U.S. patent application number 10/457002 was filed with the patent office on 2004-06-17 for condensed imidazole derivatives.
This patent application is currently assigned to Eisai Co., Ltd.. Invention is credited to Clark, Richard, Emori, Eita, Ikuta, Hironori, Kira, Kazunobu, Matsuura, Fumiyoshi, Nagakura, Tadashi, Yamazaki, Kazuto, Yasuda, Nobuyuki, Yoshikawa, Seiji.
Application Number | 20040116328 10/457002 |
Document ID | / |
Family ID | 29740540 |
Filed Date | 2004-06-17 |
United States Patent
Application |
20040116328 |
Kind Code |
A1 |
Yoshikawa, Seiji ; et
al. |
June 17, 2004 |
Condensed imidazole derivatives
Abstract
The present invention is related to compounds represented by the
following formula, or salts or hydrates thereof 1 wherein, T.sup.1
represents a 4- to 12-membered heterocyclic group containing one or
two nitrogen atoms in the ring, which is a monocyclic or bicyclic
structure that may have one or more substituents; X represents a
C.sub.1-6 alkyl group which may have one or more substituents, or
such; Z.sup.1 and Z.sup.2 each independently represent a nitrogen
atom or a group represented by the formula --CR.sup.2--; R.sup.1
and R.sup.2 independently represent a hydrogen atom, a C.sub.1-6
alkyl group which may have one or more substituents, or a C.sub.1-6
alkoxy group which may have one or more substituents, or such.
These are novel compounds that exhibit an excellent
DPPIV-inhibiting activity.
Inventors: |
Yoshikawa, Seiji;
(Kashima-gun, JP) ; Emori, Eita; (Tsuchiura-shi,
JP) ; Matsuura, Fumiyoshi; (Tsukuba-shi, JP) ;
Clark, Richard; (Tsuchiura-shi, JP) ; Ikuta,
Hironori; (Ushiku-shi, JP) ; Kira, Kazunobu;
(Tsukuba-shi, JP) ; Yasuda, Nobuyuki;
(Tsuchiura-shi, JP) ; Nagakura, Tadashi;
(Ushiku-shi, JP) ; Yamazaki, Kazuto; (Tsukuba-shi,
JP) |
Correspondence
Address: |
TOWNSEND AND TOWNSEND AND CREW, LLP
TWO EMBARCADERO CENTER
EIGHTH FLOOR
SAN FRANCISCO
CA
94111-3834
US
|
Assignee: |
Eisai Co., Ltd.
Tokyo
JP
|
Family ID: |
29740540 |
Appl. No.: |
10/457002 |
Filed: |
June 6, 2003 |
Current U.S.
Class: |
544/262 ;
514/13.3; 514/16.9; 514/19.3; 514/3.8; 514/4.8; 514/6.9;
514/7.4 |
Current CPC
Class: |
C07D 487/04 20130101;
A61P 37/02 20180101; A61P 37/08 20180101; C07D 473/30 20130101;
A61P 15/00 20180101; C07D 473/06 20130101; A61P 3/04 20180101; A61P
9/00 20180101; A61P 35/00 20180101; C07D 473/18 20130101; A61P
19/10 20180101; A61P 43/00 20180101; A61P 15/08 20180101; C07D
491/14 20130101; C07D 471/04 20130101; A61P 31/18 20180101; A61P
1/00 20180101; A61P 3/10 20180101; A61P 3/00 20180101; A61P 3/06
20180101; A61P 19/02 20180101; C07D 473/40 20130101; A61P 37/00
20180101; C07D 473/36 20130101; A61P 29/00 20180101; C07D 473/04
20130101 |
Class at
Publication: |
514/002 |
International
Class: |
A61K 038/26 |
Foreign Application Data
Date |
Code |
Application Number |
Jun 6, 2002 |
JP |
2002-166069 |
Jul 18, 2002 |
JP |
2002-209373 |
Oct 23, 2002 |
JP |
2002-307750 |
Claims
1. A compound represented by the following formula, or a salt or
hydrate thereof, 561wherein, T.sup.1 represents a monocyclic or
bicyclic 4- to 12-membered heterocyclic group containing one or two
nitrogen atoms in the ring, that may have one or more substituents;
X represents a C.sub.1-6 alkyl group which may have one or more
substituents, a C.sub.2-6 alkenyl group which may have one or more
substituents, a C.sub.2-6 alkynyl group which may have one or more
substituents, a C.sub.6-10 aryl group which may have one or more
substituents, a 5 to 10-membered heteroaryl group which may have
one or more substituents, a C.sub.6-10 aryl C.sub.1-6 alkyl group
which may have one or more substituents, or a 5 to 10-membered
heteroaryl C.sub.1-6 alkyl group which may have one or more
substituents; Z.sup.1 and Z.sup.2 each independently represent a
nitrogen atom or a group represented by the formula
--CR.sup.2.dbd.; R.sup.1 and R.sup.2 each independently represent a
group according to the formula -A.sup.0-A.sup.1-A.sup.2 (wherein
A.sup.0 represents a single bond or a C.sub.1-6 alkylene group
which may have 1 to 3 substituents selected from group B consisting
of the substituents described below; A.sup.1 represents a single
bond, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl
group, a carbonyl group, a group represented by the formula
--O--CO--, a group represented by the formula --CO--O--, a group
represented by the formula --NR.sup.A--, a group represented by the
formula --CO--NR.sup.A--, a group represented by the formula
--NR.sup.A--CO--, a group represented by the formula
--SO.sub.2--NR.sup.A--, or a group represented by the formula
--NR.sup.A--SO.sub.2--; A.sup.2 and R.sup.A each independently
represent a hydrogen atom, a halogen atom, a cyano group, a
C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, C.sub.6-10 aryl group, a
5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic
group, a 5 to 10-membered heteroaryl C.sub.1-6 alkyl group, a
C.sub.6-10 aryl C.sub.1-6 alkyl group, or a C.sub.2-7 alkylcarbonyl
group; however, A.sup.2 and R.sup.A each independently may have 1
to 3 substituents selected from the substituent group B described
below: when Z.sup.2 is a group represented by the formula
--CR.sup.2.dbd., R.sup.1, and R.sup.2 may in combination form a 5
to 7-membered ring; except in cases where: [1] R.sup.1 is a
hydrogen atom; Z.sup.1 is a nitrogen atom; and Z.sup.2 is
--CH.dbd.; and [2] Z.sup.1 is a nitrogen atom; and Z.sup.2 is
--C(OH).dbd.; <Substituent group B>Substituent group B
represents the group consisting of: a hydroxyl group, a mercapto
group, a cyano group, a nitro group, a halogen atom, a
trifluoromethyl group, a C.sub.1-6 alkyl group which may have one
or more substituents, a C.sub.3-8 cycloalkyl group, a C.sub.2-6
alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group,
a 5 to 10-membered heteroaryl group, a 4 to 8-membered heterocyclic
group, a C.sub.1-6 alkoxy group, a C.sub.1-6 alkylthio group, a
group represented by the formula --SO.sub.2--NR.sup.B1--R.sup.B2- ,
a group represented by the formula --NR.sup.B1--CO--R.sup.B2, a
group represented by the formula --NR.sup.B1--R.sup.B2 (where
R.sup.B1 and R.sup.B2 each independently represent a hydrogen atom
or a C.sub.1-6 alkyl group), a group represented by the formula
--CO--R.sup.B3 (where R.sup.B3 represents a 4 to 8-membered
heterocyclic group), a group represented by the formula
--CO--R.sup.B4--R.sup.B5 and a group represented by the formula
--CH.sub.2--CO--R.sup.B4--R.sup.B5 (where R.sup.B4 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.B6; R.sup.B5 and R.sup.B6 each independently represent a
hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to
8-membered heterocyclic C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, or a 5 to 10-membered heteroaryl C.sub.1-6
alkyl group)).
2. The compound according to claim 1, or a salt or hydrate thereof,
wherein T.sup.1 is, a group represented by the following formula:
562 (wherein, n and m each independently represent 0 or 1) which
may have one or more substituents; an azetidin-1-yl group which may
have one or more substituents; a pyrrolidin-1-yl group which may
have one or more substituents; a piperidin-1-yl group which may
have one or more substituents; or an azepan-1-yl group which may
have one or more substituents.
3. The compound according to claim 1, or a salt or hydrate thereof,
wherein T.sup.1 is, a group represented by the following formula
563 (where n and m each independently represent 0 or 1); an
azetidin-1-yl group which may have an amino group; a
pyrrolidin-1-yl group which may have an amino group; a
piperidin-1-yl group which may have an amino group; or an
azepan-1-yl group which may have an amino group.
4. The compound according to claim 1, or a salt or hydrate thereof,
wherein T.sup.1 is a piperazin-1-yl group or a
3-aminopiperidin-1-yl group.
5. The compound according to claim 1, or a salt or hydrate thereof,
wherein T.sup.1 is a piperazin-1-yl group.
6. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a group represented by the formula
--X.sup.1--X.sup.2 (where X.sup.1 represents a single bond or a
methylene group which may have one or more substituents; X.sup.2
represents a C.sub.2-6 alkenyl group which may have one or more
substituents, a C.sub.2-6 alkynyl group may have one or more
substituents, or a phenyl group which may have one or more
substituents).
7. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a group represented by the formula
--X.sup.11--X.sup.12 (where X.sup.11 represents a single bond or a
methylene group; X.sup.12 represents a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, or a phenyl group which may have one or
more substituents).
8. The compound according to claim 6 or 7, or a salt or hydrate
thereof, wherein the phenyl group that may have one or more
substituents is a phenyl group which may have at the 2-position a
substituent selected from the group consisting of a hydroxyl group,
a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a
fluoromethyl group, a vinyl group, a methoxy group, an ethoxy
group, an acetyl group, a cyano group, a formyl group, and a
C.sub.2-7 alkoxycarbonyl group.
9. The compound according to any one of claims 1 to 5, or a salt or
hydrate thereof, wherein X is a 3-methyl-2-buten-1-yl group, a
2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl group.
10. The compound according to any one of claims 1 to 5, or a salt
or hydrate thereof, wherein X is a 2-butyn-1-yl group.
11. The compound according to any one of claims 1 to 10, or a salt
or hydrate thereof, wherein either the Z.sup.1 or Z.sup.2 is a
nitrogen atom.
12. The compound according to any one of claims 1 to 10, or a salt
or hydrate thereof, wherein, Z.sup.1 is a nitrogen atom; and
Z.sup.2 is a group represented by the formula --CR.sup.2.dbd.(where
R.sup.2 is as defined above in claim 1).
13. The compound according to any one of claims 1 to 10, or a salt
or a hydrate thereof, wherein, Z.sup.2 is a nitrogen atom; and
Z.sup.1 is a group represented by the formula --CR.sup.2.dbd.(where
R.sup.2 is as defined above in claim 1).
14. The compound according to any one of claims 1 to 13, or a salt
or hydrate thereof, wherein R.sup.1 represents a hydrogen atom, or
a group represented by the formula -A.sup.10-A.sup.11-A.sup.12
(where A.sup.10 represents a C.sub.1-6 alkylene group which may
have 1 to 3 substituents selected from the substituent group C
described below; A.sup.11 represents a single bond, an oxygen atom,
a sulfur atom or a carbonyl group; A.sup.12 represents a hydrogen
atom, a C.sub.6-10 aryl group which may have 1 to 3 substituents
selected from the substituent group C described below, a 5 to
10-membered heteroaryl group which may have 1 to 3 substituents
selected from the substituent group C described below, a 5 to
10-membered heteroaryl C.sub.1-6 alkyl group which may have 1 to 3
substituents selected from the substituent group C described below,
or a C.sub.6-10 aryl C.sub.1-6 alkyl group which may have 1 to 3
substituents selected from the substituent group C described below:
<Substituent group C>Substituent group C represents the group
consisting of: a hydroxyl group, a nitro group, a cyano group, a
halogen atom, a C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkylthio group, a trifluoromethyl group, a group
represented by the formula --NR.sup.C1--R.sup.C2 (where each of
R.sup.C1 and R.sup.C2 independently represent a hydrogen atom or
C.sub.1-6 alkyl group), a group represented by the formula
--CO--R.sup.C3--R.sup.C4 and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group).
15. The compound according to any one of claims 1 to 13, or a salt
or hydrate thereof, wherein R.sup.1 is a hydrogen atom, a C.sub.1-6
alkyl group which may have 1 to 3 substituents selected from the
substituent group C described below, a 5 to 10-membered heteroaryl
C.sub.1-6 alkyl group which may have 1 to 3 substituents selected
from the substituent group C described below, or a C.sub.6-10 aryl
C.sub.1-6 alkyl group which may have 1 to 3 substituents selected
from the substituent group C described below: <Substituent group
C>Substituent group C represents the group consisting of: a
hydroxyl group, a nitro group, a cyano group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.C1--R.sup.C2 (where each of R.sup.C1 and
R.sup.C2 independently represent a hydrogen atom or a C.sub.1-6
alkyl group), a group represented by the formula
--CO--R.sup.C3--R.sup.C4 and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group);
16. The compound according to claim 14 or 15, or a salt or hydrate
thereof, wherein the substituent group C is a group consisting of a
cyano group, a C.sub.1-6 alkoxy group, a C.sub.2-7 alkoxycarbonyl
group, and a halogen atom.
17. The compound according to any one of claims 1 to 13, or a salt
or hydrate thereof, wherein R.sup.1 is a methyl group, a
cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a
2-methoxyethyl group, or a 4-methoxycarbonylpyridin-2-yl group.
18. The compound according to any one of claims 1 to 13, or a salt
or hydrate thereof, wherein R.sup.1 is a methyl group or a
2-cyanobenzyl group.
19. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof, wherein R.sup.2 is a hydrogen atom, a cyano
group, or a group represented by the formula -A.sup.21-A.sup.22
(where A.sup.21 represents a single bond, an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula
--NR.sup.A2--, a group represented by the formula
--CO--NR.sup.A2--, or a group represented by the formula
--NR.sup.A2--CO--; A.sup.22 and R.sup.A2 each independently
represent a hydrogen atom, a cyano group, a C.sub.1-6 alkyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group, a 5- to
10-membered heteroaryl group, a 4- to 8-membered heterocyclic
group, a 5to 10-membered heteroaryl C.sub.1-6 alkyl group, or a
C.sub.6-10 aryl C.sub.1-6 alkyl group; however, A.sup.22 and
R.sup.A2 each may independently have 1- to 3 substituents selected
from the substituent group D described below: <Substituent group
D>Substituent group D represents the group consisting of: a
hydroxyl group, a cyano group, a nitro group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.D1--R.sup.D2 (where R.sup.D1 and R.sup.D2 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.D3 (where
R.sup.D3 represents a 4 to 8-membered heterocyclic group), and a
group represented by the formula --CO--R.sup.D4--R.sup.D5 (where
R.sup.D4 represents a single bond, an oxygen atom, or a group
represented by the formula --NR.sup.D6--; R.sup.D5 and R.sup.D6
each independently represent a hydrogen atom, a C.sub.3-8
cycloalkyl group, or a C.sub.1-6 alkyl group)).
20. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof, wherein R.sup.2 represents a hydrogen atom, a
cyano group, a carboxy group, a C.sub.2-7 alkoxycarbonyl group, a
C.sub.1-6 alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), or a group represented by the formula -A.sup.23-A.sup.24
(where A.sup.23 represents an oxygen atom, a sulfur atom or a group
represented by the formula --NR.sup.A3--; A.sup.24 and R.sup.A3
each independently represent a hydrogen atom, a C.sub.1-6 alkyl
group which may have a substituent selected from the substituent
group D1 described below, a C.sub.3-8 cycloalkyl group which may
have a substituent selected from the substituent group D1 described
below, a C.sub.2-6 alkenyl group which may have a substituent
selected from the substituent group D1 described below, a C.sub.2-6
alkynyl group which may have a substituent selected from the
substituent group D1 described below, a phenyl group which may have
a substituent selected from the substituent group D1 described
below, or a 5 to 10-membered heteroaryl group which may have a
substituent selected from the substituent group D1 described below:
<Substituent group D1>Substituent group D1 represents the
group consisting of: a carboxy group, a C.sub.2-7 alkoxycarbonyl
group, a C.sub.1-6 alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or C.sub.1-6 alkyl group),
a pyrrolidin-1-ylcarbonyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group).
21. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof, wherein R represents a hydrogen atom, a cyano
group, a C.sub.1-6 alkoxy group, or a group represented by the
formula -A.sup.25-A.sup.26 (where A.sup.25 represents an oxygen
atom, a sulfur atom, or a group represented by the formula
--NR.sup.A4--; A.sup.26 and R.sup.A4 each independently represent a
hydrogen atom, a C.sub.1-6 alkyl group having a substituent
selected from the substituent group D1 described below, a C.sub.3-8
cycloalkyl group having a substituent selected from the substituent
group D1 described below, or a phenyl group having a substituent
selected from the substituent group D1 described below:
<Substituent group D1>Substituent group D1 represents the
group consisting of: a carboxy group, a C.sub.2-7 alkoxycarbonyl
group, a C.sub.1-6 alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), pyrrolidin-1-ylcarbonyl group, a C.sub.1-6 alkyl group, and
a C.sub.1-6 alkoxy group).
22. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof, wherein R.sup.2 is a hydrogen atom, a cyano
group, a methoxy group, a carbamoylphenyloxy group, or a group
represented by the following formula: 564(where A.sup.27 represents
an oxygen atom, a sulfur atom, or --NH--; A.sup.28 and A.sup.29
each independently represent a hydrogen atom or a C.sub.1-6 alkyl
group).
23. The compound according to any one of claims 1 to 18, or a salt
or hydrate thereof, wherein R.sup.2 is a hydrogen atom, a cyano
group, or a 2-carbamoylphenyloxy group.
24. The compound according to claim 1, or a salt or hydrate
thereof, wherein the compound of formula (I) indicated above is any
one selected from the group consisting of:
7-(2-butynyl)-2-cyano-1-methyl-8-(piperazin-
-1-yl)-1,7-dihydropurin-6-one,
3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3-
,5-dihydroimidazo[4,5-d]pyridazin-4-one,
2-(3-aminopiperidin-1-yl)-3-(2-bu-
tynyl)-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one,
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-yloxy]benzamide,
7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-
-6,7-dihydro-1H-purine-2-carbonitrile, and
2-[3-(2-butynyl)-4-oxo-2-(piper-
azin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-5-ylmethyl]benzonitrile.
25. A pharmaceutical agent comprising a compound of claim 1.
26. Adipeptidyl peptidase IV inhibitor comprising a compound of
claim 1.
27. A pharmaceutical composition comprising a compound of claim 1
and an adjuvant useful for formulation.
28. A preventive or a therapeutic agent for diabetes mellitus,
which comprises a compound of claim 1.
29. A preventive or therapeutic agent, which comprises a compound
of claim 1, for diabetes mellitus, obesity, hyperlipidemia, AIDS,
osteoporosis, a gastrointestinal disorder, angiogenesis,
infertility, an inflammatory disease, an allergic disease, or
cancer.
30. An immunomodulator, a hormone modulator, or an anti-rheumatic
drug, which comprises a compound of claim 1.
31. A therapeutic or preventive method for a disease in which the
inhibition of dipeptidyl peptidase IV is effective, wherein the
method comprises administering to a patient a compound of claim 1,
or a salt or hydrate thereof, in a pharmaceutically effective
amount.
32. The use of a compound of claim 1, or a salt or hydrate thereof,
in producing a pharmaceutical agent.
33. The use of a compound of claim 1, or a salt or hydrate thereof,
in producing a therapeutic or preventive agent for a disease in
which the inhibition of dipeptidyl peptidase IV is effective.
Description
TECHNICAL FIELD
[0001] The present invention relates to novel condensed imidazole
derivatives useful as dipeptidyl peptidase-IV (DPPIV) inhibitors
and uses thereof.
BACKGROUND ART
[0002] Dipeptidyl peptidase IV (DPPIV) is a serine protease which
specifically hydrolyzes dipeptide --X-Pro (X=arbitrary amino acid)
from the free N terminus of a polypeptide chain.
[0003] Glucose-dependent, insulin secretion-stimulating hormones,
known as incretins (GLP-1: Glucagon-Like Peptide-1 and GIP:
Glucose-dependent Insulinotropic Polypeptide) secreted in the
digestive tract following meals are rapidly hydrolyzed and
inactivated by DPPIV. When the hydrolysis by DPPIV is suppressed,
the action of incretin (GLP-1 and GIP) is enhanced, which in turn
increases the glucose-stimulated secretion of insulin from the
.beta. cells of the pancreas. This has been shown to improve
hyperglycemia in the oral glucose tolerance test (see Diabetologia
1999 November, 42(11), 1324-31). In addition, GLP-1 is known to be
involved in the suppression of appetite and food intake. GLP-1 has
also been reported to have the effect of protecting the .beta.
cells of the pancreas by enhancing cell differentiation and
proliferation. Thus, a DPPIV inhibitor can be a useful therapeutic
or preventive agent for diseases with which GLP-1 and/or GIP are
associated, such as obesity and diabetes mellitus.
[0004] Furthermore, there are many reports suggesting a
relationship between dipeptidyl peptidase IV and various diseases
as described below. Thus, a DPPIV inhibitor can be a therapeutic
agent for diseases such as:
[0005] (1) preventive and therapeutic agents for AIDS (see Science
1993, 262, 2045-2050),
[0006] (2) preventive and therapeutic agents for osteoporosis (see
Clinical chemistry 1988, 34, 2499-2501),
[0007] (3) preventive and therapeutic agents for intestinal
disorders (see Endocrinology 2000, 141, 4013-4020),
[0008] (4) preventive and therapeutic agents for diabetes mellitus,
obesity, and hyperlipidemia (see Diabetes 1998, 47, 1663-1670; and
Life Sci 2000, 66(2), 91-103),
[0009] (5) preventive and therapeutic agents for angiogenesis (see
Agents and Actions 1991, 32, 125-127),
[0010] (6) preventive and therapeutic agents for infertility (see
International Publication WO 00/56296),
[0011] (7) preventive and therapeutic agents for inflammatory
diseases, autoimmune diseases, and chronic rheumatoid arthritis
(see The Journal of Immunology 2001, 166, 2041-2048), and
[0012] (8) preventive and therapeutic agents for cancer (see Br J
Cancer 1999 March, 79(7-8), 1042-8; and J Androl 2000 March-April,
21(2), 220-6).
[0013] Some DPPIV inhibitors are disclosed in the Publication of
U.S. Pat. No. 2002/0161001; International Publication WO 03/004496;
and Publication of U.S. Pat. No. 2002/0198205. However, there is no
known DPPIV inhibitor having a hypoxanthine or imidazopyridazinone
structure backbone.
[0014] A compound having DPPIV-inhibiting activity that can be used
as a pharmaceutical agent is being anxiously sought as described
above. However, a compound with excellent DPPIV-inhibiting
activity, which is also highly useful as a clinically effective
pharmaceutical is yet to be discovered. Specifically, an objective
of the present invention is to provide compounds having
DPPIV-inhibiting activity, which can be used as preventive,
therapeutic, or alleviating agents for diabetes mellitus or such
diseases.
DISCLOSURE OF THE INVENTION
[0015] The present inventors conducted extensive studies in view of
the above background. As a result, they succeeded in synthesizing
novel condensed imidazole derivatives, including hypoxanthine and
imidazopyridazinone derivatives. To complete the present invention
they also found that these compounds had excellent DPPIV-inhibiting
activity. Specifically, the present invention comprises:
[0016] [1] a compound represented by the following formula, or a
salt or hydrate thereof, 2
[0017] wherein,
[0018] T.sup.1 represents a monocyclic or bicyclic 4- to
12-membered heterocyclic group containing one or two nitrogen atoms
in the ring, that may have one or more substituents;
[0019] X represents a C.sub.1-6 alkyl group which may have one or
more substituents, a C.sub.2-6 alkenyl group which may have one or
more substituents, a C.sub.2-6 alkynyl group which may have one or
more substituents, a C.sub.6-10 aryl group which may have one or
more substituents, a 5 to 10-membered heteroaryl group which may
have one or more substituents, a C.sub.6-10 aryl C.sub.1-6 alkyl
group which may have one or more substituents, or a 5 to
10-membered heteroaryl C.sub.1-6 alkyl group which may have one or
more substituents;
[0020] Z.sup.1 and Z.sup.2 each independently represent a nitrogen
atom or a group represented by the formula --CR.sup.2.dbd.;
[0021] R.sup.1 and R.sup.2 each independently represent a group
according to the formula -A.sup.0-A.sup.1-A.sup.2
[0022] (wherein
[0023] A.sup.0 represents a single bond or a C.sub.1-6 alkylene
group, which may have 1 to 3 substituents selected from group B
consisting of the substituents described below;
[0024] A.sup.1 represents a single bond, an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula --NR.sup.A--,
a group represented by the formula --CO--NR.sup.A--, a group
represented by the formula --NR.sup.A--CO--, a group represented by
the formula --SO.sub.2--NR.sup.A--, or a group represented by the
formula --NR.sup.A--SO.sub.2--;
[0025] A.sup.2 and R.sup.A each independently represent a hydrogen
atom, a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl
group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered
heteroaryl C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl
group, or a C.sub.2-7 alkylcarbonyl group;
[0026] however, A.sup.2 and R.sup.A each independently may have 1
to 3 substituents selected from the substituent group B described
below:
[0027] when Z.sup.2 is a group represented by the formula
--CR.sup.2.dbd., R.sup.1, and R.sup.2 may in combination form a 5
to 7-membered ring;
[0028] except in cases where: [1] R.sup.1 is a hydrogen atom;
Z.sup.1 is a nitrogen atom; and Z.sup.2 is --CH.dbd.; and [2]
Z.sup.1 is a nitrogen atom; and Z.sup.2 is --C(OH).dbd.;
[0029] <Substituent group B>
[0030] Substituent group B represents the group consisting of: a
hydroxyl group, a mercapto group, a cyano group, a nitro group, a
halogen atom, a trifluoromethyl group, a C.sub.1-6 alkyl group
which may have one or more substituents, a C.sub.3-8 cycloalkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to
8-membered heterocyclic group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkylthio group, a group represented by the formula
--SO.sub.2--NR.sup.B1--R.sup.B2, a group represented by the formula
--NR.sup.B1--CO--R.sup.B2, a group represented by the formula
--NR.sup.B1--R.sup.B2 (where R.sup.B1 and R.sup.B2 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.B3 (where
R.sup.B3 represents a 4 to 8-membered heterocyclic group), a group
represented by the formula --CO--R.sup.B4--R.sup.B5 and a group
represented by the formula --CH.sub.2--CO--R.sup.B4--R.sup.B5
(where R.sup.B4 represents a single bond, an oxygen atom, or a
group represented by the formula --NR.sup.B6--; R.sup.B5 and
R.sup.B6 each independently represent a hydrogen atom, a C.sub.1-6
alkyl group, a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group, a 5 to
10-membered heteroaryl group, a 4 to 8-membered heterocyclic
C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, or
a 5 to 10-membered heteroaryl C.sub.1-6 alkyl group)), and
[0031] [2] the compound according to [1], or a salt or hydrate
thereof, wherein T.sup.1 is,
[0032] a group represented by the following formula: 3
[0033] (wherein, n and m each independently represent 0 or 1) which
may have one or more substituents;
[0034] an azetidin-1-yl group which may have one or more
substituents;
[0035] a pyrrolidin-1-yl group which may have one or more
substituents;
[0036] a piperidin-1-yl group which may have one or more
substituents; or
[0037] an azepan-1-yl group which may have one or more
substituents;
[0038] [3] the compound according to [1], or a salt or hydrate
thereof, wherein T.sup.1 is,
[0039] a group represented by the following formula: 4
[0040] (where n and m each independently represent 0 or 1);
[0041] an azetidin-1-yl group which may have an amino group;
[0042] a pyrrolidin-1-yl group which may have an amino group;
[0043] a piperidin-1-yl group which may have an amino group; or
[0044] an azepan-1-yl group which may have an amino group;
[0045] [4] the compound according to [1], or a salt or hydrate
thereof, wherein T.sup.1 is a piperazin-1-yl group or a
3-aminopiperidin-1-yl group;
[0046] [5] the compound according to [1], or a salt or hydrate
thereof, wherein T.sup.1 is a piperazin-1-yl group;
[0047] [6] the compound according to any one of [1] to [5], or a
salt or hydrate thereof, wherein X is a group represented by the
formula --X.sup.1--X.sup.2 (where X.sub.1 represents a single bond
or a methylene group which may have one or more substituents;
X.sup.2 represents a C.sub.2-6 alkenyl group which may have one or
more substituents, a C.sub.2-6 alkynyl group may have one or more
substituents, or a phenyl group which may have one or more
substituents);
[0048] [7] the compound according to any one of [1] to [5], or a
salt or hydrate thereof, wherein X is a group represented by the
formula --X.sup.11--X.sup.12 (where X.sup.11 represents a single
bond or a methylene group; X.sup.12 represents a C.sub.2-6 alkenyl
group, a C.sub.2-6 alkynyl group, or a phenyl group which may have
one or more substituents);
[0049] [8] the compound according to [6] or [7], or a salt or
hydrate thereof, wherein the phenyl group that may have one or more
substituents is a phenyl group which may have at the 2-position a
substituent selected from the group consisting of a hydroxyl group,
a fluorine atom, a chlorine atom, a methyl group, an ethyl group, a
fluoromethyl group, a vinyl group, a methoxy group, an ethoxy
group, an acetyl group, a cyano group, a formyl group, and a
C.sub.2-7 alkoxycarbonyl group;
[0050] [9] the compound according to any one of [1] to [5], or a
salt or hydrate thereof, wherein X is a 3-methyl-2-buten-1-yl
group, a 2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl
group;
[0051] [10] the compound according to any one of [1] to [5], or a
salt or hydrate thereof, wherein X is a 2-butyn-1-yl group;
[0052] [11] the compound according to any one of [1] to [10], or a
salt or hydrate thereof, wherein either the Z.sup.1 or Z.sup.2 is a
nitrogen atom;
[0053] [12] the compound according to any one of [1] to [10], or a
salt or hydrate thereof, wherein,
[0054] Z.sup.1 is a nitrogen atom; and
[0055] Z.sup.2 is a group represented by the formula
--CR.sup.2.dbd.
[0056] (where R.sup.2 is as defined above in [1]);
[0057] [13] the compound according to any one of [1] to [10], or a
salt or a hydrate thereof, wherein,
[0058] Z.sup.2 is a nitrogen atom; and
[0059] Z.sup.1 is a group represented by the formula
--CR.sup.2.dbd.
[0060] (where R.sup.2 is as defined above in [1]);
[0061] [14] the compound according to any one of [1] to [13], or a
salt or hydrate thereof,
[0062] wherein R.sup.1 represents a hydrogen atom, or a group
represented by the formula -A.sup.10-A.sup.11-A.sup.12
[0063] (where
[0064] A.sup.10 represents a C.sub.1-6 alkylene group which may
have 1 to 3 substituents selected from the substituent group C
described below;
[0065] A.sup.11 represents a single bond, an oxygen atom, a sulfur
atom or a carbonyl group;
[0066] A.sup.12 represents a hydrogen atom, a C.sub.6-10 aryl group
which may have 1 to 3 substituents selected from the substituent
group C described below, a 5 to 10-membered heteroaryl group which
may have 1 to 3 substituents selected from the substituent group C
described below, a 5 to 10-membered heteroaryl C.sub.1-6 alkyl
group which may have 1 to 3 substituents selected from the
substituent group C described below, or a C.sub.6-10 aryl C.sub.1-6
alkyl group which may have 1 to 3 substituents selected from the
substituent group C described below:
[0067] <Substituent group C>
[0068] Substituent group C represents the group consisting of: a
hydroxyl group, a nitro group, a cyano group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.C1--R.sup.C2 (where each of R.sup.C1 and
R.sup.C2 independently represent a hydrogen atom or C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.C3--R.sup.C4
and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group));
[0069] [15] the compound according to any one of [1] to [13], or a
salt or hydrate thereof,
[0070] wherein R.sup.1 is a hydrogen atom, a C.sub.1-6 alkyl group
which may have 1 to 3 substituents selected from the substituent
group C described below, a 5 to 10-membered heteroaryl C.sub.1-6
alkyl group which may have 1 to 3 substituents selected from the
substituent group C described below, or a C.sub.6-10 aryl C.sub.1-6
alkyl group which may have 1 to 3 substituents selected from the
substituent group C described below:
[0071] <Substituent group C>
[0072] Substituent group C represents the group consisting of: a
hydroxyl group, a nitro group, a cyano group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.C1--R.sup.C2 (where each of R.sup.C1 and
R.sup.C2 independently represents a hydrogen atom or a C.sub.1-6
alkyl group), a group represented by the formula
--CO--R.sup.C3--R.sup.C4 and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group);
[0073] [16] the compound according to [14] or [15], or a salt or
hydrate thereof, wherein the substituent group C is a group
consisting of a cyano group, a C.sub.1-6 alkoxy group, a C.sub.2-7
alkoxycarbonyl group, and a halogen atom;
[0074] [17] the compound according to any one of [1] to [13], or a
salt or hydrate thereof, wherein R.sup.1 is a methyl group, a
cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a
2-methoxyethyl group, or a 4-methoxycarbonylpyridin-2-yl group;
[0075] [18] the compound according to any one of [1] to [13], or a
salt or hydrate thereof, wherein R.sup.1 is a methyl group or a
2-cyanobenzyl group;
[0076] [19] the compound according to any one of [1] to [18], or a
salt or hydrate thereof,
[0077] wherein R.sup.2 is a hydrogen atom, a cyano group, or a
group represented by the formula -A.sup.21-A.sup.22
[0078] (where
[0079] A.sup.21 represents a single bond, an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula
--NR.sup.A2--, a group represented by the formula
--CO--NR.sup.A2--, or a group represented by the formula
--NR.sup.A2--CO--;
[0080] A.sup.22 and R.sup.A2 each independently represent a
hydrogen atom, a cyano group, a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl
group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group;
[0081] however, A.sup.22 and R.sup.A2 each may independently have 1
to 3 substituents selected from the substituent group D described
below:
[0082] <Substituent group D>
[0083] Substituent group D represents the group consisting of: a
hydroxyl group, a cyano group, a nitro group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.D1--R.sup.D2 (where R.sup.D1 and R.sup.D2 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.D3 (where
R.sup.D3 represents a 4 to 8-membered heterocyclic group), and a
group represented by the formula --CO--R.sup.D4--R.sup.D5 (where
R.sup.D4 represents a single bond, an oxygen atom, or a group
represented by the formula --NR.sup.D6--; R.sup.D5 and R.sup.D6
each independently represent a hydrogen atom, a C.sub.3-8
cycloalkyl group, or a C.sub.1-6 alkyl group));
[0084] [20] the compound according to any one of [1] to [18], or a
salt or hydrate thereof,
[0085] wherein R.sup.2 represents a hydrogen atom, a cyano group, a
carboxy group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6 alkyl
group, a group represented by the formula --CONR.sup.D7R.sup.D8
(where R.sup.D7 and R.sup.D8 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group), or a group represented
by the formula -A.sup.23-A.sup.24
[0086] (where
[0087] A.sup.23 represents an oxygen atom, a sulfur atom or a group
represented by the formula --NR.sup.A3--;
[0088] A.sup.24 and R.sup.A3 each independently represent a
hydrogen atom, a C.sub.1-6 alkyl group which may have a substituent
selected from the substituent group D1 described below, a C.sub.3-8
cycloalkyl group which may have a substituent selected from the
substituent group D1 described below, a C.sub.2-6 alkenyl group
which may have a substituent selected from the substituent group D1
described below, a C.sub.2-6 alkynyl group which may have a
substituent selected from the substituent group D1 described below,
a phenyl group which may have a substituent selected from the
substituent group D1 described below, or a 5 to 10-membered
heteroaryl group which may have a substituent selected from the
substituent group D1 described below:
[0089] <Substituent group D1>
[0090] Substituent group D1 represents the group consisting of: a
carboxy group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6 alkyl
group, a group represented by the formula --CONR.sup.D7R.sup.D8
(where R.sup.D7 and R.sup.D8 each independently represent a
hydrogen atom or C.sub.1-6 alkyl group), a pyrrolidin-1-ylcarbonyl
group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group);
[0091] [21] the compound according to any one of [1] to [18], or a
salt or hydrate thereof,
[0092] wherein R.sup.2 represents a hydrogen atom, a cyano group, a
C.sub.1-6 alkoxy group, or a group represented by the formula
-A.sup.25-A.sup.26
[0093] (where
[0094] A.sup.25 represents an oxygen atom, a sulfur atom, or a
group represented by the formula --NR.sup.A4--;
[0095] A.sup.26 and R.sup.A4 each independently represent a
hydrogen atom, a C.sub.1-6 alkyl group having a substituent
selected from the substituent group D1 described below, a C.sub.3-8
cycloalkyl group having a substituent selected from the substituent
group D1 described below, or a phenyl group having a substituent
selected from the substituent group D1 described below:
[0096] <Substituent group D1>
[0097] Substituent group D1 represents the group consisting of: a
carboxy group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6 alkyl
group, a group represented by the formula --CONR.sup.D7R.sup.D8
(where R.sup.D7 and R.sup.D8 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group), pyrrolidin-1-ylcarbonyl
group, a C.sub.1-6 alkyl group, and a C.sub.1-6 alkoxy group);
[0098] [22] the compound according to any one of [1] to [18], or a
salt or hydrate thereof,
[0099] wherein R.sup.2 is a hydrogen atom, a cyano group, a methoxy
group, a carbamoylphenyloxy group, or a group represented by the
following formula: 5
[0100] (where A.sup.27 represents an oxygen atom, a sulfur atom, or
--NH--; A.sup.28 and A.sup.29 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group);
[0101] [23] the compound according to any one of [1] to [18], or a
salt or hydrate thereof, wherein R.sup.2 is a hydrogen atom, a
cyano group, or a 2-carbamoylphenyloxy group;
[0102] [24] the compound according to [1], or a salt or hydrate
thereof, wherein the compound of formula (I) indicated above is any
one selected from the group consisting of:
[0103]
7-(2-butynyl)-2-cyano-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin--
6-one,
[0104]
3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]-
pyridazin-4-one,
[0105]
2-(3-aminopiperidin-1-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimidazo-
[4,5-d]pyridazin-4-one,
[0106]
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urin-2-yloxy]benzamide,
[0107]
7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydr-
o-1H-purine-2-carbonitrile, and
[0108]
2-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]-
pyridazin-5-ylmethyl]benzonitrile;
[0109] [25] a pharmaceutical agent comprising a compound of any one
of [1] to [24];
[0110] [26] a dipeptidyl peptidase IV inhibitor comprising a
compound of any one of [1] to [24];
[0111] [27] a pharmaceutical composition comprising a compound of
any one of [1] to [24] and an adjuvant useful for formulation;
[0112] [28] a preventive or a therapeutic agent for diabetes
mellitus, which comprises a compound of any one of [1] to [24];
[0113] [29] a preventive or therapeutic agent, which comprises a
compound of any one of [1] to [24], for diabetes mellitus, obesity,
hyperlipidemia, AIDS, osteoporosis, a gastrointestinal disorder,
angiogenesis, infertility, an inflammatory disease, an allergic
disease, or cancer;
[0114] [30] an immunomodulator, a hormone modulator, or an
anti-rheumatic drug, which comprises a compound of any one of [1]
to [24];
[0115] [31] a therapeutic or preventive method for a disease in
which the inhibition of dipeptidyl peptidase IV is effective,
wherein the method comprises administering to a patient a compound
of any one of [1] to [24], or a salt or hydrate thereof, in a
pharmaceutically effective amount;
[0116] [32] the use of a compound of any one of [1] to [24], or a
salt or hydrate thereof, in producing a pharmaceutical agent;
[0117] [33] the use of a compound of any one of [1] to [24], or a
salt or hydrate thereof, in producing a therapeutic or preventive
agent for a disease in which the inhibition of dipeptidyl peptidase
IV is effective;
[0118] [34] a compound represented by the following formula, or a
salt or hydrate thereof 6
[0119] wherein,
[0120] T.sup.0 represents,
[0121] a group represented by T.sup.1 described above in [1], a
pyridyl group which may have one or more substituents, a pyridinium
group which may have one or more substituents, a group represented
by the following formula: 7
[0122] a group, which may have one or more substituents,
represented by the following formula: 8
[0123] (where n and m each independently represent 0 or 1), or a
group, which may have one or more substituents, represented by the
following formula: 9
[0124] (where n and m each independently represent 0 or 1);
[0125] X.sup.0 represents a C.sub.3-8 cycloalkyl group which may
have one or more substituents, a C.sub.1-6 alkyl group which may
have one or more substituents, a C.sub.2-6 alkenyl group which may
have one or more substituents, a C.sub.2-6 alkynyl group which may
have one or more substituents, a C.sub.6-10 aryl group which may
have one or more substituents, a 5 to 10-membered heteroaryl group
which may have one or more substituents, a C.sub.6-10 aryl
C.sub.1-6 alkyl group which may have one or more substituents, or a
5 to 10-membered heteroaryl C.sub.1-6 alkyl group which may have
one or more substituents; and
[0126] R.sup.1, Z.sup.1 and Z.sup.2 are, as defined above in
[1];
[0127] [35] a compound represented by the following formula, or a
salt or hydrate thereof, 10
[0128] wherein R.sup.1, R.sup.2, T.sup.1, Z.sup.1 and Z.sup.2 are,
as defined above in [1];
[0129] [36] a compound represented by the following formula, or a
salt or hydrate thereof, 11
[0130] wherein R.sup.1, R.sup.2, T.sup.1, Z.sup.1 and Z.sup.2 are,
as defined above in [1];
[0131] [37] a compound represented by the following formula, or a
salt or hydrate thereof, 12
[0132] wherein,
[0133] R.sup.1 is as defined above in [1]
[0134] R.sup.p5 represents a t-butoxycarbonyloxy group, a trityl
group or a group represented by the formula --SO.sub.2NH.sub.2;
and
[0135] T.sup.10 represents a halogen atom or a hydrogen atom;
[0136] [38] a compound represented by the following formula, or a
salt or hydrate thereof, 13
[0137] wherein,
[0138] R.sup.1 is as defined above in [1]; and
[0139] T.sup.11 represents a halogen atom or a group represented by
the following formula: 14
[0140] (where T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group));
[0141] [39] a compound represented by the following formula, or a
salt or hydrate thereof, 15
[0142] wherein,
[0143] R.sup.1 and X are as defined above in [1], respectively;
and
[0144] T.sup.12 represents a halogen atom;
[0145] [40] a compound represented by the following formula, or a
salt or hydrate thereof, 16
[0146] wherein,
[0147] X is as defined above in [1], except when X is a benzyl
group;
[0148] T21 and T22 each independently represent a halogen atom;
and
[0149] T.sup.11 represents a halogen atom or a group represented by
the following formula: 17
[0150] (where T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group));
[0151] [41] a compound represented by the following formula, or a
salt or hydrate thereof 18
[0152] wherein,
[0153] X and R.sup.1 are as defined above in [1], respectively;
[0154] T.sup.22 represents a halogen atom; and
[0155] T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group;
[0156] [42] a compound represented by the following formula, or a
salt or hydrate thereof 19
[0157] wherein,
[0158] the ring of T.sup.1 represents a monocyclic or bicyclic 6-
to 12-membered heterocyclic group containing two nitrogen atoms in
the ring, which may have one or more substituents;
[0159] X represents a C.sub.1-6 alkyl group which may have one or
more substituents, a C.sub.2-6 alkenyl group which may have one or
more substituents, a C.sub.2-6 alkynyl group which may have one or
more substituents, a C.sub.6-10 aryl group which may have one or
more substituents, a 5 to 10-membered heteroaryl group which may
have one or more substituents, a C.sub.6-10 aryl C.sub.1-6 alkyl
group which may have one or more substituents, or a 5 to
10-membered heteroaryl C.sub.1-6 alkyl group which may have one or
more substituents;
[0160] X may form a bond with an atom constituting the ring of
T.sup.1;
[0161] Z.sup.1 and Z.sup.2 each independently represent a nitrogen
atom or a group represented by the formula --CR.sup.2.dbd.;
[0162] R.sup.1 and R.sup.2 independently represent a hydrogen atom,
a 4- to 8-membered heterocyclic group which may have one or more
substituents, or a group represented by the formula
-A.sup.0-A.sup.1-A.sup.2
[0163] (where
[0164] A.sup.0 represents a single bond or a C.sub.1-6 alkylene
group that may have 1 to 3 substituents selected from the
substituent group B described below;
[0165] A1 represents a single bond, an oxygen atom, a sulfur atom,
a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula --NR.sup.A--,
a group represented by the formula --CO--NR.sup.A--, a group
represented by the formula --NR.sup.A--CO--, a group represented by
the formula --SO.sub.2--NR.sup.A--, or a group represented by the
formula --NR.sup.A--SO.sub.2--;
[0166] A.sup.2 and R.sup.A each independently represent a hydrogen
atom, a C.sub.1-6 alkyl group, a C.sub.3-8 cycloalkyl group, a
C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a C.sub.6-10
aryl group, a 5 to 10-membered heteroaryl group, or a 4 to
8-membered heterocyclic group. However, A.sup.2 and R.sup.A each
may independently have 1 to 3 substituents selected from the
substituent group B described below:
[0167] except in cases where: (i) both R.sup.1 and R.sup.2 are
hydrogen atoms, and (ii) R.sup.2 is a hydroxyl group.
