=6.8 Hz), 6.44-6.49 (1H, m), 6.55 (1H, d, J=8.8 Hz), 6.73 (1H, d,
J=2.8 Hz), 7.08-7.16 (2H, m), 7.16-7.24 (2H, m), 7.83-7.90 (2H, m),
8.52 (1H, s), 8.84 (1H, t, J=5.6 Hz).
Example A-155
6-(Ethoxymethyl-amino)-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide
[1365] The title compound (84 mg, 2.05 mmol, 31.5%) was obtained as
a white solid from
6-amino-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide described
in Example A-141 (220 mg, 0.65 mmol) according to an analogous
method to Example A-153.
[1366] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.03-1.10
(3H, m), 2.25 (3H, s), 3.40-3.46 (2H, m), 4.46 (2H, d, J=5.6 Hz),
4.73 (2H, d, J=6.8 Hz), 6.44-6.47 (1H, m), 6.54 (1H, d, J=8.8 Hz),
6.73 (1H, d, J=4.0 Hz), 6.83-6.96 (3H, m), 7.22 (1H, dd, J=8.0, 8.0
Hz), 7.84-7.91 (2H, m), 8.52 (1H, d, J=2.4 Hz), 8.84 (1H, t, J=5.6
Hz).
Example A-156
N-(5-(3-Fluoro-phenoxy)-thiophen-2-ylmethyl)-6-(2-methoxy-ethylamino)-nico-
tinamide
[1367] To a solution of
(5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-carbamoyl)-pyridin-2-yl)-c-
arbamic acid tert-butyl ester described in Preparation Example A+-2
(100 mg, 0.227 mmol) and methoxyethyl bromide (38 mg, 0.272 mmol)
in dimethylsulfoxide (5 mL) was added sodium hydride (11 mg, 0.272
mmol, 60% in oil), and the solution was stirred at room temperature
for 1 hour. 5N Hydrochloric acid was added to the reaction
solution, which was then stirred for 5 minutes at 80.degree. C.
Water and ethyl acetate were added to the reaction solution, which
was then partitioned, the organic layer was washed with water
twice, then, silica gel was added, the solvent was evaporated in
vacuo for adsorption, purification was carried out by silica gel
column chromatography (hexane:ethyl acetate=1:1, then ethyl
acetate), and the title compound (39 mg, 0.097 mmol, 42.8%) was
obtained as a white solid.
[1368] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.24 (3H,
s), 3.41-3.46 (4H, m), 4.47 (2H, d, J=5.6 Hz), 6.48 (1H, d, J=9.2
Hz), 6.54-6.58 (1H, m), 6.76 (1H, d, J=2.8 Hz), 6.88-7.00 (3H, m),
7.12 (1H, s), 7.36-7.44 (1H, m), 7.77 (1H, d, J=9.2 Hz), 8.48 (1H,
s), 8.77 (1H, t, J=5.6 Hz).
Example A-157
6-Methoxymethyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1369] The title compound (56 mg, 0.158 mmol, 43.9%) was obtained
as a light brown solid from 6-methoxymethylnicotinic acid (60 mg,
0.36 mmol) and C-(5-phenoxy-thiophen-2-yl)methylamine described in
Preparation Example 26 (64 mg, 0.36 mmol) according to an analogous
technique to Example Q-6.
[1370] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.38 (3H,
s), 4.53-4.57 (4H, m), 6.52 (1H, d, J=3.6 Hz), 6.81 (1H, d, J=3.6
Hz), 7.07-7.17 (3H, m), 7.35-7.42 (2H, m), 7.50 (1H, d, J=8.0 Hz),
8.22 (1H, dd, J=2.0, 8.0 Hz), 8.95 (1H, d, J=2.0 Hz), 9.31 (1H, t,
J=5.6 Hz).
Example A-158
N-(5-(3-Chloro-benzyl)-thiophen-2-ylmethyl)-6-(methoxymethyl-amino)-nicoti-
namide
[1371] To a solution of
6-amino-N-(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-nicotinamide
described in Example A-145 (110 mg, 0.3 mmol) in methanol (10 mL)
were added 5,5-dimethylimidazo phospho-2,4-dione (43 mg, 0.33 mmol)
and an aqueous solution of 37% formaldehyde (0.5 mL), and the
solution was stirred under reflux for 2 hours. NH silica gel was
added to the reaction solution, the solvent was evaporated in vacuo
for adsorption, purification was carried out by NH silica gel
column chromatography (hexane:ethyl acetate=1:1, then ethyl
acetate), and the title compound (65 mg, 0.16 mmol, 54%) was
obtained as a slightly yellow solid.
[1372] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.16 (3H,
s), 4.06 (2H, s), 4.48 (2H, d, J=6.0 Hz), 4.68 (2H, d, J=6.8 Hz),
6.54 (1H, d, J=8.4 Hz), 6.69-6.73 (1H, m), 6.76-6.80 (1H, m),
7.17-7.34 (4H, m), 7.84-7.92 (2H, m), 8.51 (1H, s), 8.81 (1H, t,
J=6.0 Hz).
Example A-159
N-(5-benzylthiophen-2-ylmethyl)-6-(methoxymethyl-amino)-nicotinamide
[1373] To a solution of
6-amino-N-(5-benzylthiophen-2-ylmethyl)-nicotinamide described in
Example A-144 (210 mg, 0.65 mmol) and 5,5-dimethylimidazo
phospho-2,4-dione (92 mg, 0.71 mmol) in methanol (15 mL) was added
an aqueous solution of 37% formaldehyde (2.5 mL) under reflux in
three time, and the solution was stirred for 1 hour. NH silica gel
was added to the reaction solution, the solvent was evaporated in
vacuo for adsorption, purification was carried out by NH silica gel
column chromatography (hexane:ethyl acetate=1:1, then ethyl
acetate), and the title compound (210 mg, 0.57 mmol, 87.6%) was
obtained as a white solid.
[1374] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.14-3.18
(3H, m), 4.03 (2H, s), 4.47 (2H, d, J=4.8 Hz), 4.68 (2H, d, J=7.2
Hz), 6.54 (1H, d, J=8.8 Hz), 6.68 (1H, s), 6.76 (1H, s), 7.14-7.30
(5H, m), 7.84-7.92 (2H, m), 8.51 (1H, s), 8.79 (1H, t, J=4.8
Hz).
Example A-160
N-(5-(3-Fluorophenoxy)thiophen-2-ylmethyl)-6-methylnicotinamide
[1375] The title compound (53 mg, 0.154 mmol, 43.0%) was obtained
as a white solid from 6-methylnicotinic acid (49 mg, 0.36 mmol) and
C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 23 (100 mg, 0.36 mmol) according to an
analogous method to Example Q-6.
[1376] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.51 (3H,
s), 4.55 (2H, d, J=6.4 Hz), 6.58-6.61 (1H, m), 6.82-6.85 (1H, m),
6.92-7.03 (3H, m), 7.34-7.46 (2H, m), 8.10 (1H, dd, J=2.0, 8.0 Hz),
8.90 (1H, d, J=2.0 Hz), 9.25 (1H, t, J=5.6 Hz).
Example A-161
6-Methyl-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1377] The title compound (31 mg, 0.095 mmol, 32.9%) was obtained
as a white solid from 6-methylnicotinic acid (40 mg, 0.29 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (49 mg, 0.24 mmol) according to an analogous method to
Example Q-6.
[1378] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.49 (3H,
s), 4.51 (2H, d, J=5.6 Hz), 6.49 (1H, d, J=4.0 Hz), 6.78 (1H, d,
J=4.0 Hz), 7.05-7.15 (3H, m), 7.32-7.40 (3H, m), 8.07 (1H, dd,
J=2.0, 8.0 Hz), 8.87 (1H, d, J=2.0 Hz), 9.21 (1H, t, J=5.6 Hz).
Example A-162
N-(5-(3-Chloro-benzyl)-thiophen-2-ylmethyl)-6-methyl-nicotinamide
[1379] The title compound (32 mg, 0.089 mmol, 26.4%) was obtained
as a white solid from C-(5-(3-chloro-benzyl-2-yl)-methylamine
described in Preparation Example 45 (80 mg, 0.34 mmol) and
6-methylnicotinic acid (46 mg, 0.34 mmol) according to an analogous
method to Example Q-6.
[1380] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.50 (3H,
s), 4.08 (2H, s), 4.54 (2H, d, 5.6 Hz), 6.75 (1H, d, J=3.6 Hz),
6.84 (1H, d, J=3.6 Hz), 7.20-7.36 (5H, m), 8.08 (1H, dd, J=2.0, 8.0
Hz), 8.88 (1H, d, J=2.0 Hz), 9.18 (1H, t, J=5.6 Hz).
Example A-163
6-Methylamino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1381] To a solution of
6-(ethoxymethyl-amino)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-153 (427 mg, 0.92 mmol) in dimethylsulfoxide
(5 mL) was added sodium borohydride (100 mg, 2.7 mmol), and the
solution was stirred for 15 minutes at 100.degree. C. Water and
ethyl acetate were added to the reaction solution, which was then
partitioned, and the organic layer was washed with water three
times. Silica gel was added to the organic layer, the solvent was
evaporated in vacuo for adsorption, and purified by silica gel
column chromatography (ethyl acetate). The solvent was evaporated
in vacuo, hexane, diethyl ether and ethyl acetate were added to the
residue for solidification, and the title compound (150 mg, 0.44
mmol, 48.1%) was obtained as a white solid.
[1382] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.78 (3H,
d, J=4.8 Hz), 4.46 (2H, d, J=5.6 Hz), 6.40 (1H, d, J=8.8 Hz), 6.47
(1H, d, J=3.6 Hz), 6.73 (1H, d, J=3.6 Hz), 6.98-7.15 (4H, m),
7.32-7.40 (2H, m), 7.79 (1H, dd, J=2.0, 8.8 Hz), 8.50 (1H, d, J=2.0
Hz), 8.75 (1H, t, J=5.6 Hz).
Example A-164
N-(5-(4-Fluoro-phenoxy)-thiophen-2-ylmethyl)-6-methylamino-nicotinamide
[1383] The title compound (120 mg, 0.30 mmol, 51.7%) was obtained
as a white solid from
6-(ethoxymethyl-amino)-N-(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-nicot-
inamide described in Example A-154 according to an analogous method
to Example A-163.
[1384] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.76-2.81
(3H, m), 4.45 (2H, d, J=5.6 Hz), 6.40 (1H, d, J=8.4 Hz), 6.44-6.48
(1H, m), 6.70-6.75 (1H, m), 6.98-7.06 (1H, m), 7.08-7.24 (4H, m),
7.79 (1H, d, J=8.4 Hz), 8.50 (1H, s), 8.75 (1H, t, J=5.6 Hz).
Example A-165
N-(5-(3-Fluoro-phenoxy)-thiophen-2-ylmethyl)-6-methylamino-nicotinamide
[1385] Ethanol (20 mL) and 5N hydrochloric acid (0.8 mL) were added
to
(5-((5-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)carbamoyl)pyridin-2-yl)meth-
yl-carbamic acid tert-butyl ester described in Preparation Example
A+-3 (87 mg, 0.19 mmol), and the solution was stirred for 25
minutes at 80.degree. C. An aqueous solution of sodium bicarbonate
and ethyl acetate were added to the reaction solution, which was
then partitioned, the organic layer was washed with water twice,
washed with brine, and the organic layer was dried over anhydrous
magnesium sulfate. The solvent was evaporated, and the title
compound (58 mg, 0.162 mmol, 85.5%) was obtained as a white
solid.
[1386] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.78 (3H,
d, J=4.8 Hz), 4.47 (2H, d, J=5.6 Hz), 6.40 (1H, d, J=8.0 Hz), 6.55
(1H, d, J=3.6 Hz), 6.76 (1H, d, J=3.6 Hz), 6.86-7.06 (4H, m),
7.36-7.44 (1H, m), 7.79 (1H, dd, J=2.0, 8.0 Hz), 8.50 (1H, d, J=2.0
Hz), 8.77 (1H, t, J=5.6 Hz).
Example A-166
N-(5-Benzyl-thiophen-2-ylmethyl)-6-methylamino-nicotinamide
[1387] To a solution of
N-(5-benzyl-thiophen-2-ylmethyl)-6-(methoxymethyl-amino)-nicotinamide
described in Example A-159 (183 mg, 0.52 mmol) in dimethylsulfoxide
(3 mL) was added sodium borohydride (120 mg, 3.12 mmol), and the
solution was stirred at 140.degree. C. for 5 hours. Water and ethyl
acetate were added to the reaction solution, which was then
partitioned, and the organic layer was washed with water twice.
Silica gel was added to the organic layer, the solvent was
evaporated in vacuo for adsorption, purification was carried out by
silica gel column chromatography (ethyl acetate, then ethyl
acetate:methanol=10:1), and the title compound (68 mg, 0.20 mmol,
38.8%) was obtained as a green solid.
[1388] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.77 (3H,
d, J=4.8 Hz), 4.03 (2H, s), 4.46 (2H, d, J=5.6 Hz), 6.39 (1H, d,
J=8.8 Hz), 6.68 (1H, d, J=3.6 Hz), 6.76 (1H, d, J=3.6 Hz),
6.96-7.04 (1H, m), 7.15-7.32 (5H, m), 7.77 (1H, dd, J=2.0, 8.8 Hz),
8.49 (1H, d, J=2.0 Hz), 8.70 (1H, t, J=5.6 Hz).
Example A-167
6-Methylamino-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide
[1389] To a solution of
6-(ethoxymethyl-amino)-N-(5-m-tolyloxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-155 (70 mg, 0.17 mmol) in dimethylsulfoxide
(5 mL) was added sodium borohydride (20 mg, 0.51 mmol), and the
solution was stirred for 20 minutes at 120.degree. C. Water and
ethyl acetate were added to the reaction solution, which was then
partitioned, the organic layer was washed with brine once. The
organic layer was passed through a glass filter lined with NH
silica gel, and eluted thoroughly with ethyl acetate. The solvent
was evaporated in vacuo, and the title compound (53 mg, 0.15 mmol,
88.2%) was obtained as a light brown solid.
[1390] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.25 (3H,
s), 2.77 (3H, d, J=4.4 Hz), 4.45 (2H, d, J=5.6 Hz), 6.40 (1H, d,
J=8.8 Hz), 6.45 (1H, d, J=3.6 Hz), 6.72 (1H, d, J=3.6 Hz),
6.83-6.96 (3H, m), 7.02 (1H, q, J=4.4 Hz), 7.22 (1H, dd, J=8.0, 8.0
Hz), 7.78 (1H, dd, J=2.4, 8.8 Hz), 8.50 (1H, d, J=2.4 Hz), 8.75
(1H, t, J=5.6 Hz).
Example A-168
2-Amino-N-(5-phenoxy-thiophen-2-ylmethyl)-6-vinyl-nicotinamide
[1391] To a mixture of
2-amino-6-chloro-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-101 (30 mg, 0.083 mmol),
tetrakis(triphenylphosphine)palladium(0) (19 mg, 0.017 mmol) and
xylene (1.5 mL) was added vinyl(tri-butyl)tin (0.073 mL, 0.25
mmol), and the solution was stirred at 130.degree. C. for 3 hours.
After cooling, water and ethyl acetate were added to the reaction
solution for extraction, which was then washed with brine. The
solvent was evaporated in vacuo, then, the residue was purified by
NH silica gel column chromatography (hexane:ethyl acetate=2:1), and
the title compound (19 mg, 0.054 mmol, 65%) was obtained as a white
solid.
[1392] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.65 (2H, d,
J=5.5 Hz), 5.49 (1H, dd, J=1.4, 10.7 Hz), 6.22 (1H, dd, J=1.4, 17.3
Hz), 6.27 (1H, brs), 6.36 (2H, brs), 6.39 (1H, d, J=3.8 Hz),
6.60-6.67 (2H, m), 6.74 (1H, d, J=3.7 Hz), 7.08-7.13 (3H, m),
7.30-7.35 (2H, m), 7.56 (1H, d, J=8.1 Hz).
Example A-169
2-Amino-N-(5-bromo-4-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1393] The title compound was obtained from
C-(5-bromo-4-phenoxy-thiophen-2-yl)-methylamine described in
Preparation Example 129 (500 mg, 1.76 mmol) and 2-amino-nicotinic
acid (267 mg, 1.94 mmol) according to an analogous method to
Example A-26. Trifluoroacetic acid salt of the title compound was
obtained by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1394] MS m/e (ESI) 405.94 (MH.sup.+)
Example A-170
2-Amino-N-(5-methyl-4-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1395] To a mixture of
2-amino-N-(5-bromo-4-phenoxy-thiophen-2-ylmethyl)-nicotinamide
described in Example A-169 (30 mg, 0.074 mmol),
dichloro(1,1'-bis(diphenylphosphino)ferrocene) nickel(II) (10 mg,
0.015 mmol) and tetrahydrofuran (1 mL) was added methylmagnesium
bromide (638 .mu.l, 0.592 mmol) at room temperature, the solution
was stirred for 2 hours at room temperature, and was further
stirred for 2 hours at 50.degree. C. After cooling, water and ethyl
acetate were added for extraction, and the solution was washed with
brine, then, the solvent was evaporated in vacuo. The residue was
purified by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and the title compound was obtained as a
trifluoroacetic acid salt.
[1396] MS m/e (ESI) 340.09 (MH.sup.+)
Example A-171
2-Amino-N-(4-chloro-5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1397] To a mixture of
2-amino-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide described in
Example A-67 (21 mg, 0.064 mmol) and N,N-dimethylformamide (1 mL)
was added N-chlorosuccinimide (13 mg, 0.096 mmol), and the solution
was stirred overnight at room temperature. The reaction solution
was purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and trifluoroacetic acid salt of
the title compound (7.4 mg, 0.016 mmol, 24%) was obtained.
[1398] MS m/e (ESI) 360.1 (MH.sup.+)
Example A-172
2-Amino-5-chloro-N-(4-chloro-5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1399] Trifluoroacetic acid salt of the title compound (1.5 mg,
0.0030 mmol, 4.6%) was obtained as a by-product of Example
A-171.
[1400] MS m/e (ESI) 394.0 (MH.sup.+)
Example A-173
2,6-Diamino-N-(4-(3-chloro-benzyloxy)-benzyl)-nicotinamide
[1401] MS m/e (ESI) 383.246 (MH.sup.+)
Example A-174
2,6-Diamino-N-(5-benzyloxy-pyridin-2-ylmethyl)-nicotinamide
[1402] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.39 (2H,
d, J=5.9 Hz), 5.16 (2H, s), 5.68 (1H, d, J=8.6 Hz), 6.09 (2H, s),
6.94 (2H, s), 7.20 (1H, d, J=8.8 Hz), 7.31-7.46 (6H, m), 7.69 (1H,
d, J=8.6 Hz), 8.25 (1H, d, J=2.9 Hz), 8.35 (1H, t, J=5.9 Hz).
Example A-175
2,6-Diamino-N-(5-phenoxymethyl-pyridin-2-ylmethyl)-nicotinamide
[1403] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.64 (2H,
s), 4.68 (2H, d, J=4.9 Hz), 5.07 (2H, s), 5.80 (1H, d, J=8.4 Hz),
6.50 (2H, s), 6.96-7.01 (3H, m), 7.26-7.35 (4H, m), 7.56 (1H, d,
J=8.4 Hz), 7.76 (1H, dd, J=2.2 Hz, 8.0 Hz), 8.61 (1H, d, J=1.7
Hz).
Example A-176
2-Amino-6-(2-cyano-ethyl)-N-(4-(6-fluoro-pyridin-2-yloxymethyl)-benzyl))-n-
icotinamide
[1404] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.78 (2H, t,
J=7.2 Hz), 2.94 (2H, t, J=7.2 Hz), 4.60 (2H, d, J=5.6 Hz), 5.33
(2H, s), 6.24 (1H, brs), 6.39 (2H, brs), 6.47-6.48 (1H, m),
6.49-6.50 (1H, m), 6.64-6.67 (1H, m), 7.35 (2H, d, J=8.4 Hz), 7.46
(2H, d, J=8.4 Hz), 7.53 (1H, d, J=8.0 Hz), 7.66 (1H, q, J=8.0
Hz).
Example A-177
2-Amino-6-(2-fluoro-ethyl)-N-(5-phenoxy-thiophen-2-ylmethyl)-nicotinamide
[1405] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.93 (2H,
td, J=6.0, 25.6 Hz), 4.47 (2H, d, J=5.6 Hz), 4.75 (2H, td, J=6.0,
47.2 Hz), 6.50 (1H, d, J=4.0 Hz), 6.53 (1H, d, J=8.0 Hz), 6.77 (1H,
d, J=4.0 Hz), 7.07-7.18 (5H, m), 7.38 (2H, t, J=8.0 Hz), 7.85 (1H,
d, J=8.0 Hz), 8.99 (1H, t, J=5.6 Hz).
Example A-178
2-Amino-6-ethoxymethyl-N-(4-(pyridin-2-yloxymethyl)-benzyl)-nicotinamide
[1406] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.27 (3H, t,
J=7.0 Hz), 3.60 (2H, q, J=7.2 Hz), 4.44 (2H, s), 4.60 (2H, d, 5.6
Hz), 5.38 (2H, s), 6.24 (1H, brs), 6.38 (2H, brs), 6.73 (1H, d,
J=8.0 Hz), 6.80 (1H, dd, J=0.8, 7.6 Hz), 6.88-6.91 (1H, m), 7.36
(2H, d, J=8.0 Hz), 7.46 (2H, d, J=8.0 Hz), 7.56-7.61 (2H, m),
8.17-8.18 (1H, m).
Example A-179
2-Amino-N-(5-isopropoxymethyl-thiophen-2-ylmethyl)-6-methoxymethyl-nicotin-
amide
[1407] MS m/e (ESI) 350 (MH.sup.+)
Example A-180
2-Amino-N-(4-(3-methoxy-benzyloxy)-benzyl)-6-methoxymethyl-nicotinamide
[1408] MS m/e (ESI) 408.27 (MH.sup.+)
[1409] .sup.1H-NMR Spectrum (CD.sub.3OD) .delta.(ppm): 3.50 (3H,
s), 3.77 (3H, s), 4.48 (2H, d, J=4 Hz), 4.57 (2H, s), 5.04 (2H, s),
6.84-6.88 (2H, m), 6.94-6.98 (4H, m), 7.23-7.29 (3H, m), 8.27-8.29
(1H, m).
Example A-181
2-Amino-N-(4-(3-chloro-benzyloxy)-benzyl)-6-methoxymethyl-nicotinamide
[1410] MS m/e (ESI) 412.26 (MH.sup.+)
Example A-182
2-Amino-N-(4-butoxymethyl-benzyl)-6-methoxymethyl-nicotinamide
[1411] MS m/e (ESI) 358 (MH.sup.+)
Example A-183
2-Amino-6-methoxymethyl-N-(4-propoxymethyl-benzyl)-nicotinamide
[1412] MS m/e (ESI) 344 (MH.sup.+)
Example A-184
2-Amino-N-(3-cyclopropylmethoxy-benzyl)-6-methoxymethyl-nicotinamide
[1413] MS m/e (ESI) 342 (MH.sup.+)
Example A-185
2-Amino-N-(4-(6-fluoro-pyridin-2-yloxymethyl)-benzyl)-6-methoxymethyl-nico-
tinamide
[1414] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.40 (2H, s), 4.61 (2H, d, J=5.6 Hz), 5.33 (2H, s), 6.26 (1H,
brs), 6.40 (2H, s), 6.49 (1H, dd, J=2.4, 7.6 Hz), 6.66 (1H, dd,
J=1.1, 7.6 Hz), 6.70 (1H, d, J=8.0 Hz), 7.36 (2H, d, J=8.0 Hz),
7.46 (2H, d, J=8.0 Hz), 7.60 (1H, d, J=8.0 Hz), 7.66 (1H, dd,
J=8.0, 8.0 Hz).
Example A-186
2-Amino-6-methoxymethyl-N-(4-(4-methyl-pyridin-2-yloxymethyl)-benzyl)-nico-
tinamide
[1415] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.30 (3H,
s), 3.45 (3H, s), 4.39 (2H, s), 4.60 (2H, d, J=5.6 Hz), 5.36 (2H,
s), 6.25 (1H, brs), 6.40 (2H, brs), 6.62 (1H, s), 6.65 (1H, d,
J=8.0 Hz), 6.72 (1H, d, J=5.2 Hz), 7.35 (2H, d, J=8.4 Hz), 7.45
(2H, d, J=8.4 Hz), 7.59 (1H, d, J=8.0 Hz), 8.02 (1H, d, J=5.2
Hz).
Example A-187
2-Amino-N-(4-(6-fluoro-pyridin-2-ylmethoxy)-benzyl)-6-methoxymethyl-nicoti-
namide
[1416] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.45 (3H,
s), 4.39 (2H, s), 4.53 (2H, d, J=5.6 Hz), 5.13 (2H, s), 6.22 (1H,
brs), 6.39 (2H, brs), 6.69 (1H, d, J=7.6 Hz), 6.87 (1H, dd, J=2.8,
8.4 Hz), 6.96 (2H, d, J=8.4 Hz), 7.28 (2H, d, J=8.4 Hz), 7.40-7.42
(1H, m), 7.58 (1H, d, J=8.0 Hz), 7.81 (1H, dd, J=8.0, 8.0 Hz).