[0168] <Substituent B group>
[0169] Substituent group B represents the group consisting of: a
hydroxyl group, a cyano group, a halogen atom, a C.sub.1-6 alkyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group, a 5 to
10-membered heteroaryl group, a 4 to 8-membered heterocyclic group,
a C.sub.1-6 alkoky group, a C.sub.1-6 alkylthio group, and a group
represented by the formula --CO--R.sup.B--R.sup.B2 (where R.sup.B
represents a single bond, an oxygen atom, or a group represented by
the formula --NR.sup.B3--; R.sup.B2 and R.sup.B3 each independently
represent a hydrogen atom, a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl
group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, a 5 to 10-membered
heteroaryl C.sub.1-6 alkyl group, a 1-pyrrolidinyl group,
1-morpholinyl group, a 1-piperazinyl group, or a 1-piperidyl
group));
DETAILED DESCRIPTION OF THE INVENTION
[0170] The present invention is illustrated in detail below.
[0171] Herein, a structural formula of a compound sometimes
represents a certain isomer for convenience of description.
However, compounds of 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 or a mixture of both
isomers. Thus, compounds of 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, compounds of 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. Compounds of the present invention also include both
anhydrous and hydrated forms. Substances produced through in vivo
metabolism of compounds of the invention are also within the scope
of claims.
[0172] The terms and symbols used herein are defined and the
present invention is described in detail below.
[0173] As used herein, the phrase "C.sub.1-6 alkyl group" refers to
a linear or branched alkyl group containing 1 to 6 carbon atoms,
which is a monovalent group obtained by removal of any one of the
hydrogen atoms from an aliphatic hydrocarbon containing 1 to 6
carbons, and specifically, includes, for example, a methyl group,
an ethyl group, a 1-propyl group, a 2-propyl group, a
2-methyl-1-propyl group, a 2-methyl-2-propyl group, a 1-butyl
group, a 2-butyl group, a 1-pentyl group, a 2-pentyl group, a
3-pentyl group, a 2-methyl-1-butyl group, a 3-methyl-1-butyl group,
a 2-methyl-2-butyl group, a 3-methyl-2-butyl group, a
2,2-dimethyl-1-propyl group, a 1-hexyl group, a 2-hexyl group, a
3-hexyl group, a 2-methyl-1-pentyl group, a 3-methyl-1-pentyl
group, a 4-methyl-1-pentyl group, a 2-methyl-2-pentyl group, a
3-methyl-2-pentyl group, a 4-methyl-2-pentyl group, a
2-methyl-3-pentyl group, a 3-methyl-3-pentyl group, a
2,3-dimethyl-1-butyl group, a 3,3-dimethyl-1-butyl group, a
2,2-dimethyl-1-butyl group, a 2-ethyl-1-butyl group, a
3,3-dimethyl-2-butyl group, and a 2,3-dimethyl-2-butyl group.
[0174] As used herein, the phrase "C.sub.2-6 alkenyl group" refers
to a linear or branched alkenyl group containing 2 to 6 carbons,
and specifically includes, for example, a vinyl group, an allyl
group, a 1-propenyl group, a 2-propenyl group, a 1-butenyl group, a
2-butenyl group, a 3-butenyl group, a pentenyl group, and a hexenyl
group.
[0175] As used herein, the phrase "C.sub.2-6 alkynyl group" refers
to a linear or branched alkynyl group containing 2 to 6 carbons,
and specifically includes, for example, an ethynyl group, a
1-propynyl group, a 2-propynyl group, a butynyl group, a pentynyl
group, and a hexynyl group.
[0176] As used herein, the phrase "C.sub.3-8 cycloalkyl group"
refers to a cyclic aliphatic hydrocarbon group containing 3 to 8
carbon atoms, and specifically includes, for example, a cyclopropyl
group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group,
a cycloheptyl group, and a cyclooctyl group.
[0177] As used herein, the phrase "C.sub.1-6 alkylene group" refers
to a divalent group obtained by removal of another arbitrary
hydrogen atom from a "C.sub.1-6 alkyl group" defined above, and
specifically includes, for example, a methylene group, a
1,2-ethylene group, a 1,1-ethylene group, a 1,3-propylene group, a
tetramethylene group, a pentamethylene group, and a hexamethylene
group.
[0178] As used herein, the phrase "C.sub.3-8 cycloalkylene group"
refers to a divalent group obtained by removal of another arbitrary
hydrogen atom from a "C.sub.3-8 cycloalkyl group" defined
above.
[0179] As used herein, the phrase "C.sub.1-6 alkoxy group" refers
to an oxy group linked to a "C.sub.1-6 alkyl group" defined above,
and specifically includes, for example, a methoxy group, an ethoxy
group, a 1-propyloxy group, a 2-propyloxy group, a
2-methyl-1-propyloxy group, a 2-methyl-2-propyloxy group, a
1-butyloxy group, a 2-butyloxy group, a 1-pentyloxy group, a
2-pentyloxy group, a 3-pentyloxy group, a 2-methyl-1-butyloxy
group, a 3-methyl-1-butyloxy group, a 2-methyl-2-butyloxy group, a
3-methyl-2-butyloxy group, a 2,2-dimethyl-1-propyloxy group , a
1-hexyloxy group, a 2-hexyloxy group, a 3-hexyloxy group, a
2-methyl-1-pentyloxy group, a 3-methyl-1-pentyloxy group, a
4-methyl-1-pentyloxy group, a 2-methyl-2-pentyloxy group, a
3-methyl-2-pentyloxy group, a 4-methyl-2-pentyloxy group, a
2-methyl-3-pentyloxy group, a 3-methyl-3-pentyloxy group, a
2,3-dimethyl-1-butyloxy group, a 3,3-dimethyl-1-butyloxy group, a
2,2-dimethyl-1-butyloxy group, a 2-ethyl-1-butyloxy group, a
3,3-dimethyl-2-butyloxy group, and a 2,3-dimethyl-2-butyloxy
group.
[0180] As used herein, the phrase "C.sub.1-6 alkylthio group"
refers to a thio group linked to a "C.sub.1-6 alkyl group" defined
above, and specifically includes, for example, a methylthio group,
an ethylthio group, a 1-propylthio group, a 2-propylthio group, a
butylthio group, and a pentylthio group.
[0181] As used herein, the phrase "C.sub.2-7 alkoxycarbonyl group"
refers to a carbonyl group linked to a "C.sub.1-6 alkoxy group"
defined above, and specifically includes, for example, a
methoxycarbonyl group, an ethoxycarbonyl group, a
1-propyloxycarbonyl group, and a 2-propyloxycarbonyl group.
[0182] As used herein, the phrase "C.sub.2-7 alkylcarbonyl group"
refers to a carbonyl group linked to a "C.sub.1-6 alkyl group"
defined above, and specifically includes, for example, a
methylcarbonyl group, an ethylcarbonyl group, a 1-propylcarbonyl
group, and a 2-propylcarbonyl group.
[0183] As used herein, the term "halogen atom" refers to a fluorine
atom, a chlorine atom, a bromine atom, or an iodine atom.
[0184] As used herein, the phrase "C.sub.6-10 aryl group" refers to
an aromatic cyclic hydrocarbon group containing 6 to 10 carbon
atoms, and specifically includes, for example, a phenyl group, a
1-naphthyl group, and a 2-naphthyl group.
[0185] As used herein, the term "heteroatom" refers to a sulfur
atom, an oxygen atom, or a nitrogen atom.
[0186] As used herein, the phrase "5 to 10-membered heteroaryl
ring" refers to an aromatic 5 to 10-membered ring containing one or
more heteroatoms, and specifically includes, for example, a
pyridine ring, a thiophene ring, a furan ring, a pyrrole ring, an
oxazole ring, an isoxazole ring, a thiazole ring, a thiadiazole
ring, an isothiazole ring, an imidazole ring, a triazole ring, a
pyrazole ring, a furazan ring, a thiadiazole ring, an oxadiazole
ring, a pyridazine ring, a pyrimidine ring, a pyrazine ring, a
triazine ring, indole ring, an isoindole ring, an indazole ring, a
chromene ring, a quinoline ring, an isoquinoline ring, a cinnoline
ring, a quinazoline ring, a quinoxaline ring, a naphthyridine ring,
a phthalazine ring, a purine ring, a pteridine ring, a thienofuran
ring, an imidazothiazole ring, a benzofuran ring, a benzothiophene
ring, a benzoxazole ring, a benzothiazole ring, a benzothiadiazole
ring, a benzimidazole ring, an imidazopyridine ring, a
pyrrolopyridine ring, a pyrrolopyrimidine ring, and a
pyridopyrimidine ring. Preferable "5 to 10-membered heteroaryl
rings" include a pyridine ring, a thiophene ring, a furan ring, a
pyrrole ring, an imidazole ring, a 1,2,4-triazole ring, a thiazole
ring, a thiadiazole ring, a pyrazole ring, a furazan ring, a
thiadiazole ring, a pyridazine ring, a pyrimidine ring, a pyrazine
ring, an isoquinoline ring, a benzoxazole ring, a benzothiazole
ring, and a benzimidazole ring. The most preferable example is a
pyridine ring.
[0187] As used herein, the phrase "5 to 10-membered heteroaryl
group" refers to a monovalent or divalent group obtained by removal
of any one or two hydrogen atoms from a "5 to 10-membered
heteroaryl ring" described above.
[0188] As used herein, the phrase "4 to 8-membered heterocyclic
ring" refers to a non-aromatic ring in which:
[0189] (i) the number of atoms constituting the ring is 4 to 8;
[0190] (ii) the atoms constituting the ring include 1 to 2
heteroatoms;
[0191] (iii) the ring may contain 1 to 2 double bonds;
[0192] (iv) the ring may contain 1 to 3 carbonyl groups; and
[0193] (v) the ring is monocyclic.
[0194] Specifically, the 4 to 8-membered heterocyclic ring
includes, for example, an azetidine ring, a pyrrolidine ring, a
piperidine ring, an azepan ring, an azocane ring, a tetrahydrofuran
ring, a tetrahydropyran ring, a morpholine ring, a thiomorpholine
ring, a piperazine ring, a thiazolidine ring, a dioxane ring, an
imidazoline ring, a thiazoline ring, and a ring represented by one
of the formulae: 20
[0195] (where s represents an integer from 1 to 3; T.sup.3x
represents a methylene group, an oxygen atom or a group represented
by the formula --NT.sup.4x-, wherein T.sup.4x represents a hydrogen
atom or C.sub.1-6 alkyl group. Preferably the "4- to 8-membered
heterocyclic rings" include a pyrrolidine ring, a piperidine ring,
an azepan ring, a morpholine ring, a thiomorpholine ring, a
piperazine ring, a dihydrofuran-2-one ring, and a thiazolidine
ring.
[0196] As used herein, the phrase "4 to 8-membered heterocyclic
group" refers to a monovalent or divalent group obtained by removal
of any one or two hydrogen atoms from a "4 to 8-membered
heterocycle" described above. Preferably, the "4 to 8-membered
heterocyclic groups" include a piperidin-1-yl group, a
pyrrolidin-1-yl group, and a morpholin-4-yl group.
[0197] As used herein, the phrase "C.sub.6-10 aryl C.sub.1-6 alkyl
group" refers to a group obtained by substitution of a "C.sub.6-10
aryl group" defined above for an arbitrary hydrogen atom in a
"C.sub.1-6 alkyl group" defined above, and specifically includes,
for example, a benzyl group, a phenethyl group, and a
3-phenyl-1-propyl group.
[0198] As used herein, the phrase "5 to 10-membered heteroaryl
C.sub.1-6 alkyl group" refers to a group obtained by substitution
of a "5 to 10-membered heteroaryl group" defined above for an
arbitrary hydrogen atom in a "C.sub.1-6 alkyl group" defined above,
and specifically, includes for example, a 2-pyridylmethyl and a
2-thienylmethyl group.
[0199] As used herein, the phrase "4 to 8-membered heterocyclic
C.sub.1-6 alkyl group" refers to a group obtained by substitution
of a "4 to 8-membered heterocyclic group" defined above for an
arbitrary hydrogen atom in a "C.sub.1-6 alkyl group" defined
above.
[0200] As used herein, the phrase "monocyclic or bicyclic 4 to
12-membered heterocyclic group containing one or two nitrogen atoms
in the ring, that may have one or more substituents" refers to a
non-aromatic cyclic group which may have one or more substituents.
In the non-aromatic cyclic groups:
[0201] (i) the number of atoms constituting the ring of the cyclic
group is 4 to 12;
[0202] (ii) the atoms constituting the ring of the cyclic group
include one or two nitrogen atoms; and
[0203] (iii) the group is a monocyclic or bicyclic structure.
[0204] Specifically, the group is represented by the formula:
21
[0205] (where n and m each independently represent 0 or 1; R.sup.31
to R.sup.44 independently represent a hydrogen atom or a
substituent selected from substituents referred to in the phrase
"which may have one or more substituents" (the substituent group S
defined below); any two of R.sup.31 to R.sup.44 may in combination
form a C.sub.1-6 alkylene group).
[0206] As used herein, the phrase "which may have one or more
substituents" means that a group may have one or more substituents
in any combination at replaceable positions. Specifically, such
substituents include, for example, a substituent selected from the
substituent group S defined below.
[0207] <Substituent group S>
[0208] This group consists of:
[0209] (1) a halogen atom,
[0210] (2) a hydroxyl group,
[0211] (3) a mercapto group,
[0212] (4) a nitro group,
[0213] (5) a cyano group,
[0214] (6) a formyl group,
[0215] (7) a carboxyl group,
[0216] (8) a trifluoromethyl group,
[0217] (9) a trifluoromethoxy group,
[0218] (10) an amino group,
[0219] (11) an oxo group,
[0220] (12) an imino group, and
[0221] (13) a group represented by the formula
-T.sup.1x-T.sup.2
[0222] (where
[0223] T.sup.1x is a single bond, a C.sub.1-6 alkylene group, an
oxygen atom, a group represented by the formula --CO--, a group
represented by the formula --S--, a group represented by the
formula --S(O)--, a group represented by the formula
--S(O).sub.2--, a group represented by the formula --O--CO--, a
group represented by the formula --CO--O--, a group represented by
the formula --NR.sup.T--, a group represented by the formula
--CO--NR.sup.T--, a group represented by the formula
--NR.sup.T--CO--, a group represented by the formula
--SO.sub.2--NR.sup.T--, a group represented by the formula
--NR.sup.T--SO.sub.2--, a group represented by the formula
--NH--CO--NR.sup.T-- or a group represented by the formula
--NH--CS--NR.sup.T--;
[0224] T.sup.2x represents a hydrogen atom, a C.sub.1-6 alkyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a phenyl group, a 1-naphthyl group, a
2-naphthyl group, a 5 to 10-membered heteroaryl group or a 4 to
8-membered heterocyclic group;
[0225] R.sup.T represents a hydrogen atom, a C.sub.1-6 alkyl group,
a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group or a
C.sub.2-6 alkynyl group;
[0226] provided that T.sup.2x and R.sup.T each may independently
have 1 to 3 substituents selected from the substituent group T
defined below).
[0227] <Substituent group T>
[0228] This group consists of: hydroxyl, cyano, a halogen atom,
C.sub.1-6 alkyl, C.sub.3-8 cycloalkyl, C.sub.2-6 alkenyl, C.sub.2-6
alkynyl, phenyl, 1-naphthyl, 2-naphthyl, 5 to 10-membered
heteroaryl, 4 to 8-membered heterocyclic ring, C.sub.1-6 alkoxy,
C.sub.1-6 alkylthio, C.sub.2-7 alkoxycarbonyl group, etc.
[0229] The <substituent group S>preferably consists of:
[0230] (1) a halogen atom,
[0231] (2) a hydroxyl group,
[0232] (3) a cyano group,
[0233] (4) a carboxyl group,
[0234] (5) a trifluoromethyl group,
[0235] (6) a trifluoromethoxy group,
[0236] (7) an amino group,
[0237] (8) a C.sub.1-6 alkyl group,
[0238] (9) a C.sub.3-8 cycloalkyl group,
[0239] (10) a C.sub.2-6 alkenyl group,
[0240] (11) a C.sub.2-6 alkynyl group,
[0241] (12) a phenyl group, and
[0242] (13) a C.sub.1-6 alkoxy group.
[0243] As used herein, the term "group represented by the formula:
22
[0244] (where n and m each independently represent 0 or 1), which
may have one or more substituents" refers to a group represented by
the formula: 23
[0245] (where R.sup.31 to R.sup.44 independently represent a
hydrogen atom or a group selected from substituents referred to in
the phrase "which may have one or more substituents" defined above
(the substituent group S defined above); n and m each independently
represent 0 or 1). The case where m=n=0 is preferred. More
preferably, the term refers to a group represented by one of the
formulae: 24
[0246] (where R.sup.31, R.sup.32, R.sup.33, R.sup.34, and R.sup.35
independently represent a hydrogen atom or a group selected from
substituent groups referred to in the phrase "which may have one or
more substituents" (the substituent group S defined above));
provided that, at least three of R.sup.31, R.sup.32, R.sup.33,
R.sup.34, and R.sup.35 are hydrogen atoms Still more preferably,
the term refers to a group represented by one of the formulae:
25
[0247] Most preferably, the term refers to a group represented by
the formula: 26
[0248] As used herein, the term "group represented by the formula:
27
[0249] (where n and m each independently represent 0 or 1)" refers
to a group represented by one of the formulae: 28
[0250] As used herein, the term "piperidin-1-yl group which may
have one or more substituents" refers to a "piperidin-1-yl group"
which may have one or more substituents selected from the groups
referred to in the phrase "which may have one or more substituents"
(the substituent group S defined above) at replaceable positions.
Preferably, the "piperidin-1-yl group which may have one or more
substituents" refers to a group represented by the formula: 29
[0251] (where R.sup.31, R.sup.32, R.sup.33, R.sup.34 and R.sup.35
each independently represent a hydrogen atom or a group selected
from the substituents referred to in the phrase "which may have one
or more substituents" (the substituent group S defined above));
provided that, at least three of R.sup.31, R.sup.32, R.sup.33,
R.sup.34, and R.sup.35 are hydrogen atoms. Preferably, the term
refers to a group represented by one of the formulae: 30
[0252] More preferably, the term refers to a group represented by
one of the formulae: 31
[0253] As used herein, the phrase "azetidin-1-yl group may have one
or more substituents" refers to an "azetidin-1-yl group" which may
have one or more groups selected from the substituents referred to
in the phrase "which may have one or more substituents" at
replaceable positions.
[0254] As used herein, the phrase "pyrrolidin-1-yl group may have
one or more substituents" refers to a "pyrrolidin-1-yl group" which
may have one or more groups selected from the substituents referred
to in the phrase "which may have one or more substituents" at
replaceable positions.
[0255] As used herein, the phrase "piperidin-1-yl group may have
one or more substituents" refers to a "piperidin-1-yl group" which
may have one or more groups selected from the substituents referred
to in the phrase "which may have one or more substituents" at
replaceable positions.
[0256] As used herein, the phrase "azepan-1-yl group may have one
or more substituents" refers to an "azepan-1-yl group" which may
have one or more groups selected from the substituents referred to
in the phrase "which may have one or more substituents" at
replaceable positions.
[0257] As used herein, the phrase "piperidin-1-yl group which may
have an amino group" refers to a "piperidin-1-yl group" which may
have an amino group at a replaceable position. Specifically, the
"piperidin-1-yl group which may have an amino group", for example,
refers to the group represented by one of the formulae: 32
[0258] and preferably, to the group represented by one of the
formulae: 33
[0259] As used herein, the phrase "azetidin-1-yl group which may
have an amino group" refers to an "azetidin-1-yl group" which may
have an amino group at a replaceable position.
[0260] As used herein, the phrase "pyrrolidin-1-yl group which may
have an amino group" refers to a "pyrrolidin-1-yl group" which may
have an amino group at a replaceable position.
[0261] As used herein, the phrase "piperidin-1-yl group which may
have an amino group" refers to a "piperidin-1-yl group" which may
have an amino group at a replaceable position.
[0262] As used herein, the phrase "azepan-1-yl group which may have
an amino group" refers to an "azepan-1-yl group" which may have an
amino group at a replaceable position.
[0263] As used herein, the phrase "C.sub.1-6 alkyl group which may
have one or more substituents" in the substituent group B defined
above refers to a "C.sub.1-6 alkyl group" which may have one or
more groups selected from the substituents referred to in the
phrase "which may have one or more substituents" at replaceable
positions. Preferably, the "C.sub.1-6 alkyl group which may have
one or more substituents" refers to a C.sub.1-6 alkyl group which
may have one or two substituents selected from the group consisting
of a cyano group, a carboxyl group, a C.sub.2-7 alkoxycarbonyl
group, a group represented by the formula --NR.sup.3TCOR.sup.4T, a
group represented by the formula --CONR.sup.3TR.sup.4T (where
R.sup.3T and R.sup.4T each independently represent a hydrogen atom
or a C.sub.1-6 alkyl group), and a C.sub.1-6 alkoxy group.
[0264] In a compound represented by formula (I) indicated above,
R.sup.1 and R.sup.2 each independently represent a group of the
formula -A.sup.0-A.sup.1-A.sup.2 (where A.sup.0, A.sup.1, and
A.sup.2 are as defined above); when both A.sup.0 and A.sup.1 are
single bonds, "-A.sup.0-A.sup.1-" represents a single bond.
[0265] In formula (I) indicated above, the phrase "when Z.sup.2
represents a group of the formula --CR.sup.2.dbd., R.sup.1, and
R.sup.2 may in combination form a 5 to 7-membered ring" means that
compounds represented by formula (I) indicated above includes
compounds (II) represented by the formula: 34
[0266] (where Z.sup.1, X, and T.sup.1 are as defined above;
A.sup.T1 represents an oxygen atom, a sulfur atom, a sulfinyl
group, a sulfonyl group, a carbonyl group, a methylene group which
may have one or more substituents, or a nitrogen atom which may
have one or more substituents; A.sup.T2 represents a C.sub.2-6
alkylene group which may have one or more substituents). In formula
(II) shown above, A.sup.T1 preferably represents an oxygen atom,
and A.sup.T2 preferably represents a C.sub.2-4 alkylene group.
[0267] As used herein, the phrase "cyanobenzyl group" refers to a
benzyl group having one cyano group, and specifically, includes,
for example, a 2-cyanobenzyl group, a 3-cyanobenzyl group, and a
4-cyanobenzyl group.
[0268] As used herein, the phrase "fluorocyanobenzyl group" refers
to a benzyl group having one fluorine atom and one cyano group, and
specifically, includes, for example, a 2-cyano-4-fluorobenzyl group
and a 2-cyano-6-fluorobenzyl group.
[0269] As used herein, the phrase "carbamoylphenoxy group" refers
to a phenoxy group having a group represented by the formula
--CONH.sub.2, and specifically, includes, for example, a
2-carbamoylphenoxy group, a 3-carbamoylphenoxy group, and a
4-carbamoylphenoxy group.
[0270] Herein, there is no limitation on the type of "salts" as
long as salts are pharmaceutically acceptable and derived from any
compound of the present invention. Such salts include, for example,
inorganic acid salts, organic acid salts, inorganic base salts,
organic base salts, and acidic or basic amino acid salts.
[0271] Examples of preferred inorganic salts include hydrochloride,
hydrobromide, sulfate, nitrate, and phosphate. Examples of
preferred organic salts include acetate, succinate, fumarate,
maleate, tartrate, citrate, lactate, stearate, benzoate,
methanesulfonate, and p-toluene sulfonate.
[0272] Examples of preferred inorganic base salts include: alkali
metal salts such as sodium salts and potassium salts; alkaline
earth metal salts such as calcium salts and magnesium salts;
aluminum salts; and ammonium salts. Examples of preferred organic
base salts include diethylamine salts, diethanolamine salts,
meglumine salts, and N,N'-dibenzylethylenediamine salts.
[0273] Examples of preferred acidic amino acid salts include
aspartate and glutamate. Examples of preferred basic amino acid
salts include arginine salts, lysine salts, and ornithine
salts.
[0274] The present invention provides compounds represented by the
following formula (I), or salts or hydrates thereof: 35
[0275] wherein,
[0276] T.sup.1 represents a monocyclic or bicyclic 4- to
12-membered heterocyclic group containing one or two nitrogen atoms
in the ring, and may have one or more substituents;
[0277] X represents a C.sub.1-6 alkyl group which may have one or
more substituents, a C.sub.2-6 alkenyl group which may have one or
more substituents, a C.sub.2-6 alkynyl group which may have one or
more substituents, a C.sub.6-10 aryl group which may have one or
more substituents, a 5- to 10-membered heteroaryl group which may
have one or more substituents, a C.sub.6-10 aryl C.sub.1-6 alkyl
group which may have one or more substituents, or a 5- to
10-membered heteroaryl C.sub.1-6 alkyl group which may have one or
more substituents;
[0278] Z.sup.1 and Z.sup.2 each independently represent a nitrogen
atom or a group represented by the formula --CR.sup.2.dbd.;
[0279] R.sup.1 and R.sup.2 each independently represent a group of
the formula -A.sup.0-A.sup.1-A.sup.2
[0280] (where
[0281] A.sup.0 represents a single bond or a C.sub.1-6 alkylene
group which may have 1 to 3 substituents selected from the
substituent group B described below;
[0282] A.sup.1 represents a single bond, an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula --NR.sup.A--,
a group represented by the formula --CO--NR.sup.A--, a group
represented by the formula --NR.sup.A--CO--, a group represented by
the formula --SO.sub.2--NR.sup.A--, or a group represented by the
formula --NR.sup.A--SO.sub.2--;
[0283] A.sup.2 and R.sup.A each independently represent a hydrogen
atom, a halogen atom, a cyano group, a C.sub.1-6 alkyl group, a
C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6
alkynyl group, a C.sub.6-10 aryl group, a 5 to 10-membered
heteroaryl group, a 4 to 8-membered heterocyclic group, a 5 to
10-membered heteroaryl C.sub.1-6 alkyl group, a C.sub.6-10 aryl
C.sub.1-6 alkyl group, or a C.sub.2-7 alkylcarbonyl group, provided
that, A2 and R.sup.A each may independently have 1 to 3
substituents selected from the substituent group B defined
below);
[0284] when Z.sup.2 represents a group of the formula
--CR.sup.2.dbd., R.sup.1 and R.sup.2 may in combination form a 5 to
7-membered ring.
[0285] However the cases where: [1] R.sup.1 is a hydrogen atom;
Z.sup.1 is a nitrogen atom; and Z.sup.2 is --CH.dbd.; and [2]
Z.sup.1 is a nitrogen atom; and Z.sup.2 is --C(OH).dbd. are
excluded.
[0286] <Substituent B group>
[0287] The substituent group B represents the group consisting of:
a hydroxyl group, a mercapto group, a cyano group, a nitro group, a
halogen atom, a trifluoromethyl group, a C.sub.1-6 alkyl group
which may have one or more substituents, a C.sub.3-8 cycloalkyl
group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl group, a
C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl group, a 4 to
8-membered heterocyclic group, a C.sub.1-6 alkoxy group, a
C.sub.1-6 alkylthio group, a group represented by the formula
--SO.sub.2--NR.sup.B1--R.sup.B2, a group represented by the formula
--NR.sup.B1--CO--R.sup.B2, a group represented by the formula
--NR.sup.B1--R.sup.B2 (where R.sup.B1 and R.sup.B2 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.B3 (where
R.sup.B3 represents a 4 to 8-membered heterocyclic group), a group
represented by the formula --CO--R.sup.B4--R.sup.B5, and a group
represented by the formula --CH.sub.2--CO--R.sup.B4--R.sup.B5
(where R.sup.B4 represents a single bond, an oxygen atom or a group
represented by the formula --NR.sup.B6--; R.sup.B5 and R.sup.B6
each independently represent a hydrogen atom, a C.sub.1-6 alkyl
group, a C.sub.3-8 cycloalkyl group, a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, a C.sub.6-10 aryl group, a 5 to
10-membered heteroaryl group, a 4 to 8-membered heterocyclic
C.sub.1-6 alkyl group, a C.sub.6-10 aryl C.sub.1-6 alkyl group, or
a 5 to 10-membered heteroaryl C.sub.1-6 alkyl group).
[0288] Preferable compounds represented by the formula (I) include,
for example, the following compounds:
[0289] (1) compounds in which either but not both of Z.sup.1 and
Z.sup.2 is a nitrogen atom;
[0290] (2) compounds in which Z.sup.1 is a nitrogen atom; Z.sup.2
is a group represented by the formula --CR.sup.2.dbd. (where
R.sup.2 has the same definition as R.sup.2 defined above);
[0291] (3) compounds in which Z.sup.2 is a nitrogen atom; Z.sup.1
is a group represented by the formula --CR.sup.2.dbd. (where
R.sup.2 has the same definition as R.sup.2 defined above);
[0292] (4) compounds in which T.sup.1 is a group which may have one
or more substituents and is represented by the formula: 36
[0293] (where n and m each independently represent 0 or 1), an
azetidin-1-yl group which may have one or more substituents, a
pyrrolidin-1-yl group which may have one or more substituents, a
piperidin-1-yl group which may have one or more substituents, or an
azepan-1-yl group which may have one or more substituents;
[0294] (5) compounds in which T.sup.1 is a group represented by the
formula: 37
[0295] (where n and m each independently represent 0 or 1), an
azetidin-1-yl group which may have an amino group, a
pyrrolidin-1-yl group which may have an amino group, a
piperidin-1-yl group which may have an amino group, or an
azepan-1-yl group which may have an amino group;
[0296] (6) compounds in which T.sup.1 is a piperazin-1-yl group or
a 3-amino piperidin-1-yl group;
[0297] (7) compounds in which T.sup.1 is a piperazin-1-yl
group;
[0298] (8) compounds in which X is a group represented by the
formula --X.sup.1--X.sup.2 (where X.sup.1 represents a single bond
or a methylene group which may have one or more substituents;
X.sup.2 represents a C.sub.2-6 alkenyl group which may have one or
more substituents, a C.sub.2-6 alkynyl group may have one or more
substituents, or a phenyl group which may have one or more
substituents);
[0299] (9) compounds in which X is a group of the formula
--X.sup.11--X.sup.12 (where X.sup.11 represents a single bond or a
methylene group; X.sup.12 represents a C.sub.2-6 alkenyl group, a
C.sub.2-6 alkynyl group, or a phenyl group which may have one or
more substituents);
[0300] (10) compounds in which, the phenyl group, which may have
one or more substituents, of X represented by the group of the
above formula --X.sup.11--X.sup.12, is a phenyl group which may
have, at the 2 position, a substituent selected from the group
consisting of: a hydroxyl group, a fluorine atom, a chlorine atom,
a methyl group, a ethyl group, a fluoromethyl group, a vinyl group,
a methoxy group, an ethoxy group, an acetyl group, a cyano group, a
formyl group, and a C.sub.2-7 alkoxycarbonyl group;
[0301] (11) compounds in which X is a 3-methyl-2-buten-1-yl group,
a 2-butyn-1-yl group, a benzyl group, or a 2-chlorophenyl
group;
[0302] (12) compounds in which X is a 2-butyn-1-yl group;
[0303] (13) compounds in which R.sup.1 is a hydrogen atom or a
group represented by the formula -A.sup.10-A.sup.11-A.sup.12
[0304] wherein
[0305] A.sup.10 represents a C.sub.1-6 alkylene group which may
have 1 to 3 substituents selected from the substituent group C
described below;
[0306] A.sup.11 represents a single bond, an oxygen atom, a sulfur
atom, or a carbonyl group;
[0307] A.sup.12 represents a hydrogen atom, a C.sub.6-10 aryl group
which may have 1 to 3 substituents selected from the substituent
group C described below, a 5 to 10-membered heteroaryl group which
may have 1 to 3 substituents selected from the substituent group C
described below, a 5 to 10-membered heteroaryl C.sub.1-6 alkyl
group which may have 1 to 3 substituents selected from the
substituent group C described below, or a C.sub.6-10 aryl C.sub.1-6
alkyl group which may have 1 to 3 substituents selected from the
substituent group C described below;
[0308] <Substituent group C>
[0309] The substituent group C represents the group consisting of:
a hydroxyl group, a nitro group, a cyano group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.C1--R.sup.C2, (where each of R.sup.C1 and
R.sup.C2 independently represent a hydrogen atom or a C.sub.1-6
alkyl group), a group represented by the formula
--CO--R.sup.C3--R.sup.C4 and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group);
[0310] (14) compounds in which R.sup.1 is a hydrogen atom, a
C.sub.1-6 alkyl group which may have 1 to 3 substituents selected
from the substituent group C described below, a 5 to 10-membered
heteroaryl C.sub.1-6 alkyl group which may have 1 to 3 substituents
selected from the substituent group C described below, or a
C.sub.6-10 aryl C.sub.1-6 alkyl group which may have 1 to 3
substituents selected from the substituent group C described
below;
[0311] <Substituent group C>
[0312] The substituent group C represents the group consisting of:
a hydroxyl group, a nitro group, a cyano group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.C1--R.sup.C2 (where R.sup.C1 and R.sup.C2 each
independently represent a hydrogen atom, or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.C3--R.sup.C4
and a group represented by the formula
--CH.sub.2--CO--R.sup.C3--R.sup.C4 (where R.sup.C3 represents a
single bond, an oxygen atom, or a group represented by the formula
--NR.sup.C5--; R.sup.C4 and R.sup.C5 each independently represent a
hydrogen atom or a C.sub.1-6 alkyl group);
[0313] (15) compounds in which, the substituent group C defined
above for a group of the formula -A.sup.10-A.sup.11-A.sup.12 that
is represented by R.sup.1, consists of a cyano group, a C.sub.1-6
alkoxy group, a C.sub.2-7 alkoxycarbonyl group, and a halogen
atom;
[0314] (16) compounds in which R.sup.1 is a methyl group, a
cyanobenzyl group, a fluorocyanobenzyl group, a phenethyl group, a
2-methoxyethyl group or a 4-methoxycarbonyl-pyridin-2-yl group;
[0315] (17) compounds in which R.sup.1 is a methyl group or a
2-cyanobenzyl group;
[0316] (18) compounds in which R.sup.2 is a hydrogen atom, a cyano
group, or a group represented by the formula
-A.sup.21-A.sup.22;
[0317] wherein
[0318] A.sup.21 represents a single bond, an oxygen atom, a sulfur
atom, a sulfinyl group, a sulfonyl group, a carbonyl group, a group
represented by the formula --O--CO--, a group represented by the
formula --CO--O--, a group represented by the formula
--NR.sup.A2--, a group represented by the formula
--CO--NR.sup.A2--, or a group represented by the formula
--NR.sup.A2--CO--;
[0319] A.sup.22 and R.sup.A2 each independently represent a
hydrogen atom, a cyano group, a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5 to 10-membered heteroaryl
group, a 4 to 8-membered heterocyclic group, a 5 to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, provided that, A.sup.22 and R.sup.A2 each
independently may have 1 to 3 substituents selected from the
substituent group D described below;
[0320] <Substituent group D>
[0321] The substituent group D represents the group consisting of a
hydroxyl group, a cyano group, a nitro group, a halogen atom, a
C.sub.1-6 alkyl group, a C.sub.1-6 alkoxy group, a C.sub.1-6
alkylthio group, a trifluoromethyl group, a group represented by
the formula --NR.sup.D1--R.sup.D2 (where R.sup.D1 and R.sup.D2 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a group represented by the formula --CO--R.sup.D3 (where
R.sup.D3 represents a 4 to 8-membered heterocyclic group), and a
group represented by the formula --CO--R.sup.D4--R.sup.D5 (where
R.sup.D4 represents a single bond, an oxygen atom, or a group
represented by the formula --NR.sup.D6--; R.sup.D5 and R.sup.D6
each independently represent a hydrogen atom, a C.sub.3-8
cycloalkyl group or a C.sub.1-6 alkyl group);
[0322] (19) a compound in which R.sup.2 is a hydrogen atom, a cyano
group, a carboxy group, a C.sub.2-7 alkoxycarbonyl group, a
C.sub.1-6 alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or C.sub.1-6 alkyl group),
a group represented by the formula -A.sup.23-A.sup.24 (where
A.sup.23 represents an oxygen atom, a sulfur atom, or a group
represented by the formula --NR.sup.A3--; A.sup.24 and R.sup.A3
each independently represent a hydrogen atom, a C.sub.1-6 alkyl
group which may have a substituent selected from the substituent
group D1 described below, a C.sub.3-8 cycloalkyl group which may
have a substituent selected from the substituent group D1 described
below, a C.sub.2-6 alkenyl group which may have a substituent
selected from the substituent group D1 described below, a C.sub.2-6
alkynyl group which may have a substituent selected from the
substituent group D1 described below, a phenyl group which may have
a substituent selected from the substituent group D1 described
below, or a 5 to 10-membered heteroaryl group which may have a
substituent selected from the substituent group D1 described
below;
[0323] <Substituent group D1>
[0324] The substituent group D1 represents the group consisting of
a carboxy group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6
alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or C.sub.1-6 alkyl group),
a pyrrolidin-1-ylcarbonyl group, a C.sub.1-6 alkyl group, and a
C.sub.1-6 alkoxy group;
[0325] (20) compounds in which R.sup.2 is a hydrogen atom, a cyano
group, a C.sub.1-6 alkoxy group, or a group of the formula
-A.sup.25-A.sup.26 (where A.sup.25 represents an oxygen atom, a
sulfur atom, or a group represented by the formula --NR.sup.A4--;
A.sup.26 and R.sup.A4 each independently represent a hydrogen atom,
a C.sub.1-6 alkyl group having a substituent selected from the
substituent group D1 described below, a C.sub.3-8 cycloalkyl group
having a substituent selected from the substituent group D1
described below, or a phenyl group having a substituent selected
from the substituent group D1 described below);
[0326] <Substituent group D1>
[0327] The substituent group D1 represents the group consisting of
a carboxyl group, a C.sub.2-7 alkoxycarbonyl group, a C.sub.1-6
alkyl group, a group represented by the formula
--CONR.sup.D7R.sup.D8 (where R.sup.D7 and R.sup.D8 each
independently represent a hydrogen atom or a C.sub.1-6 alkyl
group), a pyrrolidin-1-ylcarbonyl group, a C.sub.1-6 alkyl group,
and a C.sub.1-6 alkoxy group;
[0328] (21) compounds in which R.sup.2 is a hydrogen atom, a cyano
group, a methoxy group, a carbamoylphenyloxy group, a group
represented by one of the formulae: 38
[0329] (where
[0330] A.sup.27 represents an oxygen atom, a sulfur atom, or a
group represented by the formula --NH--;
[0331] A.sup.28 an A.sup.29 each independently represent a hydrogen
atom or a C.sub.1-6 alkyl group);
[0332] (22) compounds in which R.sup.2 is a hydrogen atom, a cyano
group, or a carbamoylphenyloxy group.
[0333] Among the compounds shown above, with respect to Z.sup.1 and
Z.sup.2, the order of preference is (1) to (3) with (3) the most
preferable; with respect to T.sup.1, the order of preference is (4)
to (7) with (7) the most preferable; with respect to X, the order
of preference is (8) to (12) with (12) the most preferable; with
respect to R.sup.1, the order of preference is (13) to (17) with
(17) the most preferable; with respect to R.sup.2, the order of
preference is (18) to (22) with (22) the most preferable.
[0334] Furthermore, preferred compounds represented by above
formula (I) include compounds defined by any 2 to 5 embodiments
selected from the groups consisting of (1)-(3), (4)-(7), (8)-(12),
(13)-(17), and (18)-(22).
[0335] Preferable compounds include, for example, compounds defined
by the following specific combinations of embodiments:
[0336] (i) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (1), (4), (8), (13), and (18) described above,
respectively;
[0337] (ii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (11), (16), and (19) described above,
respectively;
[0338] (iii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (11), (16), and (20) described above,
respectively;
[0339] (iv) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (11), (16), and (21) described above,
respectively;
[0340] (v) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (11), (16), and (22) described above,
respectively;
[0341] (vi) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (12) (17), and (19) described above,
respectively;
[0342] (vii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (12), (17), and (20) described above,
respectively;
[0343] (viii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (12), (17) and (21) described above,
respectively;
[0344] (ix) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (2), (6), (12), (17), and (22) described above,
respectively;
[0345] (x) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (11), (16), and (19) described above,
respectively;
[0346] (xi) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (11), (16), and (20) described above,
respectively;
[0347] (xii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (11), (16), and (21) described above,
respectively;
[0348] (xiii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (11), (16) and (22) described above,
respectively;
[0349] (xiv) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (12), (17), and (19) described above,
respectively;
[0350] (xv) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (12), (17), and (20) described above,
respectively;
[0351] (xvi) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (12), (17), and (21) described above,
respectively;
[0352] (xvii) compounds represented by above formula (I), in which
Z.sup.1 and Z.sup.2, T.sup.1, X, R.sup.1, and R.sup.2 represent
those in (3), (6), (12), (17) and (22) described above,
respectively.
[0353] Of these, for (ii) to (ix), preference increases in the
order (ii) to (ix) while for (x) to (xvii), preference increases in
the order (x) to (xvii).
[0354] Specific examples of compounds of the formula (I) are listed
in the following table, but are not limited thereto. 39
[0355] The abbreviations used in the table have the following
meanings:
[0356] P1, piperazin-1-yl; P2, 3-amino-piperidin-1-yl; 2Btyn,
2-butyn-1-yl; 3Me2Bten, 3-methyl-2-buten-1-yl; Me, methyl; Et,
ethyl; 2-CNBen, 2-cyanobenzyl; 6F2CNBen, 6-fluoro-2-cyanobenzyl;
Phenethyl, 2-phenylethyl; 2Ph2OxEt, 2-phenyl-2-oxoethyl;
--CR2.dbd., --CR.sup.2.dbd.
1 Z.sup.1 Z.sup.2 T.sup.1 X R.sup.1 R.sup.2 1 N --CR2.dbd. P1 2Btyn
--CH.sub.3 --H 2 N --CR2.dbd. P1 2Btyn --CH.sub.3 --CN 3 N
--CR2.dbd. P1 2Btyn --CH.sub.3 --OMe 4 N --CR2.dbd. P1 2Btyn
--CH.sub.3 --O--1-C.sub.2H.sub.4--1-CO.sub.2Et 5 N --CR2.dbd. P1
2Btyn --CH.sub.3 --O--CH.sub.2--CO.sub.2Et 6 N --CR2.dbd. P1 2Btyn
--CH.sub.3 --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 7 N --CR2.dbd. P1
2Btyn --CH.sub.3 --S--CH.sub.2--CO.sub.2Me 8 N --CR2.dbd. P1 2Btyn
--CH.sub.3 carbamoylphenyloxy 9 N --CR2.dbd. P1 2Btyn 2-CNBen --H
10 N --CR2.dbd. P1 2Btyn 2-CNBen --CN 11 N --CR2.dbd. P1 2Btyn
2-CNBen --OMe 12 N --CR2.dbd. P1 2Btyn 2-CNBen
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 13 N --CR2.dbd. P1 2Btyn
2-CNBen --O--CH.sub.2--CO.sub.2Et 14 N --CR2.dbd. P1 2Btyn 2-CNBen
--O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 15 N --CR2.dbd. P1 2Btyn
2-CNBen --S--CH.sub.2--CO.sub.2Me 16 N --CR2.dbd. P1 2Btyn 2-CNBen
carbamoylphenyloxy 17 N --CR2.dbd. P1 2Btyn 6F2CNBen --H 18 N
--CR2.dbd. P1 2Btyn 6F2CNBen --CN 19 N --CR2.dbd. P1 2Btyn 6F2CNBen
--OMe 20 N --CR2.dbd. P1 2Btyn 6F2CNBen
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 21 N --CR2.dbd. P1 2Btyn
6F2CNBen --O--CH.sub.2--CO.sub.2Et 22 N --CR2.dbd. P1 2Btyn
6F2CNBen --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 23 N --CR2.dbd. P1
2Btyn 6F2CNBen --S--CH.sub.2--CO.sub.2Me 24 N --CR2.dbd. P1 2Btyn
6F2CNBen carbamoylphenyloxy 25 N --CR2.dbd. P1 2Btyn Phenethyl --H
26 N --CR2.dbd. P1 2Btyn Phenethyl --CN 27 N --CR2.dbd. P1 2Btyn
Phenethyl --OMe 28 N --CR2.dbd. P1 2Btyn Phenethyl
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 29 N --CR2.dbd. P1 2Btyn
Phenethyl --O--CH.sub.2--CO.sub.2Et 30 N --CR2.dbd. P1 2Btyn
Phenethyl --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 31 N --CR2.dbd. P1
2Btyn Phenethyl --S--CH.sub.2--CO.sub.2Me 32 N --CR2.dbd. P1 2Btyn
Phenethyl carbamoylphenyloxy 33 N --CR2.dbd. P1 2Btyn 2Ph2OxEt --H
34 N --CR2.dbd. P1 2Btyn 2Ph2OxEt --CN 35 N --CR2.dbd. P1 2Btyn
2Ph2OxEt --OMe 36 N --CR2.dbd. P1 2Btyn 2Ph2OxEt
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 37 N --CR2.dbd. P1 2Btyn
2Ph2OxEt --O--CH.sub.2--CO.sub.2Et 38 N --CR2.dbd. P1 2Btyn
2Ph2OxEt --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 39 N --CR2.dbd. P1
2Btyn 2Ph2OxEt --S--CH.sub.2--CO.sub.2Me 40 N --CR2.dbd. P1 2Btyn
2Ph2OxEt carbamoylphenyloxy 41 N --CR2.dbd. P2 2Btyn --CH.sub.3 --H
42 N --CR2.dbd. P2 2Btyn --CH.sub.3 --CN 43 N --CR2.dbd. P2 2Btyn
--CH.sub.3 --OMe 44 N --CR2.dbd. P2 2Btyn --CH.sub.3
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 45 N --CR2.dbd. P2 2Btyn
--CH.sub.3 --O--CH.sub.2--CO.sub.2Et 46 N --CR2.dbd. P2 2Btyn
--CH.sub.3 --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 47 N --CR2.dbd. P2
2Btyn --CH.sub.3 --S--CH.sub.2--CO.sub.2Me 48 N --CR2.dbd. P2 2Btyn
--CH.sub.3 carbamoylphenyloxy 49 N --CR2.dbd. P2 2Btyn 2-CNBen --H
50 N --CR2.dbd. P2 2Btyn 2-CNBen --CN 51 N --CR2.dbd. P2 2Btyn
2-CNBen --OMe 52 N --CR2.dbd. P2 2Btyn 2-CNBen
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 53 N --CR2.dbd. P2 2Btyn
2-CNBen --O--CH.sub.2--CO.sub.2Et 54 N --CR2.dbd. P2 2Btyn 2-CNBen
--O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 55 N --CR2.dbd. P2 2Btyn
2-CNBen --S--CH.sub.2--CO.sub.2Me 56 N --CR2.dbd. P2 2Btyn 2-CNBen
carbamoylphenyloxy 57 N --CR2.dbd. P2 2Btyn 6F2CNBen --H 58 N
--CR2.dbd. P2 2Btyn 6F2CNBen --CN 59 N --CR2.dbd. P2 2Btyn 6F2CNBen
--OMe 60 N --CR2.dbd. P2 2Btyn 6F2CNBen
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 61 N --CR2.dbd. P2 2Btyn
6F2CNBen --O--CH.sub.2--CO.sub.2Et 62 N --CR2.dbd. P2 2Btyn
6F2CNBen --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 63 N --CR2.dbd. P2
2Btyn 6F2CNBen --S--CH.sub.2--CO.sub.2Me 64 N --CR2.dbd. P2 2Btyn
6F2CNBen carbamoylphenyloxy 65 N --CR2.dbd. P2 2Btyn Phenethyl --H
66 N --CR2.dbd. P2 2Btyn Phenethyl --CN 67 N --CR2.dbd. P2 2Btyn
Phenethyl --OMe 68 N --CR2.dbd. P2 2Btyn Phenethyl
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 69 N --CR2.dbd. P2 2Btyn
Phenethyl --O--CH.sub.2--CO.sub.2Et 70 N --CR2.dbd. P2 2Btyn
Phenethyl --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 71 N --CR2.dbd. P2
2Btyn Phenethyl --S--CH.sub.2--CO.sub.2Me 72 N --CR2.dbd. P2 2Btyn
Phenethyl carbamoylphenyloxy 73 N --CR2.dbd. P2 2Btyn 2Ph2OxEt --H
74 N --CR2.dbd. P2 2Btyn 2Ph2OxEt --CN 75 N --CR2.dbd. P2 2Btyn
2Ph2OxEt --OMe 76 N --CR2.dbd. P2 2Btyn 2Ph2OxEt
--O--1-C.sub.2H.sub.4--1-CO.sub.2Et 77 N --CR2.dbd. P2 2Btyn
2Ph2OxEt --O--CH.sub.2--CO.sub.2Et 78 N --CR2.dbd. P2 2Btyn
2Ph2OxEt --O--1-cC.sub.3H.sub.4--1-CO.sub.2Et 79 N --CR2.dbd. P2
2Btyn 2Ph2OxEt --S--CH.sub.2--CO.sub.2Me 80 N --CR2.dbd. P2 2Btyn
2Ph2OxEt carbamoylphenyloxy 81 --CR2.dbd. N P1 2Btyn --CH.sub.3 --H
82 --CR2.dbd. N P1 2Btyn --CH.sub.3 --CN 83 --CR2.dbd. N P1 2Btyn
--CH.sub.3 --OMe 84 --CR2.dbd. N P1 2Btyn --CH.sub.3 --CONH.sub.2
85 --CR2.dbd. N P1 2Btyn --CH.sub.3 --O--CH.sub.2--CO.sub.2Et 86
--CR2.dbd. N P1 2Btyn --CH.sub.3 carbamoylphenyloxy 87 --CR2.dbd. N
P1 2Btyn 2-CNBen --H 88 --CR2.dbd. N P1 2Btyn 2-CNBen --CN 89
--CR2.dbd. N P1 2Btyn 2-CNBen --OMe 90 --CR2.dbd. N P1 2Btyn
2-CNBen --CONH.sub.2 91 --CR2.dbd. N P1 2Btyn 2-CNBen
--O--CH.sub.2--CO.sub.2Et 92 --CR2.dbd. N P1 2Btyn 2-CNBen
carbamoylphenyloxy 93 --CR2.dbd. N P1 2Btyn 6F2CNBen --H 94
--CR2.dbd. N P1 2Btyn 6F2CNBen --CN 95 --CR2.dbd. N P1 2Btyn
6F2CNBen --OMe 96 --CR2.dbd. N 21 2Btyn 6F2CNBen --CONH.sub.2 97
--CR2.dbd. N P1 2Btyn 6F2CNBen --O--CH.sub.2--CO.sub.2Et 98
--CR2.dbd. N P1 2Btyn 6F2CNBen carbamoylphenyloxy 99 --CR2.dbd. N
P1 2Btyn Phenethyl --H 100 --CR2.dbd. N P1 2Btyn Phenethyl --CN 101
--CR2.dbd. N P1 2Btyn Phenethyl --OMe 102 --CR2.dbd. N P1 2Btyn
Phenethyl --CONH.sub.2 103 --CR2.dbd. N P1 2Btyn Phenethyl
--O--CH.sub.2--CO.sub.2Et 104 --CR2.dbd. N P1 2Btyn Phenethyl
carbamoylphenyloxy 105 --CR2.dbd. N P1 2Btyn 2Ph2OxEt --H 106
--CR2.dbd. N P1 2Btyn 2Ph2OxEt --CN 107 --CR2.dbd. N P1 2Btyn
2Ph2OxEt --OMe 108 --CR2.dbd. N P1 2Btyn 2Ph2OxEt --CONH.sub.2 109
--CR2.dbd. N P1 2Btyn 2Ph2OxEt --O--CH.sub.2--CO.sub.2Et 110
--CR2.dbd. N P1 2Btyn 2Ph2OxEt carbamoylphenyloxy 111 --CR2.dbd. N
P2 2Btyn --CH.sub.3 --H 112 --CR2.dbd. N P2 2Btyn --CH.sub.3 --CN
113 --CR2.dbd. N P2 2Btyn --CH.sub.3 --OMe 114 --CR2.dbd. N P2
2Btyn --CH.sub.3 --CONH.sub.2 115 --CR2.dbd. N P2 2Btyn --CH.sub.3
--O--CH.sub.2--CO.sub.2Et 116 --CR2.dbd. N P2 2Btyn --CH.sub.3
carbamoylphenyloxy 117 --CR2.dbd. N P2 2Btyn 2-CNBen --H 118
--CR2.dbd. N P2 2Btyn 2-CNBen --CN 119 --CR2.dbd. N P2 2Btyn
2-CNBen --OMe 120 --CR2.dbd. N P2 2Btyn 2-CNBen --CONH.sub.2 121
--CR2.dbd. N P2 2Btyn 2-CNBen --O--CH.sub.2--CO.sub.2Et 122
--CR2.dbd. N P2 2Btyn 2-CNBen carbamoylphenyloxy 123 --CR2.dbd. N
P2 2Btyn 6F2CNBen --H 124 --CR2.dbd. N P2 2Btyn 6F2CNBen --CN 125
--CR2.dbd. N P2 2Btyn 6F2CNBen --OMe 126 --CR2.dbd. N P2 2Btyn
6F2CNBen --CONH.sub.2 127 --CR2.dbd. N P2 2Btyn 6F2CNBen
--O--CH.sub.2--CO.sub.2Et 128 --CR2.dbd. N P2 2Btyn 6F2CNBen
carbamoylphenyloxy 129 --CR2.dbd. N P2 2Btyn Phenethyl --H 130
--CR2.dbd. N P2 2Btyn Phenethyl --CN 131 --CR2.dbd. N P2 2Btyn
Phenethyl --OMe 132 --CR2.dbd. N P2 2Btyn Phenethyl --CONH.sub.2
133 --CR2.dbd. N P2 2Btyn Phenethyl --O--CH.sub.2--CO.sub.2Et 134
--CR2.dbd. N P2 2Btyn Phenethyl carbamoylphenyloxy 135 --CR2.dbd. N
P2 2Btyn 2Ph2OxEt --H 136 --CR2.dbd. N P2 2Btyn 2Ph2OxEt --CN 137
--CR2.dbd. N P2 2Btyn 2Ph2OxEt --OMe 138 --CR2.dbd. N P2 2Btyn
2Ph2OxEt --CONH.sub.2 139 --CR2.dbd. N P2 2Btyn 2Ph2OxEt
--O--CH.sub.2--CO.sub.2Et 140 --CR2.dbd. N P2 2Btyn 2Ph2OxEt
carbamoylphenyloxy 141 --CR2.dbd. N P2 3Me2Bten --CH.sub.3 --H 142
--CR2.dbd. N P2 3Me2Bten --CH.sub.3 --CN 143 --CR2.dbd. N P2
3Me2Bten --CH.sub.3 --OMe 144 --CR2.dbd. N P2 3Me2Bten --CH.sub.3
--CONH.sub.2 145 --CR2.dbd. N P2 3Me2Bten --CH.sub.3
--O--CH.sub.2--CO.sub.2Et 146 --CR2.dbd. N P2 3Me2Bten --CH.sub.3
carbamoylphenyloxy 147 --CR2.dbd. N P2 3Me2Bten 2-CNBen --H 148
--CR2.dbd. N P2 3Me2Bten 2-CNBen --CN 149 --CR2.dbd. N P2 3Me2Bten
2-CNBen --OMe 150 --CR2.dbd. N P2 3Me2Bten 2-CNBen --CONH.sub.2 151
--CR2.dbd. N P2 3Me2Bten 2-CNBen --O--CH.sub.2--CO.sub.2Et 152
--CR2.dbd. N P2 3Me2Bten 2-CNBen carbamoylphenyloxy 153 --CR2.dbd.
N P2 3Me2Bten 6F2CNBen --H 154 --CR2.dbd. N P2 3Me2Bten 6F2CNBen
--CN 155 --CR2.dbd. N P2 3Me2Bten 6F2CNBen --OMe 156 --CR2.dbd. N
P2 3Me2Bten 6F2CNBen --CONH.sub.2 157 --CR2.dbd. N P2 3Me2Bten
6F2CNBen --O--CH.sub.2--CO.sub.2Et 158 --CR2.dbd. N P2 3Me2Bten
6F2CNBen carbamoylphenyloxy 159 --CR2.dbd. N P2 3Me2Bten Phenethyl
--H 160 --CR2.dbd. N P2 3Me2Bten Phenethyl --CN 161 --CR2.dbd. N P2
3Me2Bten Phenethyl --OMe 162 --CR2.dbd. N P2 3Me2Bten Phenethyl
--CONH.sub.2 163 --CR2.dbd. N P2 3Me2Bten Phenethyl
--O--CH.sub.2--CO.sub.2Et 164 --CR2.dbd. N P2 3Me2Bten Phenethyl
carbamoylphenyloxy 165 --CR2.dbd. N P2 3Me2Bten 2Ph2OxEt --H 166
--CR2.dbd. N P2 3Me2Bten 2Ph2OxEt --CN 167 --CR2.dbd. N P2 3Me2Bten
2Ph2OxEt --OMe 168 --CR2.dbd. N P2 3Me2Bten 2Ph2OxEt --CONH.sub.2
169 --CR2.dbd. N P2 3Me2Bten 2Ph2OxEt --O--CH.sub.2--CO.sub.2Et 170
--CR2.dbd. N P2 3Me2Bten 2Ph2OxEt carbamoylphenyloxy 171 --CH.dbd.
--CR2.dbd. P1 2Btyn --CH.sub.3 --H 172 --CH.dbd. --CR2.dbd. P1
2Btyn --CH.sub.3 --CN 173 --CH.dbd. --CR2.dbd. P1 2Btyn --CH.sub.3
--CO.sub.2Me 174 --CH.dbd. --CR2.dbd. P1 2Btyn 2-CNBen --H 175
--CH.dbd. --CR2.dbd. P1 2Btyn 2-CNBen --CN 176 --CH.dbd. --CR2.dbd.
P1 2Btyn 2-CNBen --CO.sub.2Me 177 --CH.dbd. --CR2.dbd. P1 2Btyn
6F2CNBen --H 178 --CH.dbd. --CR2.dbd. P1 2Btyn 6F2CNBen --CN 179
--CH.dbd. --CR2.dbd. P1 2Btyn 6F2CNBen --CO.sub.2Me 180 --CH.dbd.
--CR2.dbd. P1 2Btyn Phenethyl --H 181 --CH.dbd. --CR2.dbd. P1 2Btyn
Phenethyl --CN 182 --CH.dbd. --CR2.dbd. P1 2Btyn Phenethyl
--CO.sub.2Me 183 --CH.dbd. --CR2.dbd. P1 2Btyn 2Ph2OxEt --H 184
--CH.dbd. --CR2.dbd. P1 2Btyn 2Ph2OxEt --CN 185 --CH.dbd.
--CR2.dbd. P1 2Btyn 2Ph2OxEt --CO.sub.2Me 186 --CH.dbd. --CR2.dbd.
P1 3Me2Bten --CH.sub.3 --H 187 --CH.dbd. --CR2.dbd. P1 3Me2Bten
--CH.sub.3 --CN 188 --CH.dbd. --CR2.dbd. P1 3Me2Bten --CH.sub.3
--CO.sub.2Me 189 --CH.dbd. --CR2.dbd. P1 3Me2Bten 2-CNBen --H 190
--CH.dbd. --CR2.dbd. P1 3Me2Bten 2-CNBen --CN 191 --CH.dbd.
--CR2.dbd. P1 3Me2Bten 2-CNBen --CO.sub.2Me 192 --CH.dbd.
--CR2.dbd. P1 3Me2Bten 6F2CNBen --H 193 --CH.dbd. --CR2.dbd. P1
3Me2Bten 6F2CNBen --CN 194 --CH.dbd. --CR2.dbd. P1 3Me2Bten
6F2CNBen --CO.sub.2Me 195 --CH.dbd. --CR2.dbd. P1 3Me2Bten
Phenethyl --H 196 --CH.dbd. --CR2.dbd. P1 3Me2Bten Phenethyl --CN
197 --CH.dbd. --CR2.dbd. P1 3Me2Bten Phenethyl --CO.sub.2Me 198
--CH.dbd. --CR2.dbd. P1 3Me2Bten 2Ph2OxEt --H 199 --CH.dbd.
--CR2.dbd. P1 3Me2Bten 2Ph2OxEt --CN 200 --CH.dbd. --CR2.dbd. P1
3Me2Bten 2Ph2OxEt --CO.sub.2Me 201 --CH.dbd. --CR2.dbd. P2 2Btyn
--CH.sub.3 --H 202 --CH.dbd. --CR2.dbd. P2 2Btyn --CH.sub.3 --CN
203 --CH.dbd. --CR2.dbd. P2 2Btyn --CH.sub.3 --CO.sub.2Me 204
--CH.dbd. --CR2.dbd. P2 2Btyn 2-CNBen --H 205 --CH.dbd. --CR2.dbd.
P2 2Btyn 2-CNBen --CN 206 --CH.dbd. --CR2.dbd. P2 2Btyn 2-CNBen
--CO.sub.2Me 207 --CH.dbd. --CR2.dbd. P2 2Btyn 6F2CNBen --H 208
--CH.dbd. --CR2.dbd. P2 2Btyn 6F2CNBen --CN 209 --CH.dbd.
--CR2.dbd. P2 2Btyn 6F2CNBen --CO.sub.2Me 210 --CH.dbd. --CR2.dbd.
P2 2Btyn Phenethyl --H 211 --CH.dbd. --CR2.dbd. P2 2Btyn Phenethyl
--CN 212 --CH.dbd. --CR2.dbd. P2 2Btyn Phenethyl --CO.sub.2Me 213
--CH.dbd. --CR2.dbd. P2 2Btyn 2Ph2OxEt --H 214 --CH.dbd. --CR2.dbd.
P2 2Btyn 2Ph2OxEt --CN 215 --CH.dbd. --CR2.dbd. P2 2Btyn 2Ph2OxEt
--CO.sub.2Me 216 --CH.dbd. --CR2.dbd. P2 3Me2Bten --CH.sub.3 --H
217 --CH.dbd. --CR2.dbd. P2 3Me2Bten --CH.sub.3 --CN 218 --CH.dbd.
--CR2.dbd. P2 3Me2Bten --CH.sub.3 --CO.sub.2Me 219 --CH.dbd.
--CR2.dbd. P2 3Me2Bten 2-CNBen --H 220 --CH.dbd. --CR2.dbd. P2
3Me2Bten 2-CNBen --CN 221 --CH.dbd. --CR2.dbd. P2 3Me2Bten 2-CNBen
--CO.sub.2Me 222 --CH.dbd. --CR2.dbd. P2 3Me2Bten 6F2CNBen --H 223
--CH.dbd. --CR2.dbd. P2 3Me2Bten 6F2CNBen --CN 224 --CH.dbd.
--CR2.dbd. P2 3Me2Bten 6F2CNBen --CO.sub.2Me 225 --CH.dbd.
--CR2.dbd. P2 3Me2Bten Phenethyl --H 226 --CH.dbd. --CR2.dbd. P2
3Me2Bten Phenethyl --CN 227 --CH.dbd. --CR2.dbd. P2 3Me2Bten
Phenethyl --CO.sub.2Me 228 --CH.dbd. --CR2.dbd. P2 3Me2Bten
2Ph2OxEt --H 229 --CH.dbd. --CR2.dbd. P2 3Me2Bten 2Ph2OxEt --CN 230
--CH.dbd. --CR2.dbd. P2 3Me2Bten 2Ph2OxEt --CO.sub.2Me
[0357] Among the compounds listed above, Nos. 1, 2, 4, 6, 7, 8, 10,
13, 16, 41, 42, 44, 50, 53, 81, 85, 86, 87, 111, 141 and 183 are
preferable, and compound Nos. 2, 4, 8, 10, 81, 87 and 111 are more
preferable.
Typical Synthesis Methods
[0358] Representative methods for producing compounds of the
present invention, represented by formula (I) above are described
below.
[0359] Each symbol in the production methods is defined below.
R.sup.31 to R.sup.42, n, m, R.sup.1, R.sup.2, X, A.sup.0, A.sup.1,
A.sup.2, R.sup.A, and T.sup.1 are the same as defined above.
[0360] U.sup.1 and U.sup.3 each independently represent a leaving
group such as a chlorine atom, a bromine atom, an iodine atom, a
methanesulfonyloxy group, or a p-toluenesulfonyloxy group.
[0361] R.sup.p1, R.sup.p2, and R.sup.p3 each independently
represent an --NH-protecting group such as a pivalyloxymethyl group
and a trimethylsilylethoxymethyl group.
[0362] R.sup.p4 represents a hydroxyl group-protecting group such
as a t-butyldimethylsilyl group and a t-butyldiphenylsilyl
group.
[0363] R.sup.p5 represents an NH-protecting group such as
N,N-dimethylsulfamoyl, trityl, benzyl, and t-butoxycarbonyl.
[0364] U.sup.2and U.sup.4 each independently represent a chlorine
atom, a bromine atom, an iodine atom, a methanesulfonyloxy group, a
p-toluenesulfonyloxy group, a group represented by the formula
--B(OH).sub.2, a 4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl group,
or a group represented by the formula --Sn(R.sup.z).sub.3 (where
R.sup.z represents a C.sub.1-6 alkyl group).
[0365] R.sup.x2 is a group represented by the formula --O-A.sup.2,
a group represented by the formula --S-A.sup.2, a group represented
by the formula --N(R.sup.A)A.sup.2, or a 4- to 8-membered
heterocyclic group which may have one or more substituents (for
example, 1-pyrrolidinyl, 1-morpholinyl, 1-piperazinyl, or
1-piperidyl), etc.
[0366] R.sup.x3 represents a group of the formula
-A.sup.0-A.sup.1-A.sup.2- , such as a cyano group, a C.sub.1-6
alkyl group which may have one or more substituents, a C.sub.3-8
cycloalkyl group which may have one or more substituents, a
C.sub.2-6 alkenyl group which may have one or more substituents, a
C.sub.2-6 alkynyl group which may have one or more substituents,
and a C.sub.6-10 aryl group which may have one or more
substituents.
[0367] A.sup.2COOR represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl
group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains an ester group.
[0368] A.sup.2COOH represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl group,
a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains a carboxylic acid.
[0369] A.sup.2NO2 represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl
group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains a nitro group.
[0370] A.sup.2NH2 represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl
group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains an amino group.
[0371] A.sup.2CN represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, a C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl
group, a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains a nitrile group.
[0372] A.sup.CONH2 represents a C.sub.1-6 alkyl group, a C.sub.3-8
cycloalkyl group, a C.sub.2-6 alkenyl group, a C.sub.2-6 alkynyl
group, C.sub.6-10 aryl group, a 5- to 10-membered heteroaryl group,
a 4- to 8-membered heterocyclic group, a 5- to 10-membered
heteroaryl C.sub.1-6 alkyl group, or a C.sub.6-10 aryl C.sub.1-6
alkyl group, each of which contains a carboxylic amide group.
[0373] M represents --MgCl, --MgBr, --Sn(R.sup.z).sub.3 (where
R.sup.z is as defined above), etc.
[0374] The term "room temperature" refers to a temperature of about
20 to about 30.degree. C.
[0375] T.sup.1a is defined as the group represented by T.sup.1, or
represents a group of the formula: 40
[0376] a group represented by the formula: 41
[0377] (where R.sup.31 to R.sup.44 are as defined above, except
that any one of R.sup.31 to R.sup.44 represents --NH--R.sup.p3) or
a group represented by the formula: 42
[0378] (where R.sup.31 to R.sup.40 are as defined above, except
that any one of R.sup.31 to R.sup.40 represents
--NH--R.sup.p3).
[0379] In examples of reactions represented by the following
reaction schemes, unless otherwise specified, quantities of
reagents, catalysts, and others, to be used (equivalent, weight %,
and weight ratio) are represented as ratios to a main compound in
each reaction scheme. A main compound refers to a compound
represented by a chemical formula in the reaction scheme and having
the backbone of compounds of the present invention.
Production Method A
[0380] 4344
[0381] [Step A1]
[0382] In this step, an --NH-protecting reagent is reacted with
compound (1a) [CAS No. 56160-64-6] to give compound (2a). The
reaction conditions are selected depending on the type of
--NH-protecting reagent to be used. The reaction may be performed
under conditions that are generally used to introduce a protecting
group using the reagent.
[0383] An --NH-protecting reagent can be a reagent that is
generally used to introduce an --NH-protecting group. Specifically,
such --NH-protecting reagents include, for example, chloromethyl
pivalate. It is preferable to use 1 to 2 equivalents of a
protecting reagent. Solvents for the reaction include acetonitrile,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, and dimethoxyethane. N,N-dimethylformamide is
preferably used.
[0384] The reaction can be achieved in the presence of a base.
Examples of bases to be used in the reaction include cesium
carbonate, lithium carbonate, sodium carbonate, potassium
carbonate, and sodium hydride. Sodium hydride is preferably used.
In this case, a base is preferably used in an amount of 1 to 5
equivalents. The reaction can be conducted at a temperature ranging
from 0.degree. C. to 150.degree. C. A preferred reaction
temperature is room temperature.
[0385] [Step A2]
[0386] In this step, compound (2a) is reacted with compound (2a-2)
to give compound (3a).
[0387] Compound (2a-2) can be any compound that is an electrophilic
reagent such as an alkyl halide. Specific examples include alkyl
halides such as iodomethane, iodoethane, iodopropane, and benzyl
bromide; alkenyl halides such as allyl bromide and
1-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl
bromide and 1-bromo-2-butyne. One to two equivalents of an
electrophilic reagent are preferably used.
[0388] Solvents for the reaction include, for example, dimethyl
sulfoxide, N,N-dimethylformamide, N-methylpyrrolidone, dioxane,
tetrahydrofuran, and toluene.
[0389] The reaction can be achieved in the presence or absence of a
base. Examples of bases to be used in the reaction include lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
lithium hydride, sodium hydride, potassium hydride, butyllithium,
methyllithium, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
In this case, one to two equivalents of a base are preferably used.
The reaction can be conducted at a temperature ranging from
0.degree. C. to 150.degree. C.
[0390] [Step A3]
[0391] In this step, the benzyl group at the 7-position is removed
from compound (3a) to give compound (4a).
[0392] Specifically, compound (4a) can be prepared from compound
(3a) for example, by catalytic reduction under a hydrogen
atmosphere in the presence of a metal catalyst, but the reaction
conditions are not limited thereto.
[0393] Specific solvents for the reaction include, for example,
methanol, ethanol, propanol, acetic acid, dimethyl sulfoxide,
N,N-dimethylformamide, N-methylpyrrolidone, dioxane,
tetrahydrofuran, and toluene. Examples of metal catalysts include
palladium carbon, platinum oxide, and Raney nickel. A metal
catalyst is preferably used at 0.5 to 50 weight %. A preferred
hydrogen pressure is 1 to 5 atm. The reaction can be conducted at a
temperature ranging from 0.degree. C. to 150.degree. C.
[0394] [Step A4]
[0395] In this step, compound (4a) is reacted with compound (4a-2)
to give compound (5a).
[0396] Specific examples of compound (4a-2) are: alkyl halides such
as iodomethane, iodoethane, iodopropane, and benzyl bromide;
alkenyl halides such as allyl bromide and
1-bromo-3-methyl-2-butene; or alkynyl halides such as propargyl
bromide and 1-bromo-2-butyne. These halides are preferably used in
an amount of one to two equivalents.
[0397] Solvents for the reaction include dimethyl sulfoxide,
N,N-dimethylformamide, N-methylpyrrolidone, dioxane,
tetrahydrofuran, and toluene.
[0398] The reaction can be carried out in the presence or absence
of a base. Examples of bases to be used in the reaction include
lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
lithium hydride, sodium hydride, potassium hydride, butyllithium,
methyllithium, lithium bis(trimethylsilyl)amide, sodium
bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.
In this case, 1 to 4 equivalents of a base are preferably used. The
reaction can be conducted at a temperature ranging from 0.degree.
C. to 150.degree. C.
[0399] Compound (5a) can be obtained by reacting compound (4a) with
compound (4a-2) in the presence of a copper catalyst and a base. In
this case, it is preferable to use 0.1 to 2 equivalents of a copper
catalyst and 1 to 10 equivalents of a base.
[0400] In this reaction, compound (4a-2) may be arylboronic acid,
heteroarylboronic acid, or such, in which X is a C.sub.6-10 aryl
group which may have one or more substituents or a 5- to
10-membered heteroaryl group which may have one or more
substituents, and U.sup.2 is --B(OH).sub.2 or such. One to three
equivalents of compound (4a-2) are preferably used.
[0401] In this case, reaction solvents include dichloromethane,
chloroform, 1,4-dioxane, tetrahydrofuran, toluene, pyridine,
N,N-dimethylformamide, and N-methylpyrrolidone.
[0402] Bases include triethylamine, diisopropyl ethyl amine,
pyridine, and N,N-dimethylaminopyridine. Copper catalysts include
copper (II) acetate, copper (II) trifluoroacetate, copper (II)
chloride, and copper (II) iodide. The reaction can be conducted at
a temperature ranging from 0.degree. C. to 150.degree. C.
[0403] [Step A5]
[0404] In this step, compound (5a) is reacted with a halogenating
agent to give compound (6a).
[0405] Specific examples of halogenating agents include, for
example, N-chlorosuccinimide, N-bromosuccinimide, and
N-iodosuccinimide. A halogenating agent is preferably used in an
amount of 1 to 4 equivalents.
[0406] Solvents for the reaction include acetonitrile,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, and dimethoxyethane. The reaction can be conducted
at a temperature ranging from 0.degree. C. to 150.degree. C.
[0407] [Step A6]
[0408] In this step, compound (6a) is reacted with compound (7a) to
give compound (8a). In this case, 1 to 4 equivalents of compound
(7a) are preferably used.
[0409] The reaction can be carried out, for example, in a solvent
such as tetrahydrofuran, acetonitrile, N,N-dimethylformamide,
N-methylpyrrolidone, methanol, ethanol, 1,4-dioxane, toluene, and
xylene, or in the absence of a solvent. The reaction can be
conducted at a temperature ranging from 0.degree. C. to 200.degree.
C. in the presence or absence of a base. Examples of a base include
triethylamine, potassium carbonate, and
1,8-diazabicyclo[5,4,0]undecene. In this case, 1 to 4 equivalents
of a base are preferably used.
[0410] [Step A7]
[0411] In this step, the --NH-protecting group at the 3-position of
compound (8a) is removed to give compound (9a). The reaction
conditions are selected depending on the type of --NH-protecting
group to be removed. The deprotection reaction may be preformed
under conditions that are generally used for the protecting
group.
[0412] For example, when R.sup.p2 is a pivalyloxymethyl group, the
reaction can be carried out in methanol, or a mixed solution of
methanol and tetrahydrofuran, using a base such as sodium
methoxide, sodium hydride, or 1,8-diazabicyclo[5,4,0]-7-undecene at
a temperature of 0 to 150.degree. C. In this case, 0.1 to 2
equivalents of a base are preferably used.
[0413] Alternatively, when R.sup.p2 is a trimethylsilylethoxymethyl
group, the reaction can be carried out in a solvent such as
acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
1,4-dioxane, tetrahydrofuran, or dimethoxyethane, using a fluoride
reagent such as tetrabutyl ammonium fluoride or cesium fluoride at
a temperature of 0 to 150.degree. C. In this case, 1 to 5
equivalents of a fluoride reagent are preferably used.
[0414] [Step A8]
[0415] In this step, compound (9a) is chlorinated to give compound
(10a).
[0416] There are no particular limitations on the reaction
conditions, and the The reaction can be conducted under standard
conditions for chlorination. For example, the reaction can be
carried out at a temperature ranging from 0 to 150.degree. C. in a
solvent such as phosphorus oxychloride. In this case, it is
preferable to use a 10 to 200 times amount of halogenating agent by
weight.
[0417] When R.sup.p3 is a t-butoxycarbonyl group or such, which is
removed under the above-described conditions using phosphorus
oxychloride or such, the protecting group should be
reintroduced.
[0418] There are no particular limitations on the reaction
conditions for the protection. In the case of the t-butoxycarbonyl
group, the reaction can be carried out using an --NH-- protection
reagent such as di-t-butyl dicarbonate, in a solvent such as
acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
1,4-dioxane, tetrahydrofuran, or dimethoxyethane in the presence of
a base such as lithium hydroxide, sodium hydroxide, potassium
hydroxide, lithium carbonate, sodium carbonate, potassium
carbonate, cesium carbonate, potassium bicarbonate, sodium
bicarbonate, or triethylamine at 0 to 150.degree. C.
[0419] [Step A9]
[0420] In this step, compound (10a) is reacted with compound
(11a-2) to give compound (11a).