Example A-188
2-Amino-N-(4-butoxy-benzyl)-6-methoxymethyl-nicotinamide
[1417] MS m/e (ESI) 344 (MH.sup.+)
Example A-189
2-Amino-N-(4-(2-ethoxy-ethyl)-benzyl))-6-methoxymethyl-nicotinamide
[1418] MS m/e (ESI) 344 (MH.sup.+)
Example A-190
2-Amino-6-methoxymethyl-N-(4-(5-methyl-pyridin-2-yloxymethyl)-benzyl)-nico-
tinamide
[1419] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.25 (3H,
s), 3.45 (3H, s), 4.40 (2H, s), 4.60 (2H, d, J=5.6 Hz), 5.34 (2H,
s), 6.24 (1H, brs), 6.40 (2H, brs), 6.69 (1H, d, J=8.0 Hz), 6.71
(1H, d, J=8.0 Hz), 7.35 (2H, d, J=8.0 Hz), 7.41 (1H, dd, J=2.4, 8.4
Hz), 7.46 (2H, d, J=8.0 Hz), 7.59 (1H, d, J=8.4 Hz), 7.96 (1H,
s).
Example A-191
2-Amino-N-(6-benzyl-pyridin-3-ylmethyl)-6-methoxymethyl-nicotinamide
[1420] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.45 (3H,
s), 4.15 (2H, s), 4.39 (2H, s), 4.57 (2H, d, J=5.6 Hz), 6.32 (1H,
brs), 6.38 (2H, brs), 6.69 (1H, d, J=8.0 Hz), 7.12 (1H, d, J=8.4
Hz), 7.20-7.32 (5H, m), 7.58 (7.61 (2H, m), 8.52 (1H, d, J=2.0
Hz).
Example A-192
2-Amino-6-methoxymethyl-N-(5-phenoxymethyl-pyridin-2-ylmethyl)-nicotinamid-
e
[1421] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.46 (3H,
s), 4.41 (2H, s), 4.72 (2H, d, J=4.8 Hz), 5.09 (2H, s), 6.45 (2H,
s), 6.74 (1H, d, J=7.9 Hz), 6.96-7.02 (3H, m), 7.29-7.36 (3H, m),
7.53 (1H, s), 7.79 (2H, d, J=7.9 Hz), 8.63 (1H, d, J=1.7 Hz).
Example A-193
2-Amino-6-methoxymethyl-N-(5-phenoxy-pyridin-2-ylmethyl)-nicotinamide
[1422] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.34 (3H,
s), 4.30 (2H, s), 4.52 (2H, d, J=6.0 Hz), 6.62 (1H, d, J=8.0 Hz),
7.02-7.07 (2H, m), 7.10-7.20 (3H, m), 7.33-7.46 (4H, m), 8.02 (1H,
d, J=8.0 Hz), 8.31 (1H, d, J=2.8 Hz), 9.02 (1H, t, J=6.0 Hz).
Example A-194
2-Amino-6-methoxymethyl-N-(4-(2-propoxy-ethyl)-benzyl)-nicotinamide
[1423] MS m/e (ESI) 358 (MH.sup.+)
Example AA-1
3-Amino-pyrazine-2-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1424] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.47 (2H,
d, J=6.4 Hz), 6.47 (1H, d, J=4.0 Hz), 6.74 (1H, d, J=4.0 Hz),
7.05-7.15 (3H, m), 7.24-7.40 (2H, m), 7.50 (2H, brs), 7.80 (1H, d,
J=2.4 Hz), 8.18 (1H, d, J=2.4 Hz), 9.28 (1H, t, J=6.4 Hz).
Example AA-2
3,5-Diamino-pyrazine-2-carboxylic acid
4-(pyridin-2-yloxymethyl)-benzylamide
[1425] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.38 (2H,
d, J=6.4 Hz), 5.3 (2H, s), 6.67 (2H, s), 6.84 (1H, d, J=8.2 Hz),
6.98 (1H, t, J=7.2 Hz), 7.13 (1H, s), 7.28 (2H, d, J=8.1 Hz), 7.38
(2H, d, J=8.1 Hz), 7.71 (1H, dt, J=2.0 Hz, 7.8 Hz), 8.16 (1H, dd,
J=2.0 Hz, 4.8 Hz), 8.54 (1H, t, J=6.4 Hz).
Example B-1
4-Amino-pyrimidine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1426] The title compound (7 mg, 0.021 mmol, 4.4%) was obtained as
a white solid from 4-amino-pyrimidine-5-carboxylic acid (68 mg,
0.49 mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in
Preparation Example 26 (100 mg, 0.49 mmol) according to an
analogous technique to Example Q-6.
[1427] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.47 (2H,
d, J=5.2 Hz), 6.47-6.50 (1H, m), 6.76-6.78 (1H, m), 7.04-7.15 (3H,
m), 7.34-7.40 (2H, m), 7.77 (2H, brs), 8.40 (1H, d, J=1.6 Hz), 8.59
(1H, d, J=1.6 Hz), 9.19 (1H, t, J=5.2 Hz).
Example B-2
4-Amino-2-propylamino-pyrimidine-5-carboxylic acid
4-(pyridin-2-yloxymethyl)-benzylamide
[1428] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 0.86 (3H,
t, J=7.2 Hz), 1.44-1.55 (2H, m), 3.14-3.24 (2H, m), 4.38 (2H, d,
J=6.4 Hz), 5.32 (2H, s), 6.83-6.87 (1H, m), 6.96-7.01 (1H, m), 7.28
(2H, d, J=8.0 Hz), 7.38 (2H, d, J=8.0 Hz), 7.69-7.75 (1H, m),
8.15-8.19 (1H, m), 8.42 (1H, s), 8.60 (1H, brs).
Example C-1
(2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1429] 2-Amino-6,7-dihydro-5H-cyclopenta[b]pyridine-3-carboxylic
acid described in Preparation Example C-5 (100 mg, 0.56 mmol),
triethylamine (0.188 mL, 1.35 mmol) and
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (298 mg, 0.67 mmol) were dissolved in
N,N-dimethylformamide (3 mL),
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (138 mg, 0.67 mmol) was added, followed by stirring for
15 hours 20 minutes at room temperature. After the reaction was
completed, the reaction solution was poured into brine, and the
solution was extracted with ethyl acetate. The organic layer was
dried over anhydrous magnesium sulfate, then concentrated, the
obtained residue was purified by silica gel column chromatography
(ethyl acetate:hexane=1:1), and the title compound (77 mg, 0.21
mmol, 38%) was obtained.
[1430] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 1.95-2.03
(2H, m), 2.68-2.76 (4H, m), 4.46 (2H, d, J=5.6 Hz), 6.45 (1H, d,
J=4.0 Hz), 6.76 (1H, d, J=4.0 Hz), 6.97 (2H, brs), 7.07-7.17 (3H,
m), 7.36-7.41 (2H, m), 7.76 (1H, s), 8.88-8.93 (1H, m).
Example D-1
[1,5]Naphthylidine-2-carboxylic acid 3-phenoxybenzylamide
[1431] The title compound (14 mg, 76%) was obtained as a colorless
oil from [1,5]naphthylidine-2-carboxylic acid described in
Preparation Example D-1 (9 mg, 0.0517 mmol) and
3-phenoxybenzylamine described in Preparation Example 4 (6 mg,
0.0517 mmol) according to an analogous method to Example L-4.
[1432] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.73 (2H, d,
J=6.0 Hz), 6.92-6.94 (1H, m), 7.01-7.03 (2H, m), 7.07-7.17 (3H, m),
7.26-7.36 (3H, m), 7.70 (1H, dd, J=4.4, 8.8 Hz), 8.39 (1H, dd,
J=1.6, 8.8 Hz), 8.51 (1H, brs), 8.57 (2H, s), 9.06 (1H, dd, J=1.6,
4.4 Hz).
Example D-2
[1,5]Naphthylidine-2-carboxylic acid 4-benzyloxybenzylamide
[1433] The title compound (11 mg, 52%) was obtained as a white
solid from [1,5]naphthylidine-2-carboxylic acid described in
Preparation Example D-1 (10 mg, 0.0574 mmol) and
4-benzyloxybenzylamine described in Preparation Example 1 (12 mg,
0.0574 mmol) according to an analogous method to Example L-4.
[1434] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.68 (2H, d,
J=6.4 Hz), 5.08 (2H, s), 6.97-6.99 (2H, m), 7.32-7.45 (7H, m), 7.69
(1H, dd, J=4.4, 8.8 Hz), 8.36-8.39 (1H, m), 8.43 (1H, brs),
8.54-8.60 (2H, m), 9.04-9.06 (1H, m).
Example D-3
[1,5]Naphthylidine-2-carboxylic acid
4-phenoxymethyl-benzylamide
[1435] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.76 (2H, d,
J=6 Hz), 5.07 (2H, s), 6.94-6.99 (3H, m), 7.27-7.31 (3H, m),
7.43-7.45 (4H, m), 7.68-7.71 (1H, m), 8.37-8.40 (1H, m), 8.50 (1H,
brs), 8.55-8.60 (1H, m), 9.05-9.06 (1H, m).
Example D-4
[1,5]Naphthylidine-2-carboxylic acid
(1-(3-fluoro-benzyl)-1H-pyrrol-3-ylmethyl)-amide
[1436] To a solution of
C-(1-(3-fluoro-benzyl)-1H-pyrrol-3-yl)-methylamine described in
Preparation Example 59 (59 mg, 0.287 mmol) and
[1,5]naphthylidine-2-carboxylic acid described in Preparation
Example D-1 (50 mg, 0.287 mmol) in N,N-dimethylformamide (3 mL)
were added benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (152 mg, 0.344 mmol) and triethylamine (80
.mu.L, 0.574 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (49 mg, 47%) was obtained as a pale yellow solid.
[1437] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 4.59 (2H,
d, J=5.6 Hz), 5.03 (2H, s), 6.26-6.27 (1H, m), 6.66-6.67 (1H, m),
6.74-6.75 (1H, m), 6.81-6.84 (1H, m), 6.92-6.94 (1H, m), 6.96-7.01
(1H, m), 7.28-7.33 (1H, m), 7.67-7.70 (1H, m), 8.31 (1H, brs),
8.37-8.40 (1H, m), 8.53-8.59 (2H, m), 9.03-9.05 (1H, m).
Example D-5
[1,5]Naphthylidine-2-carboxylic acid
(5-(3-fluorophenoxy)thiophen-2-ylmethyl) amide
[1438] The title compound (66 mg, 0.17 mmol, 72.5%) was obtained as
a brown oil from [1,5]-naphthylidine-2-carboxylic acid (42 mg, 0.24
mmol) and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described
in Preparation Example 23 (54 mg, 0.24 mmol) according to an
analogous method to Example Q-6.
[1439] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.61 (2H,
d, J=6.4 Hz), 6.57 (1H, d, J=3.6 Hz), 6.83 (1H, d, J=3.6 Hz),
6.87-7.00 (3H, m), 7.36-7.42 (1H, m), 7.87 (1H, dd, J=4.0, 8.8 Hz),
8.37 (1H, d, J=8.8 Hz), 8.49 (1H, d, J=8.8 Hz), 8.59 (1H, d, J=8.8
Hz), 9.09 (1H, d, J=4.0 Hz), 9.58 (1H, t, J=6.4 Hz).
Example D-6
[1,5]Naphthylidine-2-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1440] The title compound (15 mg, 0.042 mmol, 17.3%) was obtained
as a light brown solid from [1,5]-naphthylidine-2-carboxylic acid
(42 mg, 0.24 mmol) and C-(5-phenoxy-thiophen-2-yl)methylamine
described in Preparation Example 26 (49 mg, 0.24 mmol) according to
an analogous technique to Example Q-6.
[1441] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.59 (2H,
d, J=5.6 Hz), 6.49 (1H, d, J=3.6 Hz), 6.81 (1H, d, J=3.6 Hz),
7.03-7.14 (3H, m), 7.30-7.40 (2H, m), 7.88 (1H, dd, J=4.0, 8.8 Hz),
8.36 (1H, d, J=8.8 Hz), 8.48 (1H, d, J=8.8 Hz), 8.58 (1H, d, J=8.8
Hz), 9.09 (1H, d, J=4.0 Hz), 9.56 (1H, t, J=5.6 Hz).
Example D-7
[1,5]Naphthylidine-2-carboxylic acid
(5-(4-fluoro-phenoxy)-thiophen-2-ylmethyl)-amide
[1442] To a solution of [1,5]naphthylidine-2-carboxylic acid
described in Preparation Example D-1 (20 mg, 0.115 mmol) and
described in Preparation Example
28C-(5-(4-fluorophenoxy)thiophen-2-yl)methylamine) (51 mg, 0.23
mmol) in dimethylsulfoxide (9 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (102 mg, 0.23 mmol) and triethylamine (56
.mu.L, 0.43 mmol), and the solution was stirred at 60.degree. C.
for 30 minutes. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was
sequentially washed with an aqueous solution of saturated sodium
bicarbonate, water and brine, and then, dried over anhydrous sodium
sulfate. The solvent was evaporated, the residue was sequentially
purified by silica gel column chromatography (hexane:ethyl
acetate), silica gel column chromatography (dichloromethane:ethyl
acetate), reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and the title compound (8.6 mg, 0.017 mmol, 15%)
was obtained.
[1443] MS m/e (ESI) 379.76 (MH.sup.+)
[1444] .sup.1H-NMR Spectrum (CD.sub.3OD) .delta.(ppm): 4.71 (2H, d,
J=6.4 Hz), 6.38 (1H, d, J=4.0 Hz), 6.83 (1H, d, J=4.0 Hz),
7.02-7.09 (4H, m), 7.85 (1H, dd, J=4.0, 8.8 Hz), 8.46 (1H, d, J=8.8
Hz), 8.56-8.61 (2H, m), 9.04 (1H, dd, J=1.6, 4.0 Hz), 9.55-9.64
(1H, m).
Example D-8
[1,5]Naphthylidine-2-carboxylic acid
(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-amide
[1445] MS m/e (ESI) 396.28 (MH.sup.+)
Example D-9
[1,5]Naphthylidine-2-carboxylic acid
(5-benzofuran-2-ylmethyl-thiophen-2-ylmethyl)-amide
[1446] MS m/e (ESI) 400.51 (MH.sup.+)
Example D-10
[1,5]Naphthylidine-2-carboxylic acid
4-(6-fluoro-pyridin-2-yloxymethyl)-benzylamide
[1447] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.75 (2H, d,
J=6.0 Hz), 5.34 (2H, s), 6.47-6.49 (1H, m), 6.64-6.66 (1H, m),
7.43-7.48 (4H, m), 7.62-7.70 (2H, m), 8.36-8.39 (1H, m), 8.50 (1H,
brs), 8.55-8.60 (2H, m), 9.04-9.06 (1H, m).
Example E-1
Quinoline-6-carboxylic acid (5-benzyl-furan-2-yl)-amide
[1448] The title compound (200 mg, 5.8 mmol, 54.6%) was obtained as
a slightly yellow solid from 5-benzylfuran-2-carbaldehyde described
in Preparation Example 39 and 6-quinolinecarboxylic acid according
to an analogous method to Example Q-1.
[1449] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.92 (2H,
s), 4.45 (2H, d, J=5.6 Hz), 6.02 (1H, d, J=2.8 Hz), 6.20 (1H, d,
J=2.8 Hz), 7.16-7.30 (5H, m), 7.59 (1H, dd, J=4.4, 8.0 Hz), 8.05
(1H, d, J=8.8 Hz), 8.16 (1H, dd, J=2.0, 8.8 Hz), 8.44 (1H, dd,
J=1.6, 8.0 Hz), 8.50 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.6, 4.4
Hz), 9.16 (1H, t, J=5.6 Hz).
Example E-2
Quinoline-6-carboxylic acid (5-phenoxy-furan-2-ylmethyl)-amide
[1450] The title compound (68 mg, 0.197 mmol, 17.2%) was obtained
as a white solid from quinoline-6-carboxylic acid (200 mg, 1.15
mmol) and C-(5-phenoxy-furan-2-yl)-methylamine described in
Preparation Example 49 (200 mg, 1.12 mmol) according to an
analogous method to Example Q-6.
[1451] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.45 (2H,
d, J=5.6 Hz), 5.72 (1H, d, J=3.2 Hz), 6.34 (1H, d, J=3.2 Hz),
7.02-7.08 (2H, m), 7.11-7.17 (1H, m), 7.14-7.40 (2H, m), 7.60 (1H,
dd, J=2.0, 8.0 Hz), 8.06 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=8.8 Hz),
8.45 (1H, d, J=8.0 Hz), 8.51 (1H, s), 8.97 (1H, d, J=4.0 Hz), 9.18
(1H, t, J=5.6 Hz).
Example E-3
Quinoline-6-carboxylic acid
(5-(3-fluoro-phenoxy)-furan-2-ylmethyl)-amide
[1452] To a solution of (5-(3-fluoro-phenoxy)-furan-2-yl)-methanol
described in Preparation Example 51 (1.5 g, 7.2 mmol), phthalimide
(1.1 g, 7.2 mmol) and triphenyl phosphine (1.9 g, 7.2 mmol) in
tetrahydrofuran (10 mL) was added diethyl azodicarboxylate (3.5 g,
7.9 mmol) dropwise at 0.degree. C., and the solution was stirred at
room temperature for 30 minutes. Silica gel was added to the
reaction solution, the solvent was evaporated in vacuo for
adsorption, purification was carried out by silica gel column
chromatography (hexane:ethyl acetate=2:1), and a white solid (700
mg) was obtained. Ethanol (10 mL) and hydrazine monohydrate (0.3
mL) were added to this solid (700 mg), and stirred for 15 minutes
at 90.degree. C. The solution was allowed to room temperature, the
solid was removed by filtration, and a pale yellow oil (360 mg)
containing C-(5-(3-fluoro-phenoxy)-furan-2-yl)-methylamine was
obtained. The title compound (17 mg, 0.046 mmol, 2.7%) was obtained
as a brown solid from this oil (360 mg) and quinoline-6-carboxylic
acid (300 mg, 1.7 mmol) according to an analogous method to Example
Q-6.
[1453] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.46 (2H,
d, J=5.2 Hz), 5.83 (1H, d, J=3.2 Hz), 6.36 (1H, d, J=3.2 Hz),
6.87-7.03 (3H, m), 7.38-7.45 (1H, m), 7.60 (1H, d, J=4.0, 8.4 Hz),
8.06 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=2.0, 8.8 Hz), 8.45 (1H, dd,
J=1.6, 8.4 Hz), 8.51 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.6, 4.0
Hz), 9.19 (1H, t, J=5.2 Hz).
Example E-4
Quinoline-6-carboxylic acid (5-phenyl-furan-2-ylmethyl)-amide
[1454] To a solution of quinoline-6-carboxylic acid
(5-bromo-furan-2-ylmethyl)-amide described in Preparation Example
E+-2 (200 mg, 0.60 mmol) in 1,4-dioxane (5 mL) were added
phenylboronic acid (150 mg, 1.2 mmol),
tetrakis(triphenylphosphine)palladium(0) (55 mg, 0.047 mmol) and an
aqueous solution of potassium carbonate (2 mol), and the solution
was stirred at 110.degree. C. for 2 hours. Water and ethyl acetate
were added to the reaction solution, which was then partitioned, NH
silica gel was added to the organic layer, the solvent was
evaporated in vacuo for adsorption, purification was carried out by
NH silica gel column chromatography (hexane:ethyl acetate=2:1), and
the title compound (65 mg, 0.198 mmol, 33.0%) was obtained as a
white solid.
[1455] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.59 (2H,
d, J=6.0 Hz), 6.44 (1H, d, J=3.2 Hz), 6.88 (1H, d, J=3.2 Hz),
7.23-7.28 (1H, m), 7.37-7.42 (2H, m), 7.60 (1H, dd, J=4.0, 8.4 Hz),
7.64-7.70 (2H, m), 8.07 (1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.0, 8.8
Hz), 8.45-8.50 (1H, m), 8.55 (1H, d, J=2.0 Hz), 8.97 (1H, dd,
J=1.6, 4.0 Hz), 9.26 (1H, t, J=6.0 Hz).
Example E-5
Quinoline-6-carboxylic acid
(5-(2,4-difluoro-phenoxy)-furan-2-ylmethyl)-amide
[1456] The title compound (71 mg, 0.187 mmol, 18%) was obtained
from quinoline-6-carboxylic acid (180 mg, 1.04 mmol) and
C-(5-(2,4-difluoro-phenoxy)-furan-2-yl)-methylamine described in
Preparation Example 77 (258 mg, 1.15 mmol) according to an
analogous method to Example H-1.
[1457] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.44 (2H,
d, J=5.6 Hz), 5.59 (1H, d, J=3.6 Hz), 6.31 (1H, d, J=3.6 Hz),
7.06-7.13 (1H, m), 7.27-7.34 (1H, m), 7.44-7.51 (1H, m), 7.59 (1H,
dd, J=4.0, 8.8 Hz), 8.06 (1H, d, J=9.2 Hz), 8.16 (1H, dd, J=1.2,
8.8 Hz), 8.45 (1H, d, J=9.2 Hz), 8.51 (1H, s), 8.97 (1H, dd, J=1.2,
4.0 Hz), 9.19 (1H, t, J=5.6 Hz).
Example E-6
Quinoline-6-carboxylic acid
(5-(2,5-difluoro-phenoxy)-furan-2-ylmethyl)-amide
[1458] The title compound (194 mg, 0.51 mmol, 32%) was obtained
from quinoline-6-carboxylic acid (275 mg, 1.59 mmol) and
C-(5-(2,5-difluoro-phenoxy)-furan-2-yl)-methylamine described in
Preparation Example 79 (357 mg, 1.59 mmol) according to an
analogous method to Example H-1.
[1459] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.46 (2H,
d, J=5.2 Hz), 5.78 (1H, d, J=3.2 Hz), 6.35 (1H, d, J=3.2 Hz),
7.04-7.18 (2H, m), 7.42-7.50 (1H, m), 7.60 (1H, dd, J=4.0, 8.0 Hz),
8.06 (1H, d, J=8.8 Hz), 8.17 (1H, dd, J=1.2, 8.0 Hz), 8.45 (1H, d,
J=8.8 Hz), 8.52 (1H, s), 8.97 (1H, dd, J=1.2, 4.0 Hz), 9.19 (1H, t,
J=5.2 Hz).
Example E-7
Quinoline-6-carboxylic acid
(5-(3-fluoro-benzyl)-furan-2-ylmethyl)-amide
[1460] Title compound (301 mg, 0.835 mmol, 80%) was obtained from
quinoline-6-carboxylic acid (188 mg, 1.16 mmol) and
C-(5-(3-fluoro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 84 (279 mg, 1.36 mmol) according to an
analogous method to Example H-1.
[1461] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.96 (2H,
s), 4.46 (2H, d, J=5.6 Hz), 6.07 (1H, d, J=3.2 Hz), 6.21 (1H, d,
J=3.2 Hz), 7.00-7.09 (3H, m), 7.28-7.35 (1H, m), 7.59 (1H, dd,
J=4.4, 8.4 Hz), 8.05 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=2.0, 8.4
Hz), 8.44 (1H, dd, J=1.2, 8.8 Hz), 8.50 (1H, d, J=1.2 Hz), 8.97
(1H, dd, J=2.0, 4.4 Hz), 9.17 (1H, t, J=5.6 Hz).
Example E-8
Quinoline-6-carboxylic acid 4-benzyloxybenzylamide
[1462] To a solution of 6-quinoline carboxylic acid (100 mg, 0.577
mmol) in tetrahydrofuran (50 mL) was added
N,N'-dicyclohexylcarbodiimide (1.90 g, 11.7 mmol), and the solution
was stirred at room temperature for 1 hour. Then, to this solution
was added a solution of 4-benzyloxybenzylamine described in
Preparation Example 1 (2.49 g, 11.7 mmol) in tetrahydrofuran (5
mL), and the solution was stirred overnight at room temperature.
The solvent was evaporated, the residue was purified by NH silica
gel column chromatography (hexane:ethyl acetate), and the title
compound (4.31 g, quantitatively) was obtained as a white
solid.
[1463] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.65 (2H, d,
J=5.6 Hz), 5.08 (2H, s), 6.48 (1H, brs), 6.97-7.00 (2H, m),
7.31-7.35 (3H, m), 7.37-7.45 (4H, m), 7.47 (1H, dd, J=4.4, 8.4 Hz),
8.05 (1H, dd, J=2.0, 8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.22-8.25
(1H, m), 8.32 (1H, d, J=2.0 Hz), 8.98-9.00 (1H, m).
Example E-9
Quinoline-6-carboxylic acid 3-benzyloxybenzylamide
[1464] The title compound (102 mg, 48%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (100 mg, 0.58 mmol) and
3-benzyloxybenzylamine described in Preparation Example 2 (126 mg,
0.58 mmol) according to an analogous method to Example E-8.
[1465] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.69 (2H, d,
J=5.6 Hz), 5.07 (2H, s), 6.57 (1H, brs), 6.92-6.95 (1H, m),
6.98-7.02 (2H, m), 7.27-7.32 (2H, m), 7.34-7.38 (2H, m), 7.41-7.43
(2H, m), 7.47 (1H, dd, J=4.4, 8.4 Hz), 8.05 (1H, dd, J=2.0, 8.8
Hz), 8.16 (1H, d, J=8.8 Hz), 8.22-8.25 (1H, m), 8.32 (1H, d, J=2.0
Hz), 8.98-9.00 (1H, m).
Example E-10
Quinoline-6-carboxylic acid 4-phenoxybenzylamide
[1466] The title compound (63 mg, 31%) was obtained as a colorless
solid from 6-quinolinecarboxylic acid (100 mg, 0.58 mmol) and
4-phenoxybenzylamine described in Preparation Example 3 (115 mg,
0.58 mmol) according to an analogous method to Example E-8.