[0421] Compound (11a-2) includes alcohol compounds or phenol
compounds represented by A.sup.2-OH, amine compounds represented by
A.sup.2(R.sup.A)NH or such, and thiol compounds represented by
A.sup.2-SH. In this case, compound (11a-2) is preferably used in an
amount of 1 to 10 equivalents or 5 to 100 times by weight.
[0422] Solvents for the reaction include acetonitrile,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
[0423] The reaction can be carried out in the presence or absence
of a base. Bases to be used in the reaction include lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
lithium hydride, sodium hydride, potassium hydride, butyllithium,
methyllithium, lithium bis(trimethylsilyl) amide, sodium
bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, and
triethylamine. In this case, 1 to 10 equivalents of a base is
preferably used. The reaction can be conducted at a temperature
ranging from 0.degree. C. to 150.degree. C.
[0424] [Step A10]
[0425] In this step, compound (10a) is reacted with compound (13a)
in the presence of a metal catalyst to give compound (12a). In this
case, 1 to 50 equivalents of compound (13a) are preferably
used.
[0426] Solvents for the reaction include acetonitrile,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, dimethoxyethane, methanol, and ethanol.
[0427] Metal catalysts include palladium catalyst and copper
catalyst. Palladium catalysts include tetrakis triphenylphosphine
palladium, palladium acetate, and dibenzylideneacetone palladium.
Copper catalyst include copper iodide. It is preferable to use 0.01
to 2 equivalents of a metal catalyst.
[0428] The reaction can be conducted in the presence of an
organophosphorous ligand. When the reaction is carried out in the
presence of an organophosphorous ligand, examples of the ligands
include o-tolyl phosphine and diphenylphosphinoferrocene. In this
case, it is preferable to use 1 to 5 equivalents of an
organophosphorous ligand to the metal catalyst.
[0429] The reaction can be carried out in the presence or absence
of a base. Bases to be used in the reaction include lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
lithium hydride, sodium hydride, potassium hydride, potassium
phosphate, lithium bis trimethylsilyl amide, sodium bis
trimethylsilyl amide, potassium bis trimethylsilyl amide, and
triethylamine. The reaction can be conducted at a temperature
ranging from 0.degree. C. to 150.degree. C.
[0430] [Step A11]
[0431] In this step, compound (10a) is reacted with a cyanidation
reagent to give compound (14a).
[0432] Specifically, cyanidation reagents include, for example,
sodium cyanide and potassium cyanide. It is preferably used in an
amount of 1 to 20 equivalents.
[0433] Solvents for the reaction include, for example,
acetonitrile, N,N-dimethylformamide, N-methylpyrrolidone,
1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, and
ethanol. The reaction can be conducted at a temperature ranging
from 0.degree. C. to 150.degree. C.
[0434] [Step A12]
[0435] In this step, the cyano group of compound (14a) is
hydrolyzed to give compound (15a). There are no particular
limitations on the reaction conditions, and the reaction can be
carried out under conditions generally used for the conversion of a
cyano group to a carbamoyl group by hydrolysis.
[0436] Solvents for the reaction include N,N-dimethylformamide,
N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, dimethoxyethane,
methanol, ethanol, and a mixed solvent of tetrahydrofuran and
methanol.
[0437] The reaction can be carried out in the presence or absence
of a base. When a base is used, the reaction can be carried out
using an aqueous solution of a base such as potassium hydroxide,
sodium hydroxide, lithium hydroxide, or ammonia. The reaction can
be achieved after adding an aqueous solution of hydrogen peroxide
(preferably an aqueous solution of 30% hydrogen peroxide).
[0438] The reaction can be conducted at a temperature ranging from
0.degree. C. to 150.degree. C.
[0439] [Step A13]
[0440] In this step, R.sup.p3 of compound (16a) is removed to give
compound (17a). Compounds (11a), (12a), (14a), (15a), and others
can be used as compound (16a).
[0441] The deprotection reaction for R.sup.p3 can be carried out
under standard reaction conditions for removing an --NH-protecting
group.
[0442] For example, when R.sup.p3 is a t-butoxycarbonyl group, the
reaction can be carried out in the presence of an acid such as an
anhydrous methanol solution of hydrogen chloride, an anhydrous
ethanol solution of hydrogen chloride, an anhydrous dioxane
solution of hydrogen chloride, trifluoroacetic acid, or formic
acid.
[0443] An alternative method for producing compound (10a) is
described below. 45
[0444] [Step A14]
[0445] In this step, compound (18a) is chlorinated to give compound
(19a). There are no particular limitations on the reaction
conditions, and the reaction can be conducted under standard
conditions for chlorination. For example, the reaction can be
carried out in a solvent such as phosphorus oxychloride at a
temperature ranging from 0 to 150.degree. C. Preferably 10 to 200
times by weight of chlorination reagent is used.
[0446] When R.sup.p3 is a t-butoxycarbonyl group or such, which is
removed under the above-described condition using phosphorus
oxychloride or such, the protecting group should be
reintroduced.
[0447] There are no particular limitations on the reaction
conditions for the protection, and when R.sup.p3 is a
t-butoxycarbonyl group, the reaction can be carried out using an
--NH-- protection reagent such as di-t-butyl dicarbonate, in a
solvent such as acetonitrile, N,N-dimethylformamide,
N-methylpyrrolidone, 1,4-dioxane, tetrahydrofuran, and
dimethoxyethane, in the presence of a base such as lithium
hydroxide, sodium hydroxide, potassium hydroxide, lithium
carbonate, sodium carbonate, potassium carbonate, cesium carbonate,
potassium bicarbonate, sodium bicarbonate, or triethylamine at a
temperature ranging from 0 to 150.degree. C.
[0448] [Step A15]
[0449] In this step, compound (19a) is partially hydrolyzed to give
compound (20a). The reaction is carried out in the presence of a
base such as sodium acetate, potassium carbonate, or sodium
hydroxide. One to ten equivalents of a base are preferably used.
Solvents for the reaction include dimethyl sulfoxide,
N-methylpyrrolidone, tetrahydrofuran, water, and mixtures thereof.
The reaction can be conducted at a temperature ranging from
0.degree. C. to 100.degree. C.
[0450] [Step A16]
[0451] In this step, compound (20a) is reacted with compound (21a)
to give compound (22a). The reaction can be conducted under the
same conditions as used in [Step A2] of production method A.
[0452] An alternative method for producing compound (19a) is
described below. 46
[0453] [Step A17]
[0454] In this step, a substitution reaction is carried out using
compound (23a) [CAS No. 1076-22-8] and compound (4a-2) to give
compound (24a).
[0455] The reaction can be conducted under the same conditions as
used in [Step A4] of production method A.
[0456] [Step A18]
[0457] In this step, compound (24a) is reacted with a halogenating
agent to give compound (25a).
[0458] The reaction can be conducted under the same conditions as
used in [Step A5] of production method A.
[0459] [Step A19]
[0460] In this step, compound (25a) is chlorinated to give compound
(26a).
[0461] There are no particular limitations on the reaction
conditions, and compound (25a) can be reacted with phosphorus
oxychloride, phosphorus pentachloride, or a mixture thereof in a
solvent or in the absence of a solvent at a temperature of 0 to
150.degree. C. Solvents include, for example, toluene,
acetonitrile, and dichloroethane.
[0462] [Step A20]
[0463] In this step, compound (26a) is reacted with compound (7a)
to give compound (19a).
[0464] The reaction can be conducted under the same conditions as
used in [Step A6] of production method A.
Production Method B
[0465] 47
[0466] [Step B1]
[0467] In this step, compound (1b) is benzylated and the sugar
chain is cleaved to give compound (2b).
[0468] There are no particular limitations on the reaction
conditions. Compound (2b) can be obtained by reacting compound (1b)
with benzyl bromide in a solvent such as acetonitrile,
N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide,
1,4-dioxane, tetrahydrofuran, dimethoxyethane, methanol, or
ethanol, at a temperature of 0 to 150.degree. C., adding 3 to 10
equivalents of hydrochloric acid, and incubating the mixture at a
temperature of 0 to 150.degree. C. to cleave the sugar moiety. It
is preferable to use 1 to 3 equivalents of benzyl bromide.
[0469] [Step B2]
[0470] In this step, compound (2b) is reacted with a halogenating
agent to give compound (3b). The halogenation reaction can be
conducted under the same conditions as used in [Step A5] of
production method A.
[0471] [Step B3]
[0472] In this step, compound (3b) is reacted with compound (4b) to
give compound (5b). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0473] [Step B4]
[0474] In this step, compound (5b) is reacted with compound (5b-2)
to give compound (6b). The reaction can be conducted under the same
condition as used in [Step A2] of production method A.
[0475] [Step B5]
[0476] In this step, R.sup.p3 of compound (6b) is removed to give
compound (7b). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method B-2
[0477] Compound (9b) represented by the formula: 48
[0478] can be obtained by using compound (8b) represented by
H-T.sup.1a, instead of compound (7a) in [Step A6] of production
method A described above under the same reaction conditions as used
in [Step A6], and then appropriately applying [Step A7] to [Step
A13] described above.
[0479] Compound (10b) represented by the formula: 49
[0480] can be obtained by using compound (8b) represented by
H-T.sup.1a, instead of compound (3b) in [Step B3] of production
method B described above under the same reaction conditions as used
in [Step B3] and then appropriately applying [Step B4] to [Step B6]
described above. Preferable examples of compound (8b) include
piperidin-3-yl carbamic acid t-butyl ester.
Production Method C
[0481] 5051
[0482] [Step C1]
[0483] In this step, compound (1c) is reacted with compound (1c-2)
to give compound (2c). The reaction can be conducted under the same
conditions as used in [Step A4] of production method A.
[0484] [Step C2]
[0485] In this step, compound (1c) is reacted with ethanol to give
compound (3c).
[0486] Compound (3c) can be obtained, for example, by heating an
ethanol solution of compound (2c) under reflux in the presence of
an acid such as sulfuric acid or hydrochloric acid. However, the
reaction conditions are not limited thereto. In this reaction, it
is preferable to use one to two equivalents of an acid.
[0487] [Step C3]
[0488] In this step, compound (2c) is reacted with ethanol to give
compounds (4c) and (5c). The reaction can be conducted under the
same conditions as used in [Step C2] of production method C.
[0489] [Step C4]
[0490] In this step, compound (3c) is reacted with compound (3c-2)
to give compounds (4c) and (5c). The reaction can be conducted
under the same conditions as used in [Step A4] of production method
A.
[0491] [Step C5]
[0492] In this step, compound (4c) is reacted with compound (6c) to
give compound (7c). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0493] [Step C6]
[0494] In this step, compound (7c) is thioamidated to give compound
(8c). Solvents for the reaction include methanol, ethanol,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, and dimethoxyethane. Thioamidation reagents
include ammonium sulfide, sodium sulfide, and hydrogen sulfide. It
is preferable to use 2 to 10 equivalents of a thioamidation
reagent. When hydrogen sulfide is used as the thioamidation
reagent, the reaction is carried out in the presence of a base such
as triethylamine or N,N-diisopropylethylamine. The reaction can be
conducted at a temperature ranging from 0.degree. C. to 150.degree.
C.
[0495] [Step C7]
[0496] In this step, compound (8c) is reacted with a methylating
reagent to give compound (9c). Methylating reagents include
trimethyl oxonium tetrafluoroborate, methyl sulfate, methyl iodide,
and trimethyl phosphite. It is preferable to use 1.0 to 1.5
equivalent of the methylating reagent.
[0497] When trimethyl oxonium tetrafluoroborate is used as the
methylating reagent, compound (9c) can be obtained by carrying out
the reaction in a halogenated solvent such as dichloromethane at a
temperature ranging from 0.degree. C. to 50.degree. C.
[0498] When methyl sulfate, methyl iodide, or trimethyl phosphite
is used as the methylating reagent, compound (9c) can be obtained
by carrying out the reaction in the presence of a base such as
potassium carbonate, triethylamine, or N,N-diisopropylethylamine.
In this case, it is preferable to use 1.0 to 1.5 equivalent of a
base. Solvents for the reaction include acetone,
N,N-dimethylformamide, N-methylpyrrolidone, 1,4-dioxane,
tetrahydrofuran, and dimethoxyethane. The reaction can be performed
at a temperature ranging from 0.degree. C. to 100.degree. C.
[0499] [Step C8]
[0500] In this step, compound (9c) is hydrolyzed to give compound
(10c).
[0501] There are no particular limitations on the reaction
conditions for the hydrolysis. The reaction can be carried out in a
mixed solvent of ethanol and water in the presence of an acid such
as sulfuric acid, hydrochloric acid, or p-toluenesulfonic acid, at
a temperature ranging from 0.degree. C. to 80.degree. C. In this
case, it is preferable to use 5 to 50 equivalents of the acid.
[0502] When R.sup.p3 is a group, such as a t-butoxycarbonyl group,
which is removed under the above-described condition, the
protecting group should be reintroduced. There are no particular
limitations on the reaction conditions for the introduction of this
protecting group. When R.sup.p3 is a t-butoxycarbonyl group, the
reaction can be carried out using a reagent such as t-butyl
dicarbonate in a solvent such as dichloromethane, chloroform,
N,N-dimethylformamide, or tetrahydrofuran, in the presence of a
base such as pyridine, 4-aminopyridine, triethylamine, and
N,N-diisopropylethylamine, at a temperature ranging from 0 to
80.degree. C. In this case, it is preferable to use 2 to 3
equivalents of a base.
[0503] [Step C9]
[0504] In this step, compound (10c) is reacted with a reducing
agent to give compound (11c).
[0505] There are no particular limitations on the reaction
conditions for the reduction. The reaction can be achieved by
reacting compound (10c) with hydrogen in the presence of Raney
nickel in a solvent such as benzene, ethanol, 2-propanol, or
acetone, at a temperature ranging from 0.degree. C. to 50.degree.
C., or alternatively reacting compound (10c) with a reducing agent
such as sodium borohydride, in a solvent such as methanol, ethanol,
or 2-methyl-2-propanol, or in a mixed solvent of water and
tetrahydrofuran at a temperature ranging from 0.degree. C. to
50.degree. C., or alternatively reacting compound (10c) with a
reducing agent such as sodium borohydride, in the presence of 1 to
5 equivalents of a mercury salt such as mercuric acetate in a
solvent such as methanol, ethanol, or 2-methyl-2-propanol at a
temperature ranging from 0.degree. C. to 50.degree. C. It is
preferable to use two to three equivalents of a reducing agent.
[0506] [Step C10]
[0507] In this step, compound (11c) is subjected to an oxidation
reaction to give compound (12c).
[0508] When an oxidant such as manganese dioxide, pyridinium
chlorochromate, or pyridinium dichromate is used in the oxidation
reaction, compound (12c) can be obtained by carrying out the
reaction in a solvent such as dichloromethane or chloroform, at a
temperature ranging from 20.degree. C. to 80.degree. C.
Alternatively, compound (12c) can also be obtained by carrying out
the reaction under standard conditions for the oxidation of a
primary alcohol to aldehyde, such as Swern oxidation. It is
preferable to use 5 to 20 equivalents of an oxidant.
[0509] [Step C11]
[0510] In this step, compound (12c) is reacted with compound (13c)
to give compound (17c). In this case, it is preferable to use 2 to
10 equivalents of compound (13c).
[0511] Compound (17c) can be obtained, for example, by combining
compounds (12c) and (13c) in a solvent such as methanol, ethanol,
1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or
dimethoxyethane, or in the absence of solvent, and reacting the
mixture at a temperature of 20 to 150.degree. C. However, the
reaction conditions are not limited thereto.
[0512] [Step C12]
[0513] In this step, compound (12c) is reacted with hydrazine to
give compound (15c). The reaction can be conducted under the same
conditions as used in [Step C11] of production method C. It is
preferable to use 2 to 10 equivalents of hydrazine.
[0514] [Step C13]
[0515] In this step, a substitution reaction is carried out using
compound (15c) and compound (16c) to give compound (17c). The
reaction can be conducted under the same conditions as used in
[Step A2] of production method A. It is preferable to use 1 to 3
equivalents of compound (16c).
[0516] [Step C14]
[0517] In this step, R.sup.p3 of compound (17c) is removed to give
compound (14c). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0518] [Step C15]
[0519] In this step, compound (5c) is reacted with compound (6c) to
give compound (18c). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0520] [Step C16]
[0521] In this step, compound (18c) is hydrolyzed to give compound
(19c).
[0522] There are no particular limitations on the reaction
conditions for the hydrolysis. For example, compound (19c) can be
obtained by incubating compound (18c) in the presence of a base at
a temperature ranging from 0.degree. C. to 100.degree. C.
[0523] Solvents for the reaction include methanol, ethanol,
tetrahydrofuran, water, or mixtures thereof. Bases include lithium
hydroxide, sodium hydroxide, and potassium hydroxide. It is
preferable to use 1 to 2 equivalents of a base.
[0524] [Step C17]
[0525] In this step, compound (19c) is reacted with a reducing
agent to give compound (20c). The reduction can be achieved under a
standard condition for the reduction of carboxylic acid to methyl
alcohol.
[0526] Reducing agents include borane derivatives such as
borane-tetrahydrofuran complex and borane-methyl sulfide complex,
and sodium borohydride. It is preferable to use 5 to 30 equivalents
of a reducing agent.
[0527] When a borane derivative is used as a reducing agent,
compound (20c) can be obtained by carrying out the reaction using a
solvent such as 1,4-dioxane, tetrahydrofuran, or dimethoxyethane at
a temperature ranging from -78.degree. C. to 35.degree. C.
[0528] Alternatively, when sodium borohydride is used as a reducing
agent, first, compound (19c) is reacted with an activator such as
isobutyl chloroformate, at a temperature ranging from -78.degree.
C. to 20.degree. C., then reacted with a reducing agent such as
sodium borohydride at a temperature ranging from -78.degree. C. to
35.degree. C., to obtain compound (20c). Solvents for the reaction
include 1,4-dioxane, tetrahydrofuran, and dimethoxyethane.
[0529] [Step C18]
[0530] In this step, compound (20c) is thioamidated to give
compound (21c). The reaction can be conducted under the same
conditions as used in [Step C6] of production method C.
[0531] [Step C19]
[0532] In this step, compound (21c) is reacted with a silylating
agent in the presence of a base to give compound (22c).
[0533] Solvents for the reaction include dichloromethane,
N,N-dimethylformamide, 1,4-dioxane, tetrahydrofuran, and
dimethoxyethane. Bases include imidazole, pyridine,
4-dimethylaminopyridine, triethylamine, and
N,N-diisopropylethylamine. Silylating agents include
t-butyldimethylchlorosilane, and t-butylchlorodiphenylsilane. It is
preferable to use 1.0 to 1.5 equivalent of a base and 1.0 to 1.5
equivalent of a silylating agent. The reaction can be conducted at
a temperature ranging from 0.degree. C. to 80.degree. C.
[0534] [Step C20]
[0535] In this step, compound (22c) is methylated to give compound
(23c).
[0536] The reaction can be conducted under the same condition as
used in [Step C7] of production method C.
[0537] [Step C21]
[0538] In this step, compound (23c) is hydrolyzed to give compound
(24c).
[0539] There are no particular limitations on the reaction
conditions for the hydrolysis. Compound (24c) can be obtained by
carrying out the reaction in a mixed solvent of ethanol and water
in the presence of an acid such as sulfuric acid, hydrochloric
acid, or p-toluenesulfonic acid, at a temperature ranging from
50.degree. C. to 100.degree. C.
[0540] When such a reaction results in removal of --R.sup.p3,
--NH-- is re-protected through a protection reaction. Specifically,
for example, when R.sup.p3 is a t-butoxycarbonyl group, the
reaction can be carried out using a reagent such as t-butyl
dicarbonate, in a solvent such as dichloromethane, chloroform,
N,N-dimethylformamide, or tetrahydrofuran, in the presence of a
base such as pyridine, 4-aminopyridine, triethylamine, or
N,N-diisopropyl ethylamine, at a temperature ranging from 0 to
80.degree. C. However, the reaction is not limited thereto.
Production Method D
[0541] 52
[0542] [Step D1]
[0543] In this step, compound (1d) is reacted with compound (1d-2)
to give compound (2d).
[0544] Specifically, compound (1d-2) includes, for example, alkyl
halides such as iodomethane, iodoethane, iodopropane, benzyl
bromide, 2-bromoacetophenone, chloromethyl benzyl ether, and
bromoacetonitrile; alkenyl halides such as allyl bromide and
1-bromo-3-methyl-2-butene; and alkynyl halides such as propargyl
bromide and 1-bromo-2-butyne. It is preferable to use 1 to 1.5
equivalent of compound (1d-2).
[0545] Solvents for the reaction include N,N-dimethylformamide,
N-methylpyrrolidone, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane, and dichloromethane. The reaction can be carried out
in the presence or absence of a base. Bases to be used in the
reaction include 1,8-diazabicyclo[5,4,0]undecene, triethylamine,
N,N-diisopropylethylamine- , and sodium hydride. In this case, it
is preferable to use 1 to 1.5 equivalent of the base. The reaction
can be conducted at a temperature ranging from 0.degree. C. to
150.degree. C.
[0546] [Step D2]
[0547] In this step, compound (2d) is reacted with a nitrite salt
to give compound (3d).
[0548] Solvents for the reaction include a mixed solvent of water
and a solvent from N,N-dimethylformamide, N-methylpyrrolidone,
tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane. Nitrite
salts include sodium nitrite and potassium nitrite. It is
preferable to use 3 to 5 equivalents of a nitrite. The reaction can
be conducted at a temperature ranging from 20.degree. C. to
120.degree. C.
[0549] [Step D3]
[0550] In this step, compound (3d) is reacted with ammonia to give
compound (4d). It is preferable to use 10 to 20 equivalents of
ammonia.
[0551] The reaction can be carried out in a solvent such as
methanol, ethanol, or 1,4-dioxane at a temperature ranging from
20.degree. C. to 200.degree. C.
[0552] [Step D4]
[0553] In this step, compound (4d) is subjected to catalytic
reduction under hydrogen atmosphere or in the presence of 2 to 3
equivalents of hydrazine using a metal catalyst to give compound
(5d).
[0554] Solvents for the reaction include methanol, ethanol,
N,N-dimethylformamide, tetrahydrofuran, 1,2-dimethoxyethane,
1,4-dioxane, water, or a mixed solvent thereof. Metal catalysts
include palladium carbon, platinum oxide, and Raney nickel. It is
preferable to use a metal catalyst in the amount of 0.5 to 10% by
weight. The reaction can be conducted at a temperature ranging from
0.degree. C. to 150.degree. C.
[0555] [Step D5]
[0556] In this step, compound (5d) is reacted with an orthoformate
ester to give compound (6d).
[0557] The reaction is carried out in the presence of a carboxylic
anhydride such as acetic anhydride. Orthoformate esters include
methyl orthoformate, and ethyl orthoformate. It is preferable to
use 1 to 20 times as much orthoformate ester by weight and 3 to 10
equivalents of carboxylic anhydride. The reaction can be conducted
at a temperature ranging from 20.degree. C. to 200.degree. C.
[0558] [Step D6]
[0559] In this step, the NH group at the 1-position of compound
(6d) is protected to give compound (7d).
[0560] Protecting reagents include N,N-dimethylsulfamoyl chloride,
trityl chloride, di-t-butyl dicarbonate, and benzyl bromide. It is
preferable to use 1 to 1.5 equivalent of a protecting reagent.
Solvents for the reaction include dichloromethane, chloroform,
carbon tetrachloride, toluene, N,N-dimethylformamide, and
tetrahydrofuran. Bases include pyridine, 4-dimethylaminopyridine,
1,8-diazabicyclo[5,4,0]undecene, triethylamine, and
N,N-diisopropylethylamine. In typical cases, it is preferable to
use 1.2 equivalents of a base. However, when the protecting reagent
is di-t-butyl dicarbonate, 0.005 to 0.1 equivalent of
4-dimethylaminopyridine is used preferably. The reaction can be
conducted at a temperature ranging from 20.degree. C. to
200.degree. C.
[0561] [Step D7]
[0562] In this step, compound (7d) is chlorinated to give compound
(8d).
[0563] There are no particular limitations on the reaction
conditions. For example, the reaction is carried out as follows.
Compound (7d) is reacted with a base at a temperature ranging from
-100.degree. C. to 20.degree. C., and then a chlorinating reagent
is reacted thereto. This reaction produces compound (8d). Compound
(8d) can also be obtained by reacting compound (7d) with a base in
the presence of a chlorination reagent. Solvents for the reaction
include, for example, diethyl ether, tetrahydrofuran,
1,2-dimethoxyethane, and 1,4-dioxane. Bases include n-butyllithium,
t-butyllithium, lithium diisopropylamide, lithium
bis(trimethylsilyl)amide, and magnesium diisopropylamide. It is
preferable to use 1 to 1.5 equivalent of a base. Chlorinating
reagents include hexachloroethane, and N-chloro succinimide. It is
preferable to use 1 to 3 equivalents of a chlorination reagent.
[0564] [Step D8]
[0565] In this step, compound (8d) is reacted with compound (9d) to
give compound (10d). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0566] [Step D9]
[0567] In this step, a substitution reaction is carried out using
compound (10d) and compound (10d-2) to give compound (11d). The
reaction can be conducted under the same conditions as used in
[Step A4] of production method A.
[0568] [Step D10]
[0569] In this step, R.sup.p3 of compound (11d) is removed to give
compound (12d). The reaction can be conducted under the same
condition as used in [Step A13] of production method A.
[0570] [Step D11]
[0571] In this step, the group at the 5-position of compound (11d)
is obtained by dealkylation to give compound (13d). There are no
particular limitations on the reaction conditions for the
dealkylation. For example, such a reaction can be achieved as
follows:
[0572] When R.sup.1 is a benzyloxymethyl group, compound (11d) is
reacted with 3 to 10 equivalents of boron tribromide, boron
trichloride, or such in a solution such as dichloromethane at a
temperature ranging from -100.degree. C. to 20.degree. C. This
reaction produces compound (13d).
[0573] When such a reaction results in removal of R.sup.p3, --NH--
is re-protected through a protection reaction. Specifically, for
example, when R.sup.p3 is a t-butoxycarbonyl group, the reaction
can be carried out using a reagent such as di-t-butyl dicarbonate,
in a solvent such as dichloromethane, chloroform,
N,N-dimethylformamide, or tetrahydrofuran, in the presence of a
base such as pyridine, 4-aminopyridine, triethylamine, or
N,N-diisopropylethylamine, at a temperature ranging from 0 to
80.degree. C. However, the reaction is not limited thereto.
[0574] [Step D12]
[0575] In this step, compound (13d) is reacted with compound
(13d-2) to give compound (14d). The reaction can be conducted under
the same conditions as used in [Step D1] of production method
D.
[0576] [Step D13]
[0577] In this step, R.sup.p3 of compound (14d) is removed to give
compound (12d). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0578] An alternative method for producing compound (11d) is
described below. 53
[0579] [Step D14]
[0580] In this step, compound (8d) is deprotected to give compound
(15d).
[0581] The deprotection can be achieved under standard reaction
conditions depending on the type of protecting group. For example,
in the case of a t-butoxycarbonyl group, the deprotection can be
achieved by carrying out the reaction using a base such as sodium
hydroxide, potassium carbonate, and ammonia, in tetrahydrofuran,
N,N-dimethylformamide, methanol, ethanol, water, or a mixed solvent
thereof at a temperature ranging from 0.degree. C. to 100.degree.
C. When a solvent and a base are added after chlorination in the
previous step, the deprotection can be achieved without isolating
compound (8d).
[0582] [Step D15]
[0583] In this step, X is introduced into compound (15d) to give
compound (16d). The reaction can be conducted using X-U.sup.2 under
the same conditions as used in [Step A4] of production method
A.
[0584] An alcohol (X--OH) can be introduced using Mitsunobu's
reaction. Specifically, compound (16d) can be obtained by reacting
an alcohol (X--OH) with an azodicarboxylic acid dialkyl ester and
triphenylphosphine in a solvent such as tetrahydrofuran, at a
temperature ranging from -70.degree. C. to 50.degree. C.
[0585] [Step D16]
[0586] In this step, compound (16d) is reacted with compound (9d)
to give compound (11d).
[0587] The reaction can be conducted under the same conditions as
used in [Step A6] of production method A.
Production Method E
[0588] Compound (1e) represented by the formula: 54
[0589] can be obtained by using compound (8b) represented by
H-T.sup.1a, instead of compound (6c), in [Step C5] or [Step C15] of
production method C described above under the same reaction
conditions as used in [Step C5], and then appropriately applying
[Step C6] to [Step C21] described above.
[0590] Compound (1e) represented by the formula: 55
[0591] can be obtained by using compound (8b) represented by
H-T.sup.1a, instead of compound (9d) in [Step D8] of production
method D described above under the same reaction conditions as used
in [Step D8], and then appropriately applying [Step D9] to [Step
D13] described above.
Production Method F
[0592] 56
[0593] [Step F1]
[0594] In this step, the ester group of compound (1f) is hydrolyzed
to give compound (2f). The reaction can be conducted under the same
conditions as used in [Step C16] of production method C.
[0595] [Step F2]
[0596] In this step, R.sup.p3 of compound (2f) is removed to give
compound (3f). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method G
[0597] 57
[0598] [Step G1]
[0599] In this step, the nitro group of compound (1g) is reduced to
give compound (2g).
[0600] Solvents for the reaction include methanol, ethanol,
tetrahydrofuran, water, or mixtures thereof. Reducing agents
includes, iron, tin, and zinc. Catalysts include hydrochloric acid
and ammonium salts such as ammonium chloride. The reaction can be
conducted at a temperature ranging from 20.degree. C. to
120.degree. C.
[0601] [Step G2]
[0602] In this step, R.sup.p3 of compound (2g) is removed to give
compound (3g). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method H
[0603] 58
[0604] [Step H1]
[0605] In this step, the nitrile group of compound (1h) is
hydrolyzed to give compound (2h).
[0606] There are no particular limitations on the reaction
conditions. For example, the reaction is carried out as follows.
Compound (2h) can be obtained by reacting compound (1h) with
hydrogen peroxide in the presence of a base at a temperature
ranging from -20.degree. C. to 50.degree. C. Solvents include
methanol, ethanol, tetrahydrofuran, water, or a solvent mixture
thereof. Bases include ammonia and alkyl amines such as
triethylamine.
[0607] [Step H2]
[0608] In this step, R.sup.p3 of compound (2h) is removed to give
compound (3h). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method I
[0609] 59
[0610] [Step I1]
[0611] In this step, compound (1i) is reacted with an alkyl metal
agent or an aryl metal agent to give compound (2i).
[0612] There are no particular limitations on the reaction
conditions. For example, the reaction is carried out as follows.
Compound (1i) may be reacted with an agent such as alkyllithium,
aryllithium, alkyl Grignard reagent, or aryl Grignard reagent, in a
solvent such as diethyl ether or tetrahydrofuran, at a temperature
ranging from -100.degree. C. to 100.degree. C. Alternatively, the
compound may be reacted with alkylzinc or arylzinc in a solvent
such as N,N-dimethylformamide or 1-methyl-2-pyrrolidone, at a
temperature ranging from 0.degree. C. to 50.degree. C.
[0613] [Step I2]
[0614] In this step, compound (2i) is oxidized to give compound
(3i) A typical reagent that is generally used in the oxidation of
an alcohol can be used as the oxidant. Specifically, for example,
manganese dioxide can be used as the oxidant in a solvent such as
dichloromethane or chloroform, at a temperature within the range of
20 to 100.degree. C. Alternatively, sulfur trioxide pyridine can be
used as the oxidant in a solvent such as dimethyl sulfoxide, at a
temperature within the range of 20 to 100.degree. C. Alternatively,
Dess-Martin periodinane may be used in a solvent such as
dichloromethane or chloroform, at a temperature within the range of
-50 to 50.degree. C.
[0615] [Step I3]
[0616] In this step, compound (3i) is reacted with hydrazine to
give compound (4i). The reaction can be conducted under the same
conditions as used in [Step C12] of production method C.
[0617] [Step I4]
[0618] In this step, a substitution reaction is carried out using
compound (4i) and compound (5i) to give compound (6i). The reaction
can be conducted under the same conditions as used in [Step A2] of
production method A.
[0619] [Step I5]
[0620] In this step, R.sup.p3 of compound (6i) is removed to give
compound (7i). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0621] [Step I6]
[0622] In this step, R.sup.p3 of compound (4i) is removed to give
compound (7i) when R.sup.1 of compound (7i) is H. The reaction can
be conducted under the same conditions as used in [Step A13] of
production method A.
Production Method J
[0623] 60
[0624] [Step J1]
[0625] In this step, compound (1j) is reacted with a cyanidation
agent in the presence of a catalyst to give compound (2j).
[0626] Cyanidation agents include sodium cyanide, and potassium
cyanide. Catalysts include acetic acid. Solvents include, for
example, acetonitrile. The reaction can be conducted at a
temperature ranging from 0.degree. C. to 100.degree. C.
[0627] [Step J2]
[0628] In this step, the nitrile group of compound (2j) is
hydrolyzed to give compound (3j). The reaction can be conducted
under the same conditions as used in [Step H1] of production method
H.
[0629] [Step J3]
[0630] In this step, the hydroxyl group of compound (3j) is
oxidized to give compound (4j). The reaction can be conducted under
the same conditions as used in [Step I2] of production method
I.
[0631] [Step J4]
[0632] In this step, compound (4j) is reacted with compound (5j) to
give compound (6j). The reaction can be conducted under the same
conditions as used in [Step C11] of production method C.
[0633] [Step J5]
[0634] In this step, R.sup.p3 of compound (6j) is removed to give
compound (7j). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0635] [Step J6]
[0636] In this step, the carbamoyl group of compound (6j) is
dehydrated in the presence of a base to give compound (8j).
[0637] Dehydrating agents include, for example, phosphorus
oxychloride. Bases include alkyl amines such as triethylamine.
Solvents include dichloromethane, and chloroform. Alternatively,
the reaction can be carried out in the absence of solvent. The
reaction can be conducted at a temperature ranging from 0.degree.
C. to 100.degree. C.
[0638] [Step J7]
[0639] In this step, R.sup.p3 of compound (8j) is removed to give
compound (9j). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method K
[0640] 61
[0641] [Step K1]
[0642] In this step, a substitution reaction using compound (1k)
and compound (2k) is carried out to give compound (3k). The
reaction can be conducted under the same conditions as used in
[Step A2] of production method A.
[0643] [Step K2]
[0644] In this step, a substitution reaction using compound (3k)
and compound (4k) is carried out to give compound (5k).
[0645] Compound (5k) can be obtained, for example, by reacting a
mixture of compounds (3k) and (4k) in a solvent such as methanol,
ethanol, 1-methyl-2-pyrrolidone, 1,4-dioxane, tetrahydrofuran, or
dimethoxyethane, or in the absence of solvent at a temperature
ranging from 20.degree. C. to 200.degree. C. However, the reaction
conditions are not limited thereto.
[0646] [Step K3]
[0647] In this step, compound (5k) is chlorinated to give compound
(6k). The reaction can be conducted under the same conditions as
used in [Step D7] of production method D.
[0648] [Step K4]
[0649] In this step, compound (6k) is reacted with compound (7k) to
give compound (8k). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0650] [Step K5]
[0651] In this step, R.sup.p5 of compound (8k) is removed to give
compound (9k).
[0652] The deprotection reaction for R.sup.p5 can be carried out
under standard reaction conditions for removing an --NH-protecting
group.
[0653] For example, when R.sup.p5 is a benzyl group, the reaction
can be achieved using a metal such as lithium or sodium in liquid
ammonia at a temperature within the range of -78.degree. C. to
-30.degree. C.
[0654] [Step K6]
[0655] In this step, a substitution reaction using compound (9k)
and compound (10k) is carried out to give compound (11k). The
reaction can be conducted under the same conditions as used in
[Step A4] of production method A.
[0656] [Step K7]
[0657] In this step, R.sup.p3 of compound (11k) is removed to give
compound (12k). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method L
[0658] 62
[0659] [Step L1]
[0660] In this step, compound (1l) is reacted with compound (2l) in
the presence of an oxidant to give compound (3l).
[0661] Oxidants include salts such as iron (III) chloride. Solvents
include methanol, ethanol, and water. The reaction can be conducted
at a temperature ranging from 20.degree. C. to 100.degree. C.
[0662] When such a reaction results in removal of --R.sup.p3,
--NH-- is re-protected through a protection reaction. Specifically,
for example, when Pro3 is a t-butoxycarbonyl group, the reaction
can be carried out using a reagent such as di-t-butyl dicarbonate,
in a solvent such as dichloromethane, chloroform,
N,N-dimethylformamide, or tetrahydrofuran, in the presence of a
base such as pyridine, 4-aminopyridine, triethylamine, or
N,N-diisopropylethylamine, at a temperature ranging from 0 to
80.degree. C. However, the reaction is not limited thereto.
[0663] [Step L2]
[0664] In this step, compound (3l) is reacted with compound (4l) to
give compound (5l). The reaction can be conducted under the same
conditions as used in [Step A4] of production method A.
[0665] [Step L3]
[0666] In this step, R of compound (5l) is removed to give compound
(6l). The reaction can be conducte dunder the same conditions as
used in [Step A13] of production method A.
Production Method M
[0667] 63
[0668] [Step M1]
[0669] In this step, compound (1m) is reacted with compound (2m) to
give compound (3m). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0670] [Step M2]
[0671] In this step, compound (3m) is reacted with compound (4m) to
give compound (5m). The reaction can be conducted under the same
conditions as used in [Step A4] of production method A.
[0672] [Step M3]
[0673] In this step, R.sup.p3 of compound (5m) is removed to give
compound (6m). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method N
[0674] 64
[0675] [Step N1]
[0676] In this step, compound (1n) is reacted with allylamine to
give compound (2n).
[0677] The reaction can be conducted at a temperature ranging from
20.degree. C. to 150.degree. C. Solvents for the reaction include
methanol, ethanol, water, and a mixed solvent thereof.
[0678] [Step N2]
[0679] In this step, compound (2n) is reduced while being
chlorinated to give compound (3n).
[0680] Reducing agents include tin salts such as tin chloride.
Solvents include concentrated hydrochloric acid. The reaction can
be conducted at a temperature ranging from 20.degree. C. to
150.degree. C.
[0681] [Step N3]
[0682] In this step, compound (3n) is reacted with
N,N'-disuccinimidyl carbonate to give compound (4n).
[0683] The reaction can be achieved using a solvent such as
acetonitrile or tetrahydrofuran. The reaction can be conducted at a
temperature ranging from 20.degree. C. to 100.degree. C.
[0684] [Step N4]
[0685] In this step, compound (4n) is reacted with compound (5n) to
give compound (6n). The reaction can be conducted under the same
conditions as used in [Step A4] of production method A.
[0686] [Step N5]
[0687] In this step, the allyl group is removed from compound (6n)
to give compound (7n).
[0688] Compound (7n) can be obtained, for example, by reacting
compound (6n) with osmic acid and sodium periodate in a solvent
such as tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, or water
at a temperature ranging from 20.degree. C. to 100.degree. C.
However, the reaction conditions are not limited to this
example.
[0689] [Step N6]
[0690] In this step, compound (7n) is chlorinated to give compound
(8n).
[0691] There are no particular limitations on the reaction
conditions. The reaction can be conducted under standard reaction
conditions to be used for chlorination. Compound (8n) can be
obtained, for example, by using a reagent such as phosphorus
pentachloride in a solvent such as phosphorus oxychloride, at a
temperature of 0 to 150.degree. C.
[0692] [Step N7]
[0693] In this step, compound (8n) is reacted with compound (9n) to
give compound (10n). The reaction can be conducted under the same
conditions as used in [Step A6] of production method A.
[0694] [Step N8]
[0695] In this step, R.sup.p3 of compound (10n) is removed to give
compound (11n). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method O
[0696] 65
[0697] [Step O1]
[0698] In this step, the hydroxyl group of compound (1o) is
oxidized to give compound (2o). The reaction can be conducted under
the same conditions as used in [Step I2] of production method
I.
[0699] [Step O2]
[0700] In this step, compound (2o) is reacted with ethyl
diethylphosphonoacetate in the presence of a base to give compound
(3o).
[0701] Bases include sodium hydride and lithium diisopropylamide.
Solvents include, for example, tetrahydrofuran and N,N-diformamide.
The reaction can be conducted at a temperature ranging from
0.degree. C. to 100.degree. C.
[0702] [Step O3]
[0703] In this step, the ester of compound (3o) is hydrolyzed to
give compound (4o). The reaction can be conducted under the same
condition as used in [Step C16] of production method C.
[0704] [Step O4]
[0705] In this step, compound (4o) is reacted with
diphenylphosphoryl azide in the presence of a base to give compound
(5o).
[0706] Solvents for the reaction include toluene, t-butanol,
tetrahydrofuran, and dichloromethane. Bases include tertiary amines
such as triethylamine and diisopropylethylamine. The reaction can
be conducted at a temperature ranging from -50.degree. C. to
50.degree. C.
[0707] [Step O5]
[0708] In this step, compound (5o) is rearranged to give compound
(6o).
[0709] The reaction can be achieved in t-butanol at a temperature
ranging from 50.degree. C. to 100.degree. C.
[0710] [Step O6]
[0711] In this step, the nitrile group of compound (6o) is
hydrolyzed to give compound (7o). The reaction can be conducted
under the same conditions as used in [Step H1] of production method
H.
[0712] [Step O7]
[0713] In this step, compound (7o) is reacted with an acid to give
compound (8o).
[0714] Acids include hydrochloric acid, sulfuric acid, and
trifluoroacetic acid. Solvents include methanol, ethanol,
1,4-dioxane, water, and mixtures thereof. The reaction can be
conducted at a temperature ranging from 0.degree. C. to 50.degree.
C.
Production Method P
[0715] 66
[0716] [Step P1]
[0717] In this step, compound (1p) is protected to give compound
(2p).
[0718] A typical NH group-protecting reagent that is generally used
in protecting NH groups can be used as an NH group-protecting
reagent. For example, when R.sup.p3 is a t-butoxycarbonyl group,
the reaction can be achieved at a temperature ranging from 0 to
80.degree. C. using a reagent such as di-t-butyl dicarbonate, in a
solvent such as dichloromethane, chloroform, N,N-dimethylformamide,
and tetrahydrofuran, in the presence of a base such as pyridine,
4-aminopyridine, triethylamine, and N,N-diisopropylethylamine.
[0719] [Step P2]
[0720] In this step, compound (2p) is reacted with compound (3p) to
give compound (4p). The reaction can be conducted under the same
conditions as used in [Step A2] of production method A.
[0721] [Step P3]
[0722] In this step, R.sup.p3 of compound (4p) is removed to give
compound (5p). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
Production Method Q
[0723] 67
[0724] [Step Q1]
[0725] In this step, compound (1q) is hydrolyzed to give compound
(2q) Reaction solvents include tetrahydrofuran, methanol, and
ethanol. Acids include inorganic acids such as hydrochloric acid
and sulfuric acid. The reaction can be conducted at a temperature
ranging from 0.degree. C. to 100.degree. C.
[0726] [Step Q2]
[0727] In this step, the hydroxyl group of compound (2q) is
oxidized to give compound (3q). The reaction can be conducted under
the same conditions as used in [Step I2] of production method
I.
[0728] [Step Q3]
[0729] In this step, compound (3q) is reacted with methyl
benzyloxycarbonylamino(dimethoxyphosphoryl)acetate in the presence
of a base to give compound (4q).
[0730] Bases include sodium hydride, potassium t-butoxide, and
8-diazabicyclo[5.4.0]-7-undecene. Solvents include dichloromethane,
tetrahydrofuran, and N,N-dimethylformamide. The reaction can be
conducted at a temperature ranging from 0.degree. C. to 100.degree.
C.
[0731] [Step Q4]
[0732] In this step, compound (4q) is reacted with sodium methoxide
to give compound (5q).
[0733] Methanol can be used as solvent. The reaction can be
conducted at a temperature ranging from 0.degree. C. to 80.degree.
C.
[0734] [Step Q5]
[0735] In this step, compound (5q) is reacted with compound (6q) to
give compound (7q). The reaction can be conducted under the same
conditions as used in [Step A2] of production method A.
[0736] [Step Q6]
[0737] In this step, compound (7q) is reacted with an acid to give
compound (8q). The reaction can be conducted under the same
conditions as used in [Step O7] of production method O.
[0738] [Step Q7]
[0739] In this step, R.sup.p3 of compound (8q) is removed to give
compound (9q). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0740] [Step Q8]
[0741] In this step, compound (7q) is reacted with ammonia to give
compound (10q).
[0742] Reaction solvents include methanol, ethanol, and water. The
reaction can be conducted at a temperature ranging from 20.degree.
C. to 150.degree. C.
[0743] [Step Q9]
[0744] In this step, R.sup.p3 of compound (10q) is removed to give
compound (11q). The reaction can be conducted under the same
conditions as used in [Step A13] of production method A.
[0745] The compounds indicated below, salts thereof, or hydrates
thereof, are exceedingly useful as intermediates in the synthesis
of compound (I) of the present invention.
[0746] Compounds, or salts thereof, or hydrates thereof,
represented by the formula: 68
[0747] [where
[0748] R.sup.1 is defined as in [1] above;
[0749] R.sup.p5 represents a t-butoxycarbonyloxy group, a trityl
group, or a group represented by the formula
--SO.sub.2NH.sub.2;
[0750] T.sup.10 represents a halogen atom or a hydrogen atom];
[0751] Compounds, or salts thereof, or hydrates thereof,
represented by the formula: 69
[0752] [where
[0753] R.sup.1 is defined as in [1] above;
[0754] T.sup.11 represents a halogen atom or a group represented by
the formula: 70
[0755] T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group];
[0756] Compounds, or salts thereof, or hydrates thereof,
represented by the formula: 71
[0757] [where
[0758] R.sup.1 and X are defined as in [1] above;
[0759] T.sup.12 represents a halogen atom];
[0760] Compounds, or salts thereof, or hydrates thereof,
represented by the formula: 72
[0761] [where
[0762] X is defined as in [1] above, but excluding the case where X
is a benzyl group;
[0763] T.sup.21 and T.sup.22 each independently represent a halogen
atom;
[0764] T.sup.11 represents a halogen atom or a group represented by
the formula: 73
[0765] T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group];
[0766] Compounds, or salts thereof, or hydrates thereof,
represented by the formula: 74
[0767] [where
[0768] X and R.sup.1 are defined as in [1] above;
[0769] T.sup.22 represents a halogen atom;
[0770] T.sup.13 represents a t-butoxycarbonyl group, a
benzyloxycarbonyl group, or a formyl group].
[0771] The methods indicated above are representative methods for
producing compound (I) of the present invention. The starting
compounds and various reagents to be used in the methods for
producing compounds of the present invention may be salts or
hydrates, or solvates depending on the type of starting materials,
solvents to be used, or such, and are not limited as long as they
do not inhibit the reactions. The type of solvents to be used
depends on the types of starting compounds, reagents to be used, or
such, and is not limited as long as it does not inhibit the
reactions and dissolves starting materials to some extent. When
compound (I) of the present invention is obtained in a free form,
such a compound can be converted to a salt or a hydrate, which is a
possible form of compound (I) described above, according to a
conventional method.
[0772] When compound (I) of the present invention is obtained as a
salt or a hydrate, such a product can be converted to a free form
of compound (I) described above according to a conventional
method.
[0773] In addition, various isomers of compound (I) of the present
invention (for example, geometric isomers, enantiomers on the basis
of asymmetric carbon, rotamers, stereoisomers, and tautomers) can
be purified and isolated by typical isolation means, for example,
including recrystallization, diastereomer salt method, enzyme-based
separation, and various chromatographic methods (for example, thin
layer chromatography, column chromatography, and gas
chromatography).
[0774] Compounds of the present invention, salts thereof, or
hydrates thereof, can be formulated into tablets, powders,
particles, granules, coated tablets, capsules, syrups, troches,
inhalants, suppositories, injections, ointments, eye ointments, eye
drops, nasal drops, ear drops, epithem, lotions, etc. by
conventional methods. Such formulation can be achieved by using
typical diluting agents, binders, lubricants, colorants, flavoring
agents, and if required, stabilizers, emulsifiers, absorbefacients,
surfactants, pH modulators, preservatives, antioxidants, etc., and
materials commonly used as ingredients of pharmaceutical
preparations according to conventional methods. For example, an
oral preparation can be produced by combining a compound of the
present invention or a pharmaceutically acceptable salt thereof
with a diluting agent, and if required, a binder, a disintegrating
agent, a lubricant, a colorant, a flavoring agent, or such, and
formulating the mixture into powders, particles, granules, tablets,
coated tablets, capsules, or the like according to conventional
methods. Examples of the materials include, for example, 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
isopropyl myristate; higher alcohols such as cetostearyl alcohol
and behenyl alcohol; silicon resins; silicone oils; surfactants
such as polyoxyethylene fatty acid ester, sorbitan fatty acid
ester, glycerol 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, poly-acrylic 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.
Diluting agents include, for example, lactose, corn starch, white
sugar, glucose, mannitol, sorbitol, crystal cellulose, and silicon
dioxide. Binders include, for example, polyvinyl alcohol, polyvinyl
ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth,
gelatin, shellac, hydroxypropyl methyl cellulose, hydroxypropyl
cellulose, polyvinylpyrrolidone, polypropylene
glycol-polyoxyethylene block co-polymer, and meglumine.
Disintegrating agents include, for example, starch, agar, gelatin
powder, crystalline cellulose, calcium carbonate, sodium
bicarbonate, calcium citrate, dextrin, pectin, and calcium
carboxymethyl cellulose. Lubricants include, for example, magnesium
stearate, talc, polyethylene glycol, silica, and hydrogenated
vegetable oil. Colorants include those pharmaceutically acceptable.
Flavoring agents include cocoa powder, peppermint camphor, aromatic
powder peppermint oil, Borneo camphor, and cinnamon powder. Tablets
and granules may be coated with sugar, or if required, other
appropriate coatings can be made. Solution, such as syrups or
injectable preparations, to be administered can be formulated by
combining a compound of the present invention or a pharmaceutically
acceptable salt thereof with a pH modulator, a solubilizing agent,
an isotonizing agent, or such, and if required, with an auxiliary
solubilizing agent, a stabilizer, or the like, according to
conventional methods. Methods for producing an external preparation
are not limited and such preparations can be produced by
conventional methods. Specifically, various materials typically
used for producing pharmaceuticals, quasi drugs, cosmetics, and
such can be used as base materials for the external formulation.
Specifically, base materials to be used include, for example,
animal and vegetable oils, mineral oils, ester oil, wax, higher
alcohols, fatty acids, silicone oil, surfactants, phospholipids,
alcohols, polyhydric alcohols, water-soluble polymers, clay
minerals, and pure water. Furthermore, external preparations of the
present invention can contain, as required, pH modulators,
antioxidants, chelating agents, antibacterial/antifungal agents,
coloring matters, odoriferous substances, etc. But this does not
limit the type of base materials that are to be used in an external
preparation of the present invention. If required, the preparation
may contain differentiation inducers, blood flow improving agents,
antimicrobial agents, antiphlogistics, cell activators, vitamins,
amino acids, humectants, keratolytic agents, etc. The amount of
base materials listed above is adjusted within a concentration
range used for producing typical external preparations.
[0775] When a compound of the present invention, or a salt thereof,
or a hydrate thereof is administered, the forms of a compound are
not limited and a compound can be given orally or parenterally by a
conventional method. For example, a compound can be administered as
a dosage form such as tablets, powders, granules, capsules, syrups,
troches, inhalants, suppositories, injections, ointments, eye
ointments, eye drops, nasal drops, ear drops, epithems, and
lotions. The dose of a pharmaceutical of the present invention can
be selected appropriately based on symptom severity, age, sex,
weight, forms of compounds, type of salts, specific type of
diseases, etc.
[0776] The dose varies depending on the patient's disease, symptom
severity, age and sex, drug susceptibility, etc. A pharmaceutical
agent of this invention is administered once or several times at a
dose of approx. 0.03 to approx. 1000 mg/adult/day, preferably 0.1
to 500 mg/adult/day, more preferably 0.1 to 100 mg/adult/day. An
injection can be given at a dose of approx. 1 to approx. 3000
.mu.g/kg, preferably approx. 3 to approx. 1000 .mu.g/kg.
[0777] Compounds of the present invention can be produced, for
example, by the methods described in Examples below. However, the
compounds of the present invention are under no circumstances to be
construed as being limited to specific examples described
below.
[0778] All patents and publications mentioned herein are
incorporated by reference.
PRODUCTION EXAMPLE
Production Example 1
t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyrid-
azin-2-yl]piperazin-1-carboxylate
[0779] (a) t-Butyl
5-methyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-ca-
rboxylate
[0780] A mixture consisting of 1.0 g of
5-methyl-3,5-dihydroimidazo[4,5-d]- pyridazin-4-one, 16 mg of
4-dimethylaminopyridine, 1.6 g of di-t-butyl dicarbonate, and 5 ml
of tetrahydrofuran was stirred at room temperature overnight. Then,
a 0.5-ml tetrahydrofuran solution containing 300 mg of di-t-butyl
dicarbonate was added to the solution, and the resulting mixture
was stirred at room temperature for three hours. 5 ml of t-butyl
methyl ether was added to the reaction mixture, and the mixture was
cooled with ice. The resulting crystals were collected by
filtration to give 1.63 g of the title compound.
[0781] .sup.1H-NMR(CDCl.sub.3) .delta. 1.72 (s, 9H) 3.93 (s, 3H)
8.38 (s, 1H) 8.54 (s, 1H)
[0782] (b)
2-Chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one
[0783] 8.4 ml of lithium hexamethyldisilazide (1.0 M
tetrahydrofuran solution) was added dropwise over one hour to a
300-ml tetrahydrofuran solution containing 1.68 g of t-butyl
5-methyl-4-oxo-4,5-dihydroimidazo[4- ,5-d]pyridazine-1-carboxylate
and 4.15 g of hexachloroethane under a nitrogen atmosphere at
0.degree. C. The resulting mixture was stirred for 30 minutes. 2N
ammonia water was added to the solution, and the mixture was
stirred for three hours. Then, the reaction solution was
concentrated to 50 ml, and washed with 20 ml of t-butyl methyl
ether. The solution was acidified with concentrated hydrochloric
acid. The resulting precipitate was collected by filtration, and
washed successively with 10 ml of water and 10 ml of t-butyl methyl
ether. Thus, 1.03 g of the title compound was obtained.
[0784] .sup.1H-NMR(DMSO-d6) .delta. 1.45 (s, 9H) 3.72 (s, 3H) 8.33
(s, 1H)
[0785] (c)
3-(2-Butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyrida-
zin-4-one
[0786] 7.72 g of 2-chloro-5
methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-on- e was suspended in
400 ml of tetrahydrofuran under a nitrogen atmosphere, and 14.22 g
of triphenylphosphine and 3.85 g of 2-butyn-1-ol were added
thereto. The resulting mixture was cooled to 0.degree. C. A 100-ml
tetrahydrofuran solution containing 12.55 g of azodicarboxylic acid
di-t-butyl ester was added dropwise, and the reaction mixture was
stirred for three hours. The reaction mixture was concentrated
under reduced pressure. 50 ml of dichloromethane and 50 ml of
trifluoroacetic acid were added to the residue, and the mixture was
stirred for 15 hours. The reaction mixture was concentrated under
reduced pressure. The resulting residue was dissolved in 400 ml of
ethyl acetate, and washed with a 200 ml of a 5N aqueous sodium
hydroxide solution. The aqueous layer was extracted with 100 ml of
ethyl acetate. The organic layers were combined together, dried
over magnesium sulfate, and concentrated under reduced pressure.
The resulting residue was purified by silica gel column
chromatography. Thus, 8.78 g of the title compound was obtained
from the fraction eluted with hexane-ethyl acetate (4:1).
[0787] .sup.1H-NMR(CDCl.sub.3) .delta. 1.82 (t, J=2.3 Hz, 3H) 3.87
(s, 3H) 5.32 (q, J=2.3 Hz, 2H) 8.19 (s, 1H)
[0788] (d) t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[0789] 5 ml of 1-methyl-2-pyrrolidone was added to a mixture
consisting of 1.183 g of
3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyrid-
azin-4-one, 0.829 g of potassium carbonate, and 1.395 g of t-butyl
piperazine-1-carboxylate under a nitrogen atmosphere. The resulting
mixture was heated at 130.degree. C. for 6 hours. The reaction
mixture was cooled, and 50 ml of water was added thereto. Then, the
mixture was extracted with 100 ml of ethyl acetate. The organic
layer was washed twice with 50 ml of water and then with 50 ml of
an aqueous solution saturated with sodium chloride. The organic
layer was dried over magnesium sulfate, and concentrated under
reduced pressure. The resulting residue was purified by silica gel
column chromatography. Thus, 1.916 g of the title compound was
obtained from the fraction eluted with hexane-ethyl acetate
(1:4).
[0790] .sup.1H-NMR(CDCl.sub.3) .delta. 1.52 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64 (m, 4H) 3.85 (s, 3H) 5.09 (q,
J=2.3 Hz, 2H) 8.13 (s, 1H)
Production Example 2
t-Butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine-1-carboxyla-
te
[0791] (a) 7-(2-Butynyl)-3-methyl-3,7-dihydropurine-2,6-dione
[0792] 55.3 ml of 1-bromo-2-butyne and 84.9 g of anhydrous
potassium carbonate were added to a mixture of 100 g of 3-methyl
xanthine [CAS No. 1076-22-8] and 1000 ml of N,N-dimethylformamide.
The resulting mixture was stirred at room temperature for 18 hours.
1000 ml of water was added to the reaction solution, and the
mixture was stirred at room temperature for 1 hour. The resulting
white precipitate was collected by filtration. The white solid was
washed with water and then t-butyl methyl ether. Thus, 112 g of the
title compound was obtained.
[0793] .sup.1H-NMR(DMSO-d6) .delta. 1.82 (t, J=2.2 Hz, 3H) 3.34 (s,
3H) 5.06 (q, J=2.2 Hz, 2H) 8.12 (s, 1H) 11.16 (br.s, 1H)
[0794] (b)
7-(2-Butynyl)-8-chloro-3-methyl-3,7-dihydropurine-2,6-dione
[0795] 112 g of 7-(2-butynyl)-3-methyl-3,7-dihydropurine-2,6-dione
was dissolved in 2200 ml of N,N-dimethylformamide, and 75.3 g of
N-chlorosuccinimide was added thereto. The resulting mixture was
stirred at room temperature for five hours. 2200 ml of water was
added to the reaction solution, and the mixture was stirred at room
temperature for 1.5 hour. The white precipitate was collected by
filtration, and the white solid was washed with water and, with
t-butyl methyl ether. Thus, 117 g of the title compound was
obtained.
[0796] .sup.1H-NMR(DMSO-d6) .delta. 1.78 (t, J=2.0 Hz, 3H) 3.30 (s,
3H) 5.06 (q, J=2.0 Hz, 2H) 11.34 (br.s, 1H)
[0797] (c) 7-(2-Butynyl)-2,6,8-trichloro-7H-purine
[0798] A mixture of 2.52 g of
7-(2-butynyl)-8-chloro-3-methyl-3,7-dihydrop- urine-2,6-dione and
100 ml of phosphorus oxychloride was stirred at 120.degree. C. for
14 hours. After the reaction mixture had been cooled, 4.15 g of
phosphorus pentachloride was added to the solution. The resulting
mixture was stirred at 120.degree. C. for 24 hours. After the
reaction solution had been cooled to room temperature, the solvent
was evaporated under reduced pressure. The residue was dissolved in
tetrahydrofuran. The solution was poured into a saturated sodium
bicarbonate solution, and the mixture was extracted with ethyl
acetate. The resulting organic layer was washed with water, then
saturated brine, and was then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography (ethyl
acetate:hexane=1:3) to give 2.40 g of the title compound.
[0799] .sup.1H-NMR(CDCl.sub.3) .delta. 1.82 (t, J=2.4 Hz, 3H) 5.21
(q, J=2.4 Hz, 2H)
[0800] (d) t-Butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine--
1-carboxylate
[0801] A mixture of 2.4 g of
7-(2-butynyl)-2,6,8-trichloro-7H-purine, 1.46 g of sodium
bicarbonate, 2.43 g of t-butyl piperazine-1-carboxylate, and 45 ml
of acetonitrile was stirred at room temperature for 2 hours and 20
minutes. Then, 0.73 g of sodium bicarbonate and 1.21 g of t-butyl
piperazine-1-carboxylate were added, and the resulting mixture was
stirred at room temperature for 1 hour. The reaction mixture was
extracted with ethyl acetate-water, and the organic layer was
washed with 1N hydrochloric acid, dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was triturated with diethyl ether. The crystals were collected by
filtration, and washed with diethyl ether. Thus, 3.0 g of the title
compound was obtained as a white solid.
[0802] .sup.1H-NMR(DMSO-d6) .delta. 1.42 (s, 9H) 1.83 (t, J=2 Hz,
3H) 3.48-3.55 (m, 4H) 3.57-3.63 (m, 4H) 4.89 (q, J=2 Hz, 2H)
EXAMPLE
Example 1
Ethyl
[7-(2-chlorophenyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]acetate trifluoroacetate
[0803] (a) [7-Benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate
[0804] 8.66 g of 7-benzylxanthine was dissolved in 300 ml of
N,N-dimethylformamide, and 1.57 g of sodium hydride and 7.7 ml of
chloromethyl pivalate were added thereto. The resulting mixture was
stirred at room temperature overnight. The reaction solution was
diluted with ethyl acetate, and washed with water and 1N
hydrochloric acid. The organic layer was dried over anhydrous
magnesium sulfate, then filtered. The solvent was evaporated under
reduced pressure. The residue was purified by silica gel column
chromatography. Thus, 2.66 g of the title compound was obtained
from the fraction eluted with hexane-ethyl acetate (1:1).
[0805] .sup.1H-NMR(CDCl.sub.3) .delta. 1.18 (s, 9H) 5.45 (s, 2H)
6.06 (s, 2H) 7.34-7.39 (m, 5H) 7.58 (s, 1H) 8.18 (s, 1H).
[0806] (b)
[7-Benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methy- l
2,2-dimethylpropionate
[0807] 2.66 g of
[7-benzyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate was dissolved in 30 ml of
N,N-dimethylformamide, and 1.6 g of potassium carbonate and 1 ml of
methyl iodide were added thereto. The mixture was stirred at room
temperature overnight. The reaction mixture was diluted with ethyl
acetate, and washed with water and 1N hydrochloric acid. The
organic layer was dried over anhydrous magnesium sulfate, then
filtered. The solvent was evaporated under reduced pressure. The
residue was triturated with toluene. Thus, 2.16 g of the title
compound was obtained.
[0808] .sup.1H-NMR(CDCl.sub.3) .delta. 1.18 (s, 9H) 3.41 (s, 3H)
5.49 (s, 2H) 6.11 (s, 2H) 7.26-7.39 (m, 5H) 7.57 (s, 1H).
[0809] (c) [1-Methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate
[0810] 2.349 g of
[7-benzyl-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-y- l]methyl
2,2-dimethylpropionate was dissolved in 100 ml of acetic acid, and
1 g of 10% palladium carbon was added thereto. The mixture was
stirred under a hydrogen atmosphere at room temperature overnight.
The reaction mixture was filtered and concentrated to give 1.871 g
of the title compound.
[0811] .sup.1H-NMR(CDCl.sub.3) .delta. 1.19 (s, 9H) 3.48 (s, 3H)
6.17 (s, 2H) 7.83 (s, 1H).
[0812] (d)
[7-(2-Chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin--
3-yl]methyl 2,2-dimethylopropionate
[0813] 1.60 g of
[1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate, 1.83 g of 2-chlorophenylboronic acid, and
1.5 g of copper (II) acetate were suspended in 30 ml of
N,N-dimethylformamide, and 3 ml of pyridine was added thereto. The
mixture was stirred at room temperature for 3 days. The reaction
mixture was filtered through a short column filled with silica gel,
and the filtrate was diluted with ethyl acetate. The organic layer
was washed with 1N hydrochloric acid, water, and saturated saline,
and dried over anhydrous magnesium sulfate, then filtered. The
filtrate was concentrated. The residue was suspended in ether, and
the suspension was filtered. The filtrate was purified by silica
gel column chromatography. Thus, 724 mg of the title compound was
obtained from the fraction eluted with hexane-ethyl acetate
(3:2).
[0814] (e) t-Butyl
4-[7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxymethyl-
)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxy-
late
[0815] 724 mg of
[7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-
purin-3-yl]methyl 2,2-dimethylpropionate was suspended in 15 ml of
N,N-dimethylformamide, and 760 mg of N-chlorosuccinimide was added
thereto. The reaction solution was stirred overnight, and then
diluted with ethyl acetate. The solution was washed with water and
1N hydrochloric acid, and dried over anhydrous magnesium sulfate,
then filtered. The filtrate was concentrated. Thus, 764 mg of
[8-chloro-7-(2-chlorophenyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-
-yl]methyl 2,2-dimethylpropionate was obtained. This compound was
mixed with 4 g of t-butyl piperazine-1-carboxylate. The mixture was
heated at 150.degree. C., and stirred for three hours. Ethyl
acetate and water were added to the reaction mixture, and the
mixture was separated. The organic layer was washed with 1N
hydrochloric acid, and dried over anhydrous magnesium sulfate, then
filtered. The filtrate was concentrated. The residue was purified
by silica gel column chromatography. Thus, 724 mg of the title
compound was obtained from the fraction eluted with hexane-ethyl
acetate (3:2).
[0816] (f) t-Butyl
4-[7-(2-chlorophenyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrah-
ydro-1H-purin-8-yl]piperazine-1-carboxylate
[0817] t-Butyl 4-[7-(2-chlorophenyl)-3-(2,2-dimethylpropionyloxy
methyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1--
carboxylate was dissolved in a mixture of 10 ml of methanol and 20
ml of tetrahydrofuran, and 200 mg of sodium hydride was added
thereto. The resulting mixture was stirred at room temperature
overnight. 1N hydrochloric acid was added to the reaction solution,
and the mixture was extracted with ethyl acetate. The organic layer
was dried over anhydrous magnesium sulfate, then filtered. The
filtrate was concentrated. The residue was suspended in ether and
the mixture was filtered. Thus, 450 mg of the title compound was
obtained.
[0818] .sup.1H-NMR(DMSO-d.sup.6) .delta. 1.35 (s, 9H) 3.04 (s, 3H)
3.06-3.12 (m, 4H) 3.17-3.22 (m, 4H) 7.48 (dt, J=1.6, 7.6 Hz, 1H)
7.53 (dt, J=2.0, 7.6 Hz, 1H) 7.63 (dd, J=2.0, 8.0 Hz, 1H) 7.65 (dd,
J=1.6, 8.0 Hz, 1H).
[0819] (g) t-Butyl
4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate (g-1), and t-butyl
4-[2,6-dichloro-7-(2-chlorophenyl)-7H-purin-8-yl]piperazine-1-carboxylate
(g-2)
[0820] 78 mg of t-butyl
4-[7-(2-chlorophenyl)-1-methyl-2,6-dioxo-2,3,6,7-t-
etrahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 3
ml of phosphorus oxychloride, and the mixture was stirred at
120.degree. C. overnight. The reaction solution was concentrated,
and the residue was dissolved in 1 ml of tetrahydrofuran. This
solution was poured into a suspension consisting of 50 mg of
di-t-butyl dicarbonate, 1 ml of tetrahydrofuran, and 0.5 ml of
water containing 100 mg of sodium bicarbonate. The resulting
mixture was stirred at room temperature for three hours. The
reaction mixture was diluted with ethyl acetate and washed with
water. The organic layer was dried over anhydrous magnesium
sulfate, then filtered. The filtrate was concentrated, and the
residue was purified by silica gel column chromatography. Thus, 16
mg of t-butyl
4-[2,6-dichloro-7-(2-chlorophenyl)-7H-purin-8-yl]piperazine-1-carboxylate
was obtained from the fraction eluted with hexane-ethyl acetate
(3:2), and 10 mg of t-butyl
4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7-di-
hydro-1H-purin-8-yl] piperazine-1-carboxylate was obtained from the
fraction eluted with hexane-ethyl acetate (1:9).
[0821] (h) Ethyl
[7-(2-chlorophenyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-
-dihydro-1H-purin-2-yloxy]acetate trifluoroacetate
[0822] 10 mg of t-butyl
4-[2-chloro-7-(2-chlorophenyl)-1-methyl-6-oxo-6,7--
dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl
glycolate were dissolved in 0.2 ml of N-methylpyrrolidone, and 10
mg of sodium hydride was added thereto. The mixture was stirred at
room temperature for 2 hours. The reaction solution was dissolved
in ethyl acetate, and the mixture was washed with 1N hydrochloric
acid. Thus, 24 mg of t-butyl
4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-1-methyl-6-ox-
o-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was obtained.
8 mg of this compound was dissolved in trifluoroacetic acid, and
the mixture was concentrated. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 2.11 mg of the title compound.
[0823] MS m/e (ESI) 447(MH.sup.+--CF.sub.3COOH)
Example 2
[7-(2-chlorophenyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-yloxy]acetic acid trifluoroacetate
[0824] 16 mg of t-butyl
4-[7-(2-chlorophenyl)-2-ethoxycarbonylmethoxy-1-me-
thyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was
combined with 0.4 ml of methanol and 0.1 ml of a 5N aqueous sodium
hydroxide solution, and the mixture was allowed to stand at room
temperature for two hours. 1N hydrochloric acid was added to the
reaction solution. The acidified solution was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The mixture was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 2.45 mg of the
title compound.
[0825] MS m/e (ESI) 419(MH.sup.+--CF.sub.3COOH)
Example 3
7-(2-Chlorophenyl)-2-cyclobutyloxy-8-(piperazin-1-yl)-1,7-dihydropurin-6-o-
ne
[0826] (a)
[7-Benzyl-3-(2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7--
tetrahydropurin-1-yl]methyl 2,2-dimethylpropionate
[0827] 9.54 g of 7-benzylxanthine was dissolved in 250 ml of
N,N-dimethylformamide, and 17 g of potassium carbonate and 14.2 ml
of chloromethyl pivalate were added thereto. The mixture was
stirred at 50.degree. C. overnight. The reaction mixture was
diluted with ethyl acetate, and washed with water and 1N
hydrochloric acid. The organic layer was dried over anhydrous
magnesium sulfate, then filtered. The solvent was evaporated under
reduced pressure, and the residue was purified by silica gel column
chromatography. Thus, 12.8 g of the title compound was obtained
from the fraction eluted with hexane-ethyl acetate (3:2).
[0828] (b)
[3-(2,2-Dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydr-
opurin-1-yl]methyl 2,2-dimethylpropionate
[0829] The title compound was obtained by treating
[7-benzyl-3-(2,2-dimeth- yl propionyloxy
methyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]methyl
2,2-dimethylpropionate by the same method as used in Example
(1c).
[0830] (c)
[7-(2-Chlorophenyl)-3-(2,2-dimethylpropionyloxymethyl)-2,6-diox-
o-2,3,6,7-tetrahydropurin-1-yl] methyl 2,2-dimethylpropionate
[0831] The title compound was obtained by treating
[3-(2-2-dimethylpropion-
yloxymethyl)-2-6-dioxo-2,3,6,7-tetrahydropurin-1-yl] methyl
2,2-dimethylpropionate by the same method as used in Example
(1d).
[0832] .sup.1H-NMR(CDCl.sub.3) .delta. 1.16 (s, 9H) 1.22 (s, 9H)
5.99 (s, 2H) 6.19 (s, 2H) 7.42-7.52 (m, 3H) 7.58-7.61 (m, 1H) 7.73
(s, 1H)
[0833] (d) t-Butyl
4-[7-(2-chlorophenyl)-1,3-bis-(2,2-dimethylpropionyloxy-
methyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylat-
e
[0834] The title compound was obtained by treating
[7-(2-chlorophenyl)-3-(-
2,2-dimethylpropionyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydropurin-1-yl]met-
hyl 2,2-dimethylpropionate by the same method as used in Example
(1e).
[0835] .sup.1H-NMR(CDCl.sub.3) .delta. 1.16 (s, 9H) 1.23 (s, 9H)
1.44 (s, 9H) 3.20-3.35 (m, 4H) 3.32-3.37 (m, 4H) 5.92 (s, 2H) 6.09
(s, 2H) 7.41-7.49 (m, 2H) 7.52-7.57 (m, 2H)
[0836] (e) t-Butyl
4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxymethyl-
)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate
[0837] 2.227 g of t-butyl
4-[7-(2-chlorophenyl)-1,3-bis-(2,2-dimethylpropi-
onyloxymethyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-car-
boxylate was dissolved in a mixture of 10 ml of tetrahydrofuran and
20 ml of methanol, and 0.518 ml of
1,8-diazabicyclo[5,4,0]undec-7-ene was added thereto. The mixture
was stirred at room temperature overnight. 1N hydrochloric acid was
added to the mixture, and the precipitated solid was collected by
filtration. The solid was dried to give 1.025 g of the title
compound.
[0838] .sup.1H-NMR(CDCl.sub.3) .delta. 1.16 (s, 9H) 1.44 (s, 9H)
3.22-3.24 (m, 4H) 3.33-3.35 (m, 4H) 5.90 (s, 2H) 7.43-7.47 (m, 2H)
7.51-7.57 (m, 2H) 8.71 (br, 1H)
[0839] (f)
7-(2-Chlorophenyl)-2-cyclobutyloxy-8-(piperazin-1-yl)-1,7-dihyd-
ropurin-6-one
[0840] 8 mg of t-butyl
4-[7-(2-chlorophenyl)-1-(2,2-dimethylpropionyloxyme-
thyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxylate
was dissolved in 0.3 ml of N,N-dimethylformamide, and 0.05 ml of
bromocyclobutane and 20 mg of potassium carbonate were added
thereto. The mixture was stirred at 50.degree. C. overnight. Ethyl
acetate was added to the reaction mixture, and the mixture was
washed with water. The organic layer was concentrated. The residue
was dissolved in methanol, and 5 mg of sodium hydride was added to
the solution. The mixture was stirred at room temperature for three
hours. The reaction mixture was neutralized with 1N hydrochloric
acid, and extracted with ethyl acetate. The solvent was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The mixture was concentrated, and the residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.89 mg of the title compound.
[0841] MS m/e (ESI) 375(MH.sup.+--CF.sub.3COOH)
Example 4
Methyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urin-2-yloxy]phenylacetate trifluoroacetate
[0842] (a)
[7-(2-Butynyl)-1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]-
methyl 2,2-dimethylpropionate
[0843] 1.871 g of
[1-methyl-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate was dissolved in 30 ml of
N,N-dimethylformamide, and 1.5 g of potassium carbonate and 0.7 ml
of 2-butynyl bromide were added thereto. The mixture was stirred at
room temperature overnight. The reaction mixture was diluted with
ethyl acetate, and washed with water and 1N hydrochloric acid. The
organic layer was dried over anhydrous magnesium sulfate, then
filtered. The solvent was evaporated under reduced pressure, and
the residue was purified by silica gel column chromatography. Thus,
2.12 g of the title compound was obtained from the fraction eluted
with hexane-ethyl acetate (3:2).
[0844] (b) 7-(2-Butynyl)-1-methyl-3,7-dihydropurine-2,6-dione
[0845] The title compound was obtained by treating
[7-(2-butynyl)-1-methyl-
-2,6-dioxo-1,2,6,7-tetrahydropurin-3-yl]methyl
2,2-dimethylpropionate by the same method as used in Example
(1f).
[0846] .sup.1H-NMR(CDCl.sub.3) .delta. 1.91 (t, J=2.4 Hz, 3H) 3.39
(s, 3H) 5.10 (s, 2H) 7.93 (s, 1H) 10.62 (s, 1H).
[0847] (c) t-Butyl
4-[7-(2-butynyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahydro--
1H-purin-8-yl]piperazine-1-carboxylate
[0848] The title compound was obtained by treating
7-(2-butynyl)-1-methyl-- 3,7-dihydropurine-2,6-dione by the same
method as used in Example (1e).
[0849] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.83 (t, J=2.4
Hz, 3H) 3.37 (s, 3H) 3.37-3.39 (m, 4H) 3.58-3.60 (m, 4H) 4.87 (s,
2H) 9.68 (s, 1H).
[0850] (d) Methyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-d-
ihydro-1H-purin-2-yloxy]phenylacetate trifluoroacetate
[0851] 8 mg of t-butyl
4-[7-(2-butynyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrahy-
dro-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of methyl
2-bromophenylacetate were dissolved in 0.2 ml of
N,N-dimethylformamide, and 10 mg of potassium carbonate was added
thereto. The mixture was stirred at 50.degree. C. overnight. Ethyl
acetate was added to the reaction solution, and the mixture was
washed with water and 1N hydrochloric acid. The organic layer was
concentrated. The residue was dissolved in trifluoroacetic acid,
and the mixture was concentrated. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.07 mg of the title compound.
[0852] MS m/e (ESI) 451(MH.sup.+--CF.sub.3COOH)
Example 5
7-(2-Butynyl)-2-cyclohexyloxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-
-6-one trifluoroacetate
[0853] Using iodocyclohexane instead of methyl 2-bromophenylacetate
in Example (4d), the title compound was obtained by the same method
as used in Example 4.
[0854] MS m/e (ESI) 385(MH.sup.+--CF.sub.3COOH)
Example 6
7-(2-Butynyl)-2-(2-butoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6--
one trifluoroacetate
[0855] Using 2-bromobutane instead of methyl 2-bromophenylacetate
in Example (4d), the title compound was obtained by the same method
as used in Example 4.
[0856] MS m/e (ESI) 359(MH.sup.+--CF.sub.3COOH)
Example 7
7-(2-Butynyl)-2-cyclopentyloxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[0857] Using bromocyclopentane instead of methyl
2-bromophenylacetate in Example (4d), the title compound was
obtained by the same method as used in Example 4.
[0858] MS m/e (ESI) 371(MH.sup.+--CF.sub.3COOH)
Example 8
Ethyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yloxy]butanoate trifluoroacetate
[0859] Using 2-bromobutanoic acid ethyl ester instead of methyl
2-bromophenylacetate in Example (4d), the title compound was
obtained by the same method as used in Example 4.
[0860] MS m/e (ESI) 417(MH.sup.+--CF.sub.3COOH)
Example 9
Ethyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yloxy]propionate
[0861] Using ethyl 2-bromopropionate instead of methyl
2-bromophenylacetate in Example (4d), trifluoroacetate of the title
compound was obtained by the same method as used in Example 4. The
compound was purified by chromatography using NH-silica gel (silica
gel whose surface had been modified with amino groups: Fuji Silysia
Chemical Ltd. NH-DM 2035). Thus, the title compound was obtained
from the fraction eluted with ethyl acetate-methanol (20:1).
[0862] MS m/e (ESI) 404(MH.sup.+)
Example 10
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]propionic acid trifluoroacetate
[0863] 8. mg of t-butyl
4-[7-(2-butynyl)-1-methyl-2,6-dioxo-2,3,6,7-tetrah-
ydro-1H-purin-8-yl] piperazine-1-carboxylate and 10 mg of ethyl
2-bromopropionate were dissolved in 0.2 ml of
N,N-dimethylformamide, and 10 mg of potassium carbonate was added
thereto. The mixture was stirred at 50.degree. C. overnight. Ethyl
acetate was added to the reaction solution, and the mixture was
washed with water and 1N hydrochloric acid. The organic layer was
concentrated to give t-butyl
4-[7-(2-butynyl)-2-(1-carboxyethoxy)-1-methyl-6-oxo-6,7-dihydro-1H-purin--
8-yl]piperazine-1-carboxylate. This compound was dissolved in 0.4
ml of ethanol, and 0.1 ml of a 5N aqueous sodium hydroxide solution
was added thereto. The mixture was stirred at room temperature for
3 hours. 1N-hydrochloric acid was added to the solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The mixture was concentrated, and the residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.37 mg of the title compound.
[0864] MS m/e (ESI) 375(MH.sup.+--CF.sub.3COOH)
Example 11
7-(2-Butynyl)-2-methoxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0865] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-
-purin-8-yl]piperazine-1-carboxylate (a-1), and t-butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine-1-carboxylate
(a-2)
[0866] 5.127 g of t-butyl
4-[7-(2-butynyl)-1-methyl-2,6-dioxo-2,3,6,7-tetr-
ahydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 75
ml of phosphorus oxychloride, and then the mixture was stirred at
120.degree. C. overnight. The reaction solution was concentrated,
and the residue was dissolved in 50 ml of tetrahydrofuran. This
solution was poured into a suspension consisting of 7 g of
di-t-butyl dicarbonate, 50 ml of tetrahydrofuran, 100 g of sodium
bicarbonate, and 200 ml of water, and the mixture was stirred at
room temperature for one hour. The reaction mixture was diluted
with ethyl acetate, and the mixture was washed with water. The
organic layer was dried over anhydrous magnesium sulfate, then
filtered. The filtrate was concentrated, and the residue was
purified by silica gel column chromatography. Thus, 1.348 g of
t-butyl
4-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperazine-1-carboxylate
[.sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.87 (t, J=2.4 Hz,
3H) 3.64 (m, 8H) 4.81 (q, J=2.4 Hz, 2H)] was obtained from the
fraction eluted with hexane-ethyl acetate (1:1), and 1.238 g of
t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]pipera-
zine-1-carboxylate [.sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H)
1.83 (t, J=2.4 Hz, 3H) 3.42-3.44 (m, 4H) 3.59-3.62 (m, 4H) 3.73 (s,
3H) 4.93 (q, J=2.4 Hz, 2H)] was obtained from the fraction eluted
with hexane-ethyl acetate (1:9).