[1467] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.69 (2H, d,
J=5.6 Hz), 6.59 (1H, brs), 7.00-7.03 (4H, m), 7.10-7.14 (1H, m),
7.32-7.38 (4H, m), 7.46-7.49 (1H, m), 8.05-8.08 (1H, m), 8.15-8.17
(1H, m), 8.23-8.25 (1H, m), 8.34 (1H, s), 8.98-9.00 (1H, m).
Example E-11
Quinoline-6-carboxylic acid 3-phenoxybenzylamide
[1468] The title compound (140 mg, 69%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (100 mg, 0.58 mmol) and
4-phenoxybenzylamine described in Preparation Example 3 (115 mg,
0.58 mmol) according to an analogous method to Example E-8.
[1469] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.69 (2H, d,
J=6.0 Hz), 6.63 (1H, brs), 6.92-6.95 (1H, m), 7.01-7.05 (3H, m),
7.09-7.14 (2H, m), 7.30-7.36 (3H, m), 7.47 (1H, dd, J=4.0, 8.0 Hz),
8.05 (1H, dd, J=2.0, 8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.21-8.24
(1H, m), 8.32 (1H, d, J=2.0 Hz), 8.98-8.99 (1H, m).
Example E-12
Quinoline-6-carboxylic acid 4-(pyridin-2-ylmethoxy)-benzylamide
[1470] To a solution of quinoline-6-carboxylic acid
4-hydroxybenzylamide described in Preparation Example E+-1 (20 mg,
0.0719 mmol) and 2-chloromethyl-pyridine hydrochloride (12 mg,
0.0719 mmol) in N,N-dimethyl formamide (1.0 mL) was added potassium
carbonate (298 mg, 2.16 mmol), and the solution was stirred at room
temperature for 12 hours. Ethyl acetate and water were added to the
reaction solution, which was then partitioned, and the organic
layer was dried over anhydrous magnesium sulfate. The solvent was
evaporated, the residue was purified by reverse phase high
performance liquid chromatography (acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid) was used), and
trifluoroacetic acid salt of the title compound was obtained.
[1471] MS m/e (ESI) 369.2 (MH.sup.+)
[1472] .sup.1H-NMR Spectrum (CD.sub.3OD) .delta.(ppm): 4.60 (2H,
s), 5.37 (2H, s), 7.35 (2H, d, J=8.8 Hz), 7.40 (2H, d, J=8.8 Hz),
7.74-7.77 (1H, m), 7.82-7.85 (1H, m), 7.92-7.94 (1H, m), 8.18-8.20
(1H, m), 8.29-8.35 (2H, m), 8.59-8.60 (1H, m), 8.70-8.71 (1H, m),
8.79-8.81 (1H, m), 9.08-9.09 (1H, m).
Example E-13
Quinoline-6-carboxylic acid (biphenyl-3-ylmethyl)-amide
[1473] The title compound (20 mg, 21%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (50 mg, 0.289 mmol) and
C-biphenyl-3-yl-methylamine described in Preparation Example 5 (48
mg, 0.263 mmol) according to an analogous method to Example
E-8.
[1474] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.79 (2H, d,
J=5.6 Hz), 6.62 (1H, brs), 7.34-7.49 (6H, m), 7.55-7.62 (4H, m),
8.08 (1H, dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.23-8.25
(1H, m), 8.35 (1H, d, J=2.0 Hz), 8.98-9.00 (1H, m).
Example E-14
Quinoline-6-carboxylic acid 4-(3-methyl-benzyloxy)-benzylamide
[1475] The title compound (2.5 mg, 18%) was obtained as a white
solid from quinoline-6-carboxylic acid 4-hydroxybenzylamide
obtained in Preparation Example E+-1 (10 mg, 0.0359 mmol) and
3-methylbenzyl chloride (5 mg, 0.0359 mmol) according to an
analogous method to Example E-12.
[1476] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 2.38 (3H,
s), 4.66 (2H, d, J=5.2 Hz), 5.04 (2H, s), 6.50 (1H, brs), 6.97-7.00
(2H, m), 7.14-7.16 (1H, m), 7.22-7.35 (5H, m), 7.46-7.50 (1H, m),
8.06 (1H, dd, J=2.0, 8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.23-8.26
(1H, m), 8.33 (1H, d, J=2.0 Hz), 8.99-9.00 (1H, m).
Example E-15
Quinoline-6-carboxylic acid 3-(4-fluoro-phenoxy)-benzylamide
[1477] The title compound (28 mg, 25%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (52 mg, 0.30 mmol) and
3-(4-fluorophenoxy)-benzylamine described in Preparation Example 8
(65 mg, 0.30 mmol) according to an analogous method to Example
L-4.
[1478] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.70 (2H, d,
J=5.6 Hz), 6.64 (1H, brs), 6.88-6.91 (1H, m), 6.99-7.06 (5H, m),
7.12-7.14 (1H, m), 7.31-7.35 (1H, m), 7.47-7.50 (1H, m), 8.04-8.07
(1H, m), 8.15-8.17 (1H, m), 8.23-8.25 (1H, m), 8.33 (1H, m),
9.00-9.01 (1H, m).
Example E-16
Quinoline-6-carboxylic acid 3-(4-methoxy-phenoxy)-benzylamide
[1479] The title compound (28 mg, 25%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (50 mg, 0.29 mmol) and
3-(4-methoxyphenoxy)benzylamine described in Preparation Example 9
(66 mg, 0.30 mmol) according to an analogous method to Example
L-4.
[1480] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.79 (3H,
s), 4.66 (2H, d, J=5.6 Hz), 6.55 (1H, brs), 6.84-6.89 (3H, m),
6.95-6.99 (3H, m), 7.05-7.07 (1H, m), 7.46 (2H, dd, J=4.4, 8.4 Hz),
8.03 (1H, dd, J=2.4, 8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.21-8.23
(1H, m), 8.29 (1H, d, J=2.0 Hz), 8.98 (1H, dd, J=2.0, 4.4 Hz).
Example E-17
Quinoline-6-carboxylic acid
3-(3-trifluoromethyl-phenoxy)-benzylamide
[1481] The title compound (39 mg, 32%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (50 mg, 0.29 mmol) and
3-(3-trifluoromethyl-phenoxy)-benzylamine described in Preparation
Example 10 (77 mg, 0.29 mmol) according to an analogous method to
Example L-4.
[1482] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.70 (2H, d,
J=5.6 Hz), 6.68 (1H, brs), 6.93-6.95 (1H, m), 7.05-7.06 (1H, m),
7.14-7.25 (3H, m), 7.31-7.47 (4H, m), 8.04 (1H, dd, J=1.6, 8.8 Hz),
8.13 (1H, d, J=8.8 Hz), 8.20-8.2 (1H, m), 8.31 (1H, d, J=2.0 Hz),
8.97 (1H, dd, J=1.6, 4.4 Hz).
Example E-18
Quinoline-6-carboxylic acid 3-(3-fluoro-phenoxy)-benzylamide
[1483] The title compound (70 mg, 65%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (50 mg, 0.29 mmol) and
3-(3-fluoro-phenoxy)-benzylamine described in Preparation Example
11 (63 mg, 0.29 mmol) according to an analogous method to Example
L-4.
[1484] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.71 (2H, d,
J=6.0 Hz), 6.63 (1H, brs), 6.69-6.73 (1H, m), 6.78-6.83 (2H, m),
6.96-6.98 (1H, m), 7.07 (1H, s), 7.18 (1H, d, J=7.6 Hz), 7.24-7.30
(1H, m), 7.34-7.38 (1H, m), 7.48 (1H, dd, J=4.4, 8.4 Hz), 8.06 (1H,
dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.23-8.25 (1H, m), 8.33
(1H, d, J=1.6 Hz), 8.99 (1H, dd, J=1.6, 4.4 Hz).
Example E-19
2-(3-Phenoxy-phenyl)-N-quinolin-6-yl-acetamide
[1485] The title compound (116 mg, 94%) was obtained as a colorless
oil from 6-aminoquinoline (50 mg, 3.47 mmol) and
3-phenoxyphenylacetic acid (79 mg, 3.47 mmol) according to an
analogous method to Example L-4.
[1486] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.77 (2H,
s), 6.98-7.06 (4H, m), 7.10-7.16 (2H, m), 7.34-7.44 (6H, m), 8.01
(1H, d, J=8.8 Hz), 8.09-8.16 (1H, m), 8.32 (1H, d, J=2.0 Hz), 8.83
(1H, dd, J=1.6, 4.0 Hz).
Example E-20
Quinoline-6-carboxylic acid 4-(furan-2-ylmethoxy)-benzylamide
[1487] The title compound (0.7 mg, 4%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (10 mg, 0.0577 mmol) and
4-(furan-2-ylmethoxy)-benzylamine described in Preparation Example
12 (12 mg, 0.0577 mmol) according to an analogous method to Example
L-4.
[1488] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.66 (2H, d,
J=5.6 Hz), 5.02 (2H, s), 6.48 (1H, brs), 6.99-7.02 (2H, m),
7.24-7.27 (2H, m), 7.35-7.36 (2H, m), 7.47-7.50 (2H, m), 8.05-8.08
(1H, m), 8.16-8.18 (1H, m), 8.24-8.27 (1H, m), 8.33 (1H, s), 9.00
(1H, s).
Example E-21
Quinoline-6-carboxylic acid
4-(thiophen-2-ylmethoxy)-benzylamide
[1489] The title compound (11 mg, 53%) was obtained as a colorless
solid from 6-quinolinecarboxylic acid (10 mg, 0.0577 mmol) and
4-(thiophen-2-ylmethoxy)-benzylamine described in Preparation
Example 13 (13 mg, 0.0577 mmol) according to an analogous method to
Example L-4.
[1490] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.65 (2H, d,
J=5.6 Hz), 5.23 (2H, s), 6.60 (1H, brs), 6.97-7.03 (3H, m),
7.11-7.12 (1H, m), 7.32-7.34 (3H, m), 7.45-7.48 (1H, m), 8.05-8.07
(1H, m), 8.13-8.16 (1H, m), 8.21-8.23 (1H, m), 8.32 (1H, s),
8.97-8.99 (1H, m).
Example E-22
Quinoline-6-carboxylic acid
4-(thiophen-3-ylmethoxy)-benzylamide
[1491] The title compound (78 mg, 72%) was obtained as a white
solid from 6-quinolinecarboxylic acid (50 mg, 0.289 mmol) and
4-(thiophen-3-ylmethyl)-benzylamine described in Preparation
Example 14 (63 mg, 0.289 mmol) according to an analogous method to
Example L-4.
[1492] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.65 (2H, d,
J=5.6 Hz), 5.08 (2H, s), 6.51 (1H, brs), 6.96-6.99 (2H, m),
7.14-7.16 (1H, m), 7.32-7.36 (4H, m), 7.46-7.49 (1H, m), 8.04-8.07
(1H, m), 8.15 (1H, d, J=8.8 Hz), 8.22-8.24 (1H, m), 8.32 (1H, d,
J=2.0 Hz), 8.99 (1H, dd, J=2.0, 4.4 Hz).
Example E-23
Quinoline-6-carboxylic acid 4-((S)-1-phenyl-ethoxy)-benzylamide
[1493] The title compound (219 mg, 80%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (123 mg, 0.712 mmol) and
4-((S)-1-phenyl-ethoxy)-benzylamine described in Preparation
Example 15 (172 mg, 0.712 mmol) according to an analogous method to
Example L-4.
[1494] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.64 (3H, d,
J=6.4 Hz), 4.58 (2H, d, J=5.2 Hz), 5.31 (1H, q, J=6.4 Hz), 6.47
(1H, brs), 6.86 (2H, d, J=8.8 Hz), 7.22 (2H, d, J=8.8 Hz),
7.26-7.27 (2H, m), 7.32-7.39 (3H, m), 7.46 (1H, dd, J=4.0, 8.0 Hz),
8.03 (1H, dd, J=2.0, 8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.22 (1H, d,
J=8.0 Hz), 8.30 (1H, d, J=2.0 Hz), 8.97-8.98 (1H, m).
Example E-24
Quinoline-6-carboxylic acid 3-benzylamino-benzylamide
[1495] 3-Benzylamino-benzonitrile described in Preparation Example
87 (57 mg, 0.27 mmol) was dissolved at 0.degree. C. in
tetrahydrofuran (0.5 mL), and lithium aluminum hydride (52 mg, 1.35
mmol) was added. After stirring overnight at room temperature,
water (541), an aqueous solution of 5N sodium hydroxide (52 .mu.l)
and water (156 .mu.l) were sequentially added at 0.degree. C. The
reaction solution was filtered through Celite pad, then, the
solvent was evaporated in vacuo, and
(3-aminomethyl-phenyl)-benzyl-amine (62 mg, 0.29 mmol) was obtained
as an oil.
[1496] (3-Aminomethyl-phenyl)-benzylamine (62 mg, 0.29 mmol),
quinoline-6-carboxylic acid (52 mg, 0.30 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (182 mg, 0.41 mmol) and triethylamine (114
.mu.l, 0.81 mmol) were dissolved in N,N-dimethylformamide (0.5 mL),
and the solution was stirred at room temperature for 2 hours. Water
was added to the reaction solution, which was then extracted with
ethyl acetate, the organic layer was washed with water and brine,
and dried over anhydrous magnesium sulfate. The solvent was
evaporated in vacuo, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate=1:1), and the title
compound (73 mg, 0.198 mmol, 73%) was obtained as a white
solid.
[1497] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.22 (2H,
d, J=6.0 Hz), 4.39 (2H, d, J=6.0 Hz), 6.25 (1H, t, J=6.0 Hz), 6.40
(1H, dd, J=1.6, 7.7 Hz), 6.50 (1H, d, J=7.7 Hz), 6.60 (1H, s), 6.97
(1H, t, J=7.8 Hz), 7.14 (1H, t, J=7.3 Hz), 7.23 (2H, t, J=7.8 Hz),
7.30 (2H, d, J=7.1 Hz), 7.60 (1H, dd, J=4.4, 8.4 Hz), 8.07 (1H, d,
J=8.8 Hz), 8.19 (1H, dd, J=2.0, 8.8 Hz), 8.45 (1H, d, J=7.6 Hz),
8.52 (1H, d, J=1.6 Hz), 8.97 (1H, dd, J=1.6, 4.4 Hz), 9.14 (1H, t,
J=6.0 Hz).
Example E-25
Quinoline-6-carboxylic acid 4-phenylamino-benzylamide
[1498] (4-Aminomethyl-phenyl)-phenylamine (98 mg, 0.494 mmol) was
obtained as an oil from 4-phenylamino-benzonitrile described in
Preparation Example 88 (110 mg, 0.566 mmol) according to an
analogous method to Example E-24.
[1499] Then, the title compound (52 mg, 0.147 mmol, 26%) was
obtained from the resulting (4-aminomethyl-phenyl)-phenylamine and
quinoline-6-carboxylic acid (108 mg, 0.623 mmol).
[1500] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.66 (2H, d,
J=5.5 Hz), 5.76 (1H, s), 6.50 (1H, brs), 6.96 (1H, t, J=7.4 Hz),
7.07-7.10 (4H, m), 7.29-7.32 (4H, m), 7.49 (1H, dd, J=4.2, 8.4 Hz),
8.08 (1H, dd, J=2.0, 8.6 Hz), 8.17 (1H, d, J=8.8 Hz), 8.25 (1H, d,
J=7.5 Hz), 8.34 (1H, d, J=1.8 Hz), 9.00 (1H, dd, J=1.7, 4.2
Hz).
Example E-26
Quinoline-6-carboxylic acid 4-(benzyl-methyl-amino)-benzylamide
[1501] Quinoline-6-carboxylic acid 4-benzylamino-benzylamide
described in Preparation Example E+-3 (30 mg, 82 .mu.mol), formalin
(9 .mu.l, 115 .mu.mol), triacetoxy sodium borohydride (25 mg, 115
.mu.mol) and acetic acid (several drops) were suspended in
tetrahydrofuran (1 mL), and the solution was stirred at room
temperature for 4 hours. An aqueous solution of saturated sodium
bicarbonate was added to the reaction suspension at 0.degree. C.,
which was then extracted with ethyl acetate, the organic layer was
washed with brine and dried over anhydrous magnesium sulfate. The
solvent was evaporated in vacuo, purification was carried out using
thin layer NH silica gel chromatography (hexane:ethyl acetate=1:1),
and the title compound (11 mg, 28 mmol, 35%) was obtained as a
white solid.
[1502] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.05 (3H,
s), 4.55 (2H, s), 4.59 (2H, d, J=5.1 Hz), 6.38 (1H, brs), 6.74 (2H,
d, J=8.8 Hz), 7.21-7.26 (4H, m), 7.32 (2H, t, J=7.2 Hz), 7.4 (1H,
d, J=7.0 Hz), 7.47 (1H, dd, J=4.3, 8.2 Hz), 8.05 (1H, dd, J=2.0,
8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.23 (1H, d, J=7.1 Hz), 8.30 (1H,
d, J=1.7 Hz), 8.98 (1H, dd, J=1.7, 4.2 Hz).
Example E-27
Quinoline-6-carboxylic acid 3-phenylsulfanyl-benzylamide
[1503] The title compound (50 mg, 0.14 mmol, 75%) was obtained as a
white solid from 3-phenylsulfanyl-benzylamine described in
Preparation Example 95 (38 mg, 0.18 mmol) and
quinoline-6-carboxylic acid (31 mg, 0.18 mmol) according to an
analogous method to Example A-26.
[1504] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta. (ppm): 4.67 (2H,
d, J=5.7 Hz), 6.52 (1H, brs), 7.23-7.26 (3H, m), 7.31 (4H, t, J=7.4
Hz), 7.38 (2H, d, J=6.8 Hz), 7.49 (1H, dd, J=4.2, 8.4 Hz), 8.03
(1H, dd, J=1.8, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.24 (1H, d, J=7.5
Hz), 8.31 (1H, d, J=1.8 Hz), 9.00 (1H, dd, J=1.7, 4.2 Hz).
Example E-28
Quinoline-6-carboxylic acid 4-benzylsulfanyl-benzylamide
[1505] The title compound (54 mg, 0.14 mmol, 38%) was obtained as a
white solid from 4-benzylsulfanyl-benzylamine described in
Preparation Example 101 (84 mg, 0.37 mmol) and
quinoline-6-carboxylic acid (70 mg, 0.40 mmol) according to an
analogous method to Example A-26.
[1506] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.20 (2H,
s), 4.47 (2H, d, J=5.9 Hz), 7.18-7.34 (9H, m), 7.59 (1H, dd, J=4.2,
8.4 Hz), 8.07 (1H, d, J=9.0 Hz), 8.18 (1H, dd, J=2.0, 8.8 Hz), 8.45
(1H, d, J=7.9 Hz), 8.52 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.8, 4.2
Hz), 9.24 (1H, t, J=5.9 Hz).
Example E-29
Quinoline-6-carboxylic acid 3-(3-methylbutoxy)-benzylamide
[1507] To a mixture solution of quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (13 mg,
0.048 mmol) and N,N-dimethylformamide (0.5 mL) were added potassium
carbonate (13 mg, 0.096 mmol) and 1-iodine-3-methylbutane (0.013
mL, 0.096 mmol), and the solution was stirred overnight at room
temperature. Water and dichloromethane was added to the reaction
solution for extraction, which was then washed with brine, then,
the solvent was evaporated in vacuo. The residue was purified by
silica gel column chromatography (ethyl acetate), and the title
compound (12 mg, 0.033 mmol, 69%) was obtained as a colorless
oil.
[1508] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.96 (6H, d,
J=6.6 Hz), 1.65-1.70 (2H, m), 1.80-1.87 (1H, m), 3.99 (2H, t, J=6.7
Hz), 4.68 (2H, d, J=5.7 Hz), 6.56 (1H, brs), 6.84-6.87 (1H, m),
6.93-6.98 (2H, m), 7.26-7.31 (1H, m), 7.48 (1H, dd, J=4.2, 8.2 Hz),
8.07 (1H, dd, J=2.0, 8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.23-8.25
(1H, m), 8.33 (1H, d, J=2.0 Hz), 8.99 (1H, dd, J=1.8, 4.2 Hz).
Example E-30
Quinoline-6-carboxylic acid (Z)-4-styryl-benzylamide
[1509] To a mixture of quinoline-6-carboxylic acid
4-phenylethynyl-benzylamide described in Preparation Example E+-5
(48 mg, 0.13 mmol), quinoline (26 mg, 0.20 mmol) and
tetrahydrofuran (2 mL) was added Lindlar catalyst (5.0 mg), and the
solution was stirred under hydrogen atmosphere at room temperature
for 1 hour. The interior of the reaction system was changed to
nitrogen atmosphere, then, filtration was carried out through
Celite pad. The filtrate was evaporated in vacuo, the residue was
purified by silica gel column chromatography (hexane:ethyl
acetate=1:4), and the title compound (45 mg, 0.12 mmol, 92%) was
obtained as a colorless oil.
[1510] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=6.0 Hz), 6.58-6.60 (2H, m), 7.16-7.27 (9H, m), 7.59 (1H, dd,
J=4.2, 8.2 Hz), 8.06 (1H, d, J=8.8 Hz), 8.19 (1H, dd, J=2.0, 8.8
Hz), 8.45-8.47 (1H, m), 8.54 (1H, d, J=1.7 Hz), 8.97 (1H, dd,
J=1.7, 4.2 Hz), 9.24 (1H, t, J=5.7 Hz).
Example E-31
Quinoline-6-carboxylic acid 4-phenylaminomethyl-benzylamide
[1511] The title compound (13.8 mg) was obtained according to an
analogous method to Example E-26 using quinoline-6-carboxylic acid
4-formyl-benzylamide described in Preparation Example E+-6 (50 mg,
0.172 mmol) instead of formalin, and phenylamine (31 .mu.l, 0.34
mmol) instead of quinoline-6-carboxylic acid 4-benzyl
amino-benzylamide. Trifluoroacetic acid salt of the title compound
was obtained by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used).
[1512] MS m/e (ESI) 368.5 (MH.sup.+)
Example E-32
Quinoline-6-carboxylic acid
4-((methyl-phenyl-amino)-methyl)-benzylamide
[1513] The title compound (4.25 mg) was obtained from
quinoline-6-carboxylic acid 4-phenylaminomethyl-benzylamide
described in Example E-31 (30 mg, 82 mmol) according to an
analogous method to Example E-26. Trifluoroacetic acid salt of the
title compound was obtained by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used).
[1514] MS m/e (ESI) 382.3 (MH.sup.+)
Example E-33
Quinoline-6-carboxylic acid 3-(4-nitro phenoxy)-benzylamide
[1515] To a mixture solution of quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (3.0 mg,
0.011 mmol), copper(II) acetate (2.9 mg, 0.016 mmol), molecular
sieves 4A (50 mg) and dichloromethane (2 mL) were added
triethylamine (0.0077 mL, 0.055 mmol) and 4-nitrophenylboronic acid
(1.8 mg, 0.011 mmol), and the solution was stirred in the presence
of air at room temperature for 10 days. The reaction solution was
filtered, then, water, ethyl acetate and an aqueous solution of 29%
ammonia were added for extraction, the solution was washed with
brine, then, the solvent was evaporated in vacuo. The residue was
purified by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and trifluoroacetic acid salt of the title
compound (1.14 mg, 0.0022 mmol, 20%) was obtained.
[1516] MS m/e (ESI) 400.2 (MH.sup.+)
Example E-34
Quinoline-6-carboxylic acid 3-(4-methanesulfonyl
phenoxy)-benzylamide
[1517] Trifluoroacetic acid salt of the title compound (0.21 mg,
0.00038 mmol, 3.5%) was obtained from quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (3.0 mg,
0.011 mmol) and 4-methanesulfonylphenylboronic acid (2.2 mg, 0.011
mmol) according to an analogous method to Example E-33.
[1518] MS m/e (ESI) 433.2 (MH.sup.+)
Example E-35
4-(3-(((Quinoline-6-carbonyl)amino)methyl)phenoxy)benzoic acid
methyl ester
[1519] Trifluoroacetic acid salt of the title compound (0.14 mg,
0.00027 mmol, 2.4%) was obtained from quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (3.0 mg,
0.011 mmol) and 4-methoxy-carbonyl phenylboronic acid (1.8 mg,
0.011 mmol) according to an analogous method to Example E-33.
[1520] MS m/e (ESI) 413.3 (MH.sup.+)
Example E-36
Quinoline-6-carboxylic acid 3-(3-cyanophenoxy)-benzylamide
[1521] Trifluoroacetic acid salt of the title compound (0.25 mg,
0.0005 .mu.mol, 4.6%) was obtained from quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (5.0 mg,
0.011 mmol) and 3-cyanophenylboronic acid (2.6 mg, 0.018 mmol)
according to an analogous method to Example E-33.
[1522] MS m/e (ESI) 380.1 (MH.sup.+)
Example E-37
Quinoline-6-carboxylic acid 3-(3-acetylphenoxy)-benzylamide
[1523] Trifluoroacetic acid salt of the title compound (0.17 mg,
0.00033 mmol, 3.0%) was obtained from quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (5.0 mg,
0.011 mmol) and 3-acetylphenylboronic acid (3.0 mg, 0.018 mmol)
according to an analogous method to Example E-33.
[1524] MS m/e (ESI) 397.0 (MH.sup.+)
Example E-38
Quinoline-6-carboxylic acid 3-(3-trifluoromethoxy
phenoxy)-benzylamide
[1525] Trifluoroacetic acid salt of the title compound (0.15 mg,
0.00027 mmol, 2.5%) was obtained from quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (5.0 mg,
0.011 mmol) and 3-trifluoromethoxyphenylboronic acid (3.7 mg, 0.018
mmol) according to an analogous method to Example E-330.