[0867] (b)
7-(2-Butynyl)-2-methoxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[0868] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
methanol, and 10 mg of sodium hydride was added thereto. The
mixture was stirred at room temperature for one hour. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The mixture was concentrated, and the residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.72 mg of the title compound.
[0869] MS m/e (ESI) 317(MH.sup.+--CF.sub.3COOH)
Example 12
7-(2-Butynyl)-2-ethoxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
[0870] Using ethanol instead of methanol in Example (11b), the
trifluoroacetate of the title compound was obtained by the same
method as used in Example 11. This compound was purified by
chromatography using NH-silica gel. Thus, the title compound was
obtained from the fraction eluted with ethyl acetate-methanol
(20:1).
[0871] .sup.1H-NMR(CDCl.sub.3) .delta. 1.42 (t, J=7.2 Hz, 3H) 1.82
(t, J=2.4 Hz, 3H) 3.02-3.06 (m, 4H) 3.40-3.42 (m, 4H) 3.46 (s, 3H)
4.51 (q, J=7.2 Hz, 2H) 4.90 (q, J=2.4 Hz, 2H).
[0872] MS m/e (ESI) 331(MH.sup.+)
Example 13
Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-yloxy]acetate
Example 14
[0873]
[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pur-
in-2-yloxy]acetic acid
[0874] Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro--
1H-purin-2-yloxy]acetate trifluoroacetate and
[7-(2-butynyl)-1-methyl-6-ox-
o-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]acetic acid
trifluoroacetate [MS m/e (ESI) 361(MH.sup.+--CF.sub.3COOH)] were
obtained by treating t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro--
1H-purin-8-yl]piperazine-1-carboxylate using ethyl
2-hydroxyacetate, instead of ethanol, by the same method as used in
Example 11. Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-y-
loxy] acetate trifluoroacetate was purified by chromatography using
NH-silica gel. Thus, ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-y-
l)-6,7-dihydro-1H-purin-2-yloxy]acetate [.sup.1H-NMR(CDCl.sub.3)
.delta. 1.29 (t, J=7.2 Hz, 3H) 1.83 (t, J=2.4 Hz, 3H) 3.02-3.06 (m,
4H) 3.38-3.41 (m, 4H) 3.55 (s, 3H) 4.22 (q, J=7.2 Hz, 2H) 4.90 (q,
J=2.4 Hz, 2H) 5.03 (s, 2H); MS m/e (ESI) 389(MH.sup.+)] was
obtained from the fraction eluted with ethyl acetate-methanol
(20:1)
Example 15
7-(2-Butynyl)-2-(2-methoxyethoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydrop-
urin-6-one trifluoroacetate
[0875] Using 2-methoxy ethanol instead of ethyl 2-hydroxyacetate in
Example 13, the title compound was obtained by the same method as
used in Example 13.
[0876] MS m/e (ESI) 361(MH.sup.+--CF.sub.3COOH)
Example 16
Ethyl
1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yloxy]cyclopropanecarboxylate
[0877] Using ethyl 1-hydroxycyclopropanecarboxylate instead of
ethyl 2-hydroxyacetate in Example 13, the trifluoroacetate of the
title compound was obtained by the same method as used in Example
13. The compound was purified by chromatography using NH-silica
gel. Thus, the title compound was obtained from the fraction eluted
with ethyl acetate-methanol (20:1).
[0878] .sup.1H-NMR(CDCl.sub.3) .delta. 1.19 (t, J=7.2 Hz, 3H)
1.39-1.42 (m, 2H) 1.67-1.71 (m, 2H) 1.83 (t, J=2.4 Hz, 3H)
3.02-3.05 (m, 4H) 3.37-3.40 (m, 4H) 3.49 (s, 3H) 4.14 (q, J=7.2 Hz,
2H) 4.90 (q, J=2.4 Hz, 2H)
[0879] MS m/e (ESI) 415(MH.sup.+)
Example 17
1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]cyclopropanecarboxylic acid trifluoroacetate
[0880] 20 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate and 20 mg of ethyl
1-hydroxycyclopropanecarboxylate were dissolved in 0.2 ml of
N-methylpyrrolidone, and 10 mg of sodium hydride was added thereto.
The mixture was stirred at room temperature overnight. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated to give 63 mg of t-butyl
4-[7-(2-butynyl)-2-(1-ethoxycarbonylcyclopropyloxy)-1-methyl-6-ox-
o-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate. This compound
was dissolved in a solution consisting of 0.4 ml of ethanol and 0.1
ml of a 5N aqueous sodium hydroxide solution, and the mixture was
stirred at 50.degree. C. overnight. 1N hydrochloric acid solution
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was concentrated to give 22
mg of t-butyl
4-[7-(2-butynyl)-2-(l-carboxycyclopropyloxy)-1-methyl-6-oxo-6,7-dihydro-1-
H-purin-8-yl]piperazine-1-carboxylate. 11 mg of this compound was
dissolved in trifluoroacetic acid, and the mixture was
concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.64
mg of the title compound.
[0881] MS m/e (ESI) 387(MH.sup.+--CF.sub.3COOH)
Example 18
1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]cyclopropanecarboxylic amide trifluoroacetate
[0882] 11 mg of t-butyl
4-[7-(2-butynyl)-2-(1-carboxycyclopropyloxy)-1-met-
hyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was
dissolved in 1 ml of tetrahydrofuran, and 0.05 ml of triethylamine
and 0.05 ml of ethyl chlorocarbonate were added thereto. The
mixture was stirred at room temperature for 15 minutes. 0.1 ml of
20% ammonia water was added to the solution, and the mixture was
stirred at room temperature for 15 minutes. Water was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The mixture was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 1.18 mg of the
title compound.
[0883] MS m/e (ESI) 386(MH.sup.+--CF.sub.3COOH)
Example 19
7-(2-Butynyl)-1-methyl-2-(2-oxotetrahydrofuran-3-yloxy)-8-(piperazin-1-yl)-
-1,7-dihydropurin-6-one trifluoroacetate
[0884] Using 3-hydroxydihydrofuran-2-one instead of ethyl
2-hydroxyacetate in Example 13, the title compound was obtained by
the same method as used in Example 13.
[0885] MS m/e (ESI) 387(MH.sup.+--CF.sub.3COOH)
Example 20
7-(2-Butynyl)-1-methyl-2-phenoxy-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0886] Using phenol instead of ethyl 2-hydroxyacetate in Example
13, the title compound was obtained by the same method as used in
Example 13.
[0887] MS m/e (ESI) 379(MH.sup.+--CF.sub.3COOH)
Example 21
Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-yl]acetate trifluoroacetate
[0888] Using ethyl 2-(t-butoxycarbonyl)acetate instead of ethyl
2-hydroxyacetate in Example 13, the title compound was obtained by
the same method as used in Example 13.
[0889] MS m/e (ESI) 373(MH.sup.+--CF.sub.3COOH)
Example 22
7-(2-Butynyl)-1,2-dimethyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0890] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate and 2 mg of
tetrakis(triphenylphosphine)palladium were dissolved in 0.2 ml of
dioxane, and 0.2 ml of methylzinc chloride (1.5 M tetrahydrofuran
solution) was added thereto. The mixture was stirred at 50.degree.
C. for 0.5 hour. The reaction solution was concentrated, and the
residue was dissolved in trifluoroacetic acid. The mixture was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.56
mg of the title compound.
[0891] MS m/e (ESI) 301(MH.sup.+--CF.sub.3COOH)
Example 23
7-(2-Butynyl)-1-methyl-2-butyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0892] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate and 2 mg of
tetrakis(triphenylphosphine)palladium were dissolved in 0.2 ml of
dioxane, and 0.3 ml of a mixed solution consisting of 0.5 ml of
butylmagnesium chloride (2.0 M diethyl ether solution) and 2 ml of
zinc chloride (0.5 M tetrahydrofuran solution) was added thereto.
The resulting mixture was stirred at 50.degree. C. for five hours.
The reaction solution was concentrated, and the residue was
dissolved in trifluoroacetic acid. The mixture was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 3.38 mg of the
title compound.
[0893] MS m/e (ESI) 343(MH.sup.+--CF.sub.3COOH)
Example 24
7-(2-Butynyl)-1-methyl-2-benzyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0894] The title compound was obtained using a mixed solution
consisting of 0.5 ml of benzylmagnesium chloride (2.0 M diethyl
ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran
solution) by the same method as used in Example 23.
[0895] MS m/e (ESI) 377(MH.sup.+--CF.sub.3COOH)
Example 25
7-(2-Butynyl)-1-methyl-2-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-dihydropur-
in-6-one trifluoroacetate
[0896] The title compound was obtained using a mixed solution
consisting of 0.5 ml of phenethylmagnesium chloride (2.0 M diethyl
ether solution) and 2 ml of zinc chloride (0.5 M tetrahydrofuran
solution) by the same method as used in Example 23.
[0897] MS m/e (ESI) 391(MH.sup.+--CF.sub.3COOH)
Example 26
7-(2-Butynyl)-1-methyl-2-phenyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0898] 10 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate and 2 mg of
tetrakis(triphenylphosphine)palladium and 20 mg of
phenyltributyltin were dissolved in 0.2 ml of dioxane, and the
mixture was stirred at 80.degree. C. for 5 hours. The reaction
solution was concentrated, and the residue was dissolved in
trifluoroacetic acid. The mixture was concentrated, and the residue
was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 4.62 mg of the
title compound.
[0899] MS m/e (ESI) 363(MH.sup.+--CF.sub.3COOH)
Example 27
7-(2-Butynyl)-1-methyl-2-amino-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[0900] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
20% aqueous ammonia solution, and the mixture was stirred at
80.degree. C. for 5 hours. The reaction solution was concentrated,
and the residue was dissolved in trifluoroacetic acid. The mixture
was concentrated, and the residue was purified by reverse-phase
high performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.82
mg of the title compound.
[0901] MS m/e (ESI) 302(MH.sup.+--CF.sub.3COOH)
Example 28
7-(2-Butynyl)-1-methyl-2-methylamino-(8-piperazin-1-yl)-1,7-dihydropurin-6-
-one trifluoroacetate
[0902] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
an aqueous solution of 40% methyl amine, and the mixture was
stirred at 80.degree. C. for 5 hours. The reaction solution was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The mixture was concentrated, and the residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 6.95 mg of the title compound.
[0903] MS m/e (ESI) 316(MH.sup.+--CF.sub.3COOH)
Example 29
7-(2-Butynyl)-1-methyl-2-dimethylamino-8-(piperazin-1-yl)-1,7-dihydropurin-
-6-one trifluoroacetate
[0904] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.2 ml
of an aqueous solution of 40% dimethylamine, and the mixture was
stirred at 80.degree. C. for 5 hours. The reaction solution was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The mixture was concentrated, and the residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 6.95 mg of the title compound.
[0905] .sup.1H-NMR(CDCl.sub.3) .delta. 1.82 (t, J=2.4 Hz, 3H) 2.83
(s, 6H) 3.02-3.05 (m, 4H) 3.39-3.42 (m, 4H) 3.56 (s, 3H) 4.90 (d,
J=2.4 Hz, 2H)
[0906] MS m/e (ESI) 330(MH.sup.+--CF.sub.3COOH)
Example 30
Ethyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-ylamino]acetate trifluoroacetate
[0907] 10 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 15 mg of glycine ethyl ester
hydrochloride and 50 .mu.l of triethylamine were added thereto. The
mixture was stirred at 80.degree. C. for 12 hours. Then, the
reaction solution was concentrated by flushing with nitrogen gas.
The residue was dissolved in 0.40 ml of trifluoroacetic acid, and
the solution was concentrated by flushing with nitrogen gas. The
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 7.60 mg of the
title compound.
[0908] MS m/e (ESI) 388(MH.sup.+--CF.sub.3COOH)
Example 31
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yl-
amino]acetic acid trifluoroacetate
[0909] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2pyrrolidone, and 15 mg of glycine t-butyl ester
hydrochloride and 50 .mu.l of triethylamine were added thereto.
After the mixture had been stirred at 80.degree. C. for 12 hours,
the reaction solution was concentrated by flushing with nitrogen
gas. The resulting residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.36
mg of the title compound.
[0910] MS m/e (ESI) 360(MH.sup.+--CF.sub.3COOH)
Example 32
Ethyl
[N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urin-2-yl]methylamino]acetic acid trifluoroacetate
[0911] Using N-methyl glycine ethyl ester hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 2.06 mg of the
title compound was obtained by the same method as used in Example
30.
[0912] MS m/e (ESI) 402(MH.sup.+--CF.sub.3COOH)
Example 33
Methyl
(S)-1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro--
1H-purin-2-yl]pyrrolidine-2-carboxylate trifluoroacetate
[0913] Using L-proline methyl ester hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 1.35 mg of the
title compound was obtained by the same method as used in Example
30.
[0914] MS m/e (ESI) 414(MH.sup.+--CF.sub.3COOH)
Example 34
[N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-yl]methylamino]acetic acid trifluoroacetate
[0915] Using N-methyl glycine t-butyl ester hydrochloride instead
of glycine ethyl ester hydrochloride in Example 30, 3.16 mg of the
title compound was obtained by the same method as used in Example
30.
[0916] MS m/e (ESI) 374(MH.sup.+--CF.sub.3COOH)
Example 35
Methyl
(R)-1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro--
1H-purin-2-yl]pyrrolidine-2-carboxylate trifluoroacetate
[0917] Using D-proline methyl ester hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 0.74 mg of the
title compound was obtained by the same method as used in Example
30.
[0918] MS m/e (ESI) 414(MH.sup.+--CF.sub.3COOH)
Example 36
Methyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urin-2-ylamino]propionate trifluoroacetate
[0919] Using DL-alanine methyl ester hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 1.20 mg of the
title compound was obtained by the same method as used in Example
30.
[0920] MS m/e (ESI) 388(MH.sup.+--CF.sub.3COOH)
Example 37
Methyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urin-2-ylamino]-2-methylpropionate trifluoroacetate
[0921] Using methyl 2-aminoisobutylate hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 1.18 mg of the
title compound was obtained by the same method as used in Example
30.
[0922] MS m/e (ESI) 402(MH.sup.+--CF.sub.3COOH)
Example 38
Ethyl
(S)-2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1-
H-purin-2-ylamino]propionate trifluoroacetate
[0923] Using L-alanine ethyl ester hydrochloride instead of glycine
ethyl ester hydrochloride in Example 30, 2.38 mg of the title
compound was obtained by the same method as used in Example 30.
[0924] MS m/e (ESI) 402(MH.sup.+--CF.sub.3COOH)
Example 39
(S)-2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-ylamino]propionic acid trifluoroacetate
[0925] Using L-alanine t-butyl ester hydrochloride instead of
glycine ethyl ester hydrochloride in Example 30, 0.76 mg of the
title compound was obtained by the same method as used in Example
30.
[0926] MS m/e (ESI) 374(MH.sup.+--CF.sub.3COOH)
Example 40
Ethyl
3-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-ylamino]propionate trifluoroacetate
[0927] Using P-alanine ethyl ester hydrochloride instead of glycine
ethyl ester hydrochloride in Example 30, 0.85 mg of the title
compound was obtained by the same method as used in Example 30.
[0928] MS m/e (ESI) 402(MH.sup.+--CF.sub.3COOH)
Example 41
7-(2-Butynyl)-2-(2-ethoxyethylamino)-1-methyl-8-(piperazin-1-yl)-1,7-dihyd-
ro-purin-6-one trifluoroacetate
[0929] 10 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl] piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 20 .mu.l of 2-ethoxyethylamine was
added thereto. After the mixture had been stirred at 80.degree. C.
for 12 hours, the reaction solution was concentrated by flushing
with nitrogen. The resulting residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the mixture was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.95
mg of the title compound.
[0930] MS m/e (ESI) 374(MH.sup.+--CF.sub.3COOH)
Example 42
7-(2-Butynyl)-1-methyl-2-(morpholin-4-yl)-8-(piperazin-1-yl)-1,7-dihydropu-
rin-6-one trifluoroacetate
[0931] Using morpholine instead of 2-ethoxyethylamine in Example
41, 7.31 mg of the title compound was obtained by the same method
as used in Example 41.
[0932] MS m/e (ESI) 372(MH.sup.+--CF.sub.3COOH)
Example 43
2-Benzylamino-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-
-one trifluoroacate
[0933] Using benzylamine instead of 2-ethoxyethylamine in Example
41, 8.40 mg of the title compound was obtained by the same method
as used in Example 41.
[0934] MS m/e (ESI) 392(MH.sup.+--CF.sub.3COOH)
Example 44
Ethyl
1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yl]piperidine-4-carboxylate trifluoroacetate
[0935] Using ethyl isonipecotate instead of 2-ethoxyethylamine in
Example 41, 7.43 mg of the title compound was obtained by the same
method as used in Example 41.
[0936] MS m/e (ESI) 442(MH.sup.+--CF.sub.3COOH)
Example 45
2-(N-benzylmethylamino)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihy-
dropurin-6-one trifluoroacetate
[0937] Using N-methylbenzylamine instead of 2-ethoxyethylamine in
Example 41, 2.38 mg of the title compound was obtained by the same
method as used in Example 41.
[0938] MS m/e (ESI) 406(MH.sup.+--CF.sub.3COOH)
Example 46
7-(2-Butynyl)-2-(4-chlorobenzylamino)-1-methyl-8-(piperazin-1-yl)-1,7-dihy-
dropurin-6-one trifluoroacetate
[0939] Using 4-chlorobenzylamine instead of 2-ethoxyethylamine in
Example 41, 2.84 mg of the title compound was obtained by the same
method as used in Example 41.
[0940] MS m/e (ESI) 426(MH.sup.+--CF.sub.3COOH)
Example 47
7-(2-Butynyl)-2-(4-methoxybenzylamino)-1-methyl-8-(piperazin-1-yl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[0941] Using 4-methoxybenzylamine, 3.77 mg of the title compound
was obtained by the same method as used in Example 41.
[0942] MS m/e (ESI) 422(MH.sup.+--CF.sub.3COOH)
Example 48
7-(2-Butynyl)-1-methyl-2-(2-phenylethylamino)-8-(piperazin-1-yl)-1,7-dihyd-
ropurin-6-one trifluoroacetate
[0943] Using phenethylamine instead of 2-ethoxyethylamine in
Example 41, 2.70 mg of the title compound was obtained by the same
method as used in Example 41.
[0944] MS m/e (ESI) 406(MH.sup.+--CF.sub.3COOH)
Example 49
7-(2-Butynyl)-1-methyl-2-[N-(2-phenylethyl)methylamino]-8-(piperazin-1-yl)-
-1,7-dihydropurin-6-one trifluoroacetate
[0945] Using N-methylphenethylamine instead of 2-ethoxyethylamine
in Example 41, 2.17 mg of the title compound was obtained by the
same method as used in Example 41.
[0946] MS m/e (ESI) 420(MH.sup.+--CF.sub.3COOH)
Example 50
Ethyl
1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yl]piperidine-3-carboxylate trifluoroacetate
[0947] Using ethyl nipecotate instead of 2-ethoxyethylamine in
Example 41, 2.93 mg of the title compound was obtained by the same
method as used in Example 41.
[0948] MS m/e (ESI) 442(MH.sup.+--CF.sub.3COOH)
Example 51
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyridin-2-ylmethylamino)-1,7--
dihydropurin-6-one trifluoroacetate
[0949] Using 2-aminomethylpyridine instead of 2-ethoxyethylamine in
Example 41, 1.62 mg of the title compound was obtained by the same
method as used in Example 41.
[0950] MS m/e (ESI) 393(MH.sup.+--CF.sub.3COOH)
Example 52
Ethyl
1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yl]piperidine-2-carboxylate trifluoroacetate
[0951] Using ethyl pipecolate instead of 2-ethoxyethylamine in
Example 41, 0.97 mg of the title compound was obtained by the same
method as used in Example 41.
[0952] MS m/e (ESI) 442(MH.sup.+--CF.sub.3COOH)
Example 53
(S)-1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-yl]pyrrolidine-2-carboxylic acid trifluoroacetate
[0953] Using L-proline t-butyl ester instead of 2-ethoxyethylamine
in Example 41, 4.07 mg of the title compound was obtained by the
same method as used in Example 41.
[0954] MS m/e (ESI) 400(MH.sup.+--CF.sub.3COOH)
Example 54
7-(2-Butynyl)-2-diethylamino-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin--
6-one trifluoroacetate
[0955] Using diethylamine instead of 2-ethoxyethylamine in Example
41, 2.24 mg of the title compound was obtained by the same method
as used in Example 41.
[0956] MS m/e (ESI) 358(MH.sup.+--CF.sub.3COOH)
Example 55
7-(2-Butynyl)-2-(N-ethylmethylamino)-1-methyl-8-(piperazin-1-yl)-1,7-dihyd-
ropurin-6-one trifluoroacetate
[0957] Using N-ethylmethylamine instead of 2-ethoxyethylamine in
Example 41, 3.27 mg of the title compound was obtained by the same
method as used in Example 41.
[0958] MS m/e (ESI) 344(MH.sup.+--CF.sub.3COOH)
Example 56
Ethyl
(R)-1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1-
H-purin-2-yl]piperidine-3-carboxylate trifluoroacetate
[0959] Using ethyl (R)-nipecotate instead of 2-ethoxyethylamine in
Example 41, 0.87 mg of the title compound was obtained by the same
method as used in Example 41.
[0960] MS m/e (ESI) 442(MH.sup.+--CF.sub.3COOH)
Example 57
Ethyl
(S)-1-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1-
H-purin-2-yl]piperidine-3-carboxylate trifluoroacetate
[0961] Using ethyl (L)-nipecotate instead of 2-ethoxyethylamine in
Example 41, 2.94 mg of the title compound was obtained by the same
method as used in Example 41.
[0962] MS m/e (ESI) 442(MH.sup.+--CF.sub.3COOH)
Example 58
[N-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-yl]methylamino]acetonitrile trifluoroacetate
[0963] Using methylaminoacetonitrile instead of 2-ethoxyethylamine
in Example 41, 1.00 mg of the title compound was obtained by the
same method as used in Example 41.
[0964] MS m/e (ESI) 355(MH.sup.+--CF.sub.3COOH)
Example 59
7-(2-Butynyl)-2-isopropylamino-1-methyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[0965] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 50 .mu.l of isopropylamine was added
thereto. The mixture was stirred at 60.degree. C. for five hours,
and then concentrated by flushing with nitrogen gas. The residue
was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture
was concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 2.28 mg of the title compound.
[0966] MS m/e (ESI) 344(MH.sup.+--CF.sub.3COOH)
Example 60
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyridin-2-ylamino)-1,7-dihydr-
opurin-6-one trifluoroacetate
[0967] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 50 .mu.l of 2-aminopyridine was
added thereto. The mixture was stirred at 110.degree. C. for 12
hours, and then the reaction solution was concentrated by flushing
with nitrogen gas. The residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the mixture was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.10
mg of the title compound.
[0968] MS m/e (ESI) 379(MH.sup.+--CF.sub.3COOH)
Example 61
7-(2-Butynyl)-1-methyl-2-phenylamino-8-(piperazin-1-yl)-1,7-dihydropurin-6-
-one trifluoroacetate
[0969] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 100 .mu.l of aniline was added
thereto. The mixture was stirred at 110.degree. C. for 12 hours,
and then concentrated by flushing with nitrogen gas. The residue
was dissolved in 0.40 ml of trifluoroacetic acid, and the mixture
was concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 3.23 mg of the title compound.
[0970] MS m/e (ESI) 378(MH.sup.+--CF.sub.3COOH)
Example 62
1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yl]piperidine-3-carboxylic acid trifluoroacetate
[0971] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 20 .mu.l of ethyl nipecotate was
added thereto. The mixture was stirred at 80.degree. C. for 12
hours, and then concentrated by flushing with nitrogen gas. The
residue was dissolved in a solution consisting of 0.20 ml of
ethanol and 0.20 ml of a 5N aqueous sodium hydroxide solution. The
mixture was stirred at room temperature for five hours, and then
concentrated by flushing with nitrogen gas. The residue was
dissolved in 0.40 ml of trifluoroacetic acid, and the mixture was
concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 1.92 mg of the title compound.
[0972] MS m/e (ESI) 414(MH.sup.+--CF.sub.3COOH)
Example 63
(R)-1-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-yl]pyrrolidine-2-carboxylic acid trifluoroacetate
[0973] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 15 mg of D-proline methyl ester
hydrochloride and 50 .mu.l of triethylamine were added thereto.
After the resulting mixture had been stirred at 80.degree. C. for
12 hours, the reaction solution was concentrated by flushing with
nitrogen gas. The residue was dissolved in a solution consisting of
0.20 ml of ethanol and 0.20 ml of a 5N aqueous sodium hydroxide
solution. The mixture was stirred at room temperature for five
hours, and then concentrated by flushing with nitrogen gas. The
residue was dissolved in 0.40 ml of trifluoroacetic acid, and the
mixture was concentratedby flushing with nitrogen gas. The
residuewas purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 3.42 mg of the
title compound.
[0974] MS m/e (ESI) 400(MH.sup.+--CF.sub.3COOH)
Example 64
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylamino]propionic acid trifluoroacetate
[0975] Using DL-alanine methyl ester hydrochloride instead of
D-proline methyl ester hydrochloride in Example 63, 1.12 mg of the
title compound was obtained by the same method as used in Example
63.
[0976] MS m/e (ESI) 374(MH.sup.+--CF.sub.3COOH)
Example 65
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyridin-2-yl-methyloxy)-1,7-d-
ihydropurin-6-one trifluoroacetate
[0977] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 25 .mu.l of pyridin-2-ylmethanol and
5 mg of sodium hydride were added thereto. The mixture was stirred
at room temperature for five hours, and then concentrated by
flushing with nitrogen gas. The residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the mixture was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.58
mg of the title compound.
[0978] MS m/e (ESI) 394(MH.sup.+--CF.sub.3COOH)
Example 66
7-(2-Butynyl)-2-isopropoxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6--
one trifluoroacetate
[0979] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 0.10 ml of isopropanol and 5 mg of
sodium hydride were added thereto. After the mixture was stirred at
room temperature for five hours, an aqueous solution saturated with
ammonium chloride was added to the reaction solution. The resulting
mixture was extracted with ethyl acetate. The organic layer was
concentrated. The residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the mixture was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.68
mg of the title compound.
[0980] MS m/e (ESI) 345(MH.sup.+--CF.sub.3COOH)
Example 67
7-(2-Butynyl)-2-(2-butynyloxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[0981] Using 2-butyn-1-ol instead of isopropanol in Example 66,
3.40 mg of the title compound was obtained by the same method as
used in Example 66.
[0982] MS m/e (ESI) 355(MH.sup.+--CF.sub.3COOH)
Example 68
Methyl
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pur-
in-2-ylsulfanyl]acetate trifluoroacetate
[0983] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 20 .mu.l of methyl mercaptoacetate
and 6 mg of potassium carbonate were added thereto. The mixture was
stirred at room temperature for five hours. An aqueous solution
saturated with ammonium chloride was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
organic layer was concentrated, and the residue was dissolved in
0.40 ml of trifluoroacetic acid. The solution was concentrated by
flushing with nitrogen gas. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 4.83 mg of the title compound.
[0984] MS m/e (ESI) 391(MH.sup.+--CF.sub.3COOH)
Example 69
Ethyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-ylsulfanyl]propionate trifluoroacetate
[0985] Using ethyl 2-mercaptopropionate instead of methyl
mercaptoacetate in Example 68, 4.30 mg of the title compound was
obtained by the same method as used in Example 68.
[0986] MS m/e (ESI) 419(MH.sup.+--CF.sub.3COOH)
Example 70
Ethyl
3-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-ylsulfanyl]propionate trifluoroacetate
[0987] Using ethyl 3-mercaptopropionate instead of methyl
mercaptoacetate in Example 68, 3.75 mg of the title compound was
obtained by the same method as used in Example 68.
[0988] MS m/e (ESI) 419(MH.sup.+--CF.sub.3COOH)
Example 71
7-(2-Butynyl)-2-ethylsulfanyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-
-6-one trifluoroacetate
[0989] Using ethanethiol instead of methyl mercaptoacetate in
Example 68, 4.70 mg of the title compound was obtained by the same
method as used in Example 68.
[0990] MS m/e (ESI) 347(MH.sup.+--CF.sub.3COOH)
Example 72
7-(2-Butynyl)-2-(2-hydroxyethylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7-d-
ihydropurin-6-one trifluoroacetate
[0991] Using 2-mercaptoethanol instead of methyl mercaptoacetate in
Example 68, 3.57 mg of the title compound was obtained by the same
method as used in Example 68.
[0992] MS m/e (ESI) 363(MH.sup.+--CF.sub.3COOH)
Example 73
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyridin-2-ylsulfanyl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[0993] Using 2-mercaptopyridine instead of methyl mercaptoacetate
in Example 68, 4.66 mg of the title compound was obtained by the
same method as used in Example 68.
[0994] MS m/e (ESI) 396(MH.sup.+--CF.sub.3COOH)
Example 74
7-(2-Butynyl)-1-methyl-2-methylsulfanyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[0995] Using methyl mercaptan (30%; methanol solution) instead of
methyl mercaptoacetate in Example 68, 4.08 mg of the title compound
was obtained by the same method as used in Example 68.
[0996] MS m/e (ESI) 333(MH.sup.+--CF.sub.3COOH)
Example 75
7-(2-Butynyl)-2-cyclohexylsulfanyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[0997] Using cyclohexanethiol instead of methyl mercaptoacetate in
Example 68, 4.13 mg of the title compound was obtained by the same
method as used in Example 68.
[0998] MS m/e (ESI) 401(MH.sup.+--CF.sub.3COOH)
Example 76
7-(2-Butynyl)-2-isopropylsulfanyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydrop-
urin-6-one trifluoroacetate
[0999] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 15 mg of the sodium salt of
propane-2-thiol was added thereto. The mixture was stirred at room
temperature for five hours. A saturated ammonium chloride solution
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was concentrated, and the
residue was dissolved in 0.40 ml of trifluoroacetic acid. The
solution was concentrated by flushing with nitrogen gas. The
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 4.56 mg of the
title compound.
[1000] MS m/e (ESI) 361(MH.sup.+--CF.sub.3COOH)
Example 77
2-t-Butylsulfanyl-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropur-
in-6-one trifluoroacetate
[1001] Using the sodium salt of 2-methyl-2-propanethiol instead of
the sodium salt of propane-2-thiol in Example 76, 2.58 mg of the
title compound was obtained by the same method as used in Example
76.
[1002] MS m/e (ESI) 375(MH.sup.+--CF.sub.3COOH)
Example 78
7-(2-Butynyl)-2-mercapto-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-on-
e trifluoroacetate
Example 79
[1003]
[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pur-
in-2-ylsulfanyl]acetic acid trifluoroacetate
[1004] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of N-methylpyrrolidone, and 20 .mu.l of methyl mercaptoacetate and
6 mg of potassium carbonate were added thereto. After the mixture
had been stirred at room temperature for five hours, an aqueous
solution saturated with ammonium chloride was added to the reaction
solution. The mixture was extracted with ethyl acetate. The organic
layer was concentrated. The resulting residue was dissolved in a
solution consisting of 0.20 ml of ethanol and 0.20 ml of a 5N
aqueous sodium hydroxide solution. The mixture was stirred at room
temperature overnight, and then concentrated by flushing with
nitrogen gas. The residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.96
mg of
7-(2-butynyl)-2-mercapto-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-o-
ne trifluoroacetate [MS m/e (ESI) 319(MH.sup.+--CF.sub.3COOH)] and
0.61 mg of
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin--
2-ylsulfanyl]acetic acid trifluoroacetate [MS m/e (ESI)
377(MH.sup.+--CF.sub.3COOH).
Example 80
7-(2-Butynyl)-2-ethanesulfinyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[1005] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 20 .mu.l of ethanethiol and 6 mg of
potassium carbonate were added thereto. The mixture was stirred at
room temperature for 5 hours. A saturated ammonium chloride
solution was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The organic layer was concentrated.
The residue was dissolved in 0.30 ml of dichloromethane, and the
mixture was cooled to -78.degree. C. 5 mg of m-chloroperbenzoic
acid was added to the solution, and the mixture was stirred at
-78.degree. C. for 15 minutes. An aqueous solution saturated with
sodium sulfite was added to the reaction solution, and the mixture
was extracted with dichloromethane. The organic layer was
concentrated. The residue was dissolved in 0.40 ml of
trifluoroacetic acid, and the solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 3.21
mg of the title compound.
[1006] MS m/e (ESI) 363(MH.sup.+--CF.sub.3COOH)
Example 81
7-(2-Butynyl)-2-ethanesulfonyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[1007] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and 20 .mu.l of ethanethiol and 6 mg of
potassium carbonate were added thereto. The mixture was stirred at
room temperature for 5 hours. A saturated ammonium chloride
solution was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The organic layer was concentrated.
The residue was dissolved in 0.3 ml of dichloromethane, and the
solution was cooled to -78.degree. C. 10 mg of m-chloroperbenzoic
acid was added to the solution. The mixture was stirred at
-78.degree. C. for 15 minutes and then at 0.degree. C. for 15
minutes. An aqueous solution saturated with sodium sulfite was
added to the reaction solution, and the mixture was extracted with
dichloromethane. The organic layer was concentrated. The residue
was dissolved in trifluoroacetic acid, and the solution was
concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.19
mg of the title compound.
[1008] MS m/e (ESI) 379(MH.sup.+--CF.sub.3COOH)
Example 82
7-(2-Butynyl)-2-cyano-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1009] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
N-methylpyrrolidone, and 10 mg of sodium cyanide was added thereto.
The mixture was stirred at 50.degree. C. for 1 hour. Water was
added to the reaction mixture, and the mixture was extracted with
ethyl acetate. The organic layer was concentrated to give 14 mg of
t-butyl
4-[7-(2-butynyl)-2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperaz-
ine-1-carboxylate. 5 mg of this compound was dissolved in
trifluoroacetic acid, and the solution was concentrated. The
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 4.12 mg of the
title compound.
[1010] MS m/e (ESI) 312(MH.sup.+--CF.sub.3COOH)
Example 83
7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-ca-
rboxamide
[1011] (a) t-Butyl
4-[7-(2-butynyl)-2-carbamoyl-1-methyl-6-oxo-6,7-dihydro-
-1H-purin-8-yl]piperazine-1-carboxylate
[1012] 176 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2 ml of
N-methylpyrrolidone, and 100 mg of sodium cyanide was added
thereto. The mixture was stirred at 50.degree. C. for 0.5 hour.
Water was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The organic layer was concentrated to
give 170 mg of t-butyl
4-[7-(2-butynyl)-2-cyano-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperaz-
ine-1-carboxylate. 98 mg of this compound was dissolved in a
mixture of 3 ml of tetrahydrofuran and 2 ml of methanol, and 0.5 ml
of an aqueous solution of 20% ammonia and 0.5 ml of an aqueous
solution of 30% hydrogen peroxide were added thereto. The mixture
was stirred at room temperature overnight. Ethyl acetate was added
to the reaction solution, and the mixture was washed with water.
The organic layer was dried over anhydrous magnesium sulfate, then
filtered. The solvent was evaporated under reduced pressure. The
residue was purified by silica gel column chromatography. Thus, 77
mg of the title compound was obtained from the fraction eluted with
ethyl acetate-methanol.
[1013] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=1.2
Hz, 3H) 3.42-3.49 (m, 4H) 3.58-3.65 (m, 4H) 3.95 (s, 3H) 5.01 (d,
J=2.4 Hz, 2H) 5.54 (br, 1H) 7.61 (br, 1H)
[1014] (b)
7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H--
purine-2-carboxamide
[1015] 77 mg of t-butyl
4-[7-(2-butynyl)-2-carbamoyl-1-methyl-6-oxo-6,7-di-
hydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 1 ml
of trifluoroacetic acid, and the solution was concentrated. The
residue was purified by chromatography using NH-silica gel. Thus,
49 mg of the title compound was obtained from the fraction eluted
with ethyl acetate-methanol (5:1).
[1016] .sup.1H-NMR(CDCl.sub.3) .delta. 1.83 (t, J=2.4 Hz, 3H)
3.05-3.07 (m, 4H) 3.45-3.48 (m, 4H) 3.94 (s, 3H) 4.98 (s, 2H) 5.57
(br, 1H) 7.65 (br, 1H)
Example 84
7-(2-Butynyl)-2-carboxy-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
Example 85
[1017]
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1018] 12.5 mg of t-butyl
4-[7-(2-butynyl)-2-carbamoyl-1-methyl-6-oxo-6,7--
dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.3
ml of tetrahydrofuran and 0.2 ml of methanol, and 0.05 ml of 2N
sodium hydroxide was added thereto. The mixture was stirred at
50.degree. C. for 2 hours. The reaction solution was concentrated,
and the residue was dissolved in trifluoroacetic acid. The mixture
was concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.44
mg of 7-(2-butynyl)-2-carboxy-1-methy-
l-8-(piperazin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate [MS
m/e (ESI) 331(MH.sup.+--CF.sub.3COOH)] and 6.4 mg of
7-(2-butynyl)-1-methyl-8-(pipe- razin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate [.sup.1H-NMR(CDCl.sub.3) .delta. 1.81 (t, J=2.4
Hz, 3H) 3.54 (br, 4H) 3.63 (s, 3H) 3.83 (br, 4H) 5.02 (s, 2H) 8.20
(s, 1H); MS m/e (ESI) 287(MH.sup.+--CF.sub.3COOH)].
Example 86
7-(2-Butynyl)-2-methoxy-1-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-dihydropu-
rin-6-one hydrochloride
[1019]
(a)[7-Benzyl-2,6-dioxo-1-(2-phenylethyl)-1,2,6,7-tetrahydropurin-3--
yl]methyl 2,2-dimethylpropionate
[1020] A mixture consisting of 500 mg of
[7-benzyl-2,6-dioxo-1,2,6,7-tetra- hydropurin-3-yl]methyl
2,2-dimethylpropionate, 0.38 ml of 2-bromoethyl benzene, 390 mg of
anhydrous potassium carbonate, and 5 ml of N,N-dimethylformamide
was stirred in an oil bath at 50.degree. C. for two hours. The
reaction mixture was extracted with ethyl acetate and water, and
the organic layer was washed with water and then with saturated
saline. The organic liquid was dried over anhydrous magnesium
sulfate, and then concentrated under reduced pressure. The residue
was crystallized with ethyl acetate-hexane to give 540 mg of the
title compound.
[1021] .sup.1H-NMR(CDCl.sub.3) .delta. 1.19 (s, 9H) 2.92-2.98 (m,
2H) 4.19-4.25 (m, 2H) 5.48 (s, 2H) 6.11 (s, 2H) 7.17-7.40 (m, 10H)
7.54 (s, 1H)
[1022]
(b)[7-(2-Butynyl)-8-chloro-2,6-dioxo-1-(2-phenylethyl)-1,2,6,7-tetr-
ahydropurin-3-yl]methyl 2,2-dimethyl propionate
[1023] A mixture consisting of 540 mg of
[7-benzyl-2,6-dioxo-1-(2-phenylet-
hyl)-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethylpropionate, 50
mg of 10% palladium carbon, and 8 ml of acetic acid was stirred
under a hydrogen atmosphere at room temperature overnight. The
reaction mixture was filtered and then concentrated under reduced
pressure to give 410 mg of residue.
[1024] The entire residue was combined with 0.15 ml of
1-bromo-2-butyne, 300 mg of anhydrous potassium carbonate, and 5 ml
of N,N-dimethylformamide. The mixture was stirred at room
temperature for 2 hours. The reaction solution was extracted with
ethyl acetate and water. The organic layer was washed with water
and then with saturated brine. The organic liquid was dried over
anhydrous magnesium sulfate and concentrated under reduced pressure
to give 470 mg of residue.
[1025] The entire residue was combined with 180 mg of
N-chlorosuccinimide and 5 ml of N,N-dimethylformamide. The mixture
was stirred at room temperature for 2 hours. After 0.5 ml of an
aqueous solution of 1M sodium thiosulfate had been added to the
reaction solution, the mixture was extracted with ethyl acetate and
water. The organic layer was washed with water and then with
saturated brine. The organic liquid was dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
380 mg of the title compound was obtained by crystallization using
ethyl acetate-hexane.
[1026] .sup.1H-NMR(CDCl.sub.3) .delta. 1.21 (s, 9H) 1.83 (t, J=2
Hz, 3H) 2.92-2.98 (m, 2H) 4.19-4.25 (m, 2H) 5.11 (q, J=2 Hz, 2H)
6.05 (s, 2H) 7.18-7.32 (m, 5H)
[1027] (c) t-Butyl
4-[7-(2-butynyl)-2,6-dioxo-1-(2-phenylethyl)-2,3,6,7-te-
trahydro-1H-purin-8-yl]piperazine-1-carboxylate
[1028] A mixture consisting of 380 mg of
[7-(2-butynyl)-8-chloro-2,6-dioxo-
-1-(2-phenylethyl)-1,2,6,7-tetrahydropurin-3-yl]methyl 2,2-dimethyl
propionate, 460 mg of t-butyl piperazine-1-carboxylate, and 0.5 ml
of N-methylpyrrolidone was stirred in an oil bath at 150.degree. C.
for 15 minutes. The reaction mixture was extracted with ethyl
acetate and water, and the organic layer was washed with water and
then with saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, and then concentrated under reduced
pressure. The residue was dissolved in ethyl acetate/hexane (1/1).
The solution was filtered through a small amount of silica gel, and
then washed with ethyl acetate/hexane (1/1). The filtrate was
combined with the washing solution. The mixed solution was
concentrated under reduced pressure to give 570 mg of residue.
[1029] The entire residue was combined with 5 ml of tetrahydrofuran
and 2.5 ml of methanol. 33 mg of sodium hydride was added to the
mixture, and the resulting mixture was stirred at room temperature
for 30 minutes. 1 ml of 1 N hydrochloric acid was added to the
reaction solution, and then the mixture was extracted with ethyl
acetate and water, then was washed with water and then with
saturated brine. The organic liquid was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure to give
350 mg of the title compound.
[1030] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.85 (t, J=2
Hz, 3H) 2.91-2.98 (m, 2H) 3.37 (br.s, 4H) 3.56-3.62 (m, 4H)
4.15-4.22 (m, 2H) 4.87 (q, J=2 Hz, 2H) 7.18-7.35 (m, 5H)
[1031] (d) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-d-
ihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1032] A mixture consisting of 290 mg of t-butyl
4-[7-(2-butynyl)-2,6-diox-
o-1-(2-phenylethyl)-2,3,6,7-tetrahydro-1H-purin-8-yl]piperazine-1-carboxyl-
ate and 4 ml of phosphorus oxychloride was heated and stirred in an
oil bath at 120.degree. C. for 8 hours. The reaction solution was
concentrated under reduced pressure, and the residue was dissolved
in 5 ml of tetrahydrofuran. This solution was added dropwise to a
mixture consisting of 250 mg of di-t-butyl dicarbonate, 10 ml of a
saturated sodium bicarbonate solution, and 10 ml of tetrahydrofuran
while the mixture was being stirred and cooled with ice. The
mixture was incubated at room temperature for 4 hours, and then
extracted with ethyl acetate. The organic layer was washed with
water then with saturated brine, dried over anhydrous magnesium
sulfate, and then concentrated under reduce pressure. The residue
was purified by silica gel column chromatography using 30 to 50%
ethyl acetate/hexane. Then, the material was further purified by
reverse-phase column chromatography using 50 to 100% methanol/water
to give 60 mg of the title compound.
[1033] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.84 (t, J=2
Hz, 3H) 3.10-3.16 (m, 2H) 3.40-3.46 (m, 2H) 3.57-3.63 (m, 4H)
4.42-4.49 (m, 4H) 4.94 (q, J=2 Hz, 2H) 7.21-7.34 (m, 5H)
[1034] (e)
7-(2-Butynyl)-2-methoxy-1-(2-phenylethyl)-8-(piperazin-1-yl)-1,-
7-dihydropurin-6-one hydrochloride
[1035] 10 mg of sodium hydride (60%; oily) was added to a mixture
consisting of 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenyl-
ethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate and 0.5
ml of methanol. The mixture was stirred at room temperature for 20
minutes. Water was added to the reaction solution. The mixture was
extracted with ethyl acetate. The organic layer was washed with
water and then with saturated brine, and concentrated. 0.5 ml of
trifluoroacetic acid was added to the residue. The mixture was
stirred at room temperature for 30 minutes, and then concentrated.
The residue was purified by reverse-phase column chromatography
using 20 to 80% methanol/water (containing 0.1% concentrated
hydrochloric acid) to give 4.3 mg of the title compound.
[1036] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (br.s, 3H) 2.85 (t, J=7
Hz, 2H) 3.28 (br.s, 4H) 3.48-3.54 (m, 4H) 3.83 (s, 3H) 4.15 (t, J=7
Hz, 2H) 4.97 (br.s, 2H) 7.16-7.24 (m, 3H) 7.29 (t, J=8 Hz, 2H) 9.08
(br.s, 2H)
Example 87
7-(2-Butynyl)-2-ethoxy-1-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-dihydropur-
in-6-one hydrochloride
[1037] Using ethanol instead of methanol in Example 86(e), the
title compound was synthesized by the same method as used in
Example 86(e).
[1038] .sup.1H-NMR(DMSO-d6) .delta. 1.28 (t, J=7 Hz, 3H) 1.80 (s,
3H) 2.86 (t, J=7 Hz, 2H) 3.27 (br.s, 4H) 3.46-3.53 (m, 4H) 4.15 (t,
J=7 Hz, 2H) 4.25 (q, J=7 Hz, 2H) 4.97 (s, 2H) 7.17 (d, J=7 Hz, 2H)
7.22 (t, J=7 Hz, 1H) 7.29 (t, J=7 Hz, 2H) 9.04 (br.s, 2H)
Example 88
Methyl
[7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-dihyd-
ro-1H-purin-2-ylsulfanyl]acetate hydrochloride
[1039] Using methyl thioglycolate instead of methanol and using
potassium carbonate as a base in Example 86(e), the title compound
was synthesized by the same method as used in Example 86.
[1040] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 2.96 (t, J=8 Hz,
2H) 3.29 (br.s, 4H) 3.50-3.56 (m, 4H) 3.68 (s, 3H) 4.16 (s, 2H)
4.23 (t, J=8 Hz, 2H) 4.99 (s, 2H) 7.24-7.38 (m, 5H) 8.96 (br.s,
2H)
Example 89
Ethyl
[7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-dihydr-
o-1H-purin-2-ylamino]acetate hydrochloride
[1041] Using glycine ethyl ester hydrochloride instead of methanol
and using potassium carbonate as a base in Example 86(e), the title
compound was synthesized by the same method as used in Example
86.
[1042] .sup.1H-NMR(DMSO-d6) .delta. 1.22 (t, J=7 Hz, 3H) 1.78 (s,
3H) 2.87 (t, J=8 Hz, 2H) 3.26 (br.s, 4H) 3.47 (br.s, 4H) 4.05 (d,
J=6 Hz, 2H) 4.12 (q, J=7 Hz, 2H) 4.21 (t, J=8 Hz, 2H) 4.89 (br.s,
2H) 7.17-7.35 (m, 5H) 7.51 (t, J=6 Hz, 1H) 8.93 (br.s, 2H)
Example 90
2-[7-(2-Butynyl)-6-oxo-1-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-ylamino]acetamide hydrochloride
[1043] Using glycine amide hydrochloride instead of methanol and
using potassium carbonate as a base in Example 86(e), the title
compound was synthesized by the same method as used in Example
86.
[1044] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 3H) 2.87 (t, J=8 Hz,
2H) 3.26 (br.s, 4H) 3.52 (br.s, 4H) 3.84 (d, J=5 Hz, 2H) 4.19 (t,
J=8 Hz, 2H) 4.91 (s, 2H) 7.02 (s, 1H) 7.16-7.40 (m, 7H) 9.08 (br.s,
2H)
Example 91
Ethyl
N-[7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-dihy-
dro-1H-purin-2-yl]-N-methylaminoacetate hydrochloride
[1045] Using N-methylglycine ethyl ester hydrochloride instead of
methanol and using potassium carbonate as a base in Example 86(e)
the title compound was synthesized by the same method as used in
Example 86.
[1046] .sup.1H-NMR(DMSO-d6) .delta. 1.17 (t, J=7 Hz, 3H) 1.80 (s,
3H) 2.76 (s, 3H) 2.96 (t, J=8 Hz, 2H) 3.28 (br.s, 4H) 3.46-3.52 (m,
4H) 3.88 (s, 2H) 4.09 (q, J=7 Hz, 2H) 4.27 (t, J=8 Hz, 2H) 4.98 (s,
2H) 7.15-7.30 (m, 5H) 8.95 (br.s, 2H)
Example 92
Methyl
[7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-8-(piperazin-1-yl)-6,7-dihyd-
ro-1H-purin-2-yloxy]acetate hydrochloride
[1047] Using methyl glycolate instead of methanol in Example 86(e),
the title compound was synthesized by the same method as used in
Example 86.
[1048] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 2.93 (t, J=8 Hz,
2H) 3.28 (br.s, 4H) 3.49 (br.s, 4H) 3.72 (s, 3H) 4.20 (t, J=8 Hz,
2H) 4.96 (s, 2H) 5.02 (s, 2H) 7.20-7.34 (m, 5H) 8.87 (br.s, 2H)
Example 93
7-(2-Butynyl)-2-(2-hydroxyethoxy)-1-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-
-dihydropurin-6-one hydrochloride
[1049] Using ethylene glycol instead of methanol in Example 86(e),
the title compound was synthesized by the same method as used in
Example 86.
[1050] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 2.88 (t, J=8 Hz,
2H) 3.29 (br.s, 4H) 3.49 (br.s, 4H) 3.71 (t, J=6 Hz, 2H) 4.18 (t,
J=8 Hz, 2H) 4.28 (t, J=6 Hz, 2H) 4.97 (s, 2H) 7.16-7.32 (m, 5H)
8.90 (br.s, 2H)
Example 94
7-(2-Butynyl)-2-dimethylamino-1-(2-phenylethyl)-8-(piperazin-1-yl)-1,7-dih-
ydropurin-6-one hydrochloride
[1051] Using an aqueous solution of 50% dimethylamine instead of
methanol in Example 86(e), the title compound was synthesized by
the same method as used in Example 86.
[1052] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 2.60 (s, 6H) 2.89
(t, J=8 Hz, 2H) 3.28 (br.s, 4H) 3.49 (br.s, 4H) 4.26 (t, J=8 Hz,
2H) 4.98 (s, 2H) 7.06-7.27 (m, 5H) 8.93 (br.s, 2H)
Example 95
7-(2-Butynyl)-2-chloro-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1053] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8--
yl]piperazine-1-carboxylate
[1054] A mixture consisting of 1.0 g of t-butyl
4-[7-(2-butynyl)-2,6-dichl-
oro-7H-purin-8-yl]piperazine-1-carboxylate, 580 mg of sodium
acetate, and 10 ml of dimethyl sulfoxide was stirred in an oil bath
at 80.degree. C. for 24 hours. The reaction solution was extracted
with ethyl acetate and water. The organic layer was washed with
water and then with saturated brine, then was dried over anhydrous
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography using 50
to 70% ethyl acetate/hexane and crystallized with ethyl
acetate-hexane to give 800 mg of the title compound.
[1055] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2
Hz, 3H) 3.44 (br.s, 4H) 3.56-3.63 (m, 4H) 4.94 (q, J=2 Hz, 2H)
[1056] (b)
7-(2-Butynyl)-2-chloro-8-(piperazin-1-yl)-1,7-dihydropurin-6-on- e
trifluoroacetate
[1057] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-puri-
n-8-yl]piperazine-1-carboxylate was dissolved in trifluoroacetic
acid, and the solution was concentrated. The residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.45 mg of the title compound.
[1058] MS m/e (ESI) 307(MH.sup.+--CF.sub.3COOH)
Example 96
2-[7-(2-Butynyl)-2-dimethylamino-6-oxo-8-(piperazin-1-yl)-6,7-dihydropurin-
-1-ylmethyl]benzonitrile hydrochloride
[1059] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7-d-
ihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1060] A mixture consisting of 100 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-
-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate, 60 mg of
2-cyanobenzyl bromide, 68 mg of anhydrous potassium carbonate, and
1 ml of N,N-dimethylformamide was stirred at room temperature for 4
hours. Ethyl acetate/hexane (1/1) and water were added to the
reaction solution. The insoluble material was removed by
filtration. The filtrate was extracted with ethyl acetate. The
organic layer was washed with water and then with saturated brine,
dried over anhydrous magnesium sulfate, and then concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography using 30 to 50% ethyl acetate/hexane to give 50 mg
of the title compound.
[1061] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2
Hz, 3H) 3.43-3.49 (m, 4H) 3.58-3.64 (m, 4H) 4.95 (q, J=2 Hz, 2H)
5.72 (s, 2H) 7.06 (d, J=8 Hz, 1H) 7.39 (t, J=8 Hz, 1H) 7.51 (t, J=8
Hz, 1H) 7.71 (d, J=8 Hz, 1H)
[1062] (b) t-Butyl
4-[7-(2-butynyl)-1-(2-cyanobenzyl)-2-dimethylamino-6-ox-
o-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1063] A mixture consisting of 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-
-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]
piperazine-1-carboxylate- , 20 .mu.l of an aqueous solution of 50%
dimethylamine, and 0.2 ml of N,N-dimethylformamide was stirred at
room temperature for 2 hours. The reaction solution was extracted
with ethyl acetate and water. The organic layer was washed with
water and with saturated brine, and concentrated. The residue was
separated by silica gel thin-layer chromatography using 70% ethyl
acetate/hexane to give 6.5 mg of the title compound.
[1064] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.81 (t, J=2
Hz, 3H) 2.73 (s, 6H) 3.38-3.45 (m, 4H) 3.56-3.64 (m, 4H) 4.91, (q,
J=2 Hz, 2H) 5.55 (s, 2H) 7.07 (d, J=8 Hz, 1H) 7.32 (t, J=8 Hz, 1H)
7.46, (t, J=8 Hz, 1H) 7.65 (d, J=8 Hz, 1H)
[1065] (c)
2-[7-(2-Butynyl)-2-dimethylamino-6-oxo-8-(piperazin-1-yl)-6,7-d-
ihydropurin-1-ylmethyl]benzonitrile hydrochloride
[1066] 6.5 mg of t-butyl
4-[7-(2-butynyl)-1-(2-cyanobenzyl)-2-dimethylamin-
o-6-oxo-6,7-dihydro-1H-purin-8-yl] piperazine-1-carboxylate was
dissolved in 0.5 ml of trifluoroacetic acid, and the mixture was
allowed to stand at room temperature for 20 minutes. The reaction
solution was concentrated, and the residue was purified by
reverse-phase column chromatography using 20 to 80% methanol/water
(containing 0.1% concentrated hydrochloric acid) to give 6.4 mg of
the title compound.
[1067] .sup.1H-NMR(DMSO-d6) .delta. 1.76 (s, 3H) 2.69 (s, 6H) 3.28
(br.s, 4H) 3.51 (br.s, 4H) 4.91 (s, 2H) 5.40 (s, 2H) 7.04 (d, J=8
Hz, 1H) 7.43 (t, J=8 Hz, 1H) 7.60 (t, J=8 Hz, 1H) 7.83 (d, J=8 Hz,
1H) 8.90 (br.s, 2H)
Example 97
Methyl
[7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihyd-
ro-1H-purin-2-ylsulfanyl]acetate hydrochloride
[1068] Using methyl thioglycolate instead of dimethylamine and
using anhydrous potassium carbonate as a base in Example 96(b), the
title compound was synthesized by the same method as used in
Example 96.
[1069] .sup.1H-NMR(DMSO-d6) .delta. 1.79(s, 3H) 3.29 (br.s, 4H)
3.56 (br.s, 4H) 3.65 (s, 3H) 4.12 (s, 2H) 4.99 (s, 2H) 5.48 (s, 2H)
7.10 (d, J=8 Hz, 1H) 7.50 (t, J=8 Hz, 1H) 7.65 (t, J=8 Hz, 1H) 7.92
(d, J=8 Hz, 1H) 8.95 (br.s, 2H)
Example 98
2-[7-(2-Butynyl)-2-methoxy-6-oxo-8-(piperazin-1-yl)-6,7-dihydropurin-1-ylm-
ethyl]benzonitrile hydrochloride
[1070] Using methanol instead of dimethylamine and using anhydrous
potassium carbonate as a base in Example 96(b), the title compound
was synthesized by the same method as used in Example 96.
[1071] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 3H) 3.28 (br.s, 4H)
3.48-3.56 (m, 4H) 3.91 (s, 3H) 4.97 (s, 2H) 5.32 (s, 2H) 7.19 (d,
J=8 Hz, 1H) 7.48 (t, J=8 Hz, 1H) 7.63 (t, J=8 Hz, 1H) 7.87 (d, J=8
Hz, 1H) 9.05 (br.s, 2H)
Example 99
Methyl
[7-(2-butynyl)-1-cyanomethyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1-
H-purin-2-ylsulfanyl]acetate hydrochloride
[1072] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-1-cyanomethyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate
[1073] Using bromoacetonitrile instead of dimethylamine in Example
96(b), the title compound was synthesized by the same method as
used in Example 96(a).
[1074] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.84 (t, J=2
Hz, 3H) 3.43-3.49 (m, 4H) 3.58-3.63 (m, 4H) 4.91 (q, J=2 Hz, 2H)
5.18 (s, 2H)
[1075] (b) Methyl
[7-(2-butynyl)-1-cyanomethyl-6-oxo-8-(piperazin-1-yl)-6,-
7-dihydro-1H-purin-2-ylsulfanyl]acetate hydrochloride
[1076] Using the compound obtained in Example 99(a) described above
instead of the compound obtained in Example 96(a) in Example 97,
the title compound was synthesized by the same method as used in
Example 97.
[1077] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 3.29 (br.s, 4H)
3.55 (br.s, 4H) 3.68 (s, 3H) 4.22 (s, 2H) 4.98 (s, 2H) 5.21 (s, 2H)
8.93 (br.s, 2H)
Example 100
Methyl
[1,7-bis(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-ylsulfanyl]acetate hydrochloride
[1078] (a) t-Butyl
4-[1,7-bis(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-pur-
in-8-yl]piperazine-1-carboxylate
[1079] Using 1-bromo-2-butyne instead of 2-cyanobenzyl bromide in
Example 96(a), the title compound was synthesized by the same
method as used in Example 96(a).
[1080] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.80 (t, J=2
Hz, 3H) 1.83 (t, J=2 Hz, 3H) 3.40-3.45 (m, 4H) 3.57-3.62 (m, 4H)
4.93 (q, J=2 Hz, 2H) 4.98 (q, J=2 Hz, 2H)
[1081] (b) Methyl
[1,7-bis(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
-1H-purin-2-ylsulfanyl]acetate hydrochloride
[1082] Using the compound obtained in Example 100(a) described
above instead of the compound obtained in Example 96(a) in Example
97, the title compound was synthesized by the same method as used
in Example 97.
[1083] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 6H) 3.28 (br.s, 4H)
3.53 (br.s, 4H) 3.67 (s, 3H) 4.15 (s, 2H) 4.83 (s, 2H) 4.98 (s, 2H)
9.02 (br.s, 2H)
Example 101
1,7-Bis(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-carbon-
itrile hydrochloride
[1084] Using sodium cyanide instead of methyl thioglycolate in
Example 100, the title compound was synthesized by the same method
as used in Example 100.
[1085] .sup.1H-NMR(DMSO-d6) .delta. 1.81 (s, 3H) 1.82 (s, 3H) 3.28
(br.s, 4H) 3.56-3.63 (m, 4H) 4.95 (q, J=2 Hz, 2H) 5.07 (q, J=2 Hz,
2H) 9.04 (br.s, 2H)
Example 102
1,7-Bis(2-butynyl)-2-methoxy-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
hydrochloride
[1086] Using methanol instead of methyl thioglycolate and using
sodium hydride as the base in Example 100, the title compound was
synthesized by the same method as used in Example 100.
[1087] .sup.1H-NMR(DMSO-d6) .delta. 1.75 (s, 3H) 1.80 (s, 3H) 3.28
(br.s, 4H) 3.47-3.55 (m, 4H) 3.98 (s, 3H) 4.66 (s, 2H) 4.96 (s, 2H)
9.01 (br.s, 2H)
Example 103
Methyl
[1-allyl-7-(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-puri-
n-2-ylsulfanyl]acetate hydrochloride
[1088] (a) t-Butyl
4-[1-allyl-7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H--
purin-8-yl]piperazine-1-carboxylate
[1089] Using allyl bromide instead of 2-cyanobenzyl bromide in
Example 96(a), the title compound was synthesized by the same
method as used in Example 96(a).
[1090] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2
Hz, 3H) 3.38-3.45 (m, 4H) 3.55-3.63 (m, 4H) 4.90 (d, J=5 Hz, 2H)
4.93 (q, J=2 Hz, 2H) 5.19-5.29 (m, 2H) 5.93 (ddt, J=10, 17, 5 Hz,
1H)
[1091] (b) Methyl
[1-allyl-7-(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihy-
dro-1H-purin-2-ylsulfanyl]acetate hydrochloride
[1092] Using the compound obtained in Example 103(a) described
above instead of the compound obtained in Example 96(a) in Example
97, the title compound was synthesized by the same method as used
in Example 97.
[1093] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 3H) 3.27 (br.s, 4H)
3.48-3.56 (m, 4H) 3.66 (s, 3H) 4.12 (s, 2H) 4.70 (d, J=5 Hz, 2H)
4.98 (br.s, 2H) 5.07 (d, J=17 Hz, 1H) 5.21 (d, J=10 Hz, 1H) 5.89
(ddt, J=10, 17, 5 Hz, 1H) 9.07 (br.s, 2H)
Example 104
1-Allyl-7-(2-butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-car-
bonitrile hydrochloride
[1094] The title compound was synthesized by using sodium cyanide,
instead of allyl bromide by the same method as used in Example
103.
[1095] .sup.1H-NMR(DMSO-d6) .delta. 1.81 (t, J=2 Hz, 3H) 3.29
(br.s, 4H) 3.57-3.64 (m, 4H) 4.81 (d, J=5 Hz, 2H) 5.04-5.10 (m, 3H)
5.26 (d, J=10 Hz, 1H) 6.00 (ddt, J=10, 17, 5 Hz, 1H) 9.12 (br.s,
2H)
Example 105
1-Allyl-7-(2-butynyl)-2-methoxy-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
hydrochloride
[1096] Using methanol instead of methyl thioglycolate and using
sodium hydride as a base in Example 103, the title compound was
synthesized by the same method as used in Example 103.
[1097] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (t, J=2 Hz, 3H) 3.27
(br.s, 4H) 3.48-3.56 (m, 4H) 3.93 (s, 3H) 4.55 (d, J=5 Hz, 2H)
4.94-5.02 (m, 3H) 5.12 (d, J=10 Hz, 1H) 5.87 (ddt, J=10, 17, 5 Hz,
1H) 9.04 (br.s, 2H)
Example 106
Methyl
[7-(2-butynyl)-1-(2-methoxyethyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihy-
dro-1H-purine-2-ylsulfanyl]acetate hydrochloride
[1098] (a) t-Butyl
4-[7-(2-butynyl)-1-(2-methoxyethyl)-2-chloro-6-oxo-6,7--
dihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1099] Using 2-bromoethyl methyl ether instead of 2-cyanobenzyl
bromide in Example 96(a), the title compound was synthesized by the
same method as used in Example 96(a).
[1100] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2
Hz, 3H) 3.36 (s, 3H) 3.39-3.45 (m, 4H) 3.56-3.61 (m, 4H) 3.69 (t,
J=6 Hz, 2H) 4.50 (t, J=6 Hz, 2H) 4.92 (q, J=2 Hz, 2H)
[1101] (b) Methyl
[7-(2-butynyl)-1-(2-methoxyethyl)-6-oxo-8-(piperazin-1-y-
l)-6,7-dihydro-1H-purine-2-ylsulfanyl]acetate hydrochloride
[1102] Using the compound obtained in Example 106(a) described
above instead of the compound obtained in Example 96(a) in Example
97, the title compound was synthesized by the same method as used
in Example 97.
[1103] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s,3H) 3.25-3.32 (m, 7H)
3.50-3.55 (m, 4H) 3.61 (t, J=6 Hz, 2H) 3.67 (s, 3H) 4.14 (s, 2H)
4.25 (t, J=6 Hz, 2H) 4.98 (s, 2H) 9.00 (br.s, 2H)
Example 107
7-(2-Butynyl)-1-(2-methoxyethyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-p-
urine-2-carbonitrile hydrochloride
[1104] Using sodium cyanide instead of methyl thioglycolate in
Example 106, the title compound was synthesized by the same method
as used in Example 106.
[1105] .sup.1H-NMR(DMSO-d6) .delta. 1.81 (s, 3H) 3.25 (s, 3H) 3.29
(br.s, 4H) 3.55-3.64 (m, 6H) 4.34 (t, J=5 Hz, 2H) 5.08 (s, 2H) 9.05
(br.s, 2H)
Example 108
7-(2-Butynyl)-1-(2-methoxyethyl)-2-methoxy-8-(piperazin-1-yl)-1,7-dihydrop-
urin-6-one hydrochloride
[1106] Using methanol instead of methyl thioglycolate and using
anhydrous potassium carbonate as the base in Example 106, the title
compound was synthesized by the same method as used in Example
106.
[1107] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 3H) 3.23 (s, 3H) 3.27
(br.s, 4H) 3.46-3.55 (m, 6H) 3.94 (s, 3H) 4.13 (t, J=6 Hz, 2H),
4.96 (s, 2H), 9.03 (br.s, 2H)
Example 109
7-Benzyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1108] (a) 7-Benzyl-1,7-dihydropurin-6-one
[1109] 18.23 g of inosine was dissolved in 90 ml of dimethyl
sulfoxide, and 16 ml of benzyl bromide was added thereto. The
mixture was stirred at room temperature overnight. The reaction
solution was poured into 3 L of ethyl acetate. The resulting
supernatant was removed and the precipitated oil was dissolved in
10% hydrochloric acid (135 ml). The solution was heated at
70.degree. C. with stirring for 4 hours. The solution was cooled to
room temperature, and then neutralized to pH 7 using a 5N aqueous
sodium hydroxide solution. The precipitated solid was collected by
filtration, and dried to give 12.748 g of the title compound.
[1110] (b) t-Butyl
4-(7-benzyl-6-oxo-6,7-dihydro-1H-purin-8-yl)piperazine--
1-carboxylate
[1111] 12.748 g of 7-benzyl-1,7-dihydropurin-6-one was dissolved in
150 ml of N,N-dimethylformamide, and 7.9 g of N-chlorosuccinimide
was added thereto. The reaction solution was stirred overnight, and
then diluted with ethyl acetate. The solution was washed with water
and 1N hydrochloric acid, and dried over anhydrous magnesium
sulfate. The solution was filtered, and the filtrate was
concentrated to give 6.103 g of
7-benzyl-8-chloro-1,7-dihydropurin-6-one. This compound was
combined with 20 g of t-butyl piperazine-1-carboxylate, and the
mixture was heated at 150.degree. C. After being stirred for one
hour, the reaction mixture was combined with ethyl acetate and
water, and partitioned. The organic layer was washed with 1N
hydrochloric acid, and dried over anhydrous magnesium sulfate.
After filtration, the filtrate was concentrated. The residue was
purified by silica gel column chromatography. Thus, 1.539 g of the
title compound was obtained from the fraction eluted with ethyl
acetate-methanol (10:1).
[1112] .sup.1H-NMR(CDCl.sub.3) .delta. 1.39 (s, 9H) 3.07-3.10 (m,
4H) 3.35-3.39 (m, 4H) 5.44 (s, 2H) 7.16-7.18 (m, 2H) 7.22-7.32 (m,
3H) 7.91 (s, 1H) 12.18 (s, 1H)
[1113] (c)
7-Benzyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1114] 15 mg of t-butyl
4-(7-benzyl-6-oxo-6,7-dihydro-1H-purin-8-yl)pipera-
zine-1-carboxylate was dissolved in 1 ml of N,N-dimethylformamide,
and 10 mg of sodium hydride and 10 .mu.l of methyl iodide were
added thereto. The mixture was stirred at room temperature for 3
days, then ethyl acetate and water were added and the layers
separated. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated.
The residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 4.31 mg of the
title compound.
[1115] MS m/e (ESI) 325(MH.sup.+--CF.sub.3COOH)
Example 110
7-Benzyl-1-ethyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1116] The title compound was obtained by using iodoethane, instead
of methyl iodide, by the same method as used in Example 109.
[1117] MS m/e (ESI) 339(MH.sup.+--CF.sub.3COOH)
Example 111
Ethyl
[7-benzyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydropurin-1-yl]acetate
trifluoroacetate
[1118] The title compound was obtained by using ethyl bromoacetate,
instead of methyl iodide, by the same method as used in Example
109.
[1119] MS m/e (ESI) 397(MH.sup.+--CF.sub.3COOH)
Example 112
7-Benzyl-1-(2-methoxyethyl)-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1120] The title compound was obtained by using 2-methoxyethyl
bromide, instead of methyl iodide, by the same method as used in
Example 109.
[1121] MS m/e (ESI) 369(MH.sup.+--CF.sub.3COOH)
Example 113
7-Benzyl-1-(2-propynyl)-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1122] The title compound was obtained by using propargyl bromide,
instead of methyl iodide, by the same method as used in Example
109.
[1123] MS m/e (ESI) 349(MH.sup.+--CF.sub.3COOH)
Example 114
7-Benzyl-1-cyanomethyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1124] The title compound was obtained by using bromoacetonitrile,
instead of methyl iodide, by the same method as used in Example
109.
[1125] MS m/e (ESI) 350(MH.sup.+--CF.sub.3COOH)
Example 115
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one trifluoroacetate
[1126] (a) Ethyl
2-bromo-3-(2-butynyl)-5-cyano-3H-imidazole-4-carboxylate
[1127] 4.56 ml of sulfuric acid was added to 170 ml of ethanol
containing 16.80 g of 2-bromo-1H-imidazole-4,5-dicarbonitrile [CAS
No. 50847-09-1], and the mixture was heated under reflux for 48
hours. The solution was cooled, and then 500 ml of ethyl acetate
and 200 ml of water were added thereto. The organic layer was dried
over anhydrous magnesium sulfate, filtered, and concentrated under
reduced pressure. The residue was dissolved in
N,N-dimethylformamide, and 14.1 g of potassium carbonate and 8.6 ml
of 2-butynyl bromide were added thereto. The mixture was stirred at
room temperature for 18 hours. 500 ml of ethyl acetate was added to
the solution, and the mixture was washed three times with 300 ml of
water, and then with 300 ml of a saturated sodium chloride
solution. Then, the solution was dried over anhydrous magnesium
sulfate, and filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 4.09 g of the title compound was obtained
from the fraction eluted with hexane-ethyl acetate (9:1).
[1128] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.2 Hz, 3H) 1.81
(s, 3H) 4.47 (q, J=7.2 Hz, 2H) 5.16 (s, 2H)
[1129] (b) t-Butyl
4-[1-(2-butynyl)-4-cyano-5-ethoxycarboxyl-1H-imidazol-2-
-yl]piperazine-1-carboxylate
[1130] 4.09 g of ethyl
2-bromo-3-(2-butynyl)-5-cyano-3H-imidazole-4-carbox- ylate was
combined with 7.70 g of t-butyl piperazine-1-carboxylate, and the
mixture was heated to 150.degree. C. with stirring for 50 minutes.
The reaction mixture was dissolved in toluene. The mixture was
purified by silica gel column chromatography. Thus, 4.47 g of the
title compound was obtained from the fraction eluted with
hexane-ethyl acetate (2:1).
[1131] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.2 Hz, 3H) 1.47
(s, 9H) 1.82 (t, J=2.3 Hz, 3H) 3.08-3.13 (m, 4H) 3.57-3.61 (m, 4H)
4.44 (q, J=7.2 Hz, 2H) 4.89 (q, J=2.3 Hz, 2H)
[1132] (c) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-thiocarbamoyl-1H-im-
idazol-2-yl]piperazine-1-carboxylate
[1133] 5 ml of an aqueous solution of 50% ammonium sulfide was
added to a 20-ml ethanol solution containing 0.80 g of t-butyl
4-[1-(2-butynyl)-4-cyano-5-ethoxycarbonyl-1H-imidazol-2-yl]
piperazine-1-carboxylate, and the mixture was heated at 60.degree.
C. for 14 hours. 100 ml of ethyl acetate and 50 ml of water were
added to the mixture, and the organic layer was washed successively
with 50 ml of water and 50 ml of a saturated sodium chloride
solution. The reaction solution was dried over anhydrous magnesium
sulfate, then filtered. The filtrate was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.58 g of the title compound was obtained
from the fraction eluted with hexane-ethyl acetate (3:2).
[1134] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.2 Hz, 3H) 1.48
(s, 9H) 1.82 (t, J=2.3 Hz, 3H) 3.12-3.16 (m, 4H) 3.54-3.59 (m, 4H)
4.44 (q, J=7.2 Hz, 2H) 4.89 (q, J=2.3 Hz, 2H) 7.41 (br.s, 1H) 8.88
(br.s, 1H)
[1135] (d) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methylsulfanylcarbo-
nimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1136] 0.235 of trimethyl oxonium tetrafluoroborate was added to a
20-ml dichloromethane solution of 0.58 g of t-butyl
4-[1-(2-butynyl)-5-ethoxyca-
rbonyl-4-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate,
and the mixture was stirred at room temperature for 18 hours. 50 ml
of dichloromethane was added to the solution, and the mixture was
washed with 20 ml of a saturated sodium bicarbonate solution. The
mixture was dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give 0.55 g of the title
compound.
[1137] .sup.1H-NMR(CDCl.sub.3) .delta. 1.41 (t, J=7.2 Hz, 3H) 1.47
(s, 9H) 1.81 (t, J=2.3 Hz, 3H) 2.39 (s, 3H) 3.12-3.16 (m, 4H)
3.56-3.59 (m, 4H) 4.42 (q, J=7.2 Hz, 2H) 4.80 (q, J=2.3 Hz, 2H)
[1138] (e) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methylsulfanylcarbo-
nyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1139] 5 ml of a 2N aqueous solution of hydrochloric acid was added
to a 30-ml ethanol solution of 0.55 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarb- onyl-4-methyl
sulfanylcarbonimidoyl-1H-imidazol-2-yl] piperazine-1-carboxylate,
and the mixture was heated at 60.degree. C. for 5 hours. After the
reaction solution had been concentrated under reduced pressure, 25
ml of ethyl acetate and 1N sodium hydroxide solution were added
thereto. The aqueous layer was extracted with 25 ml of ethyl
acetate, and the organic layers were combined together. The mixture
was washed with 10 ml of a saturated sodium chloride solution
containing 1 ml of 1N sodium hydroxide solution, and dried over
anhydrous magnesium sulfate. The solution was filtered, and the
filtrate was concentrated under reduced pressure. The residue was
dissolved in 10 ml of dichloromethane, and 0.10 ml of triethylamine
and 0.256 g of di-t-butyl dicarbonate were added thereto. The
mixture was stirred at room temperature for 15 hours, and then 25
ml of ethyl acetate was added thereto. The mixture was washed
successively with 10 ml of 0.1N hydrochloric acid, 10 ml of a
saturated sodium bicarbonate solution, and 10 ml of a saturated
sodium chloride solution, and then dried over anhydrous magnesium
sulfate. The solution was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography. Thus,
0.15 g of the title compound was obtained from the fraction eluted
with hexane-ethyl acetate (4:1).
[1140] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.1 Hz, 3H) 1.48
(s, 9H) 1.81 (t, J=2.3 Hz, 3H) 2.40 (s, 3H) 3.16-3.20 (m, 4H)
3.55-3.59 (m, 4H) 4.35 (q, J=7.1 Hz, 2H) 4.80 (q, J=2.3 Hz, 2H)
[1141] (f) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-hydroxymethyl-1H-im-
idazol-2-yl]piperazine-1-carboxylate
[1142] 0.187 g of mercury (II) acetate and 0.090 of sodium
borohydride were added to 8 ml of an ethanol solution containing
0.265 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-methylsulfanyl
carbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate at 0.degree. C.,
and the mixture was stirred at room temperature for 4 hours. After
0.187 g of mercury (II) acetate and 0.090 of sodium borohydride had
been added to the solution, the mixture was stirred at room
temperature for 15 hours. 100 ml of ethyl acetate and 50 ml of 0.5N
hydrochloric acid were added to the solution, and the organic layer
was washed successively with 50 ml of water and 50 ml of a
saturated sodium chloride solution. The mixture was dried over
anhydrous magnesium sulfate, and concentrated under reduced
pressure. The residue was purifiedby silica gel column
chromatography. 0.172 g of the starting material was collected from
the fraction eluted with hexane-ethyl acetate (4:1). Then, 0.061 g
of the title compound was obtained from the fraction eluted with
hexane-ethyl acetate (1:4).
[1143] .sup.1H-NMR(CDCl.sub.3) .delta. 1.42 (t, J=7.1 Hz, 3H) 1.48
(s, 9H) 1.81 (t, J=2.3 Hz, 3H) 3.17-3.21 (m, 4H) 3.41 (t, J=4.8 Hz,
1H) 3.56-3.60 (m, 4H) 4.36 (q, J=7.1 Hz, 2H) 4.75 (d, J=4.8 Hz, 2H)
4.81 (q, J=2.3 Hz, 2H)
[1144] (g) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol--
2-yl]piperazine-1-carboxylate
[1145] 0.120 g of manganese dioxide was added to a 2-ml
dichloromethane solution of 0.061 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-hydrox-
ymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the mixture
was stirred at room temperature for 15 hours. The reaction solution
was filtered through celite, and the filtrate was concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography. Thus, 0.055 g of the title compound was
obtained from the fraction eluted with hexane-ethyl acetate
(7:3).
[1146] .sup.1H-NMR(CDCl.sub.3) .delta. 1.42 (t, J=7.1 Hz, 3H) 1.48
(s, 9H) 1.82 (t, J=2.3 Hz, 3H) 3.23-3.26 (m, 4H) 3.55-3.59 (m, 4H)
4.45 (q, J=7.1 Hz, 2H) 4.89 (q, J=2.3 Hz, 2H) 10.36 (s, 1H)
[1147] (h) t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1148] 0.05 ml of methylhydrazine was added to a 2.5-ml ethanol
solution of 0.055 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imida- zol-2-yl]
piperazine-1-carboxylate. The mixture was stirred at 80.degree. C.
for 15 hours, and then heated at 130.degree. C. for 14 hours. The
reaction solution was concentrated under reduced pressure. Then,
the residue was purified by silica gel column chromatography. Thus,
0.035 g of the title compound was obtained from the fraction eluted
with hexane-ethyl acetate (1:1).
[1149] .sup.1H-NMR(CDCl.sub.3) .delta. 1.52 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64 (m, 4H) 3.85 (s, 3H) 5.09 (q,
J=2.3 Hz, 2H) 8.13 (s, 1H)
[1150] MS m/e (ESI) 387.4(MH.sup.+)
[1151] (i)
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,-
5-d]pyridazin-4-one trifluoroacetate
[1152] 0.4 ml of trifluoroacetic acid was added to a 0.4-ml
dichloromethane solution of 0.0351 g of t-butyl
4-[1-(2-butynyl)-6-methyl-
-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylat-
e, and the mixture was stirred at room temperature for one hour.
The solvent was concentrated. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 0.0295 g of the title compound.
[1153] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 3.83 (s, 3H) 5.15 (q, J=2.3 Hz,
2H) 8.20 (s, 1H)
[1154] MS m/e (ESI) 287.09(MH.sup.+--CF.sub.3COOH)
Example 116
5-Benzyloxymethyl-3-(2-butynyl)-2-(piperazin-1-yl)-3,5-dihydro-imidazo[4,5-
-d]pyridazin-4-one trifluoroacetate
[1155] (a)
5-Benzyloxymethyl-4-oxo-4,5-dihydroimidazo[4,5-d]pyridazine-1-s-
ulfonic acid dimethylamide
[1156] 2.08 g of triethylamine, 2.80 g of N,N-dimethyl sulfamoyl
chloride, and 0.22 g of 4-dimethylaminopyridine were added to 50 ml
of a dichloromethane solution of 3.04 g of 5-benzyloxy
methylimmidazo[4,5-d]py- ridazin-4-one [CAS NO. 82137-50-6] (R.
Paul Gagnier, Michael J. Halat, and Brian A. Otter Journal of
Heterocyclic Chemistry, 21, p481, 1984), and the mixture was heated
under reflux for 4 hours. 250 ml of ethyl acetate was added to the
solution, and the mixture was washed successively with 50 ml of an
aqueous solution of 1N hydrochloric acid, 50 ml of a saturated
sodium bicarbonate solution, and 50 ml of a saturated sodium
chloride solution. The mixture was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography. Thus, 2.86 g of the
title compound was obtained from the fraction eluted with
hexane-ethyl acetate (2:3).