[1526] MS m/e (ESI) 439.0 (MH.sup.+)
Example E-39
Quinoline-6-carboxylic acid
(3'-fluorobiphenyl-3-ylmethyl)-amide
[1527] To a mixture of quinoline-6-carboxylic acid
3-bromobenzylamide described in Preparation Example E+-8 (4.0 mg,
0.012 mmol), toluene (1 mL) and methanol (0.25 mL) were added an
aqueous solution of 2M sodium carbonate (0.5 mL),
tetrakis(triphenylphosphine)palladium(0) (1.4 mg, 0.0012 mmol) and
3-fluorophenylboronic acid (1.7 mg, 0.012 mmol), and the solution
was stirred at 70.degree. C. for 4 hours. After cooling, water,
ethyl acetate and acetic acid were added for extraction, the
solution was washed with brine, then, the solvent was evaporated in
vacuo. The residue was purified by reverse phase high performance
liquid chromatography (acetonitrile-water mobile phase (containing
0.1% trifluoroacetic acid) was used), and trifluoroacetic acid salt
of the title compound (0.47 mg, 0.0010 mmol, 8.3%) was
obtained.
[1528] MS m/e (ESI) 357.2 (MH.sup.+)
Example E-40
Quinoline-6-carboxylic acid 3-benzyl-benzylamide
[1529] To a mixture of quinoline-6-carboxylic acid
3-bromobenzylamide described in Preparation Example E+-8 (8.0 mg,
0.023 mmol), dichloro(1,1'-bis(diphenylphosphino)ferrocene)
nickel(II) (3.2 mg, 0.0047 mmol) and tetrahydrofuran (1 mL) was
added benzylmagnesium chloride (1.1M tetrahydrofuran solution,
0.088 mL, 0.094 mmol) at room temperature, and the solution was
stirred for 30 minutes at 50.degree. C. After cooling, water and
ethyl acetate were added for extraction, the solution was washed
with brine, the solvent was then evaporated in vacuo. The residue
was purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and trifluoroacetic acid salt of
the title compound (2.1 mg, 0.0045 mmol, 19%) was obtained.
[1530] MS m/e (ESI) 353.2 (MH.sup.+)
Example E-41
Quinoline-6-carboxylic acid 4-benzyl-benzylamide
[1531] Trifluoroacetic acid salt of the title compound (1.5 mg,
0.0032 mmol, 14%) was obtained from quinoline-6-carboxylic acid
4-bromobenzylamide described in Preparation Example E+-9 (8.0 mg,
0.023 mmol) according to an analogous method to Example E-40.
[1532] MS m/e (ESI) 353.3 (MH.sup.+)
Example E-42
Quinoline-6-carboxylic acid 4-phenethyl-benzylamide
[1533] Trifluoroacetic acid salt of the title compound (0.39 mg,
0.00081 mmol, 3.5%) was obtained from quinoline-6-carboxylic acid
4-bromobenzylamide described in Preparation Example E+-9 (8.0 mg,
0.023 mmol) and phenethylmagnesium chloride (1.0M tetrahydrofuran
solution, 0.094 mL, 0.094 mmol) according to an analogous method to
Example E-40.
[1534] MS m/e (ESI) 367.3 (MH.sup.+)
Example E-43
Quinoline-6-carboxylic acid 3-cyclopropylmethoxy-benzylamide
[1535] To a mixture of quinoline-6-carboxylic acid
3-hydroxybenzylamide described in Preparation Example E+-4 (87 mg,
0.31 mmol) and tetrahydrofuran (2 mL) was added an aqueous solution
of 1N sodium hydroxide (0.31 mL, 0.3 .mu.mol), and the solvent was
evaporated in vacuo. To a mixture of a portion (5.0 mg) of the
residue (93 mg) and N,N-dimethylformamide (1 mL) were added
cyclopropylmethyl bromide (2.7 mg, 0.020 mmol) and catalytic amount
of sodium iodide at room temperature, followed by stirring for 3
hours at the same temperature. The reaction solution was purified
by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and trifluoroacetic acid salt of the title
compound (1.50 mg, 0.0034 mmol, 20%) was obtained.
[1536] MS m/e (ESI) 333.0 (MH.sup.+)
Example E-44
N-(4-Benzyloxy-benzyl)-N'-methoxy-quinoline-6-carboxamidine
[1537] To a mixture of quinoline-6-carbothioic acid
4-benzyloxy-benzylamide described in Preparation Example E+-10 (57
mg, 0.15 mmol) and acetonitrile (3 mL) was added
2-(bromomethyl)naphthalene (200 mg, 0.94 mmol), which was then
refluxed for 2 hours. After cooling, the solvent was evaporated in
vacuo, and the residue was washed with diethyl ether three times. A
mixture of a portion (29 mg) of the resulting crude product (57
mg), methoxylamine hydrochloride (2.9 mg, 0.035 mmol), an aqueous
solution of 1N sodium hydroxide (0.035 mL, 0.035 mmol) and
N-methylpyrrolidinone (1 mL) was stirred at room temperature for 25
minutes. The reaction solution was directly purified by reverse
phase high performance liquid chromatography (acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid) was used), and
ditrifluoroacetic acid salt of the title compound (1.9 mg, 0.0030
mmol, 6.4%) was obtained.
[1538] MS m/e (ESI) 398.5 (MH.sup.+)
Example E-45
N-(4-Benzyloxy-benzyl)-N'-cyano-quinoline-6-carboxamidine
[1539] To a mixture of quinoline-6-carbothioic acid
4-benzyloxy-benzylamide described in Preparation Example E+-10 (57
mg, 0.15 mmol) and toluene (2 mL) was added benzyl bromide (0.089
mL, 0.74 mmol), which was then stirred under reflux for 90 minutes.
After cooling, the solvent was evaporated in vacuo, and the residue
was washed with diethyl ether twice.
[1540] A mixture of a portion (16 mg) of the resulting crude
product (72 mg), cyanamide (20 mg, 0.48 mmol) and
N-methylpyrrolidinone (1 mL) was stirred for 2.5 hours at
120.degree. C. After cooling, the reaction solution was filtered
through a membrane filter, the filtrate was directly purified by
reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and trifluoroacetic acid salt of the title
compound (0.76 mg, 0.0015 mmol, 4.5%) was obtained.
[1541] MS m/e (ESI) 393.5 (MH.sup.+)
Example E-46
Quinoline-6-carboxylic acid 4-(3-chloro-benzyloxy)-benzylamide
[1542] Trifluoroacetic acid salt of the title compound was obtained
from quinoline-6-carboxylic acid 4-hydroxybenzylamine described in
Preparation Example E+-1 and 3-chlorobenzyl chloride according to
an analogous method to Example E-12.
[1543] MS m/e (ESI) 403 (MH.sup.+)
Example E-47
Quinoline-6-carboxylic acid 4-(3-fluoro-benzyloxy)-benzylamide
[1544] Trifluoroacetic acid salt of the title compound was obtained
from quinoline-6-carboxylic acid 4-hydroxybenzylamine described in
Preparation Example E+-1 and 3-fluorobenzyl bromide according to an
analogous method to Example E-12.
[1545] MS m/e (ESI) 387 (MH.sup.+)
Example E-48
Quinoline-6-carboxylic acid
4-(benzo[1,3]dioxol-5-ylmethoxy)-benzylamide
[1546] Trifluoroacetic acid salt of the title compound was obtained
from quinoline-6-carboxylic acid 4-hydroxybenzylamine described in
Preparation Example E+-1 and methanesulfonic acid
benzo[1,3]dioxol-5-ylmethyl ester according to an analogous method
to Example E-12.
[1547] MS m/e (ESI) 413 (MH.sup.+)
Example E-49
6-Quinolinecarboxylic acid
3-(3-methyl-2-butenyloxy)-benzylamide
[1548] 6-Quinolinecarboxylic acid (100 mg, 0.577 mmol),
3-(3-methyl-2-butenyloxy)-benzylamine described in Preparation
Example 134 (112 mg, 0.635 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (306 mg, 0.693 mmol) and triethylamine (0.12
mL, 0.87 mmol) were dissolved in tetrahydrofuran (5 mL), and the
solution was stirred at room temperature for 3 hours. The solvent
was evaporated in vacuo, the obtained residue was purified by NH
silica gel column chromatography (hexane:ethyl acetate=4:1), and
the title compound (153 mg, 80.1%) was obtained as a white
solid.
[1549] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.73 (3H,
s), 1.78 (3H, s), 4.51 (2H, d, J=6.8 Hz), 4.68 (2H, d, J=5.6 Hz),
5.48 (1H, t, J=6.8 Hz), 6.62 (1H, t, J=5.6 Hz), 6.87 (1H, dd,
J=2.4, 8.4 Hz), 6.95 (1H, d, J=2.4 Hz), 6.96 (1H, d, J=8.4 Hz),
7.28 (1H, t, J=8.4 Hz), 7.47 (1H, dd, J=4.0, 8.0 Hz), 8.05 (1H, dd,
J=2.0, 8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.23 (1H, dd, J=1.2, 8.0
Hz), 8.32 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.2, 4.0 Hz).
Example E-50
6-Quinolinecarboxylic acid 3-(2-methylpropenyl)-benzylamide
[1550] The title compound (150 mg, 0.475 mmol, 82.2%) was obtained
as a white solid from 6-quinolinecarboxylic acid (100 mg, 0.577
mmol) and 3-(2-methyl-propenyl)-benzylamine described in
Preparation Example 137 (93 mg, 0.577 mmol) according to an
analogous method to Example E-49.
[1551] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.87 (3H,
s), 1.90 (3H, s), 4.70 (2H, d, J=5.6 Hz), 6.27 (1H, s), 6.62 (1H,
t, J=5.6 Hz), 7.20-7.46 (4H, m), 7.47 (1H, dd, J=4.0, 8.0 Hz), 8.05
(1H, dd, J=2.0, 8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.23 (1H, dd,
J=1.2, 8.0 Hz), 8.32 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.2, 4.0
Hz).
Example E-51
6-Quinolinecarboxylic acid 3-cyclopentylydenemethylbenzylamide
[1552] The title compound (150 mg, 0.457 mol, 79.3%) was obtained
as a white solid from 6-quinolinecarboxylic acid (100 mg, 0.577
mmol) and 3-cyclopentylydenemethyl-benzylamine described in
Preparation Example 139 (108 mg, 0.577 mmol) according to an
analogous method to Example E-49.
[1553] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.65-1.79
(4H, m), 2.47-2.58 (4H, m), 4.70 (2H, d, J=5.6 Hz), 6.36 (1H,$),
6.54 (1H, t, J=5.6 Hz), 7.20-7.35 (4H, m), 7.47 (1H, dd, J=4.0, 8.0
Hz), 8.05 (1H, dd, J=2.0, 8.8 Hz), 8.13 (1H, d, J=8.8 Hz), 8.23
(1H, dd, J=1.2, 8.0 Hz), 8.32 (1H, d, J=2.0 Hz), 8.97 (1H, dd,
J=1.2, 4.0 Hz).
Example E-52
6-Quinolinecarboxylic acid 3-isobutylbenzylamide
[1554] The title compound (75 mg, 0.236 mol, 66.2%) was obtained as
a white solid from 6-quinolinecarboxylic acid (60 mg, 0.356 mmol)
and 3-isobutylbenzylamine described in Preparation Example 146 (58
mg, 0.356 mmol) according to an analogous method to Example
E-49.
[1555] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.90 (6H, d,
J=6.8 Hz), 1.87 (1H, dq, J=7.6 Hz, 6.8 Hz), 2.48 (2H, d, J=7.6 Hz),
4.69 (2H, d, J=6.0 Hz), 6.52 (1H, t, J=6.0 Hz), 7.10-7.30 (4H, m),
7.47 (1H, dd, J=4.0, 8.0 Hz), 8.05 (1H, dd, J=2.0, 8.8 Hz), 8.13
(1H, d, J=8.8 Hz), 8.23 (1H, dd, J=1.2, 8.0 Hz), 8.32 (1H, d, J=2.0
Hz), 8.97 (1H, dd, J=1.2, 4.0 Hz).
Example E-53
Quinoline-6-carboxylic acid 4-benzyloxy-2-fluoro-benzylamide
[1556] To a mixture of lithium aluminum hydride (84 mg, 2.2 mmol)
and tetrahydrofuran (2 mL) was added
4-benzyloxy-2-fluoro-benzonitrile described in Preparation Example
118 (100 mg, 0.44 mmol) on an ice bath, and the solution was
stirred at room temperature for 1 hour. Water (0.084 mL), an
aqueous solution of 5N sodium hydroxide (0.084 mL) and water (0.25
mL) were added sequentially on an ice bath, and the solution was
stirred at room temperature for 90 minutes. The reaction solution
was filtered through Celite pad, then, the solvent was evaporated
in vacuo. The title compound (140 mg, 0.35 mmol, 90%) was obtained
as a white solid from the obtained residue (91 mg) and
quinoline-6-carboxylic acid (68 mg, 0.39 mmol) according to an
analogous method to Example Q-6.
[1557] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.68 (2H, d,
J=5.7 Hz), 5.05 (2H, s), 6.62 (1H, br s), 6.71-6.78 (2H, m),
7.34-7.43 (6H, m), 7.47 (1H, dd, J=4.3, 8.3 Hz), 8.04 (1H, dd,
J=2.0, 8.8 Hz), 8.15 (1H, d, J=8.8 Hz), 8.23-8.25 (1H, m), 8.31
(1H, d, J=2.0 Hz), 8.98 (1H, dd, J=1.8, 4.3 Hz).
Example E-54
Quinoline-6-carboxylic acid 4-benzyloxy-3-chloro-benzylamide
[1558] Trifluoroacetic acid salt of the title compound (29 mg,
0.057 mmol, 10%) was obtained from quinoline-6-carboxylic acid
4-benzyloxybenzylamide described in Example E-8 (200 mg, 0.54 mmol)
according to an analogous method to Example A-171.
[1559] MS m/e (ESI) 403.1 (MH.sup.+)
Example E-55
Quinoline-6-carboxylic acid
(4-phenoxy-pyridine-2-ylmethyl)-amide
[1560] The title compound (9 mg, 8%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (52 mg, 0.30 mmol) and
C-(4-phenoxy-pyridine-2-yl)-methylamine described in Preparation
Example 7 (60 mg, 0.30 mmol) according to an analogous method to
Example L-4.
[1561] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.74 (2H, d,
J=4.4 Hz), 6.79 (1H, dd, J=2.4 Hz, 5.6 Hz), 6.88 (1H, d, J=2.4 Hz),
7.10-7.12 (2H, m), 7.43-7.49 (4H, m), 7.81 (1H, brs), 8.14-8.19
(2H, m), 8.26-8.28 (1H, m), 8.40-8.44 (2H, m), 8.99-9.0 (1H,
m).
Example E-56
Quinoline-6-carboxylic acid
(6-phenoxy-pyridin-2-ylmethyl)-benzylamide
[1562] The title compound (32 mg, 28%) was obtained as a colorless
oil from 6-quinolinecarboxylic acid (56 mg, 0.325 mmol) and
C-(6-phenoxy-pyridin-2-yl)-methylamine described in Preparation
Example 16 (65 mg, 0.325 mmol) according to an analogous method to
Example L-4.
[1563] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.73 (2H, d,
J=4.4 Hz), 6.89-6.91 (1H, m), 7.04-7.06 (1H, m), 7.21-7.23 (2H, m),
7.30-7.34 (1H, m), 7.44-7.52 (3H, m), 7.64 (1H, brs), 7.65-7.68
(1H, m), 7.73-7.77 (1H, m), 8.11 (1H, d, J=8.4 Hz), 8.26 (1H, d,
J=8.0 Hz), 8.32 (1H, d, J=1.6 Hz), 9.01-9.03 (1H, m).
Example E-57
Quinoline-6-carboxylic acid
(1-benzyl-1H-pyrrol-3-ylmethyl)-amide
[1564] 7N Ammonia/methanol (80 mL) and Raney nickel (2 g) were
added to 1-benzyl-1H-pyrrole-3-carbaldehyde described in
Preparation Example 57 (800 mg, 4.3 mmol), and the solution was
stirred at room temperature for 22 hours under hydrogen atmosphere
at ordinary pressure. The catalyst was removed by filtrating
through Celite pad, then, the solvent was evaporated in vacuo and
C-(1-benzyl-1H-pyrrolo-3-yl)methylamine was quantitatively obtained
as a brown oil. The title compound (110 mg, 0.32 mmol, 24.8%) was
obtained as a white solid from the resulting
C-(1-benzyl-1H-pyrrolo-3-yl)methylamine (240 mg, 1.3 mmol) and
6-quinolinecarboxylic acid (180 mg, 1.04 mmol) according to an
analogous method to Example Q-6.
[1565] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.32 (2H,
d, 5.6 Hz), 5.02 (2H, s), 6.02 (1H, s), 6.74 (1H, s), 6.76 (1H, s),
6.18-7.34 (5H, m), 7.58 (1H, dd, J=4.0, 8.4 Hz), 8.03 (1H, d, J=8.8
Hz), 8.16 (1H, dd, J=2.0, 8.8 Hz), 8.43 (1H, dd, J=1.6, 8.4 Hz),
8.49 (1H, d, J=2.0 Hz), 8.97 (1H, t, J=5.6 Hz), 8.95 (1H, dd,
J=1.6, 4.0 Hz).
Example E-58
Quinoline-6-carboxylic acid
(1-benzo[1,3]-dioxol-5-ylmethyl-1H-pyrrol-3-ylmethyl)-amide
[1566] The title compound (30 mg, 0.077 mmol, 18.1%) was obtained
as a white solid from
C-(1-benzo[1,3]dioxol-5-ylmethyl-1H-pyrrol-3-yl)-methylamine
described in Preparation Example 61 (100 mg, 0.43 mmol) and
6-quinolinecarboxylic acid (75 mg, 0.43 mmol) according to an
analogous method to Example Q-6.
[1567] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.28-4.34
(2H, m), 4.90 (2H, s), 5.95 (2H, s), 6.00 (1H, s), 6.70-6.86 (5H,
m), 7.55-7.60 (1H, m), 8.01-8.05 (1H, m), 8.14-8.20 (1H, m),
8.40-8.46 (1H, m), 8.48-8.51 (1H, m), 8.39-8.98 (2H, m).
Example E-59
Quinoline-6-carboxylic acid
(1-phenethyl-1H-pyrrol-3-ylmethyl)-amide
[1568] The title compound (108 mg, 0.304 mmol, 30.4%) was obtained
as a slightly yellow solid from
1-phenethyl-1H-pyrrole-3-carbaldehyde described in Preparation
Example 62 and quinoline-6-carboxylic acid (173 mg, 1.0 mmol)
according to an analogous method to Example E-57.
[1569] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.96 (2H,
t, J=7.6 Hz), 4.03 (2H, t, J=7.6 Hz), 4.31 (2H, d, J=5.6 Hz), 5.96
(1H, s), 6.64 (1H, s), 6.73 (1H, s), 7.14-7.28 (5H, m), 7.58 (1H,
dd, J=4.0, 8.0 Hz), 8.04 (1H, d, J=8.8 Hz), 8.17 (1H, d, J=8.8 Hz),
8.43 (1H, d, J=8.0 Hz), 8.50 (1H, s), 8.90 (1H, t, J=5.6 Hz),
8.95-8.99 (1H, m).
Example E-60
Quinoline-6-carboxylic acid
(1-benzyloxy-1H-pyrrol-3-ylmethyl)-amide
[1570] Diethyl azodicarboxylate (154 mg, 0.869 mmol) was added
dropwise to a solution of (1-benzyloxy-1H-pyrrol-3-yl)-methanol
described in Preparation Example 64 (168 mg, 0.828 mmol),
phthalimide (130 mg, 0.869 mmol) and triphenylphosphine (230 mg,
0.869 mmol) in dichloromethane at 0.degree. C., and then, the
solution was stirred at room temperature for 8 minutes. NH silica
gel was added to the reaction solution, the solvent was evaporated
in vacuo for adsorption, purification was carried out by NH silica
gel column chromatography (hexane:ethyl acetate=4:1), and a
colorless oil (100 mg) was obtained. Ethanol (5 mL) and hydrazine
monohydrate (0.1 mL) were added to this oil (100 mg), and the
solution was stirred under reflux for 15 minutes. The reaction
solution was allowed to room temperature, solid was eliminated by
filtration, then, the solvent was evaporated, and an oil containing
C-(1-benzyloxy-1H-pyrrol-3-yl)methylamine was obtained (80 mg). The
title compound (31 mg, 0.086 mmol) was obtained as a colorless oil
from this oil (80 mg) and quinoline-6-carboxylic acid according to
an analogous method to Example Q-6.
[1571] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.28 (2H,
d, J=5.6 Hz), 5.11 (2H, s), 5.86-5.89 (1H, m), 6.78-6.81 (1H, m),
6.88-6.91 (1H, m), 7.34-7.42 (5H, m), 7.59 (1H, dd, J=4.0, 8.0 Hz),
8.04 (1H, d, J=8.8 Hz), 8.16 (1H, d, J=8.8 Hz), 8.44 (1H, d, J=8.0
Hz), 8.49 (1H, s), 8.92-8.98 (2H, m).
Example E-61
Quinoline-6-carboxylic acid
(1-phenyl-1H-pyrrol-3-ylmethyl)-amide
[1572] The title compound (136 mg, 0.415 mmol, 47.8%) was obtained
as a white solid from C-(1-phenyl-1H-pyrrol-3-yl)-methylamine
described in Preparation Example 74 (150 mg, 0.87 mmol) and
quinoline-6-carboxylic acid (150 mg, 0.87 mmol) according to an
analogous method to Example Q-6.
[1573] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.42 (2H,
d, J=5.6 Hz), 6.28-6.31 (1H, m), 7.18-7.24 (1H, m), 7.29-7.35 (2H,
m), 7.40-7.45 (2H, m), 7.50-7.65 (2H, m), 7.59 (1H, dd, J=4.0, 8.0
Hz), 8.05 (1H, d, J=8.8 Hz), 8.20 (1H, dd, J=2.0, 8.8 Hz),
8.43-8.48 (1H, m), 8.53 (1H, d, J=2.0 Hz), 8.96 (1H, dd, J=1.6, 4.0
Hz), 9.01 (1H, t, J=5.6 Hz).
Example E-62
Quinoline-6-carboxylic acid
(2-benzyl-2H-tetrazol-5-ylmethyl)-amide
[1574] Sodium azide (260 mg, 4.0 mmol) and ammonium chloride (210
mg, 4.0 mmol) were suspended in a solution of
quinoline-6-carboxylic acid cyanomethyl-amide described in
Preparation Example E-1 (420 mg, 2.0 mmol) in N,N-dimethylformamide
(15 mL), and the solution was stirred at 100.degree. C. for 12
hours. Benzyl bromide (0.12 mL, 1.0 mmol) and potassium carbonate
(400 mg, 3.0 mmol) were added to a solution having half the amount
of the solution containing quinoline-6-carboxylic acid
(2H-tetrazol-5-ylmethyl)amide obtained, which was then stirred for
20 minutes at 50.degree. C. Water and ethyl acetate were added to
the reaction solution, which was then partitioned, NH silica gel
was added to the organic layer, and the solvent was evaporated in
vacuo for adsorption, purification was carried out by NH silica gel
column chromatography, and the title compound (20 mg, 0.058 mmol)
was obtained as a white solid.
[1575] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.78 (2H,
d, J=5.6 Hz), 5.92 (2H, s), 7.34-7.43 (5H, m), 7.62 (1H, dd, J=4.0,
8.4 Hz), 8.09 (1H, d, J=8.8 Hz), 8.19 (1H, dd, J=2.0, 8.8 Hz), 8.48
(1H, dd, J=1.2, 8.4 Hz), 8.54 (1H, d, J=2.0 Hz), 9.00 (1H, dd,
J=1.2, 4.0 Hz), 9.44 (1H, t, J=5.6 Hz).
Example E-63
Quinoline-6-carboxylic acid
(2-phenoxy-thiazol-5-ylmethyl)-amide
[1576] The title compound (17 mg, 46 .mu.mol, 91%) was obtained as
a white solid from C-(2-phenoxy-thiazol-5-yl)-methylamine described
in Preparation Example 117 (10 mg, 50 .mu.mol) and
quinoline-6-carboxylic acid (11 mg, 60 .mu.mol) according to an
analogous method to Example A-26.
[1577] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.55 (2H,
d, J=5.7 Hz), 7.23 (1H, s), 7.27-7.31 (3H, m), 7.45 (2H, dd, J=7.2,
8.8 Hz), 7.59 (1H, dd, J=4.2, 8.8 Hz), 8.06 (1H, d, J=8.8 Hz), 8.14
(1H, dd, J=1.8, 8.8 Hz), 8.46 (1H, d, J=7.1 Hz), 8.5 (1H, d, J=1.8
Hz), 8.97 (1H, dd, J=1.7, 4.2 Hz), 9.39 (1H, t, J=5.7 Hz).
Example E-64
Quinoline-6-carboxylic acid
(5-(3-cyano-phenoxy)-thiophen-2-ylmethyl)-amide
[1578] To a solution of
C-(5-(3-bromophenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 17 (200 mg, 0.703 mmol) and
6-quinolinecarboxylic acid (123 mg, 0.703 mmol) in tetrahydrofuran
(5 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (373 mg, 0.844 mmol) and triethylamine (0.2 mL,
1.41 mmol), and the solution was stirred at room temperature for 2
hours. Ethyl acetate and water were added to the reaction solution,
which was then partitioned, the organic layer was washed with
water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and a mixture of
quinoline-6-carboxylic acid
(5-(3-bromophenoxy)-thiophene-2-ylmethyl)-amide and debrominated
compound (170 mg, 55%) was obtained as a colorless oil.
[1579] Next, to a solution of the mixture of quinoline-6-carboxylic
acid (5-(3-bromophenoxy)-thiophene-2-ylmethyl)-amide and
debrominated compound (130 mg, 0.303 mmol) in N,N-dimethylformamide
(5.0 mL) were added zinc cyanide (71 mg, 0.605 mmol) and
tetrakis(triphenylphosphine)palladium(0) (70 mg, 0.061 mmol) under
nitrogen atmosphere, the solution was stirred at 100.degree. C. for
1 hour, and the solution was stirred at 140.degree. C. for 3 hours.
The reaction solution was allowed to room temperature, ethyl
acetate and water were added to the reaction solution, which was
then partitioned, the organic layer was washed with water and dried
over anhydrous magnesium sulfate. The solvent was evaporated, then,
the residue was purified by NH silica gel column chromatography
(hexane:ethyl acetate), and title compound (25 mg, 21%) was
obtained as a colorless oil.
[1580] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.80 (2H, d,
J=5.2 Hz), 6.49 (1H, d, J=4.0 Hz), 6.68 (1H, brs), 6.85 (1H, d,
J=3.6 Hz), 7.30-7.45 (4H, m), 7.48 (1H, dd, J=4.4, 8.4 Hz), 8.07
(1H, dd, J=2.0, 8.8 Hz), 8.17 (1H, d, J=8.8 Hz), 8.24-8.27 (1H, m),
8.35 (1H, d, J=2.0 Hz), 8.99-9.01 (1H, m).
Example E-65
Quinoline-6-carboxylic acid
(5-(3-fluorophenoxy)thiophen-2-ylmethyl) amide
[1581] The title compound (100 mg, 0.265 mmol, 29.4%) was obtained
as a reddish brown oil from
C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 23 and 6-quinolinecarboxylic acid according to
an analogous method to Example Q-6.
[1582] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.59 (2H,
d, J=5.6 Hz), 6.59 (1H, d, J=3.6 Hz), 6.84 (1H, d, J=3.6 Hz),
6.90-7.7.02 (3H, m), 7.39 (1H, ddd, J=8.0, 8.0, 8.0 Hz), 7.60 (1H,
dd, J=4.0, 8.0 Hz), 8.06 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=1.6,
8.8 Hz), 8.45 (1H, d, J=8.0 Hz), 8.51 (1H, s), 8.97 (1H, d, J=4.0
Hz), 9.37 (1H, t, J=5.6 Hz).
Example E-66
Quinoline-6-carboxylic acid (5-phenoxythiophen-2-ylmethyl)
amide
[1583] Sodium hydride (3 g, 74 mmol, 60% in oil) was added to a
solution of phenol (7 g, 74 mmol) in dimethylsulfoxide (40 mL),
which was then stirred at room temperature for 10 minutes, and
5-nitrothiophene-2-carbaldehyde (10 g, 64 mmol) was further added,
followed by stirring for 15 minutes. Water and ethyl acetate were
added to the reaction solution, which was then partitioned, the
organic layer was washed with an aqueous solution of 2N sodium
hydroxide twice and with water three times, then, passed through a
glass filter lined with silica gel, and eluted with ethyl acetate.
The solvent was evaporated in vacuo, and a yellow oil containing
5-phenoxy thiophene-2-carbaldehyde was obtained (500 mg). This oil
(500 mg) was dissolved in 7N ammonia/methanol solution (30 mL),
Raney nickel (1.5 g) was added thereto, and the solution was
stirred overnight under hydrogen atmosphere. Raney nickel was
removed by filtering through Celite pad, then, the filtrate was
concentrated in vacuo, the residue was purified by silica gel
chromatography (ethyl acetate, then ethyl acetate methanol=4:1) and
a brown oil containing C-(5-phenoxythiophen-2-yl)methylamine was
obtained (40 mg).
[1584] Then, to a solution of the obtained oil (40 mg, 0.195 mmol)
and 6-quinolinecarboxylic acid (41 mg, 0.234 mmol) in
N,N-dimethylformamide (5 mL) were added
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (100 mg, 0.234 mmol) and triethylamine (0.054
mL, 0.39 mmol), and the solution was stirred for 30 minutes at
60.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water twice, NH silica gel was added to this organic layer,
the solvent was evaporated in vacuo for adsorption, and
purification was carried out by NH silica gel column chromatography
(hexane:ethyl acetate=3:1, then 1:1, then ethyl acetate). The
solvent was evaporated in vacuo, then, the solid generated by
adding diethyl ether to the residue was collected by filtration,
and the title compound (40 mg, 0.111 mmol, 56.9%) was obtained as a
pale yellow solid.
[1585] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=5.6 Hz), 6.51 (1H, d, J=3.6 Hz), 6.81 (1H, d, J=3.6 Hz),
7.06-7.15 (3H, m), 7.23-7.40 (2H, m), 7.59 (1H, dd, J=4.0, 8.0 Hz),
8.06 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=2.0, 8.8 Hz), 8.45 (1H, dd,
J=1.6, J=8.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.6, 4.0
Hz), 9.36 (1H, t, J=5.6 Hz).
Example E-67
Quinoline-6-carboxylic acid
(5-(4-fluorophenoxy)thiophen-2-yl)methyl amide
[1586] The title compound (38 mg, 0.100 mmol, 27.8%) was obtained
as a white solid from
C-(5-(4-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 28 and 6-quinolinecarboxylic acid according to
an analogous method to Example Q-6.
[1587] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=6.0 Hz), 6.49 (1H, d, J=3.6 Hz), 6.80 (1H, d, J=3.6 Hz),
7.10-7.17 (2H, m), 7.17-7.24 (2H, m), 7.59 (1H, dd, J=4.0, 8.0 Hz),
8.06 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=2.0, J=8.8 Hz), 8.45 (1H,
dd, J=1.6, 8.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.6,
4.0 Hz), 9.36 (1H, t, J=6.0 Hz).
Example E-68
Quinoline-6-carboxylic acid
(5-(4-chloro-phenoxy)-thiophen-2-ylmethyl)-amide
[1588] The title compound (87 mg, 0.22 mmol, 76.1%) was obtained as
a brown oil from the resulting
C-(5-(4-chlorophenoxy)thiophen-2-yl)methylamine (70 mg, 0.29 mmol)
and 6-quinolinecarboxylic acid (51 mg, 0.29 mmol) according to an
analogous method to Example E-66.
[1589] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.58 (2H,
d, 5.6 Hz), 6.55 (1H, d, J=4.0 Hz), 6.83 (1H, d, J=4.0 Hz),
7.08-7.14 (2H, m), 7.38-7.45 (2H, m), 7.59 (1H, dd, J=4.4, 8.0 Hz),
8.06 (1H, d, J=8.8 Hz), 8.16 (1H, dd, J=2.0, 8.8 Hz), 8.46 (1H, dd,
J=1.6, 8.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.97 (1H, dd, J=1.6, 4.4
Hz), 9.36 (1H, t, J=5.6 Hz).
Example E-69
Quinoline-6-carboxylic acid
(4-(3-fluoro-phenoxy)-thiophen-2-ylmethyl)-amide
[1590] The title compound (24 mg, 0.063 mmol, 39.7%) was obtained
as a white solid from
C-(4-(3-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 35 (35 mg, 0.16 mmol) and 6-quinolinecarboxylic
acid (33 mg, 0.19 mmol) according to an analogous method to Example
Q-6.
[1591] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.63 (2H,
d, J=6.0 Hz), 6.83-6.97 (5H, m), 7.38 (1H, ddd, J=8.0, 8.0, 8.0
Hz), 7.60 (1H, dd, J=4.4, 8.0 Hz), 8.07 (1H, d, J=8.8 Hz), 8.17
(1H, dd, J=2.0, 8.8 Hz), 8.47 (1H, dd, J=2.0, 8.0 Hz), 8.53 (1H, d,
J=2.0 Hz), 8.97 (1H, dd, J=2.0, 4.4 Hz), 9.39 (1H, t, J=6.0
Hz).
Example E-70
Quinoline-6-carboxylic acid
(5-benzyl-thiophen-2-ylmethyl)-amide
[1592] The title compound (40 mg, 0.111 mmol, 41.3%) was obtained
as a white solid from quinoline-6-carboxylic acid (46 mg, 0.27
mmol) and C-(5-benzyl-thiophen-2-yl)-methylamine described in
Preparation Example 42 (54 mg, 0.27 mmol) according to an analogous
method to Example Q-6.
[1593] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.04 (2H,
s), 4.57 (2H, d, J=5.6 Hz), 6.71 (1H, d, J=3.6 Hz), 6.84 (1H, d,
J=3.6 Hz), 7.14-7.30 (5H, m), 7.58 (1H, dd, J=4.0, 8.4 Hz), 8.04
(1H, d, J=8.8 Hz), 8.14 (1H, dd, J=2.0, 8.8 Hz), 8.44 (1H, dd,
J=2.0, 8.4 Hz), 8.49 (1H, d, J=2.0 Hz), 8.96 (1H, dd, J=2.0, 4.0
Hz), 9.29 (1H, t, J=5.6 Hz).
Example E-71
Quinoline-6-carboxylic acid
(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-amide
[1594] The title compound (73 mg, 0.18 mmol, 85.7%) was obtained as
a white solid from C-(5-(3-chloro-benzyl)-2-yl)-methylamine
described in Preparation Example 45 (50 mg, 0.2 .mu.mol) and
6-quinolinecarboxylic acid (40 mg, 0.23 mmol) according to an
analogous method to Example Q-6.
[1595] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.07 (2H,
s), 4.58 (2H, d, J=5.2 Hz), 6.74 (1H, d, J=2.4 Hz), 6.84 (1H, d,
J=2.4 Hz), 7.17-7.34 (4H, m), 7.59 (1H, dd, J=4.0, 8.4 Hz), 8.05
(1H, d, J=8.4 Hz), 8.14 (1H, d, J=8.4 Hz), 8.44 (1H, d, J=8.4 Hz),
8.49 (1H, s), 8.95 (1H, d, J=4.0 Hz), 9.30 (1H, t, J=5.2 Hz).
Example E-72
Quinoline-6-carboxylic acid
(5-(3-fluoro-benzyl)-thiophen-2-ylmethyl)-amide
[1596] The title compound (75 mg, 0.199 mmol, 80.2%) was obtained
as a light brown solid from quinoline-6-carboxylic acid (43 mg,
0.248 mmol) and 5-(3-fluoro-benzyl)-thiophene-2-carbaldehyde
described in Preparation Example 53 (50 mg, 0.226 mmol) according
to an analogous method to Example A-146.
[1597] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.08 (2H,
s), 4.58 (2H, d, J=5.6 Hz), 6.74 (1H, d, J=3.2 Hz), 6.85 (1H, d,
J=3.2 Hz), 6.98-7.10 (3H, m), 7.28-7.35 (1H, m), 7.59 (1H, dd,
J=4.0, 8.0 Hz), 8.05 (1H, d, J=8.8 Hz), 8.15 (1H, dd, J=1.6, 8.8
Hz), 8.44 (1H, d, J=8.0 Hz), 8.49 (1H, d, J=1.6 Hz), 8.95-8.99 (1H,
m), 9.30 (1H, t, J=5.6 Hz).
Example E-73
Quinoline-6-carboxylic acid
(5-(5-methyl-thiophen-2-ylmethyl)-thiophen-2-ylmethyl)-amide
[1598] To a solution of
(5-(5-methyl-thiophen-2-ylmethyl)-thiophen-2-yl)-methanol described
in Preparation Example 67 (640 mg, 2.86 mmol), phthalimide (420 mg,
2.86 mmol) and triphenylphosphine (750 mg, 2.86 mmol) in
tetrahydrofuran (7 mL) was added diethyl azodicarboxylate (500 mg,
2.86 mmol) dropwise at 0.degree. C., which was then stirred at room
temperature for 15 minutes. Water and ethyl acetate were added to
the reaction solution, which was then partitioned, silica gel was
added, the solvent was concentrated in vacuo for adsorption, and
purification was carried out by silica gel column chromatography
(hexane:ethyl acetate=8:1). The solvent was evaporated in vacuo, a
brown solid (360 mg, 1.02 mmol, 35.6%) was obtained.
[1599] Ethanol (5 mL) and hydrazine monohydrate (180 mg, 3.06 mmol)
were added to the resulting solid (360 mg), and the solution was
stirred for 20 minutes at 90.degree. C. The solution was allowed to
room temperature, the solid was eliminated by filtration, and a
pale yellow oil containing
C-5-(5-methyl-thiophen-2-ylmethyl)-thiophen-2-yl)-methylamine was
obtained (200 mg, 0.896 mmol, 89.6%). The title compound (101 mg,
0.267 mmol, 29.8%) was obtained as a white solid from this oil (200
mg, 0.896 mmol) and quinoline-6-carboxylic acid (160 mg, 0.896
mmol) according to an analogous method to Example Q-6.
[1600] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.35 (3H,
s), 4.20 (2H, s), 4.61 (2H, d, J=5.6 Hz), 6.58-6.62 (1H, m), 6.69
(1H, d, J=3.2 Hz), 6.75 (1H, d, J=3.2 Hz), 6.86 (1H, d, J=3.2 Hz),
7.61 (1H, dd, J=4.0, 8.4 Hz), 8.08 (1H, d, J=8.8 Hz), 8.18 (1H, dd,
J=2.0, 8.8 Hz), 8.47 (1H, d, J=8.4 Hz), 8.52 (1H, d, J=2.0 Hz),
8.97-9.01 (1H, m), 9.34 (1H, t, J=5.6 Hz).
Example E-74
Quinoline-6-carboxylic acid
(5-(5-methyl-furan-2-ylmethyl)-thiophen-2-ylmethyl)-amide
[1601] The title compound (3.0 mg, 0.008 mmol) was obtained as a
brown oil from
(5-(5-methyl-furan-2-ylmethyl)-thiophen-2-yl)-methanol described in
Preparation Example 70 (210 mg, 1.0 mmol) according to an analogous
method to Example E-73.
[1602] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.18 (3H,
s), 4.04 (2H, s), 4.61 (2H, d, J=5.6 Hz), 5.94 (1H, d, J=3.2 Hz),
6.03 (1H, d, J=3.2 Hz), 6.74 (1H, d, J=3.2 Hz), 6.87 (1H, d, J=3.2
Hz), 7.61 (1H, dd, J=4.0, 8.0 Hz), 8.07 (1H, d, J=8.4 Hz), 8.17
(1H, dd, J=1.6, 8.4 Hz), 8.47 (1H, dd, J=2.0, 4.0 Hz), 8.52 (1H, d,
J=1.6 Hz), 8.98 (1H, dd, J=2.0, 4.0 Hz), 9.33 (1H, t, J=5.6
Hz).
Example E-75
Quinoline-6-carboxylic acid
(5-benzofuran-2-ylmethyl-thiophen-2-ylmethyl)-amide
[1603] The title compound (55 mg, 0.13 mmol) was obtained as a
white solid from (5-benzofuran-2-ylmethyl-thiophene)-methanol
described in Preparation Example 72 according to an analogous
method to Example E-73.
[1604] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.31 (2H,
s), 4.62 (2H, d, J=5.6 Hz), 6.68 (1H, s), 6.85 (1H, d, J=3.6 Hz),
6.91 (1H, d, J=3.6 Hz), 7.16-7.26 (2H, m), 7.46-7.64 (3H, m), 8.07
(1H, d, J=8.8 Hz), 8.17 (1H, dd, J=2.0, 8.8 Hz), 8.44-8.48 (1H, m),
8.52 (1H, d, J=2.0 Hz), 8.96-9.00 (1H, m), 9.34 (1H, t, J=5.6
Hz).
Example E-76
Quinoline-6-carboxylic acid
(5-benzyloxy-thiophen-2-ylmethyl)-amide
[1605] To a solution of 5-benzyloxy-thiophene-2-carbonitrile
described in Preparation Example 81 (30 mg, 0.14 mmol) in
tetrahydrofuran (3 mL) was added lithium aluminum hydride (21 mg,
0.557 mmol), which was then stirred for 1.5 hours at room
temperature. Sodium fluoride (240 mg, 5.72 mmol) was added to the
reaction mixture, which was stirred for 2 hours, then, on an ice
bath, 10% hydrous tetrahydrofuran (2 mL) was added. The reaction
mixture was filtered through Celite pad, the filtrate was
concentrated and C-(5-benzyloxy-thiophen-2-yl)methylamine (32 mg,
0.147 mmol) was obtained as a crude product. The title compound (3
mg, 0.008 mmol, 5.4%) was obtained from this and
quinoline-6-carboxylic acid (26 mg, 0.15 mmol) according to an
analogous method to Example H-1.
[1606] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.74 (2H, d,
J=4.4 Hz), 5.09 (2H, s), 6.15 (1H, d, J=4.0 Hz), 6.52-6.62 (1H, m),
6.71 (1H, d, J=4.0 Hz), 7.32-7.47 (5H, m), 7.50 (1H, dd, J=4.0, 8.4
Hz), 8.07 (1H, dd, J=2.0, 8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.27
(1H, dd, J=1.6, 8.4 Hz), 8.34 (1H, d, J=2.0 Hz), 9.02 (1H, dd,
J=1.6, 4.0 Hz).
Example E-77
Quinoline-6-carboxylic acid
(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-amide
[1607] The title compound (9.53 mg) was obtained from
C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Example A-73 (30 mg, 0.13 mmol) and quinoline-6-carboxylic acid (22
mg, 0.13 mmol) according to an analogous method to Example E-24.
Trifluoroacetic acid salt of the title compound was obtained by
reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1608] MS m/e (ESI) 395.35 (MH.sup.+)
Example E-78
6-Quinolinecarboxylic acid
(5-(2-methylpropenyl)thiophen-2-ylmethyl) amide
[1609] The title compound (15 mg, 0.0466 mmol, 56.1%) was obtained
as a white solid from 6-quinolinecarboxylic acid (15 mg, 0.083
mmol) and C-(5-(2-methylpropenyl)-thiophen-2-yl)-methylamine
described in Preparation Example 145 (14 mg, 0.083 mmol) according
to an analogous method to Example E-49.
[1610] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 1.91 (3H,
s), 1.96 (3H, s), 4.83 (2H, d, J=5.2 Hz), 6.33 (1H, s), 6.62 (1H,
t, J=5.2 Hz), 6.75 (1H, d, J=3.6 Hz), 6.96 (1H, d, J=3.6 Hz), 7.47
(1H, dd, J=4.0, 8.0 Hz), 8.05 (1H, dd, J=2.0, 8.8 Hz), 8.13 (1H, d,
J=8.8 Hz), 8.23 (1H, dd, J=1.2, 8.0 Hz), 8.32 (1H, d, J=2.0 Hz),
8.97 (1H, dd, J=1.2, 4.0 Hz).
Example E-79
Quinoline-6-carboxylic acid
(5-(2-fluoro-phenoxy)-thiophen-2-ylmethyl)-amide
[1611] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.55 (2H, d,
J=6.0 Hz), 6.47 (1H, d, J=4.0 Hz), 6.78 (1H, d, J=3.6 Hz),
7.16-7.26 (3H, m), 7.32-7.39 (1H, m), 7.59 (1H, dd, J=4.0, J=8.0
Hz), 8.06 (1H, d, J=8.8 Hz), 8.15 (1H, dd, J=2.0, J=8.8 Hz), 8.45
(1H, d, J=8.0 Hz), 8.51 (1H, d, J=2.0 Hz), 8.95-8.98 (1H, m), 9.35
(1H, t, J=6.0 Hz).
Example E-80
Quinoline-6-carboxylic acid
(5-pyridin-2-ylmethyl-thiophen-2-ylmethyl)-amide
[1612] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.20 (2H,
s), 4.60 (2H, d, J=5.6 Hz), 6.77 (1H, d, J=3.2 Hz), 6.86 (1H, d,
J=3.2 Hz), 7.22 (1H, dd, J=5.2, J=7.6 Hz), 7.31 (1H, d, J=7.6 Hz),
7.61 (1H, dd, J=4.0, 8.0 Hz), 7.71 (1H, ddd, J=1.6, J=7.6, J=7.6
Hz), 8.07 (1H, d, J=8.0 Hz), 8.17 (1H, dd, J=2.0, J=8.0 Hz),
8.42-8.51 (2H, m), 8.52 (1H, d, J=2.0 Hz), 8.98 (1H, dd, J=1.2,
J=4.0 Hz), 9.32 (1H, t, J=5.6 Hz).
Example E-81
Quinoline-6-carboxylic acid
(5-benzo[1,3]dioxol-5-ylmethyl-thiophen-2-ylmethyl)-amide
[1613] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.97 (2H,
s), 4.59 (2H, d, J=6.0 Hz), 5.95 (2H, s), 6.69-6.75 (2H, m),
6.78-6.87 (3H, m), 7.61 (1H, dd, J=4.4, J=8.4 Hz), 8.07 (1H, d,
J=8.8 Hz), 8.17 (1H, dd, J=2.0, J=8.8 Hz), 8.46 (1H, dd, J=1.6,
J=8.4 Hz), 8.51 (1H, d, J=2.0 Hz), 8.98 (1H, dd, J=1.6, J=4.4 Hz),
9.31 (1H, t, J=6.0 Hz).
Example E-82
Quinoline-6-carboxylic acid
(5-(3-hydroxy-phenoxy)-thiophen-2-ylmethyl)-amide
[1614] To a solution of
C-(5-(3-benzyloxy-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 18 (180 mg, 0.578 mmol) and
6-quinolinecarboxylic acid (100 mg, 0.578 mmol) in tetrahydrofuran
(5 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (307 mg, 0.694 mmol) and triethylamine (0.16
mL, 1.16 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and
quinoline-6-carboxylic acid
(5-(3-benzyloxy-phenoxy)-thiophen-2-ylmethyl)-amide (73 mg, 27%)
was obtained as a pale yellow solid.
[1615] Trifluoroacetic acid (1.0 mL) and thioanisole (100 .mu.l)
were added to the resulting quinoline-6-carboxylic acid
(5-(3-benzyloxy-phenoxy)-thiophene-2-ylmethyl)-amide (73 mg, 0.156
mmol), and the solution was stirred for 30 minutes at room
temperature. The reaction solution was neutralized with an aqueous
solution of saturated sodium bicarbonate, then, extracted with
ethyl acetate and dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (ethyl acetate:methanol), and the title
compound (47 mg, 80%) was obtained as a colorless solid.
[1616] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.73 (2H, d,
J=5.6 Hz), 6.39 (1H, d, J=3.6 Hz), 6.59-6.62 (2H, m), 6.64-6.67
(1H, m), 6.74 (1H, d, J=3.6 Hz), 6.83 (1H, brs), 7.17 (1H, t, J=8.4
Hz), 7.49 (1H, dd, J=4.4, 8.4 Hz), 8.05 (1H, dd, J=2.0, 8.4 Hz),
8.14 (1H, d, J=8.4 Hz), 8.24-8.26 (1H, m), 8.33 (1H, d, J=2.0 Hz),
8.98-8.99 (1H, m).
Example F-1
Cinnoline-6-carboxylic acid 3-phenoxy-benzylamide
[1617] To a solution of cinnoline-6-carboxylic acid methyl ester
described in Preparation Example F-4 (16 mg, 0.085 mmol) in ethanol
(1 mL) was added an aqueous solution of 1N sodium hydroxide (0.7
mL), and the solution was stirred at room temperature for 2 hours.
1N Hydrochloric acid was added to the reaction mixture to adjust
the pH to 4, toluene was added, and the solution was concentrated
in vacuo. To a solution of the obtained residue in
N,N-dimethylformamide (2 mL) were added 4-phenoxybenzylamine
described in Preparation Example 3 (17 mg, 0.085 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (48 mg, 0.108 mmol) and triethylamine (24
.mu.l, 0.172 mmol), and the solution was stirred at room
temperature for 14 hours. Water was added to the reaction mixture,
which was extracted with ethyl acetate, the organic layer was
washed with an aqueous solution of saturated sodium bicarbonate,
and then concentrated. The residue was purified by reverse phase
high performance liquid chromatography (acetonitrile-water mobile
phase (containing 0.1% trifluoroacetic acid) was used), and the
title compound (4.4 mg, 0.0093 mmol, 11%) was obtained as a
trifluoroacetic acid salt.
[1618] MS m/e (ESI) 356.44 (MH.sup.+)
Example G-1
Isoquinoline-6-carboxylic acid 3-phenoxybenzylamide
[1619] The title compound (3.4 mg, 33%) was obtained as a colorless
oil from isoquinoline-6-carboxylic acid described in Preparation
Example G-1 (5 mg, 0.0289 mmol) and 4-phenoxybenzylamine described
in Preparation Example 3 (6 mg, 0.0289 mmol) according to an
analogous method to Example L-4.
[1620] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.70 (2H, d,
J=5.6 Hz), 6.57 (1H, brs), 6.94-6.96 (1H, m), 7.02-7.04 (3H, m),
7.11-7.15 (2H, m), 7.32-7.37 (3H, m), 7.72-7.74 (1H, m), 7.96-7.98
(1H, m), 8.05-8.07 (1H, m), 8.26 (1H, s), 8.61-8.62 (1H, m),
9.32-9.33 (1H, m).
Example H-1
Quinazoline-6-carboxylic acid 3-phenoxybenzylamide
[1621] To a solution of quinazoline-6-carboxylic acid obtained in
Preparation Example H-3 (9 mg, 0.052 mmol) in N,N-dimethylformamide
(3 mL) were added 3-phenoxybenzylamine described in Preparation
Example 4 (11 mg, 0.052 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (28 mg, 0.062 mmol) and triethylamine (17
.mu.l, 0.125 mmol), and the solution was stirred for 2 days at room
temperature. Water was added to the reaction mixture, which was
extracted with ethyl acetate, and concentrated. The residue was
purified by NH silica gel column chromatography (hexane-ethyl
acetate), and the title compound (11 mg, 0.03 .mu.mol, 50%) was
obtained.
[1622] .sup.1H-NMR Spectrum (CD.sub.3OD) .delta.(ppm): 4.62 (2H,
s), 6.88 (1H, dd, J=8.0, 1.2 Hz), 6.98 (2H, dd, J=1.2, 8.0 Hz),
7.09 (1H, s), 7.07 (1H, dd, J=7.6, 8.0 Hz), 7.15 (1H, d, J=7.6 Hz),
7.29-7.35 (3H, m), 8.10 (1H, d, J=8.8 Hz), 8.40 (1H, dd, J=2.0, 8.8
Hz), 8.57 (1H, d, J=2.0 Hz), 9.32 (1H, s), 9.61 (1H, s).
Example I-1
Quinoxaline-6-carboxylic acid 3-phenoxybenzylamide
[1623] To a solution of quinoxaline-6-carboxylic acid described in
Preparation Example I-1 (15 mg, 0.063 mmol) and
4-phenoxybenzylamine described in Preparation Example 3 (13 mg,
0.063 mmol) in N,N-dimethylformamide (2 mL) were added
benzotriazol-1-yloxytris(pyrrolidino)phosphonium
hexafluorophosphate (36 mg, 0.069 mmol) and triethylamine (19
.mu.l, 0.14 mmol), which was then stirred at room temperature for
24 hours. The reaction mixture was concentrated, the residue was
purified by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and the title compound (12 mg, 0.025 mmol, 40%)
was obtained as a trifluoroacetic acid salt.
[1624] MS m/e (ESI) 356.37 (MH.sup.+)
Example J-1
[1,8]Naphthylidine-3-carboxylic acid 3-phenoxybenzylamide
[1625] Tetrahydrofuran (1 mL), methanol (0.1 mL) and water (0.1 mL)
were added to [1,8]naphthylidine-3-carboxylic acid ethyl ester
described in Preparation Example J-7 (8.1 mg, 0.040 mmol) and
lithium hydroxide monohydrate (3.4 mg, 0.080 mmol), and the
solution was stirred at 50.degree. C. for 1 hour. The solvent was
evaporated in vacuo, then, the obtained residue and
3-phenoxybenzylamine (5.0 mg, 0.025 mmol) were reacted according to
an analogous method to Example Q-6, and trifluoroacetic acid salt
of the title compound (3.7 mg, 0.0079 mmol, 20%) was obtained.
[1626] MS m/e (ESI) 356.3 (MH.sup.+)
Example K-1
2-Methyl-benzoxazole-6-carboxylic acid 3-phenoxybenzylamide
[1627] The title compound (22 mg, 0.061 mmol, 72%) was obtained
from 2-methyl-benzoxazole-6-carboxylic acid described in
Preparation Example K-2 (15 mg, 0.085 mmol) and
4-phenoxybenzylamine described in Preparation Example 3 (17 mg,
0.085 mmol) according to an analogous method to Example H-1.
[1628] .sup.1H-NMR Spectrum (CD.sub.3OD) .delta.(ppm): 2.66 (3H,
s), 4.56 (2H, s), 6.80-7.15 (6H, m), 7.22-7.78 (3H, m), 7.62-7.68
(1H, m), 7.81-7.86 (1H, m), 8.00-8.04 (1H, m), 9.08 (1H, brs).
Example L-1
Benzothiazole-6-carboxylic acid
(5-(3-fluoro-benzyl)-furan-2-ylmethyl)-amide
[1629] The title compound (290 mg, 0.791 mmol, 76%) was obtained
from benzothiazole-6-carboxylic acid (188 mg, 1.05 mmol) and
C-(5-(3-fluoro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 84 (236 mg, 1.15 mmol) according to an
analogous method to Example H-1 (with the proviso that only the
reaction temperature was changed to 60.degree. C.).
[1630] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.96 (2H,
s), 4.43 (2H, d, J=5.2 Hz), 6.06 (1H, d, J=3.2 Hz), 6.20 (1H, d,
J=3.2 Hz), 7.00-7.09 (3H, m), 7.29-7.36 (1H, m), 7.99 (1H, dd,
J=1.6, 8.4 Hz), 8.12 (1H, d, J=8.4 Hz), 8.64 (1H, d, J=1.6 Hz),
9.07 (1H, t, J=5.2 Hz), 9.51 (1H, s).
Example L-2
Benzothiazole-6-carboxylic acid 4-benzyloxybenzylamide
[1631] The title compound (41 mg, 47%) was obtained as a white
solid from benzothiazole-6-carboxylic acid (42 mg, 0.234 mmol) and
4-benzyloxybenzylamine described in Preparation Example 1 (50 mg,
0.234 mmol) according to an analogous method to Example E-8.
[1632] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.62 (2H, d,
J=5.2 Hz), 5.08 (2H, s), 6.40 (1H, brs), 6.98 (2H, d, J=8.8 Hz),
7.30-7.35 (3H, m), 7.37-7.45 (4H, m), 7.85-7.88 (1H, m), 8.16 (1H,
d, J=8.4 Hz), 8.49 (1H, d, J=1.6 Hz), 9.11 (1H, s).
Example L-3
Benzothiazole-6-carboxylic acid 3-phenoxybenzylamide
[1633] To a solution of 3-phenoxybenzylamine described in
Preparation Example 4 (33 mg, 0.167 mmol) and
benzothiazole-6-carboxylic acid (30 mg, 0.167 mmol) in
tetrahydrofuran (1 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (89 mg, 0.20 mmol) and triethylamine (28 .mu.l,
0.20 mmol), and the solution was stirred at room temperature for 17
hours. The solvent was evaporated, the residue was purified by NH
silica gel column chromatography (hexane:ethyl acetate), and the
title compound (37 mg, 62%) was obtained as a colorless oil.
[1634] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.68 (2H, d,
J=6.0 Hz), 6.50 (1H, brs), 6.94 (1H, dd, J=2.0, 8.0 Hz), 7.02-7.04
(3H, m), 7.11-7.15 (2H, m), 7.31-7.37 (3H, m), 7.88 (1H, dd, J=1.6,
8.8 Hz), 8.18 (1H, d, J=8.8 Hz), 8.49 (1H, d, J=1.6 Hz), 9.13 (1H,
s).
Example L-4
Benzothiazole-6-carboxylic acid
4-(3-fluoro-benzyloxy)-benzylamide
[1635] To a solution of 4-(3-fluorobenzyloxy)-benzylamine described
in Preparation Example 6 (129 mg, 0.558 mmol) and
benzothiazole-6-carboxylic acid (100 mg, 0.558 mmol) in
tetrahydrofuran (5 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (296 mg, 0.670 mmol) and triethylamine (93
.mu.l, 0.670 mmol), and the solution was stirred overnight at room
temperature. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (148 mg, 68%) was obtained as a white solid.
[1636] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.64 (2H, d,
J=5.6 Hz), 5.08 (2H, s), 6.42 (1H, brs), 6.97 (2H, d, J=8.8 Hz),
7.02 (1H, td, J=2.8, 8.4 Hz), 7.15-7.21 (2H, m), 7.31-7.38 (3H, m),
7.88 (1H, dd, J=1.6 Hz, 8.4 Hz), 8.17 (1H, d, J=8.8 Hz), 8.50 (1H,
d, J=1.6 Hz), 9.12 (1H, s).
Example L-5
N-Benzothiazol-6-yl-2-(3-phenoxy-phenyl)-acetamide
[1637] The title compound (118 mg, 95%) was obtained as a colorless
oil from 6-aminobenzothiazole (50 mg, 3.33 mmol) and
3-phenoxyphenylacetic acid (76 mg, 3.33 mmol) according to an
analogous method to Example L-4.
[1638] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.75 (2H,
s), 6.97-7.22 (6H, m), 7.31 (1H, brs), 7.34-7.40 (4H, m), 8.01 (1H,
d, J=8.8 Hz), 8.50 (1H, d, J=2.0 Hz), 8.91 (1H, s).
Example L-6
Benzothiazole-6-carboxylic acid
(5-(3-fluorophenoxy)thiophene-2-ylmethyl) amide
[1639] The title compound (100 mg, 0.26 mmol, 48.2%) was obtained
as a white solid from benzotriazole-6-carboxylic acid (96 mg, 0.54
mmol) and C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described
in Preparation Example 23 (120 mg, 0.54 mmol) according to an
analogous method to Example Q-6.
[1640] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, 5.6 Hz), 6.58 (1H, d, J=3.6 Hz), 6.83 (1H, d, J=3.6 Hz),
6.89-7.00 (3H, m), 7.39 (1H, ddd, J=8.0, 8.0, 8.0 Hz), 8.00 (1H,
dd, J=1.6, 8.8 Hz), 8.14 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=1.6 Hz),
9.27 (1H, t, J=5.6 Hz), 9.51 (1H, s).
Example L-7
Benzothiazole-6-carboxylic acid
(5-phenoxythiophen-2-ylmethyl)-amide
[1641] The title compound (97 mg, 0.265 mmol, 54.0%) was obtained
as a light brown solid from benzothiazole-6-carboxylic acid (87 mg,
0.49 mmol) and C-(5-phenoxy-thiophen-2-yl)-methylamine described in
Preparation Example 26 (100 mg, 0.49 mmol) according to an
analogous method to Example Q-6.
[1642] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.55 (2H,
d, J=5.6 Hz), 6.49 (1H, d, J=3.6 Hz), 6.79 (1H, d, J=3.6 Hz),
7.05-7.15 (3H, m), 7.30-7.40 (2H, m), 7.99 (1H, dd, J=1.6, 8.8 Hz),
8.13 (1H, d, J=8.8 Hz), 8.66 (1H, d, J=1.6 Hz), 9.25 (1H, t, J=5.6
Hz), 9.51 (1H, s).
Example L-8
Benzothiazole-6-carboxylic acid
(5-(3-chloro-benzyl)-thiophen-2-ylmethyl)-amide
[1643] The title compound (64 mg, 0.16 mmol, 47.2%) was obtained as
a white solid from C-(5-(3-chloro-benzyl-2-yl)-methylamine
described in Preparation Example 45 (80 mg, 0.34 mmol) and
benzothiazole-6-carboxylic acid (66 mg, 0.37 mmol) according to an
analogous method to Example Q-6.
[1644] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.06 (2H,
s), 4.56 (2H, d, J=5.6 Hz), 6.74 (1H, d, J=3.6 Hz), 6.84 (1H, d,
J=3.6 Hz), 7.18-7.34 (4H, m), 7.98 (1H, dd, J=2.0, 8.8 Hz), 8.12
(1H, d, J=8.8 Hz), 8.64 (1H, d, J=2.0 Hz), 9.21 (1H, t, J=5.6 Hz),
9.51 (1H, s).
Example L-9
Benzothiazole-6-carboxylic acid
(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl) amide
[1645] The title compound (7.28 mg) was obtained from
C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Example A-73 (30 mg, 0.13 mmol) and benzothiazole-6-carboxylic acid
(22 mg, 0.13 mmol) according to an analogous method to Example
E-24. Trifluoroacetic acid salt of the title compound (7.28 mg) was
obtained by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1646] MS m/e (ESI) 401.32 (MH.sup.+)
Example L-10
Benzothiazole-6-carboxylic acid
(5-(2-fluoro-phenoxy)-thiophen-2-ylmethyl)-amide
[1647] Trifluoroacetic acid salt of the title compound (10.7 mg,
0.021 mmol, 14.3%) was obtained as a brown oil from
benzothiazole-6-carboxylic acid (27.4 mg, 0.15 mmol) and
C-(5-(2-fluoro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 161 (33.5 mg, 0.15 mmol) according to an
analogous method to Example A-75.
[1648] MS m/e (ESI) 385 (MH.sup.+)
Example L-11
Benzothiazole-6-carboxylic acid
((5-(3-cyano-phenoxy)-thiophen-2-ylmethyl)-amide
[1649] To a solution of
C-(5-(3-bromophenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 17 (141 mg, 0.496 mmol) and
benzothiazole-6-carboxylic acid (89 mg, 0.496 mmol) in
tetrahydrofuran (5 mL) were added
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (263 mg, 0.595 mmol) and triethylamine (0.14
mL, 0.992 mmol), and the solution was stirred at room temperature
for 3 hours. Ethyl acetate and water were added to the reaction
solution, which was then partitioned, the organic layer was washed
with water, and then, dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and a mixture of
benzothiazole-6-carboxylic acid
(5-(3-bromophenoxy)-thiophene-2-ylmethyl)-amide and debrominated
compound (120 mg, 53%) was obtained as a yellow oil.
[1650] Next, to a solution of the mixture of
benzothiazole-6-carboxylic acid
(5-(3-bromophenoxy)-thiophene-2-ylmethyl)-amide and debrominated
compound (120 mg, 0.269 mmol) in N,N-dimethylformamide (3.0 mL)
were added zinc cyanide (63 mg, 0.538 mmol) and
tetrakis(triphenylphosphine)palladium(0) (62 mg, 0.054 mmol) under
nitrogen atmosphere, which was then stirred at 140.degree. C. for
14 hours, and the solution was stirred at 140.degree. C. for 3
hours. The reaction solution was allowed to room temperature, ethyl
acetate and water were added to the reaction solution, which was
then partitioned, the organic layer was washed with water and dried
over anhydrous magnesium sulfate. After removing the solvent, the
residue was purified by NH silica gel column chromatography
(hexane:ethyl acetate), and the title compound (6.2 mg, 6%) was
obtained as a colorless oil.
[1651] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.78 (2H, d,
J=6.0 Hz), 6.48 (1H, d, J=4.0 Hz), 6.57 (1H, brs), 6.83 (1H, d,
J=4.0 Hz), 7.30 (1H, s), 7.32-7.35 (1H, m), 7.39-7.43 (2H, m), 7.90
(1H, dd, J=1.6, 8.8 Hz), 8.19 (1H, d, J=8.8 Hz), 8.51 (1H, d, J=1.6
Hz), 9.13 (1H, s).
Example M-1
Benzo[1,2 5]thiadiazole-5-carboxylic acid 3-phenoxybenzylamide
[1652] The title compound (43 mg, 71%) was obtained as a colorless
solid from 2,1,3-benzothiadiazole-5-carboxylic acid (30 mg, 0.167
mmol) obtained by hydrolysis of
benzo-2,1,3-thiadiazole-5-carboxylic acid methyl ester with sodium
hydroxide and 4-phenoxybenzylamine described in Preparation Example
3 (33 mg, 0.167 mmol) according to an analogous method to Example
L-4.
[1653] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.67 (2H, d,
J=6.0 Hz), 6.65 (1H, brs), 6.94 (1H, dd, J=2.4 Hz, 8.4 Hz),
7.01-7.03 (3H, m), 7.10-7.14 (2H, m), 7.30-7.36 (3H, m), 8.01-8.07
(2H, m), 8.37 (1H, s).
Example O-1
2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1654] The title compound (15 mg, 43 .mu.mol, 47%) was obtained as
a white solid from
2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid described
in Preparation Example O-2 (15 mg, 91 .mu.mol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (19 mg, 91 .mu.mol) according to an analogous method to
Example A-26.
[1655] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 2.99 (2H,
t, J=9.0 Hz), 3.53 (2H, t, J=8.6 Hz), 4.46 (2H, d, J=6.0 Hz), 6.49
(1H, d, J=3.8 Hz), 6.74 (1H, d, J=3.7 Hz), 7.00 (1H, s), 7.09 (2H,
d, J=8.6 Hz), 7.14 (1H, t, J=7.5 Hz), 7.38 (2H, t, J=7.5 Hz), 7.63
(1H, s), 8.25 (1H, s), 8.71-8.77 (1H, m).
Example P-1
Furo[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1656] Furo[2,3-b]pyridine-5-carboxylic acid (31 mg) was obtained
as a lithium salt from furo[2,3-b]pyridine-5-carboxylic acid ethyl
ester described in Preparation Example P-4 (33 mg, 0.17 mmol)
according to an analogous method to Example T-2.
[1657] The title compound (28 mg, 80 .mu.mol, 79%) was obtained as
a white solid from the lithium salt (17 mg) of the resulting
furo[2,3-b]pyridine-5-carboxylic acid (31 mg) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (23 mg, 0.11 mmol).
[1658] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=5.9 Hz), 6.52 (1H, d, J=3.8 Hz), 6.82 (1H, d, J=3.7 Hz),
7.09-7.17 (4H, m), 7.39 (2H, t, J=8.4 Hz), 8.21 (1H, d, J=2.6 Hz),
8.58 (1H, d, J=2.2 Hz), 8.79 (1H, d, J=2.2 Hz), 9.34 (1H, t, J=6.0
Hz).
Example Q-1
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-benzyl-furan-2-ylmethyl)-amide
[1659] 7N Ammonia/methanol (40 mL) and Raney nickel(3 g) were added
to 5-benzyl-furan-2-carbaldehyde described in Preparation Example
39 (2.5 g, 13 mmol), and the solution was stirred for 22 hours
under hydrogen atmosphere at room temperature. After removing the
catalyst by filtering through Celite pad, the solvent was
evaporated in vacuo and C-(5-benzyl-furan-2-yl)methylamine (1.6 g,
8.6 mmol, 65.8%) was obtained.
[1660] The title compound (150 mg, 0.45 mmol, 45.3%) was obtained
as a white solid from the resulting
C-(5-benzylfuran-2-yl)methylamine (200 mg, 1.07 mmol) and
imidazo[1,2-a]pyridine-6-carboxylic acid (170 mg, 1.07 mmol)
according to an analogous method to Example Q-6.
[1661] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.92 (2H,
s), 4.41 (2H, d, J=5.2 Hz), 6.01 (1H, d, J=2.4 Hz), 6.19 (1H, d,
J=2.4 Hz), 7.16-7.30 (5H, m), 7.56-7.66 (3H, m), 8.03 (1H, s), 9.00
(1H, t, J=5.2 Hz), 9.10 (1H, s).
Example Q-2
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-(3-fluoro-benzyl)-furan-2-ylmethyl)-amide
[1662] The title compound (363 mg, 1.04 mmol, 90%) was obtained
from imidazo[1,2-a]pyridine-6-carboxylic acid (188 mg, 1.16 mmol)
and C-(5-(3-fluoro-benzyl)-furan-2-yl)-methylamine described in
Preparation Example 84 (286 mg, 1.39 mmol) according to an
analogous technique to Example H-1 (with the proviso that only the
reaction temperature was changed to 60.degree. C.).
[1663] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 3.97 (2H,
s), 4.42 (2H, d, J=5.2 Hz), 6.07 (1H, d, J=3.2 Hz), 6.21 (1H, d,
J=3.2 Hz), 7.00-7.08 (3H, m), 7.29-7.37 (1H, m), 7.56-7.66 (3H, m),
8.04 (1H, s), 9.01 (1H, t, J=5.2 Hz), 9.10 (1H, dd, J=1.2, 1.6
Hz).
Example Q-3
Imidazo[1,2-a]pyridine-6-carboxylic acid 4-benzyloxybenzylamide
[1664] The title compound (121 mg, 55%) was obtained as a white
solid from imidazo[1,2-a]pyridine-6-carboxylic acid (100 mg, 0.617
mmol) and 4-benzyloxybenzylamine described in Preparation Example 1
(132 mg, 0.617 mmol) according to an analogous method to Example
E-8.
[1665] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.59 (2H, d,
J=5.6 Hz), 5.07 (2H, s), 6.44 (1H, brs), 6.96-6.98 (2H, m),
7.27-7.30 (3H, m), 7.33-7.44 (5H, m), 7.59-7.61 (1H, m), 7.65-7.66
(1H, m), 7.69-7.70 (1H, m), 8.83-8.84 (1H, m).
Example Q-4
Imidazo[1,2-a]pyridine-6-carboxylic acid 3-phenoxybenzylamide
[1666] The title compound (22 mg, 35%) was obtained as a colorless
oil from imidazo[1,2-a]pyridine-6-carboxylic acid (30 mg, 0.185
mmol) and 4-phenoxybenzylamine described in Preparation Example 3
(37 mg, 0.185 mmol) according to an analogous method to Example
L-3.
[1667] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.64 (2H, d,
J=5.6 Hz), 6.60 (1H, brs), 6.92-6.94 (1H, m), 7.00-7.02 (3H, m),
7.08-7.14 (2H, m), 7.30-7.41 (4H, m), 7.59-7.61 (1H, m), 7.69 (1H,
s), 7.69-7.70 (1H, m), 8.83 (1H, s).
Example Q-5
Imidazo[1,2-a]pyridine-6-carboxylic acid
4-(3-fluoro-benzyloxy)-benzylamide
[1668] The title compound (64 mg, 45%) was obtained as a white
solid from 4-(3-fluorobenzyloxy)-benzylamine described in
Preparation Example 6 (87 mg, 0.376 mmol) and
imidazo[1,2-a]pyridine-6-carboxylic acid (61 mg, 0.376 mmol)
according to an analogous method to Example L-4.
[1669] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.60 (2H, d,
J=5.6 Hz), 5.07 (2H, s), 6.44 (1H, brs), 6.96 (2H, d, J=8.8 Hz),
7.02 (1H, dt, J=2.4, 8.4 Hz), 7.15 (1H, d, J=9.6 Hz), 7.19 (1H, d,
J=8.4 Hz), 7.30 (2H, d, J=8.4 Hz), 7.32-7.40 (2H, m), 7.61 (1H, d,
J=9.6 Hz), 7.67 (1H, s), 7.70 (1H, s), 8.84 (1H, s).
Example Q-6
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-(3-fluorophenoxy)thiophen-2-ylmethyl) amide
[1670] To a solution of imidazo[1,2-a]pyridine-6-carboxylic acid
(87 mg, 0.54 mmol) and
C-(5-(3-fluorophenoxy)thiophen-2-yl)methylamine described in
Preparation Example 23 (120 mg, 0.54 mmol) in N,N-dimethylformamide
(5 mL) were added benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (240 mg, 0.54 mmol) and triethylamine (0.15 mL,
1.08 mmol), and the solution was stirred for 40 minutes at
80.degree. C. Water and ethyl acetate were added to the reaction
solution, which was then partitioned, and the organic layer was
washed with water twice. Silica gel was added to the organic layer,
the solvent was evaporated in vacuo for adsorption, purification
was carried out by silica gel column chromatography (hexane:ethyl
acetate=1:1, then ethyl acetate), and the title compound (90 mg,
0.25 mmol, 45.4%) was obtained as a light brown oil.
[1671] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.55 (2H,
d, J=5.6 Hz), 6.58 (1H, d, J=4.0 Hz), 6.83 (1H, d, J=4.0 Hz),
6.90-7.00 (3H, m), 7.40 (1H, ddd, J=8.0, 8.0, 8.0 Hz), 7.57-7.66
(3H, m), 8.04 (1H, s), 9.12 (1H, d, J=0.8 Hz), 9.20 (1H, t, J=5.6
Hz).
Example Q-7
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1672] The title compound (160 mg, 0.458 mmol, 93.5%) was obtained
as a light brown oil from imidazo[1,2-a]pyridine-6-carboxylic acid
(80 mg, 0.49 mmol) and C-(5-phenoxythiophen-2-yl)methylamine
described in Preparation Example 26 (100 mg, 0.49 mmol) according
to an analogous method to Example Q-6.
[1673] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.53 (2H,
d, J=5.6 Hz), 6.50 (1H, d, J=4.0 Hz), 6.79 (1H, d, J=4.0 Hz),
7.04-7.15 (3H, m), 7.32-7.40 (2H, m), 7.56-7.66 (3H, m), 8.03 (1H,
s), 9.08-9.13 (1H, m), 9.19 (1H, t, J=5.6 Hz).
Example Q-8
Imidazo[1,2-a]pyridine-6-carboxylic acid
(5-(3-chloro-phenoxy)-thiophen-2-ylmethyl)-amide
[1674] To a solution of
C-(5-(3-chloro-phenoxy)-thiophen-2-yl)-methylamine described in
Preparation Example 167 (104 mg, 0.434 mmol) and
imidazo[1,2-a]pyridine-6-carboxylic acid (77 mg, 0.477 mmol) in
N,N-dimethylformamide (3 mL) were added benzotriazol-1-yloxy
tris(dimethylamino)phosphonium hexafluorophosphate (250 mg, 0.564
mmol) and triethylamine (181 mL) at room temperature, and the
solution was stirred at room temperature for 4 hours. Water was
added to the reaction solution, which was then extracted with ethyl
acetate, and the organic layer was washed with water and brine.
Anhydrous magnesium sulfate was added to the organic layer for
drying, filtration was carried out, then, the solvent was
evaporated in vacuo, the residue was purified by NH silica gel
column chromatography (ethyl acetate/methanol=40/1), and the title
compound (149 mg, 89%) was obtained as a white solid.
[1675] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.55 (2H,
d, J=5.3 Hz), 6.59 (1H, dd, J=1.1, 3.7 Hz), 6.83 (1H, d, J=3.7 Hz),
7.06 (1H, dd, J=1.1, 8.2 Hz), 7.13 (1H, s), 7.20 (1H, d, J=8.1 Hz),
7.40 (1H, t, 8.1 Hz), 7.58-7.64 (3H, m), 8.05 (1H, s), 9.12 (1H,
s), 9.23 (1H, t, J=5.5 Hz).
Example R-1
1H-Pyrrolo[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1676] The title compound (22 mg, 63 .mu.mol, 68%) was obtained
from 1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid described in
Preparation Example R-7 (15 mg, 93 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (19 mg, 93 mmol) according to an analogous method to
Example A-26. Trifluoroacetic acid salt of the title compound was
obtained by reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used).
[1677] MS m/e (ESI) 350.26 (MH.sup.+)
Example R-2
6-Amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1678] To a solution of
6-amino-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethyl ester
described in Preparation Example R-2 (95 mg, 0.46 mmol) in ethanol
(10 mL) was added an aqueous solution of 1N sodium hydroxide (5 mL,
5 mmol), which was then heated for 3 hours in an oil bath at
98.degree. C. After cooling the reaction solution, the reaction
solution was concentrated until it reached 1/3 of its volume,
neutralized with 1N hydrochloric acid, and further concentrated.
The resulting crude product was suspended in N,N-dimethylformamide
(5 mL), triethylamine (0.096 mL, 0.69 mmol),
benzotriazol-1-yloxytris(dimethylamino)phosphonium
hexafluorophosphate (153 mg, 0.35 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (71 mg, 0.35 mmol) were added thereto, followed by
stirring at room temperature for 15 hours. After the reaction was
completed, the reaction solution was poured into brine, and
extracted with ethyl acetate. The organic layer was dried over
anhydrous magnesium sulfate, then concentrated, the obtained
residue was purified by silica gel column chromatography (ethyl
acetate:hexane=2:1), and the title compound (31 mg, 0.085 mmol,
18.5%) was obtained.
[1679] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.49 (2H,
d, J=5.6 Hz), 6.24 (1H, dd, J=2.0, 3.6 Hz), 6.50 (1H, d, J=4.0 Hz),
6.78 (1H, d, J=4.0 Hz), 6.80 (2H, brs), 7.04 (1H, dd, J=2.0, 3.2
Hz), 7.07-7.16 (3H, m), 7.35-7.41 (2H, m), 8.14 (1H, s), 8.91-8.95
(1H, m), 11.0 (1H, brs).
Example S-1
Pyrrolo[3,2-b]pyridine-1-carboxylic acid 3-phenoxy-benzylamide
[1680] 1H-Pyrrolo[3,2-b]pyridine described in Preparation Example
S-4 (44 mg, 0.37 mmol) was dissolved in N,N-dimethylformamide (3
mL), sodium hydride (18 mg, 0.45 mmol, 60% in oil) was added
thereto, followed by stirring at room temperature for 30 minutes.
Next, (4-phenoxy-benzyl)-carbamic acid phenyl ester described in
Preparation Example 75 (143 mg, 0.45 mmol) was added, and the
solution was stirred at room temperature for 2 hours. After the
reaction was completed, the reaction solution was poured into
brine, which was then extracted with ethyl acetate, and
concentrated. The obtained residue was purified by silica gel
column chromatography (ethyl acetate:hexane=1:1), and the title
compound (11 mg, 0.032 mmol, 8.7%) was obtained.
[1681] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.16 (2H,
d, J=6.0 Hz), 6.49 (1H, d, J=3.6 Hz), 6.56 (1H, dd, J=2.0, 8.0 Hz),
6.65-6.73 (3H, m), 6.77-6.85 (2H, m), 6.93 (1H, dd, J=4.4, 8.0 Hz),
7.01-7.06 (3H, m), 7.85 (1H, d, J=3.6 Hz), 8.10-8.17 (2H, m), 8.58
(1H, t, J=6.0 Hz).
Example T-1
6-Amino-thieno[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1682] The title compound (30 mg, 78 .mu.mol, 76%) was obtained as
a white solid from 6-amino-thieno[2,3-b]pyridine-5-carboxylic acid
described in Preparation Example T-6 (20 mg, 0.10 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (21 mg, 0.10 mmol) according to an analogous method to
Example A-26.
[1683] MS m/e (ESI) 382.35 (MH.sup.+)
[1684] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.52 (2H,
d, J=6.0 Hz), 6.52 (1H, d, J=3.7 Hz), 6.81 (1H, d, J=3.7 Hz),
7.09-7.19 (6H, m), 7.33 (1H, dd, J=1.1, 5.9 Hz), 7.39 (2H, t, J=8.6
Hz), 8.34 (1H, s), 9.21 (1H, m).
Example T-2
Thieno[2,3-b]pyridine-5-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1685] Thieno[2,3-b]pyridine-5-carboxylic acid methyl ester
described in Preparation Example T-10 (4.0 mg, 21 mmol) and lithium
hydroxide monohydrate (0.9 mg, 21 .mu.mol) were dissolved in a
mixture solvent of tetrahydrofuran (0.5 mL), methanol (50 .mu.l)
and water (50 .mu.l), and the solution was heated under reflux for
1 hour. The reaction solution was cooled to room temperature, then,
removal in vacuo was carried out, and
thieno[2,3-b]pyridine-5-carboxylic acid was obtained as a lithium
salt.
[1686] Then, the lithium salt of the resulting
thieno[2,3-b]pyridine-5-carboxylic acid,
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (4.7 mg, 23 mmol),
benzotriazol-1-yl-tris(dimethylamino)phosphonium
hexafluorophosphate (14 mg, 32 .mu.mol) and triethylamine (9 .mu.l,
63 .mu.mol) were dissolved in N,N-dimethylformamide (0.5 mL), and
the solution was stirred at room temperature for 2 hours. Water and
ethyl acetate were added to the reaction solution, the organic
layer was partitioned, and washed with brine. The solvent was
evaporated in vacuo, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate=1:1), and the title compound
(3.0 mg, 8.2 .mu.mol, 40%) was obtained as a white solid.
[1687] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.75 (2H, d,
J=5.2 Hz), 6.40 (1H, d, J=3.6 Hz), 6.77 (1H, s), 6.93 (1H, d, J=3.2
Hz), 7.08-7.12 (3H, m), 7.30-7.34 (3H, m), 7.62 (1H, d, J=6.4 Hz),
8.51 (1H, d, J=2.0 Hz), 8.92 (1H, d, J=2.0 Hz).
Example U-1
5-Amino-thieno[3,2-b]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1688] The title compound (85 mg, 0.22 mmol, 87%) was obtained as a
white solid from 5-amino-thieno[3,2-b]pyridine-6-carboxylic acid
described in Preparation Example U-4 (50 mg, 0.26 mmol) and
C-(5-phenoxy-thiophen-2-yl)-methylamine described in Preparation
Example 26 (53 mg, 0.26 mmol) according to an analogous method to
Example A-26.
[1689] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.52 (2H,
d, J=5.7 Hz), 6.52 (1H, d, J=3.7 Hz), 6.82 (1H, d, J=3.8 Hz), 6.99
(2H, s), 7.10 (2H, d, J=7.5 Hz), 7.15 (1H, t, J=7.3 Hz), 7.18 (1H,
d, J=5.5 Hz), 7.39 (2H, dd, J=7.3, 8.8 Hz), 8.08 (1H, d, J=5.5 Hz),
8.49 (1H, s), 9.17 (1H, t, J=5.5 Hz).
Example U-2. Thieno[3,2-b]pyridine-6-carboxylic acid
(5-phenoxy-thiophen-2-ylmethyl)-amide
[1690] The title compound (7 mg, 19 mmol, 89%) was obtained as a
white solid from trifluoromethanesulfonic acid
6-((5-phenoxy-thiophen-2-ylmethyl)-carbamoyl)-thieno[3,2-b]pyridin-5-yl
ester described in Preparation Example U+-2 (11 mg, 21 mmol)
according to an analogous method to Preparation Example T-10.
[1691] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 4.57 (2H,
d, J=5.7 Hz), 6.50 (1H, d, J=3.7 Hz), 6.81 (1H, d, J=3.7 Hz), 7.08
(2H, d, J=8.1 Hz), 7.12 (1H, t, J=7.5 Hz), 7.36 (2H, t, J=7.7 Hz),
7.62 (1H, d, J=5.7 Hz), 8.31 (1H, d, J=5.5 Hz), 8.90 (1H, s), 9.08
(1H, d, J=2.0 Hz), 9.32-9.38 (1H, m).
Example V-1
1H-Indole-5-carboxylic acid 3-phenoxybenzylamide
[1692] The title compound was obtained from 1H-indole-5-carboxylic
acid and 4-phenoxybenzylamine described in Preparation Example 3
according to an analogous method to Example H-1.
[1693] MS m/e (ESI) 343.15 (MH.sup.+)
Example W-1
(4-Benzyloxy-phenyl)-quinolin-6-ylmethyl-amine
[1694] To a solution of lithium aluminum hydride (52 mg, 1.37 mmol)
in tetrahydrofuran (10 mL) was added a solution of
quinoline-6-carboxylic acid (4-benzyloxyphenyl)-amide described in
Preparation Example Z+-2 (194 mg, 19%) in tetrahydrofuran, and the
solution was stirred under reflux for 3 hours. The reaction
solution was allowed to room temperature, an aqueous solution of
saturated ammonium chloride was added thereto, the solution was
extracted with ethyl acetate and dried over anhydrous magnesium
sulfate. The solvent was evaporated, the residue was purified by NH
silica gel column chromatography (hexane:ethyl acetate), and the
title compound (62 mg, 33%) was obtained as a pale yellow
solid.
[1695] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 3.97 (1H,
brs), 4.49 (2H, s), 4.98 (2H, s), 6.61-6.64 (2H, m), 6.84-6.86 (2H,
m), 7.30-7.42 (6H, m), 7.73 (1H, dd, J=1.6, 8.4 Hz), 7.80 (1H, s),
8.09 (1H, d, J=8.8 Hz), 8.12 (1H, d, J=8.4 Hz), 8.89-8.90 (1H,
m).
Example W-2
(4-Benzyloxy-benzyl)-quinolin-6-yl-amine
[1696] To a solution of lithium aluminum hydride (58 mg, 1.54 mmol)
in tetrahydrofuran (10 mL) was added a solution of
4-benzyloxy-N-quinolin-6-yl-benzamide described in Preparation
Example Z+-3 (218 mg, 0.615 mmol) in tetrahydrofuran (1 mL), and
the solution was stirred under reflux for 7 hours. The reaction
solution was allowed to room temperature, an aqueous solution of
saturated ammonium chloride was added, the solution was extracted
with ethyl acetate and dried over anhydrous magnesium sulfate. The
solvent was evaporated, the residue was purified by NH silica gel
column chromatography (hexane:ethyl acetate), and the title
compound (147 mg, 70%) was obtained as a yellow solid.
[1697] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 4.27 (1H,
m), 4.36 (2H, d, J=4.8 Hz), 5.07 (2H, s), 6.73 (1H, d, J=2.4 Hz),
6.98 (2H, d, J=8.8 Hz), 7.12 (1H, dd, J=2.8, 9.2 Hz), 7.24-7.27
(1H, m), 7.31-7.45 (7H, m), 7.87-7.91 (2H, m), 8.61-8.62 (1H,
m).
Example W-3
2-(3-Benzyloxy-phenyl)-1-quinolin-6-yl-ethanone
[1698] A mixture of 1-quinolin-6-yl-ethanone described in
Preparation Example 131 (171 mg, 1 mmol),
1-benzyloxy-3-bromo-benzene (289 mg, 1 mmol),
bis(dibenzylideneacetone)palladium (3 mg, 0.0052 mmol),
1,1'-bis(diphenylphosphino)ferrocene (5 mg, 0.009 mmol), potassium
tert-butoxide (236 mg, 2.1 mmol) and tetrahydrofuran (15 mL) were
stirred under nitrogen atmosphere for 7 hours at 70.degree. C.
Silica gel (80 mL) was added to the reaction solution at room
temperature, filtration was carried out by silica gel column
chromatography (hexane:ethyl acetate=4:6), the filtrate was
concentrated in vacuo, and a residue of yellow oil (0.191 g) was
obtained. This residue was purified by thin layer silica gel
chromatography (hexane:ethyl acetate=1:10), and a yellow oily
residue (98 mg) was obtained. In addition, the residue was purified
by NH silica gel column chromatography (hexane:ethyl
acetate=85:15), and the title compound (50 mg, 0.14 mmol, 14%) was
obtained as a pale yellow oil.
[1699] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 4.51
(2H, s), 5.10 (2H, s), 6.89-6.91 (1H, m), 6.96-6.98 (1H, m), 7.07
(1H, m), 7.25 (1H, t, J=4.4 Hz), 7.29-7.33 (1H, m), 7.35-7.39 (2H,
m), 7.44-7.47 (2H, m), 7.61 (1H, dd, J=8.4, 4.4 Hz), 8.11 (1H, d,
J=8.8 Hz), 8.31 (1H, dd, J=8.8, 2.0 Hz), 8.50-8.53 (1H, m), 8.81
(1H, d, J=2.0 Hz), 9.02 (1H, m).
Example W-4
2-(3-Phenoxy-phenyl)-1-quinolin-6-yl-ethanone
[1700] According to an analogous method to Example
W-3,1-quinolin-6-yl-ethanone described in Preparation Example 131
(171 mg, 1 mmol), 1-phenoxy-3-bromo-benzene (274 mg, 1.1 mmol),
bis(dibenzylideneacetone)palladium (10 mg, 0.0187 mmol),
1,1'-bis(diphenylphosphino)ferrocene (12.5 mg, 0.0225 mmol),
potassium tert-butoxide (236 mg, 2.1 mmol) and tetrahydrofuran (15
mL) were stirred at 70.degree. C. for 6 hours under nitrogen
atmosphere, and the title compound (64 mg, 0.189 mmol, 19%) was
obtained as a pale yellow oily substance.
[1701] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 4.56
(2H, s), 6.88-6.91 (1H, m), 6.98-7.00 (2H, m), 7.06-7.16 (3H, m),
7.32-7.37 (3H, m), 7.62 (1H, dd, J=8.4, 4.4 Hz), 8.12 (1H, d, J=8.8
Hz), 8.31 (1H, dd, J=8.8, 2.0 Hz), 8.49-8.52 (1H, m), 8.81 (1H, d,
J=2.0 Hz), 9.02 (1H, m).
Example W-5
6-(4-Benzyloxy-benzyloxy)-quinoline
[1702] To a solution of quinoline-6-ol (37 mg, 0.25 mmol),
1-benzyloxy-4-chloromethyl-benzene (70 mg, 0.30 mmol) in
dimethylsulfoxide (2.5 mL) was added potassium tert-butoxide (43
mg, 0.38 mmol) under nitrogen atmosphere, and the solution was
stirred for 13 hours at room temperature. This reaction solution
was purified by thin layer silica gel chromatography (hexane:ethyl
acetate=1:1), and the title compound (74 mg, 0.217 mmol, 86%) was
obtained as a pale yellow solid.
[1703] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 5.16
(2H, s), 5.19 (2H, s), 7.05-7.09 (2H, m), 7.31-7.35 (1H, m),
7.38-7.46 (5H, m), 7.46-7.51 (4H, m), 7.95 (1H, d, J=8.8 Hz), 8.19
(1H, dd, J=8.4, 0.8 Hz), 8.74 (1H, dd, J=4.0, 1.6 Hz).
Example W-6
6-(3-Phenoxy-benzylsulfanyl)-quinoline
[1704] To a solution of (3-phenoxy-phenyl)-methanol (2.0 g, 10
mmol) in tetrahydrofuran (50 ml) was added potassium tert-butoxide
(1.35 g, 12 mmol) under nitrogen atmosphere and an ice-cold
stirring, then, 4-methyl-benzenesulfonyl chloride (2.48 g, 13 mmol)
was added, and the solution was stirred at room temperature for 21
hours. An aqueous solution of saturated ammonium chloride was
added, the solution was extracted with ethyl acetate (200 ml),
washed with brine (150 ml), dried over anhydrous magnesium sulfate,
then, the solvent was evaporated, and a residue of pale yellow oil
(3.97 g) was obtained. This residue was purified by silica gel
column chromatography (hexane:ethyl acetate=4:1), and
toluene-4-sulfonic acid 3-phenoxybenzyl ester (2.93 g, 8.27 mmol,
82%) was obtained as a white solid.
[1705] To a solution of dithiocarbonic acid O-ethyl ester
S-quinolin-6-yl ester described in Preparation Example W-1 (50 mg,
0.201 mmol), toluene-4-sulfonic acid 3-phenoxybenzyl ester (110 mg,
0.313 mmol) and methanol (1 ml) in tetrahydrofuran (5 ml) was added
potassium tert-butoxide (135 mg, 1.20 mmol) under nitrogen
atmosphere, which was then stirred at room temperature for 24
hours. This reaction solution was purified by thin layer silica gel
chromatography (hexane:ethyl acetate=1:1), and the title compound
(39 mg, 0.114 mmol, 57%) was obtained as a yellow oil.
[1706] .sup.1H-NMR Spectrum (Acetone-d.sub.6) .delta.(ppm): 4.36
(2H, s), 6.85-6.90 (3H, m), 7.02-7.03 (1H, m), 7.07-7.11 (1H, m),
7.20-7.22 (1H, m), 7.27-7.34 (3H, m), 7.49 (1H, dd, J=8.4, 4.0 Hz),
7.69 (1H, dd, J=8.8, 2.0 Hz), 7.84-7.85 (1H, m), 7.94 (1H, d, J=8.8
Hz), 8.18-8.20 (1H, m), 8.84-8.85 (1H, m).
Example X-1
(4-tert-Butyl-benzyl)-quinazolin-4-yl-amine
[1707] To a solution of 4-chloro-quinazoline described in
Preparation Example X-1 (8 mg, 0.049 mmol) in
1-methyl-2-pyrrolidone (0.5 mL) were added 4-tert-butyl-benzylamine
(10 .mu.l, 0.059 mmol) and N,N-diisopropylethylamine (17 .mu.l,
0.098 mmol), and the solution was stirred for 5 hours at
160.degree. C. The reaction mixture was directly purified by
reverse phase high performance liquid chromatography
(acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid) was used), and the title compound (16.5 mg, 0.041 mmol, 72%)
was obtained as a trifluoroacetic acid salt.
[1708] MS m/e (ESI) 292.20 (MH.sup.+)
Example X-2
(4-Benzyloxy-benzyl)-quinazolin-4-yl-amine
[1709] The title compound (9.63 mg, 0.02 .mu.mol, 38%) was obtained
as a trifluoroacetic acid salt from 4-chloro-quinazoline described
in Preparation Example X-1 (9 mg, 0.055 mmol) and
4-benzyloxy-benzylamine described in Preparation Example 1 (12 mg,
0.055 mmol) according to an analogous method to Example X-1.
[1710] MS m/e (ESI) 342.27 (MH.sup.+)
Example Y-1
N*4*-(4-Benzyloxy-benzyl)-pyrido[2,3-d]pyrimidine-2,4-diamine
[1711] To a mixture of
2-amino-N-(4-benzyloxy-benzyl)-thionicotinamide described in
Example A-22 (30 mg, 0.083 mmol) and toluene (1 mL) was added
benzyl bromide (0.044 mL, 0.37 mmol), and the solution was refluxed
for 3 hours. After cooling, the solvent was evaporated in vacuo,
and the residue was washed with diethyl ether twice. A mixture of a
portion (13 mg) of the resulting crude product (33 mg), cyanamide
(20 mg, 0.48 mmol) and N-methylpyrrolidinone (1 mL) was stirred for
2 hours at 120.degree. C. After cooling, the reaction solution was
directly purified by reverse phase high performance liquid
chromatography (acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid) was used), and ditrifluoroacetic acid salt of
the title compound (0.75 mg, 0.0013 mmol, 4.2%) was obtained.
[1712] MS m/e (ESI) 358.2 (MH.sup.+)
Example Z-1
(4-Butyl-3-methyl-phenyl)-quinolin-6-yl-metanone
[1713] To a solution of
(4-butyl-3-methyl-phenyl)-quinoline-6-yl-methanol described in
Preparation Example Z+-1 (152 mg, 0.50 mmol) in chloroform (1.0 mL)
was added active manganese dioxide (510 mg, 5.0 mmol), and the
solution was stirred at room temperature for 5 hours. Manganese
dioxide was removed by filtering through Celite pad, the filtrate
was concentrated, the residue was purified by silica gel column
chromatography (hexane:ethyl acetate), and the title compound (56
mg, 37%) was obtained as a pale yellow oil.
[1714] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 0.98 (3H, t,
J=7.2 Hz), 1.40-1.49 (2H, m), 1.58-1.66 (2H, m), 2.39 (3H, s), 2.70
(2H, t, J=8.0 Hz), 7.26-7.28 (1H, m), 7.48-7.51 (1H, m), 7.60-7.62
(1H, m), 7.67 (1H, s), 8.13-8.16 (1H, m), 8.20-8.22 (1H, m),
8.25-8.27 (2H, m), 9.03-9.04 (1H, m).
Example Z-2
Quinoline-6-carboxylic acid (3-benzyloxyphenyl)-amide
[1715] Thionyl chloride (2 mL) was added to 6-quinolinecarboxylic
acid (100 mg, 0.577 mmol), and the solution was stirred for 2 hours
under reflux. Then, the solution was allowed to cool to room
temperature, and excess thionyl chloride was evaporated in vacuo.
The obtained residue was dissolved in N,N-dimethylformamide (2 mL),
3-benzyloxyaniline (115 mg, 0.577 mmol), triethylamine (0.12 mL,
0.866 mmol) and dimethylaminopyridine (1 mg) were added, and the
solution was stirred overnight at room temperature. Ethyl acetate
and water were added to the reaction solution, which was then
partitioned, the organic layer was washed with water and dried over
anhydrous magnesium sulfate. The solvent was evaporated, the
residue was purified by silica gel column chromatography
(hexane:ethyl acetate=1:1), and the title compound (53 mg, 26%) was
obtained as a white solid.
[1716] .sup.1H-NMR Spectrum (CDCl.sub.3) .delta.(ppm): 5.12 (2H,
s), 6.80-6.83 (1H, m), 7.16-7.18 (1H, m), 7.27-7.35 (2H, m),
7.38-7.42 (2H, m), 7.45-7.47 (2H, m), 7.49-7.52 (1H, m), 7.58-7.59
(1H, m), 8.03 (1H, s), 8.13 (1H, dd, J=2.0, 8.8 Hz), 8.21 (1H, d,
J=8.8 Hz), 8.25-8.28 (1H, m), 8.38 (1H, d, J=2.0 Hz), 9.01-9.03
(1H, m).
Example Z-3
3-Phenoxy-N-quinolin-6-yl-benzamide
[1717] To a solution of 6-aminoquinoline (250 mg, 1.04 mmol) in
N,N-dimethylformamide (15 mL) were added 3-phenoxybenzoic acid (371
mg, 1.73 mmol), O-benzotriazol-1-yl-N,N,N',N'-tetramethyluronium
hexafluorophosphate (722 mg, 1.90 mmol) and triethylamine (603
.mu.l, 4.33 mmol), and the solution was stirred for 2 days at room
temperature. Water was added to the reaction mixture, which was
extracted with ethyl acetate, the organic layer was washed with
water, an aqueous solution of saturated sodium bicarbonate and
brine, dried over anhydrous magnesium sulfate, and then,
concentrated in vacuo. The obtained residue was purified by silica
gel column chromatography (hexane-ethyl acetate), and the title
compound (328 mg, 0.964 mmol, 93%) was obtained.
[1718] .sup.1H-NMR Spectrum (DMSO-d.sub.6) .delta.(ppm): 7.08 (2H,
d, J=8.4 Hz), 7.18 (1H, t, J=7.6 Hz), 7.24 (1H, d, J=8.0 Hz), 7.43
(2H, dd, J=7.6, 8.4 Hz), 7.48 (1H, dd, J=4.0, 8.4 Hz), 7.56 (1H,
dd, J=7.6, 8.0 Hz), 7.63 (1H, s), 7.79 (1H, d, J=7.6 Hz), 7.94-8.15
(2H, m), 8.29 (1H, d, J=8.0 Hz), 8.50 (1H, s), 8.80 (1H, dd, J=2.0,
4.0 Hz), 10.6 (1H, s).
Example Z-4
1H-Indole-5-carboxylic acid (4-benzyloxy-phenyl) amide
[1719] The title compound was obtained from 1H-indole-5-carboxylic
acid and 4-benzyloxy-phenylamine hydrochloride according to an
analogous method to Example H-1 MS m/e (ESI) 343.30 (MH.sup.+)
[1720] The structural formulae of the compounds obtained in the
above preparation examples and examples are shown in the following
Table 1 to Table 51.
TABLE-US-00001 TABLE 1 Preparation Example A-1 ##STR00047##
Preparation Example A-2 ##STR00048## Preparation Example A-3
##STR00049## Preparation Example A-4 ##STR00050## Preparation
Example A-5 ##STR00051## Preparation Example A-6 ##STR00052##
Preparation Example A-7 ##STR00053## Preparation Example A-8
##STR00054## Preparation Example A-9 ##STR00055## Preparation
Example A-10 ##STR00056## Preparation Example A-11 ##STR00057##
Preparation Example A-12 ##STR00058## Preparation Example A-13
##STR00059## Preparation Example A-14 ##STR00060## Preparation
Example A-15 ##STR00061## Preparation Example A-16 ##STR00062##
Preparation Example A-17 ##STR00063## Preparation Example A-18
##STR00064##
TABLE-US-00002 TABLE 2 Preparation Example A-19 ##STR00065##
Preparation Example A-20 ##STR00066## Preparation Example A-21
##STR00067## Preparation Example A-22 ##STR00068## Preparation
Example A-23 ##STR00069## Preparation Example A-24 ##STR00070##
Preparation Example A-25 ##STR00071## Preparation Example A-26
##STR00072## Preparation Example A-27 ##STR00073## Preparation
Example A-28 ##STR00074## Preparation Example AA-1 ##STR00075##
Preparation Example AA-2 ##STR00076## Preparation Example B-1
##STR00077##
TABLE-US-00003 TABLE 3 Preparation Example A+-1 ##STR00078##
Preparation Example A+-2 ##STR00079## Preparation Example A+-3
##STR00080## Preparation Example A+-4 ##STR00081## Preparation
Example A+-5 ##STR00082## Preparation Example A+-6 ##STR00083##
Preparation Example A+-7 ##STR00084## Preparation Example A+-8
##STR00085## Preparation Example A+-9 ##STR00086## Preparation
Example A+-10 ##STR00087## Preparation Example A+-11 ##STR00088##
Preparation Example A+-12 ##STR00089##
TABLE-US-00004 TABLE 4 Preparation Example A+-13 ##STR00090##
Preparation Example A+-14 ##STR00091## Preparation Example A+-15
##STR00092## Preparation Example A+-16 ##STR00093## Preparation
Example A+-17 ##STR00094## Preparation Example A+-18 ##STR00095##
Preparation Example A+-19 ##STR00096## Preparation Example A+-20
##STR00097## Preparation Example A+-21 ##STR00098## Preparation
Example A+-22 ##STR00099## Preparation Example A+-23 ##STR00100##
Preparation Example A+-24 ##STR00101## Preparation Example A+-25
##STR00102## Preparation Example A+-26 ##STR00103##
TABLE-US-00005 TABLE 5 Preparation Example C-1 ##STR00104##
Preparation Example C-2 ##STR00105## Preparation Example C-3
##STR00106## Preparation Example C-4 ##STR00107## Preparation
Example C-5 ##STR00108## Preparation Example D-1 ##STR00109##
Preparation Example E-1 ##STR00110## Preparation Example F-1
##STR00111## Preparation Example F-2 ##STR00112## Preparation
Example F-3 ##STR00113## Preparation Example F-4 ##STR00114##
Preparation Example G-1 ##STR00115## Preparation Example H-1
##STR00116## Preparation Example H-2 ##STR00117## Preparation
Example H-3 ##STR00118## Preparation Example I-1 ##STR00119##
TABLE-US-00006 TABLE 6 Preparation Example E+-1 ##STR00120##
Preparation Example E+-2 ##STR00121## Preparation Example E+-3
##STR00122## Preparation Example E+-4 ##STR00123## Preparation
Example E+-5 ##STR00124## Preparation Example E+-6 ##STR00125##
Preparation Example E+-7 ##STR00126## Preparation Example E+-8
##STR00127## Preparation Example E+-9 ##STR00128## Preparation
Example E+-10 ##STR00129## Preparation Example Q+-1
##STR00130##
TABLE-US-00007 TABLE 7 Preparation Example J-1 ##STR00131##
Preparation Example J-2 ##STR00132## Preparation Example J-3
##STR00133## Preparation Example J-4 ##STR00134## Preparation
Example J-5 ##STR00135## Preparation Example J-6 ##STR00136##
Preparation Example J-7 ##STR00137## Preparation Example K-1
##STR00138## Preparation Example K-2 ##STR00139## Preparation
Example O-1 ##STR00140## Preparation Example O-2 ##STR00141##
Preparation Example P-1 ##STR00142## Preparation Example P-2
##STR00143## Preparation Example P-3 ##STR00144## Preparation
Example P-4 ##STR00145## Preparation Example S-1 ##STR00146##
Preparation Example S-2 ##STR00147## Preparation Example S-3
##STR00148## Preparation Example S-4 ##STR00149##
TABLE-US-00008 TABLE 8 Preparation Example R-1 ##STR00150##
Preparation Example R-2 ##STR00151## Preparation Example R-3
##STR00152## Preparation Example R-4 ##STR00153## Preparation
Example R-5 ##STR00154## Preparation Example R-6 ##STR00155##
Preparation Example R-7 ##STR00156## Preparation Example T-1
##STR00157## Preparation Example T-2 ##STR00158## Preparation
Example T-3 ##STR00159## Preparation Example T-4 ##STR00160##
Preparation Example T-5 ##STR00161## Preparation Example T-6
##STR00162## Preparation Example T-7 ##STR00163## Preparation
Example T-8 ##STR00164## Preparation Example T-9 ##STR00165##
Preparation Example T-10 ##STR00166##
TABLE-US-00009 TABLE 9 Preparation Example U-1 ##STR00167##
Preparation Example U-2 ##STR00168## Preparation Example U-3
##STR00169## Preparation Example U-4 ##STR00170## Preparation
Example W-1 ##STR00171## Preparation Example X-1 ##STR00172##
Preparation Example Z-1 ##STR00173## Preparation Example Z-2
##STR00174## Preparation Example U+-1 ##STR00175## Preparation
Example U+-2 ##STR00176## Preparation Example Z+-1 ##STR00177##
Preparation Example Z+-2 ##STR00178## Preparation Example Z+-3
##STR00179##
TABLE-US-00010 TABLE 10 Preparation Example 1 ##STR00180##
Preparation Example 2 ##STR00181## Preparation Example 3
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5 ##STR00184## Preparation Example 6 ##STR00185## Preparation
Example 7 ##STR00186## Preparation Example 8 ##STR00187##
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##STR00189## Preparation Example 11 ##STR00190## Preparation
Example 12 ##STR00191## Preparation Example 13 ##STR00192##
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Example 17 ##STR00196## Preparation Example 18 ##STR00197##
TABLE-US-00011 TABLE 11 Preparation Example 19 ##STR00198##
Preparation Example 20 ##STR00199## Preparation Example 21
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Example 23 ##STR00202## Preparation Example 24 ##STR00203##
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TABLE-US-00021 TABLE 21 Example A-1 ##STR00377## Example A-2
##STR00378## Example A-3 ##STR00379## Example A-4 ##STR00380##
Example A-5 ##STR00381## Example A-6 ##STR00382## Example A-7
##STR00383## Example A-8 ##STR00384## Example A-9 ##STR00385##
Example A-10 ##STR00386## Example A-11 ##STR00387## Example A-12
##STR00388##
TABLE-US-00022 TABLE 22 Example A-13 ##STR00389## Example A-14
##STR00390## Example A-15 ##STR00391## Example A-16 ##STR00392##
Example A-17 ##STR00393## Example A-18 ##STR00394## Example A-19
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Example B-1 ##STR00572## Example B-2 ##STR00573## Example C-1
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Example D-5 ##STR00579## Example D-6 ##STR00580## Example D-7
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Example D-10 ##STR00584##
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Example E-29 ##STR00613## Example E-30 ##STR00614## Example E-31
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Example E-65 ##STR00649## Example E-66 ##STR00650## Example E-67
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Example E-77 ##STR00661## Example E-78 ##STR00662## Example E-79
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Example E-82 ##STR00666##
TABLE-US-00046 TABLE 46 Example F-1 ##STR00667## Example G-1
##STR00668## Example H-1 ##STR00669## Example I-1 ##STR00670##
Example J-1 ##STR00671##
TABLE-US-00047 TABLE 47 Example K-1 ##STR00672## Example L-1
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Example L-4 ##STR00676## Example L-5 ##STR00677## Example L-6
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TABLE-US-00048 TABLE 48 Example M-1 ##STR00684## Example O-1
##STR00685## Example P-1 ##STR00686## Example Q-1 ##STR00687##
Example Q-2 ##STR00688## Example Q-3 ##STR00689## Example Q-4
##STR00690## Example Q-5 ##STR00691## Example Q-6 ##STR00692##
Example Q-7 ##STR00693## Example Q-8 ##STR00694##
TABLE-US-00049 TABLE 49 Example R-1 ##STR00695## Example R-2
##STR00696## Example S-1 ##STR00697## Example T-1 ##STR00698##
Example T-2 ##STR00699## Example U-1 ##STR00700## Example U-2
##STR00701## Example V-1 ##STR00702##
TABLE-US-00050 TABLE 50 Example W-1 ##STR00703## Example W-2
##STR00704## Example W-3 ##STR00705## Example W-4 ##STR00706##
Example W-5 ##STR00707## Example W-6 ##STR00708## Example X-1
##STR00709## Example X-2 ##STR00710## Example Y-1 ##STR00711##
TABLE-US-00051 TABLE 51 Example Z-1 ##STR00712## Example Z-2
##STR00713## Example Z-3 ##STR00714## Example Z-4 ##STR00715##
[1721] The heterocyclic compounds (I) according to the present
invention, or salts, or hydrates thereof, demonstrate excellent
inhibitory activity on the GPI-anchored protein transport process,
anti-Candida activity, anti-Aspergillus activity. In addition, it
is also excellent in terms of property, safety and metabolic
stability, and is extremely useful as a preventive agent or
therapeutic agent against fungal infection.
[Pharmacological Test Example]
[1722] In order to demonstrate the usefulness of the compounds (1)
according to the present invention, 1. the inhibitory activity on
the GPI-anchored protein transport process, 2. the anti-Candida
activity and the anti-Aspergillus activity, 3. the activity in the
experimental systemic candida infection model in mice, and 4. the
activity in the experimental respiratory aspergillus infection
model in mice, were measured for the antifungal activity of the
compounds (I) according to the present invention.
1. Inhibitory Activity on the GPI-Anchored Protein Transport
Process
[1723] A reporter system that reflects the GPI-anchored protein
transport process was constructed using cephalosporinase to which
the CWP2 carboxyl-terminal sequence, which is known as the cell
wall transport signal of a GPI-anchored protein (Van Der Vaat J M
et al, J. Bacteriol., 177:3104-3110, 1995), was added. Then, using
the constructed reporter system, the activity of the present
invention compound that inhibits the transport process of the
GPI-anchored protein was measured.
[1724] (1). Construction of the Reporter Gene
[1725] With pESH plasmid containing the ENO1 promoter, a secretion
signal, and a lysozyme gene (Ichikawa K et al, Biosci. Biotech.
Biochem., 57(10), 1686-1690, 1993) as template and the
oligonucleotides listed in SEQ ID NO. 1 and SEQ ID NO. 2 as
primers, the DNA containing a promoter sequence-secretion signal
portion was amplified by PCR, and this was subcloned into the
BamHI-NotI site of pUC19 (a). In addition, with the C. freundii
chromosomal DNA as template and the oligonucleotides listed in SEQ
ID NO. 3 and SEQ ID NO. 4 as primers, the cephalosporinase gene was
PCR-amplified, and this was subcloned into the NspV-XbaI site of
pUC19 (b). Similarly, with the S. cerevisiae chromosomal DNA as
template and the oligonucleotides listed in SEQ ID NO. 5 and SEQ ID
NO. 6 as primers, the CWP2 gene was PCR-amplified, and this was
subcloned into the XbaI-HindIII site of pUC19 (c). Furthermore,
with pYES2 (INVITROGEN) as template and the oligonucleotides listed
in SEQ ID NO. 7 and SEQ ID NO. 8 as primers, the CYC1 terminator
was PCR-amplified, and this was subcloned into the NotI-KpnI site
of pUC19 (d).
[1726] After producing the full length ENO1 promoter and secretion
signal portion by inserting the BamHI-SalI fragment of pESH into
the BamHI-SalI cleavage site of the plasmid into which (a) had been
inserted, the cephalosporinase gene (b) excised with NspV-XbaI and
the CWP2 gene (c) excised with XbaI-HindIII were inserted into the
NspV-HindIII cleavage site. Next, pRCW63T was produced by excising
with EcoRI-HindIII, inserting this fragment into the integration
vector pRS306 (Sikorski R S et al, Genetics. 122(1):19-27, 1989),
and then inserting the CYC1 terminator (d) into the HindIII-KpnI
cleavage site
[1727] (2). Introduction of the Reporter Gene into S.
cerevisiae
[1728] The S. cerevisiae G2-10 strain was cultured by shaking in 10
ml of YPD culture medium at 30.degree. C., and the cells were
collected at the late logarithmic growth phase (2 to
5.times.10.sup.7 cells/ml). After washing with sterilized water,
pRCW63T produced in (1) was introduced by the lithium acetate
method (described in the YEASTMAKER.TM. Yeast Transformation System
User Manual) using the YEASTMAKER.TM. Yeast Transformation System
(Clontech). pRCW63T in which the URA3 gene was cleaved with ApaI
was used. After culturing in SD(Ura-) culture medium for 3 days at
30.degree. C., the grown colonies were cultured in YPD culture
medium.
[1729] When the localization of the cephalosporinase activity was
confirmed; the activity was mainly localized in the cell wall, the
C-terminal sequence of CWP2 was confirmed to function as a
transport signal to the cell wall.
[1730] (3). Measurement by a Reporter System of the Inhibitory
Activity on the GPI-Anchored Protein Transport Process
[1731] A screening of the compounds was performed using S.
cerevisiae in which pRCW63T was introduced (S. cerevisiae CW63
strain).
[1732] After a standing culture in a YPD liquid culture medium for
48 hours at 30.degree. C., 75 .mu.l/well of a fungal suspension
diluted 10-fold with YPD liquid culture medium (3 to
5.times.10.sup.5 cells/ml) was used to inoculate a V-bottomed 96
well plate containing 25 .mu.l/well of test compound dilute
solution, and a standing culture was carried out for 48 hours at
30.degree. C. The plate was centrifuged, then, 25 .mu.l of
supernatant was sampled into a 96 well flat-bottomed plate, the
resulting solution serving as the culture medium supernatant
fraction.
[1733] The precipitated cells were suspended, 75 .mu.l/well of
zymolyase (Seikagaku Kogyo) solution prepared with 2.4M sorbitol
was added, and allowed to act for 1 hour at 30.degree. C. The plate
was centrifuged, then, 10 .mu.l of supernatant was sampled in a 96
well flat-bottomed plate, 15 .mu.l of phosphate buffer was added,
the resulting solution serving as the cell wall fraction.
[1734] The pooled sample was added 200 .mu.M of nitrocefin
solution, after a predetermined time, the reaction was stopped with
a citric acid buffer, then, the optical density at 490 nm was
measured, to measure the cephalosporinase activity in the culture
medium and the cell wall fraction. A compound that increases the
cephalosporinase activity in the culture medium supernatant
fraction, or decreases the cephalosporinase activity in the cell
wall fraction, was considered as a compound that inhibits the
transport process of GPI-anchored protein to the cell wall.
[1735] In addition, fungal growth in the presence of the test
compound was visually determined.
2. Anti-Candida Activity and Anti-Aspergillus Activity
[1736] (1). Preparation of Fungal Suspension
[1737] For the C. albicans E81022 strain, a fungal suspension from
a standing culture for 48 hours at 30.degree. C. in a Sabouraud
dextrose liquid culture medium (SDB) was diluted 10,000-fold with a
1.3-fold concentrated SDB to adjust to a fungal suspension of 1 to
2.times.10.sup.4 cells/ml. For the A. fumigatus Tsukuba strain,
-80.degree. C. stored strain was diluted 1,000-fold with a 1.3-fold
concentrated SDB to adjust to a fungal suspension of 2 to
3.times.10.sup.3 cells/ml.
[1738] (2). Preparation of an Agent Dilution Plate
[1739] Using a U-bottomed 96 well plate, 8 samples/plate (A to H)
of sample dilution solutions were prepared. On the 3.sup.rd row of
each plate was dispensed 240 .mu.l of sterilized and distilled
water, and on the 2.sup.nd and 4.sup.th to 12.sup.th rows were
dispensed 125 .mu.l of 4% dimethylsulfoxide solution. Weighed
sample was dissolved in dimethylsulfoxide to prepare a 2.5 to 20
mg/ml solution, 10 .mu.l of this solution was then added to the
3.sup.rd row of the prepared plate, and 10 steps of two-fold step
dilutions (125 .mu.l of solution+125 .mu.l of 4% dimethylsulfoxide)
were performed on the plate. This sample dilution solution was
dispensed in the amount of 25 .mu.l to a V-bottomed or
flat-bottomed 96 well plate for MIC measurement to prepare a sample
dilution plate.
[1740] (3). Inoculation of Fungal Suspension and Culture
[1741] The fungal suspension prepared in (1) was used in the amount
of 75 .mu.l/well to inoculate a V-bottomed or flat-bottomed 96 well
plate containing 25 .mu.l/well of test compound dilution solution
prepared in (2), and a standing culture was carried out aerobically
for 48 hours at 30 to 35.degree. C.
[1742] (4). MIC Measurement
[1743] The minimum concentration that clearly inhibited fungal
growth as compared to the control by visual inspection was
determined as the minimum inhibitory concentration (MIC).
[1744] The following representative compounds prepared in the
examples were measured for their inhibitory activity on the
GPI-anchored protein transport process, anti-candida activity and
anti-aspergillus activity by the measurement methods described in 1
and 2. As a result, as shown in Table 52 to Table 54, it was found
that the compounds according to the present invention inhibited the
GPI-anchored protein transport process, and have anti-candida
activity and anti-aspergillus activity.
TABLE-US-00052 TABLE 52 Reporter System Inhibitory Example Activity
Nos. (.mu.g/ml) A-5 0.2 A-8 3.13 A-10 0.2 A-22 0.2 A-37 0.1 A-39
0.78 A-53 0.1 A-54 0.2 A-68 0.05 A-70 0.025 A-81 1.56 A-82 0.2 A-92
3.13 A-98 0.2 A-99 0.78 A-101 0.1 A-112 3.13 A-116 0.39 A-124 1.56
A-126 1.56 A-131 0.39 A-136 0.78 A-137 0.78 A-139 0.78 A-170 0.39
A-171 0.1 B-1 3.13 C-1 0.1 D-2 0.39 E-8 0.1 E-11 0.2 E-13 0.2 E-19
0.2 E-25 0.2 E-43 0.1 E-44 0.78 E-45 0.78 E-51 0.2 E-53 0.2 E-57
0.1 E-64 0.39 E-65 0.1 E-67 0.025 E-69 0.2 E-71 0.1 E-73 0.2 F-1
1.56 G-1 1.56 H-1 1.56 I-1 0.2 K-1 0.39 L-4 0.2 L-7 0.1 M-1 0.39
Q-7 0.39 R-1 0.2 U-2 0.2 V-1 0.78 W-1 0.78 W-2 0.39 Y-1 0.2
TABLE-US-00053 TABLE 53 Anti-Candida Example Activity Nos.
(.mu.g/ml) A-5 0.2 A-8 3.13 A-10 0.78 A-22 0.78 A-37 0.39 A-39 1.56
A-53 0.39 A-54 0.78 A-68 0.05 A-70 0.05 A-81 3.13 A-82 0.2 A-92
3.13 A-98 0.39 A-99 3.13 A-101 0.1 A-112 3.13 A-116 0.39 A-124 1.56
A-126 0.78 A-131 1.56 A-136 1.56 A-137 1.56 A-139 1.56 A-170 0.78
A-171 0.2 B-1 3.13 C-1 0.1 D-2 0.78 E-8 0.2 E-11 0.39 E-13 0.78
E-19 0.78 E-25 1.56 E-43 0.39 E-44 3.13 E-45 3.13 E-51 0.78 E-53
1.56 E-57 0.2 E-64 0.2 E-65 0.1 E-67 0.39 E-69 0.1 E-71 0.2 E-73
0.2 F-1 3.13 G-1 6.25 I-1 0.78 K-1 0.78 L-4 0.2 L-7 0.1 M-1 1.56
Q-7 0.39 R-1 0.39 U-2 0.78 W-1 0.39 W-2 1.56 Y-1 0.78
TABLE-US-00054 TABLE 54 Anti- Aspergillus Example Activity Nos.
(.mu.g/ml) A-5 0.78 A-8 6.25 A-10 1.56 A-22 3.13 A-37 3.13 A-39
1.56 A-53 0.78 A-54 1.56 A-68 0.78 A-70 0.78 A-81 6.25 A-82 1.56
A-98 1.56 A-99 6.25 A-101 0.39 A-112 6.25 A-116 3.13 A-126 6.25
A-131 6.25 A-139 1.56 A-171 1.56 B-1 6.25 D-2 0.78 E-8 0.2 E-11
1.56 E-13 1.56 E-19 1.56 E-45 3.13 E-51 3.13 E-53 3.13 E-57 6.25
E-64 6.25 E-65 1.56 E-67 0.78 E-69 1.56 E-71 1.56 E-73 0.78 I-1
1.56 K-1 1.56 L-4 0.2 L-7 0.78 M-1 1.56 Q-7 6.25 R-1 3.13 U-2 3.13
V-1 6.25 W-1 0.78 W-2 0.78 Y-1 6.25
[1745] 3. Experimental Systemic candida Infection Model in Mice
[1746] (1). Preparation of Fungal Inoculum
[1747] A standing culture of C. albicans E81022 strain was carried
out for 48 hours at 30.degree. C. in Sabouraud dextrose agar medium
(SDA), the recovered fungal cells were suspended in sterilized
physiological saline. By counting the fungal number on a cytometry
plate, the suspension was diluted to 2.times.10.sup.7 cells/ml with
sterilized physiological saline to serve as fungal inoculum.
[1748] (2). Infection
[1749] The fungal inoculum was used in the amounts of 0.2 ml to
inoculate 4.5 to 5.5 week-old female ICR mice in the tail vein
(4.times.10.sup.6 cells/mouse).
[1750] (3). Treatment
[1751] From 0.5 to 1 hour after fungal inoculation, 0.2 ml of agent
solution (dissolved or suspended in sterilized physiological saline
containing 6.5% dimethylsulfoxide and 3.5% Tween 80) was
administered into the stomach using a peroral probe, 3 times every
4 hours. The agent concentration was 2.5 mg/kg, and the number of
animals in one group was 5 animals.
[1752] (4). Determination of the Effect
[1753] The protective effect was determined by observing life/death
until 14 days after infection and calculating the mean survival
days.
[1754] As a result, as shown in Table 55, mice administered with
the compounds according to the present invention survived for a
long time as compared to the untreated group, and the compounds
according to the present invention have been also found to
demonstrate anti-candida activity in vivo.
TABLE-US-00055 TABLE 55 Mean Survival Example Days Nos. (Days) A-10
12.5 A-53 13.4 A-54 10.0 A-68 10.6 A-70 12.6 A-137 12.8 E-65 11.6
R-1 10.4 Non- 2.2~4.0 Administered Group
[1755] 4. Aspergillus Respiratory Infection
[1756] (1). Increasing Susceptibility of Mice to Infection
[1757] In order to increase susceptibility of the mice to
infection, 200 mg/kg of 5-fluorouracil was administered
subcutaneously 6 days prior to infection.
[1758] (2). Test Strain
[1759] A. fumigatus Tsukuba strain was used.
[1760] (3). Preparation of Fungal Inoculum
[1761] A spore suspension of the infection strain was used to coat
a potato dextrose agar medium (PDA), a standing culture was carried
out for 4 to 7 days at 35.degree. C., spore was then suspended in a
sterilized physiological saline containing 0.05% Tween 80. By
counting the pore count on a cytometry plate, the suspension was
diluted to 6.times.10.sup.5 cells/ml with sterilized physiological
saline containing 0.05% Tween 80 to serve as fungal inoculum.
[1762] (4). Infection
[1763] Under ketalar anesthesia, 50 .mu.l of fungal inoculum was
used to inoculate 8 to 9 week-old female DBA/2N mice in the nose
(3.times.10.sup.4 cells/mouse).
[1764] (5). Treatment
[1765] From 1 hour after fungal inoculation, 0.2 ml of agent
solution (dissolved or suspended in sterilized physiological saline
containing 6.5% DMSO and 3.5% Tween 80), was administered into the
stomach using a peroral probe 3 times per day for 3 days. The agent
dosage was from 20 or 40 mg/kg, and the number of animals in one
group was 5 animals.
[1766] (6). Determination of the Effect
[1767] The protective effect was determined by observing life/death
until 14 days after infection and calculating the mean survival
days.
[1768] As a result, as shown in Table 56, mice administered with
the compounds according to the present invention survived for a
long time as compared to the untreated group, and the compounds
according to the present invention have been also found to
demonstrate anti-aspergillus activity in vivo.
TABLE-US-00056 TABLE 56 Mean Survival Example Days Nos. (Days) A-11
10.4 A-31 11.2 A-32 11.8 A-55 12.6 A-56 10.8 D-4 10.8 D-7 10.6 Non-
4.0~4.2 Administered Group
INDUSTRIAL APPLICABILITY
[1769] The heterocyclic compounds (1) according to the present
invention, or a salt or a hydrate thereof, 1) demonstrate effects
against occurrence, development and persistence of infectious
disease by inhibiting the expression of cell wall surface layer
protein and inhibiting cell wall assembly, while at the same time,
inhibiting adhesion of fungus onto the cells, preventing the
pathogen from showing pathogenicity, in addition, 2) are also
excellent in terms of property, safety and metabolic stability, and
extremely useful as a preventive or therapeutic agent of fungal
infection.
Sequence CWU 1
1
8133DNAArtificial Sequencean artificially synthesized primer
sequence 1cccggatcct gtttgcagca tgagacttgc ata 33242DNAArtificial
Sequencean artificially synthesized primer sequence 2cccgcggccc
cttccaattc gaaaaccttc cccagagcag cc 42332DNAArtificial Sequencean
artificially synthesized primer sequence 3ggttcgaagc cgcaaaaaca
gaacaacaaa tt 32432DNAArtificial Sequencean artificially
synthesized primer sequence 4ggtctagatt gcagtttttc aagaatgcgc ca
32533DNAArtificial Sequencean artificially synthesized primer
sequence 5ccctctagaa ctgacggtca aatccaagct act 33632DNAArtificial
Sequencean airtificially synthesized primer sequence 6ggaagctttt
ataacaacat agcggcagca ga 32748DNAArtificial Sequencean artificially
synthesized primer sequence 7cccgcggccg cttgatagta agcttgcttg
ggccgcatca tgtaatta 48833DNAArtificial Sequencean artificially
synthesized primer sequence 8cccggtacca aattaaagcc ttcgagcctc cca
33
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