[1157] .sup.1H-NMR(CDCl.sub.3) .delta. 2.98 (s, 6H) 4.77 (s, 2H)
5.74 (s, 2H) 7.30-7.39 (m, 5H) 8.21 (s, 1H) 8.46 (s, 1H)
[1158] (b)
5-Benzyloxymethyl-2-chloro-4-oxo-4,5-dihydroimidazo[4,5-d]pyrid-
azine-1-sulfonic acid dimethylamide
[1159] 5.3 ml of n-butyl lithium (2.0 M cyclohexane solution) was
added to a 150-ml tetrahydrofuran solution of 3.34 g of
5-benzyloxymethyl-4-oxo-4,-
5-dihydroimidazo[4,5-d]pyridazine-1-sulfonic acid dimethylamide
under a nitrogen atmosphere at -78.degree. C., and the mixture was
stirred at -78.degree. C. for one hour. Then, 20 ml of a
tetrahydrofuran solution of 3.26 g of hexachloroethane was added to
this solution. The mixture was allowed to warm to room temperature.
25 ml of a 5% aqueous solution of ammonium chloride was added to
the solution, and the mixture was extracted with 50 ml of ethyl
acetate. The organic layer was washed successively with 25 ml of
water and 25 ml of a saturated sodium chloride solution, and then
dried over anhydrous magnesium sulfate. The organic liquid was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography. Thus, 2.31 g of the title
compound was obtained from the fraction eluted with hexane-ethyl
acetate (2:3).
[1160] .sup.1H-NMR(CDCl.sub.3) .delta. 3.12 (s, 6H) 4.77 (s, 2H)
5.70 (s, 2H) 7.30-7.39 (m, 5H) 8.48 (s, 1H)
[1161] (c) t-Butyl
4-(6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d-
]pyridazin-2-yl)piperazine-1-carboxylate
[1162] A mixture consisting of 2.31 g of
5-benzyloxymethyl-2-chloro-4-oxo--
4,5-dihydroimidazo[4,5-d]pyridazine-1-sulfonic acid dimethylamide
and 4.49 g of t-butyl piperazine-1-carboxylate was heated at
150.degree. C. under nitrogen atmosphere for 2.5 hours. The residue
was purified by silica gel column chromatography. Thus, 1.94 g of
the title compound was obtained from the fraction eluted with ethyl
acetate.
[1163] .sup.1H-NMR(CDCl.sub.3) .delta. 3.54-3.58 (m, 4H) 3.71-3.75
(m, 4H) 4.68 (s, 2H) 5.65 (s, 2H) 7.25-7.35 (m, 5H) 8.21 (s, 1H)
12.58 (br.s, 1H)
[1164] (d) t-Butyl
4-[6-benzyloxymethyl-1-(2-butynyl)-7-oxo-6,7-dihydro-1H-
-imidazo[4,5-d] pyridazin-2-yl]piperazine-1-carboxylate
[1165] 0.74 g of potassium carbonate and 0.078 g of 2-butynyl
bromide were added to a 20-ml N,N-dimethylformamide solution of
0.216 g of t-butyl
4-(6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo
[4,5-d]pyridazin-2-yl)p- iperazine-1-carboxylate, and the mixture
was stirred at room temperature for 16 hours. Then, 50 ml of ethyl
acetate was added to the solution. The organic layer was washed
three times with 20 ml of water, and then with 10 ml of a saturated
sodium chloride solution. The solution was dried over anhydrous
magnesium sulfate, and then concentrated under reduced pressure.
The residue was purified by silica gel column chromatography. Thus,
0.139 g of the title compound was obtained from the fraction eluted
with hexane-ethyl acetate (3:2).
[1166] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.86 (t, J=2.3
Hz, 3H) 3.38-3.44 (m, 4H) 3.61-3.66 (m, 4H) 4.72 (s, 2H) 5.10 (q,
J=2.3 Hz, 2H) 5.65 (s, 2H) 7.25-7.38 (m, 5H) 8.18 (s, 1H)
[1167] (e)
5-Benzyloxymethyl-3-(2-butynyl)-2-(piperazin-1-yl)-3,5-dihydroi-
midazo[4,5-d]pyridazin-4-one trifluoroacetate
[1168] 0.0043 g of the title compound was obtained by treating
0.0073 g of t-butyl
4-[6-benzyloxymethyl-1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4-
,5-d]pyridazin-2-yl]piperazine-1-carboxylate and purifying the
product by the same method as used in Example 115(i).
[1169] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.3 Hz, 2H)
3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 4.69 (s, 2H) 5.15 (q, J=2.3 Hz,
2H) 5.64 (s, 2H) 7.17-7.32 (m, 5H) 8.20 (s, 1H)
[1170] MS m/e (ESI) 393.28(MH.sup.+--CF.sub.3COOH)
Example 117
3-(2-Butynyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one
trifluoroacetate
[1171] 8 ml of a dichloromethane solution of 0.123 g of t-butyl
4-[6-benzyloxymethyl-1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyr-
idazin-2-yl]piperazine-1-carboxylate was cooled to -78.degree. C.
under a nitrogen atmosphere, and 1.9 ml of boron trichloride (1.0 M
dichloromethane solution) was added thereto. The mixture was
stirred at -78.degree. C. for five hours, and 10 ml of a 1:1 mixed
solvent of dichloromethane-methanol was added thereto. The mixture
was stirred at -78.degree. C. for two hours, and then allowed to
warm to room temperature. The solvent was concentrated under
reduced pressure, and 10 ml of methanol was added thereto. Then,
the solution was again concentrated under reduced pressure. The
residue was dissolved in 3 ml of pyridine, and the mixture was
heated under reflux for two hours. 0.3 ml of this solution was
concentrated under reduced pressure. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 0.005 g of the title compound.
[1172] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 5.16 (q, J=2.3 Hz, 2H) 8.21 (s,
1H)
[1173] MS m/e (ESI) 273.16 (MH.sup.+--CF.sub.3COOH)
Example 118
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzamide hydrochloride
[1174] (a) t-Butyl
4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl-6-oxo--
6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1175] 200 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 2.0 ml
of 1-methyl-2-pyrrolidone, and 85 mg of salicylamide and 129 mg of
potassium carbonate were added thereto. The mixture was stirred at
100.degree. C. for2 hours. After the reaction mixture had been
cooled to room temperature, 5.0 ml of water was added thereto.
After the mixture had been stirred at room temperature for 1 hour,
the white precipitate was collected by filtration. The resulting
white solid was washed with water and ether to give of 221 mg of
the title compound (89%).
[1176] .sup.1H-NMR(DMSO-d6) .delta. 1.43 (s, 9H) 1.79 (t, J=2.5 Hz,
3H) 3.23-3.27 (m, 4H) 3.36 (s, 3H) 3.48-3.52 (m, 4H) 4.95 (q, 2.5
Hz, 2H) 6.59 (td, J=8.0, 1.0 Hz, 1H) 6.63 (dd, J=8.0, 1.0 Hz, 1H)
7.14 (ddd, J=8.0, 7.5, 2.0 Hz, 1H) 7.80 (dd, J=7.5, 2.0 Hz, 1H)
[1177] MS m/e (ESI) 522(MH.sup.+)
[1178] (b)
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro--
1H-purin-2-yloxy]benzamide hydrochloride
[1179] 210 mg of t-butyl
4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl--
6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was
combined with 3.5 ml of methanol and 2.1 ml of 4N hydrochloric
acid-ethyl acetate solution. After the mixture had been stirred at
room temperature for 4 hours, the reaction solution was
concentrated by flushing with nitrogen gas. The resulting residue
was washed with ethanol and ethyl acetate to give 177 mg of the
title compound (96%).
[1180] .sup.1H-NMR(DMSO-d6) .delta. 1.82 (t, J=2.3 Hz, 3H)
3.28-3.32 (m, 4H) 3.48 (s, 3H) 3.54-3.58 (m, 4H) 5.04 (q, 2.3 Hz,
2H) 6.96 (br.t, J=7.0 Hz, 1H) 6.99 (br.d, J=8.0 Hz, 1H) 7.46 (ddd,
J=8.0, 7.0, 1.5 Hz, 1H) 7.93 (br.d, J=8.0 Hz, 1H)
[1181] MS m/e (ESI) 422(MH.sup.+--HCl)
Example 119
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one
[1182] (a)
5-Methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one
[1183] 78.8 g of 5-methyl-1,5-dihydroimidazo [4,5-d]
pyridazin-4-one [CAS No. 76756-58-6] (Shih-Fong Chen and Raymond P.
Panzica, Journal of Organic Chemistry 46, p2467, 1981) was
suspended in 2.5 L of dichloromethane at room temperature, and 78.8
of triethylamine was added thereto. 176 g of trityl chloride was
added to the mixture, which was then stirred for three hours. 7.5 L
of ethyl acetate was added to the mixture. After being washed
successively with 3 L of water and 3 L of a saturated sodium
chloride solution, the mixture was dried over anhydrous magnesium
sulfate and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography. Thus, 136.5 g of the
title compound was obtained from the fraction eluted with
hexane-ethyl acetate (20:80 to 0:100).
[1184] .sup.1H-NMR(CDCl.sub.3) .delta. 3.79 (s, 3H) 6.92 (s, 1H)
7.07-7.13 (m, 6H) 7.32-7.40 (m, 9H) 7.87 (s, 1H)
[1185] (b)
2-Chloro-5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-
one
[1186] 220 ml of lithium hexamethyldisilazide (1.0 M
tetrahydrofuran solution) was added to a 4-L tetrahydrofuran
solution of 68.3 g of
5-methyl-1-trityl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one at
-75.degree. C. under a nitrogen atmosphere, and the mixture was
stirred at -75.degree. C. for 1 hour. Then, 200 ml of a
tetrahydrofuran solution of 82.3 g of hexachloroethane was added to
the solution. The mixture was allowed to warm to -20.degree. C. 5 L
of 5% aqueous ammonium chloride was added, and the mixture was
extracted with 4 L of ethyl acetate. The organic layer was washed
successively with 5 L of water and 5 L of a saturated sodium
chloride solution. The solution was dried over anhydrous magnesium
sulfate, and concentrated under reduced pressure. The residue was
suspended in 150 ml of t-butyl methyl ether, and then collected by
filtration. The solid was washed twice with 100 ml of t-butyl
methyl ether to give 69.7 g of the title compound.
[1187] .sup.1H-NMR(CDCl.sub.3) .delta. 3.78 (s, 3H) 5.81 (s, 1H)
7.25-7.27 (m, 6H) 7.28-7.38 (m, 9H)
[1188] (c) t-Butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazi-
n-2-yl)piperazine-1-carboxylate
[1189] 69.7 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo
[4,5-d] pyridazin-4-one was combined with 153.4 g of t-butyl
piperazine-1-carboxylate, and the mixture was stirred and heated to
100.degree. C. under nitrogen atmosphere. When the reaction mixture
became easily stirrable, the temperature was raised to 150.degree.
C. The mixture was kept at this temperature for one hour. The
reaction solution allowed to cool and then suspended in 250 ml of
t-butyl methyl ether. The suspended material was collected by
filtration. The solid was washed twice with 200 ml of t-butyl
methyl ether and three times with 200 ml of water. The solid was
again washed twice with 200 ml of t-butyl methyl ether, and dried
to give 50.3 g of the title compound.
[1190] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 3.56-3.62 (m,
4H) 3.73-3.80 (m, 4H) 3.87 (s, 3H) 8.16 (s, 1H) 12.65 (br.s,
1H)
[1191] (d) t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1192] 43.9 g of potassium carbonate and 27.8 ml of 2-butynyl
bromide were successively added to a 5.5-L N,N-dimethylformamide
solution of 88.4 g of t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]
pyridazin-2-yl)piperazine-1-carboxylate at 15.degree. C. under a
nitrogen atmosphere. The reaction solution was stirred at room
temperature for 22 hours, and then poured into 10 L of water. The
mixture was extracted with 5 L of ethyl acetate. The organic layer
was successively washed twice with 5 L of water, and with 5 L of a
saturated sodium chloride solution. The aqueous layer was extracted
twice with 3 L of ethyl acetate. The organic layers were combined
together, and then dried over anhydrous magnesium sulfate. The
organic layer was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography. Thus, 54.3 g of
the title compound was obtained from the fraction eluted with
hexane-ethyl acetate (3:2 to 3:7).
[1193] .sup.1H-NMR(CDCl.sub.3) .delta. 1.52 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.38-3.42 (m, 4H) 3.61-3.64 (m, 4H) 3.85 (s, 3H) 5.09 (q,
J=2.3 Hz, 2H) 8.13 (s, 1H)
[1194] (e)
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,-
5-d]pyridazin-4-one
[1195] 200 ml of trifluoroacetic acid was added to 200 ml of a
dichloromethane solution containing 54.3 g of t-butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate, and the mixture was stirred at room
temperature for 1 hour. The mixture was concentrated under reduced
pressure, the residue was dissolved in 500 ml of ethyl acetate. 1 L
of 10% aqueous sodium bicarbonate solution was gradually added.
Then, 1 L of ethyl acetate and 500 ml of a 5N aqueous sodium
hydroxide solution were added to the solution. The organic layer
was separated. Then, the aqueous layer was extracted five times
with 1 L of dichloromethane. The organic layers were combined
together, washed with 500 ml of an aqueous solution of 2N sodium
hydroxide, dried over anhydrous magnesium sulfate, and concentrated
under reduced pressure. The residue was recrystallized from ethyl
acetate to give 30.5 g of the crystalline title compound.
[1196] .sup.1H-NMR(CDCl.sub.3) .delta. 1.84 (t, J=2.3 Hz, 3H)
3.05-3.09 (m, 4H) 3.38-3.44 (m, 4H) 3.85 (s, 3H) 5.06 (q, J=2.3 Hz,
2H) 8.13 (s, 3H)
Example 119-2
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one toluene-4-sulfonate
[1197] 98.7 mg of
3-(2-butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimi-
dazo[4,5-d]pyridazin-4-one was dissolved in 1 ml of ethanol, and
then 1 ml of an ethanol solution of 101 mg of p-toluenesulfonic
acid monohydrate was added thereto while the solution was being
stirred. The mixture was cooled with ice for two hours while being
stirred. The precipitate was collected by filtration, and then
dried under reduced pressure at 50.degree. C. for one hour to give
153.2 mg of the title compound.
[1198] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (t, J=2 Hz, 3H) 2.27 (s,
3H) 3.25-3.35 (m, 4H) 3.50-3.54(m, 4H) 3.70 (s, 3H) 5.13 (d, J=2
Hz, 2H) 7.10 (d, J=8 Hz, 2H) 7.47 (d, J=8 Hz, 2H) 8.25 (s, 1H) 8.79
(br.s, 2H)
[1199] Furthermore, 107.95 mg of the title compound was
recrystallized from acetone, yielding 84.9 mg of crystalline
product.
Example 120
2-(3-Aminopiperidin-1-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimidazo[4,5-d]-
pyridazin-4-one trifluoroacetate
[1200] (a) 9H-fluoren-9-ylmethyl
3-t-butoxycarbonylaminopiperidine-1-carbo- xylate
[1201] 1.84 g of diisopropylethylamine and 4.71 g of
diphenylphosphorylazide were added to 10 ml of a t-butanol solution
of 5.01 g of 9H-fluoren-9-ylmethyl
3-carboxypiperidine-1-carboxylate, and the mixture was heated at
60.degree. C. under a nitrogen atmosphere for 18 hours. The
reaction solution was cooled, and 150 ml of ethyl acetate was added
thereto. The organic layer was washed successively with 100 ml of
5% aqueous sulfuric acid, 100 ml of 5% aqueous sodium bicarbonate
solution, 100 ml of water, and 100 ml of a saturated sodium
chloride solution, and then dried over anhydrous magnesium sulfate.
The organic layer was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography. Thus,
1.88 g of the title compound was obtained from the fraction eluted
with hexane-ethyl acetate (4:1).
[1202] .sup.1H-NMR(CDCl.sub.3) .delta. 1.45 (s, 9H) 1.45-1.72 (m,
3H) 1.82-1.87 (br.s, 1H) 3.09-3.30 (br.s, 2H) 3.58 (br.s, 2H)
3.82-3.98 (br.s, 1H) 4.24 (t, J=7.2 Hz, 1H) 4.27-4.48 (br.s, 2H)
4.52-4.59 (br.s, 1H) 7.32 (dd, J=10.3, 10.0 Hz, 2H) 7.39 (t, J=10.0
Hz, 2H) 7.59 (d, J=10.0 Hz, 2H) 7.75 (d, J=10.3 Hz, 2H)
[1203] (b) t-Butyl piperidin-3-ylcarbamate
[1204] 25 ml of diethylamine was added to 250 ml of an ethanol
solution of 1.88 g of 9H-fluoren-9-ylmethyl
3-t-butoxycarbonylaminopiperidine-1-carbo- xylate, and the mixture
was stirred at room temperature for 18 hours. After the solution
had been concentrated under reduced pressure, the residue was
dissolved in a mixture consisting of 150 ml of toluene and 100 ml
of 10% aqueous citric acid solution. The aqueous layer was made
alkaline with a 5N aqueous sodium hydroxide solution, and then
extracted twice with 100 ml of dichloromethane. The organic layers
were combined together, dried over anhydrous magnesium sulfate, and
concentrated under reduced pressure to give 0.79 g of the title
compound.
[1205] .sup.1H-NMR(CDCl.sub.3) .delta. 1.45 (s, 9H) 1.41-1.53 (m,
2H) 1.65-1.72 (m, 1H) 1.79-1.86 (m, 1H) 2.48-2.56 (m, 1H) 2.64-2.70
(m, 1H) 2.78-2.86 (m, 1H) 3.06 (dd, J=12.0, 4.0 Hz, 1H) 3.48-3.62
(br.s, 1H) 4.71-4.88 (br.s, 1H)
[1206] (c)
2-(3-Aminopiperidin-1-yl)-3-(2-butynyl)-5-methyl-3,5-dihydroimi-
dazo[4,5-d]pyridazin-4-one trifluoroacetate
[1207] 0.020 g of 2-chloro-5-methyl-1-trityl-1,5-dihydroimidazo
[4,5-d]pyridazine-4-one and 0.040 g of t-butyl
piperidin-3-ylcarbamate were combined together, and the mixture was
heated under a nitrogen atmosphere at 150.degree. C. for 1 hour.
The reaction mixture was purified by silica gel column
chromatography. Thus, 0.016 g of t-butyl
[1-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperidin--
3-yl]carbamate was obtained from the fraction eluted with ethyl
acetate. 0.0080 g of this compound was dissolved in 0.6 ml of
N,N-dimethylformamide, and then 0.0038 g of potassium carbonate and
0.003 ml of 2-butynyl bromide were added thereto. The mixture was
stirred at room temperature for 18 hours. The reaction mixture was
partitioned between 1 ml of ethyl acetate and 1 ml of water, and
the organic layer was concentrated. The residue was dissolved in
0.5 ml of dichloromethane, and then 0.5 ml of trifluoroacetic acid
was added thereto. After 1 hour, the reaction solution was
concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.0046
g of the title compound.
[1208] .sup.1H-NMR(CDCl.sub.3) .delta. 1.74-1.80 (br.s, 1H) 1.82
(br.s, 3H) 1.96-2.19 (br.m, 3H) 3.43-3.79 (br.m, 5H) 3.86 (s, 3H)
5.05 (br.d, J=16.0 Hz, 1H) 5.23 (br.d, J=16.0 Hz, 1H) 8.15 (s,
1H)
Example 121
2-(3-Aminopiperidin-1-yl)-5-methyl-3-(3-methyl-2-butenyl)-3,5-dihydroimida-
zo[4,5-d]pyridazin-4-one trifluoroacetate
[1209] 0.0034 g of the title compound was obtained using 0.0080 g
of t-butyl
[1-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)pi-
peridin-3-yl]-carbamate and 0.004 ml of 4-bromo-2-methyl-2-butene
by the same method as used in Example 120.
[1210] .sup.1H-NMR(CDCl.sub.3) .delta. 1.66-1.74 (br.s, 1H) 1.76
(s, 3H) 1.80 (s, 3H) 1.96-2.20 (br.m, 3H) 3.20-3.79 (br.m, 5H) 3.85
(s, 3H) 4.90-5.05 (m, 2H) 5.37-5.42 (m, 1H) 8.15 (s, 1H)
Example 122
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzamide
[1211] 53.0 g of t-butyl
4-[7-(2-butynyl)-2-(2-carbamoylphenoxy)-1-methyl--
6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was
dissolved in 160 ml of trifluoroacetic acid, and the mixture was
stirred at room temperature for one hour. 1250 ml of a 2 M aqueous
sodium hydroxide solution was added drop wise to the reaction
solution, and the mixture was stirred at room temperature for one
hour and 50 minutes. The resulting white precipitate was collected
by filtration. The white solid was washed with water and then with
ethanol, and dried at 60.degree. C. overnight to give 42.8 g of the
title compound.
[1212] .sup.1H-NMR(DMSO-d6) .delta. 1.78 (t, J=2.4 Hz, 3H)
2.82-2.86 (m, 4H) 3.18-3.22 (m, 4H) 3.36 (s, 3H) 4.91 (q, 2.4 Hz,
2H) 6.58 (td, J=8.4, 1.2 Hz, 1H) 6.63 (dd, J=8.0, 0.8 Hz, 1H) 7.14
(ddd, J=8.0, 7.2, 2.0 Hz, 1H) 7.80 (dd, J=7.6, 2.0 Hz, 1H)
[1213] MS m/e (ESI) 422(MH.sup.+)
Example 123
7-(2-Butynyl)-2-(3-hydroxypropylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7--
dihydropurin-6-one trifluoroacetate
[1214] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 20 .mu.l of
3-mercapto-1-propanol and 6 mg of potassium carbonate were added
thereto. The mixture was stirred at room temperature for five
hours. A saturated ammonium chloride solution was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and 0.5 ml of 5N
aqueous hydrochloric acid was added to the residue. The mixture was
concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 3.15 mg of the title compound.
[1215] MS m/e (ESI) 377(MH.sup.+--CF.sub.3COOH)
Example 124
7-(2-Butynyl)-2-(2-hydroxypropylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7--
dihydropurin-6-one trifluoroacetate
[1216] 1.70 mg of the title compound was obtained by using
1-mercapto-2-propanol, instead of 3-mercapto-1-propanol, by the
same method as used in Example 123.
[1217] MS m/e (ESI) 377(MH.sup.+--CF.sub.3COOH)
Example 125
7-(2-Butynyl)-2-(2,3-dihydroxypropylsulfanyl)-1-methyl-8-(piperazin-1-yl)--
1,7-dihydropurin-6-one trifluoroacetate
[1218] 2.63 mg of the title compound was obtained by using
3-mercapto-1,2-propanediol, instead of 3-mercapto-1-propanol, by
the same method as used in Example 123.
[1219] MS m/e (ESI) 393(MH.sup.+--CF.sub.3COOH)
Example 126
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]propionic acid trifluoroacetate
[1220] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 20 .mu.l of 3-mercaptopropionic
acid and 6 mg of potassium carbonate were added thereto. The
mixture was stirred at room temperature for five hours. A saturated
ammonium chloride solution was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in 0.40 ml of
trifluoroacetic acid. The solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 4.60
mg of the title compound.
[1221] MS m/e (ESI) 391(MH.sup.+--CF.sub.3COOH)
Example 127
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]propionic acid trifluoroacetate
[1222] 6.10 mg of the title compound was obtained by using
2-mercaptopropionic acid, instead of 3-mercaptopropionic acid, by
the same method as used in Example 126.
[1223] MS m/e (ESI) 391(MH.sup.+--CF.sub.3COOH)
Example 128
2-s-Butylsulfanyl-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropur-
in-6-one trifluoroacetate
[1224] 4.68 mg of the title compound was obtained by using
butane-2-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1225] MS m/e (ESI) 375(MH.sup.+--CF.sub.3COOH)
Example 129
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-propylsulfanyl-1,7-dihydropuri-
n-6-one trifluoroacetate
[1226] 4.61 mg of the title compound was obtained by using
propane-1-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1227] MS m/e (ESI) 361(MH.sup.+--CF.sub.3COOH)
Example 130
7-(2-Butynyl)-1-methyl-2-cyclopentylsulfanyl-8-(piperazin-1-yl)-1,7-dihydr-
opurin-6-one trifluoroacetate
[1228] 5.15 mg of the title compound was obtained by using
cyclopentanethiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1229] MS m/e (ESI) 387(MH.sup.+--CF.sub.3COOH)
Example 131
7-(2-Butynyl)-2-dodecylsulfanyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropur-
in-6-one trifluoroacetate
[1230] 4.96 mg of the title compound was obtained by using
dodecane-1-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1231] MS m/e (ESI) 487(MH.sup.+--CF.sub.3COOH)
Example 132
2-(2-Aminoethylsulfanyl)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[1232] 3.98 mg of the title compound was obtained by using
2-aminoethanethiol, instead of 3-mercaptopropionic acid, by the
same method as used in Example 126.
[1233] MS m/e (ESI) 362(MH.sup.+--CF.sub.3COOH)
Example 133
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(thiophen-2-ylsulfanyl)-1,7-di-
hydropurin-6-one trifluoroacetate
[1234] 5.11 mg of the title compound was obtained by using
thiophene-2-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1235] MS m/e (ESI) 401(MH.sup.+--CF.sub.3COOH)
Example 134
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(1H-[1,2,4]triazol-3-ylsulfany-
l)-1,7-dihydropurin-6-one trifluoroacetate
[1236] 2.54 mg of the title compound was obtained by using
1H-[1,2,4]triazole-3-thiol, instead of 3-mercaptopropionic acid, by
the same method as used in Example 126.
[1237] MS m/e (ESI) 386(MH.sup.+--CF.sub.3COOH)
Example 135
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyridin-4-ylsulfanyl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[1238] 0.77 mg of the title compound was obtained by using
pyridine-4-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1239] MS m/e (ESI) 396(MH.sup.+--CF.sub.3COOH)
Example 136
7-(2-Butynyl)-1-methyl-2-phenylsulfanyl-8-(piperazin-1-yl)-1,7-dihydropuri-
n-6-one trifluoroacetate
[1240] 1.44 mg of the title compound was obtained by using benzene
thiol, instead of 3-mercaptopropionic acid, by the same method as
used in Example 126.
[1241] MS m/e (ESI) 395(MH.sup.+--CF.sub.3COOH)
Example 137
(R)-2-Amino-3-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-
-1H-purin-2-ylsulfanyl]propionic acid trifluoroacetate
[1242] 4.38 mg of the title compound was obtained by using
L-cystine, instead of 3-mercaptopropionic acid, by the same method
as used in Example 126.
[1243] MS m/e (ESI) 406(MH.sup.+--CF.sub.3COOH)
Example 138
7-(2-Butynyl)-2-(2-methylpropylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7-d-
ihydropurin-6-one trifluoroacetate
[1244] 4.52 mg of the title compound was obtained by using
2-methylpropane-1-thiol, instead of 3-mercaptopropionic acid, by
the same method as used in Example 126.
[1245] MS m/e (ESI) 375(MH.sup.+--CF.sub.3COOH)
Example 139
7-(2-Butynyl)-2-(1,2-dimethyl
propylsulfanyl)-1-methyl-8-(piperazin-1-yl)--
1,7-dihydropurin-6-one trifluoroacetate
[1246] 3.03 mg of the title compound was obtained by using
3-methylbutane-2-thiol, instead of 3-mercaptopropionic acid, by the
same method as used in Example 126.
[1247] MS m/e (ESI) 389(MH.sup.+--CF.sub.3COOH)
Example 140
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyrimidin-2-ylsulfanyl)-1,7-d-
ihydropurin-6-one trifluoroacetate
[1248] 3.60 mg of the title compound was obtained by using
pyrimidine-2-thiol, instead of 3-mercaptopropionic acid, by the
same method as used in Example 126.
[1249] MS m/e (ESI) 397(MH.sup.+--CF.sub.3COOH)
Example 141
7-(2-Butynyl)-2-(1H-imidazol-2-ylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7-
-dihydropurin-6-one trifluoroacetate
[1250] 5.75 mg of the title compound was obtained by using
1H-imidazole-2-thiol, instead of 3-mercaptopropionic acid, by the
same method as used in Example 126.
[1251] MS m/e (ESI) 385(MH.sup.+--CF.sub.3COOH)
Example 142
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(thiazol-2-ylsulfanyl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[1252] 3.86 mg of the title compound was obtained by using
thiazole-2-thiol, instead of 3-mercaptopropionic acid, by the same
method as used in Example 126.
[1253] MS m/e (ESI) 402(MH.sup.+--CF.sub.3COOH)
Example 143
7-(2-Butynyl)-2-(furan-2-ylmethylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7-
-dihydropurin-6-one trifluoroacetate
[1254] 4.84 mg of the title compound was obtained by using
(furan-2-yl)methanethiol, instead of 3-mercaptopropionic acid, by
the same method as used in Example 126.
[1255] MS m/e (ESI) 399(MH.sup.+--CF.sub.3COOH)
Example 144
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]acetamide trifluoroacetate
[1256] 1.86 mg of the title compound was obtained by using
2-mercaptoacetamide, instead of 3-mercaptopropionic acid, by the
same method as used in Example 126.
[1257] MS m/e (ESI) 376(MH.sup.+--CF.sub.3COOH)
Example 145
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(thiophen-2-ylmethyl
sulfanyl)-1,7-dihydropurin-6-one trifluoroacetate
[1258] 3.35 mg of the title compound was obtained by using
(thiophen-2-yl)methanethiol, instead of 3-mercaptopropionic acid,
by the same method as used in Example 126.
[1259] MS m/e (ESI) 415(MH.sup.+--CF.sub.3COOH)
Example 146
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-[1-(thiophen-2-yl)
ethylsulfanyl]-1,7-dihydropurin-6-one trifluoroacetate
[1260] 0.51 mg of the title compound was obtained by using
1-(thiophen-2-yl)ethanethiol, instead of 3-mercaptopropionic acid,
by the same method as used in Example 126.
[1261] MS m/e (ESI) 429(MH.sup.+--CF.sub.3COOH)
Example 147
7-(2-Butynyl)-1-methyl-2-(1-methyl-1H-imidazol-2-ylsulfanyl)-8-(piperazin--
1-yl)-1,7-dihydropurin-6-one trifluoroacetate
[1262] 5 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 10 mg of
1-methyl-1H-imidazole-2-thiol and 8 mg of potassium carbonate were
added thereto. The mixture was stirred at room temperature for five
hours. A saturated ammonium chloride solution was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in 0.40 ml of trifluoroacetic acid. The solution was
concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 3.75 mg of the title compound.
[1263] MS m/e (ESI) 399(MH.sup.+--CF.sub.3COOH)
Example 148
7-(2-Butynyl)-1-methyl-2-(4-methylpyrimidin-2-ylsulfanyl)-8-(piperazin-1-y-
l)-1,7-dihydropurin-6-one trifluoroacetate
[1264] 4.00 mg of the title compound was obtained by using
4-methylpyrimidine-2-thiol, instead of
1-methyl-1H-imidazole-2-thiol, by the same method as used in
Example 147.
[1265] MS m/e (ESI) 411(MH.sup.+--CF.sub.3COOH)
Example 149
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyrazin-2-ylsulfanyl)-1,7-dih-
ydropurin-6-one trifluoroacetate
[1266] 4.00 mg of the title compound was obtained by using
pyrazine-2-thiol, instead of 1-methyl-1H-imidazole-2-thiol, by the
same method as used in Example 147.
[1267] MS m/e (ESI) 411(MH.sup.+--CF.sub.3COOH)
Example 150
2-(Benzothiazol-2-ylsulfanyl)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,-
7-dihydropurin-6-one trifluoroacetate
[1268] 0.07 mg of the title compound was obtained by using
benzothiazole-2-thiol, instead of 1-methyl-1H-imidazole-2-thiol, by
the same method as used in Example 147.
[1269] MS m/e (ESI) 452(MH.sup.+--CF.sub.3COOH)
Example 151
2-(1H-benzimidazol-2-ylsulfanyl)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-
-1,7-dihydropurin-6-one trifluoroacetate
[1270] 3.18 mg of the title compound was obtained by using
1H-benzimidazole-2-thiol, instead of 1-methyl-1H-imidazole-2-thiol,
by the same method as used in Example 147.
[1271] MS m/e (ESI) 435(MH.sup.+--CF.sub.3COOH)
Example 152
2-(5-Amino-[1,3,4]thiadiazol-2-ylsulfanyl)-7-(2-butynyl)-1-methyl-8-(piper-
azin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
[1272] 3.62 mg of the title compound was obtained by using
5-amino-[1,3,4]thiadiazole-2-thiol, instead of
1-methyl-1H-imidazole-2-th- iol, by the same method as used in
Example 147.
[1273] MS m/e (ESI) 418(MH.sup.+--CF.sub.3COOH)
Example 153
6-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]nicotinic acid trifluoroacetate
[1274] 1.01 mg of the title compound was obtained by using
6-mercaptonicotinic acid, instead of 1-methyl-1H-imidazole-2-thiol,
by the same method as used in Example 147.
[1275] MS m/e (ESI) 440(MH.sup.+--CF.sub.3COOH)
Example 154
7-(2-Butynyl)-2-(4-methoxyphenylsulfanyl)-1-methyl-8-(piperazin-1-yl)-1,7--
dihydropurin-6-one trifluoroacetate
[1276] 4.14 mg of the title compound was obtained by using
4-methoxybenzenethiol, instead of 1-methyl-1H-imidazole-2-thiol, by
the same method as used in Example 147.
[1277] MS m/e (ESI) 425(MH.sup.+--CF.sub.3COOH)
Example 155
7-(2-Butynyl)-1-methyl-2-(4-nitrophenylsulfanyl)-8-(piperazin-1-yl)-1,7-di-
hydropurin-6-one trifluoroacetate
[1278] 1.52 mg of the title compound was obtained by using
4-nitrobenzenethiol, instead of 1-methyl-1H-imidazole-2-thiol, by
the same method as used in Example 147.
[1279] MS m/e (ESI) 440(MH.sup.+--CF.sub.3COOH)
Example 156
N-[2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-ylsulfanyl]ethyl]acetamide trifluoroacetate
[1280] 2.39 mg of the title compound was obtained by using
N-(2-mercaptoethyl)acetamide, instead of
1-methyl-1H-imidazole-2-thiol, by the same method as used in
Example 147.
[1281] MS m/e (ESI) 404(MH.sup.+--CF.sub.3COOH)
Example 157
7-(2-Butynyl)-1-methyl-2-(5-methyl-[1,3,4]thiadiazol-2-ylsulfanyl)-8-(pipe-
razin-1-yl)-1,7-dihydropurin-6-one trifluoroacetate
[1282] 1.24 mg of the title compound was obtained by using
5-methyl-[1,3,4]thiadiazole-2-thiol, instead of
1-methyl-1H-imidazole-2-t- hiol, by the same method as used in
Example 147.
[1283] MS m/e (ESI) 417(MH.sup.+--CF.sub.3COOH)
Example 158
7-(2-Butynyl)-2-(4,6-dimethylpyrimidin-2-ylsulfanyl)-1-methyl-8(piperazin--
1-yl)-1,7-dihydropurin-6-one trifluoroacetate
[1284] 3.11 mg of the title compound was obtained by using
4,6-dimethylpyrimidine-2-thiol, instead of
1-methyl-1H-imidazole-2-thiol, by the same method as used in
Example 147.
[1285] MS m/e (ESI) 425(MH.sup.+--CF.sub.3COOH)
Example 159
7-(2-Butynyl)-1-methyl-2-(4-methylthiazol-2-ylsulfanyl)-8-(piperazin-1-yl)-
-1,7-dihydropurin-6-one trifluoroacetate
[1286] 4.01 mg of the title compound was obtained by using
4-methylthiazol-2-thiol, instead of 1-methyl-1H-imidazole-2-thiol,
by the same method as used in Example 147.
[1287] MS m/e (ESI) 416(MH.sup.+--CF.sub.3COOH)
Example 160
2-(Benzoxazol-2-ylsulfanyl)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7--
dihydropurin-6-one trifluoroacetate
[1288] 0.84 mg of the title compound was obtained by using
benzoxazole-2-thiol, instead of 1-methyl-1H-imidazole-2-thiol, by
the same method as used in Example 147.
[1289] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 161
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-([1,3,4]thiadiazol-2-ylsulfany-
l)-1,7-dihydropurin-6-one trifluoroacetate
[1290] 1.95 mg of the title compound was obtained by using
[1,3,4]thiadiazole-2-thiol, instead of
1-methyl-1H-imidazole-2-thiol, by the same method as used in
Example 147.
[1291] MS m/e (ESI) 403(MH.sup.+--CF.sub.3COOH)
Example 162
2-Allylsulfanyl-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-
-6-one trifluoroacetate
[1292] 2.85 mg of the title compound was obtained by using allyl
mercaptan, instead of 1-methyl-1H-imidazole-2-thiol, by the same
method as used in Example 147.
[1293] MS m/e (ESI) 359(MH.sup.+--CF.sub.3COOH)
Example 163
7-(2-Butynyl)-1-methyl-2-(3-methylsulfanylphenylamino)-8-(piperazin-1-yl)--
1,7-dihydropurin-6-one trifluoroacetate
[1294] 1.32 mg of the title compound was obtained by using
3-methylsulfanylphenylamine, instead of
1-methyl-1H-imidazole-2-thiol, by the same method as used in
Example 147.
[1295] MS m/e (ESI) 424(MH.sup.+--CF.sub.3COOH)
Example 164
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(thiomorpholin-4-yl)-1,7-dihyd-
ropurin-6-one trifluoroacetate
[1296] 5.33 mg of the title compound was obtained by using
thiomorpholine, instead of 1-methyl-1H-imidazole-2-thiol, by the
same method as used in Example 147.
[1297] MS m/e (ESI) 388(MH.sup.+--CF.sub.3COOH)
Example 165
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]-2-methylpropionic acid trifluoroacetate
[1298] 1.63 mg of the title compound was obtained by using
2-mercapto-2-methylpropionic acid, instead of
1-methyl-1H-imidazole-2-thi- ol, by the same method as used in
Example 147.
[1299] MS m/e (ESI) 405(MH.sup.+--CF.sub.3COOH)
Example 166
7-(2-Butynyl)-2-(N-isopropylmethylamino)-1-methyl-8-(piperazin-1-yl)-1,7-d-
ihydropurin-6-one trifluoroacetate
[1300] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 30 .mu.l of
N-isopropylmethylamine was added thereto. After the mixture was
stirred at 80.degree. C. for 12 hours, the reaction solution was
concentrated by flushing with nitrogen gas. The resulting residue
was dissolved in 0.60 ml of trifluoroacetic acid. The solution was
concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 1.66 mg of the title compound.
[1301] MS m/e (ESI) 358(MH.sup.+--CF.sub.3COOH)
Example 167
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzonitrile trifluoroacetate
[1302] 5 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
1-methyl-2-pyrrolidone, and then 5 mg of 3-cyanophenol and 8 mg of
sodium hydride were added thereto. The mixture was stirred at
90.degree. C. for three hours. 1N hydrochloric acid was added to
the reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 1.02 mg of the
title compound.
[1303] MS m/e (ESI) 404(MH.sup.+--CF.sub.3COOH)
Example 168
4-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzonitrile trifluoroacetate
[1304] 2.76 mg of the title compound was obtained by using
4-cyanophenol, instead of 3-cyanophenol, by the same method as used
in Example 167.
[1305] MS m/e (ESI) 404(MH.sup.+--CF.sub.3COOH)
Example 169
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(3-tolyloxy)-1,7-dihydropurin--
6-one trifluoroacetate
[1306] 3.14 mg of the title compound was obtained by using
3-methylphenol, instead of 3-cyanophenol, by the same method as
used in Example 167.
[1307] MS m/e (ESI) 393(MH.sup.+--CF.sub.3COOH)
Example 170
7-(2-Butynyl)-1-methyl-2-(2-methylsulfanylphenoxy)-8-(piperazin-1-yl)-1,7--
dihydropurin-6-one trifluoroacetate
[1308] 3.50 mg of the title compound was obtained by using
2-methylsulfanylphenol, instead of 3-cyanophenol, by the same
method as used in Example 167.
[1309] MS m/e (ESI) 425(MH.sup.+--CF.sub.3COOH)
Example 171
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzoic acid trifluoroacetate
[1310] 5 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl
3-hydroxybenzoate were dissolved in 0.2 ml of N-methylpyrrolidone,
and then 8 mg of sodium hydride was added thereto. The mixture was
stirred at 90.degree. C. for 3 hours. 1N hydrochloric acid was
added to the reaction solution, and the mixture was extracted with
ethyl acetate. The organic layer was concentrated, and the residue
was dissolved in a mixture consisting of 0.4 ml of ethanol and 0.1
ml of a 5N aqueous sodium hydroxide solution. The mixture was
stirred at 50.degree. C. overnight. 1N hydrochloric acid was added
to the reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 1.09 mg of the
title compound.
[1311] MS m/e (ESI) 423(MH.sup.+--CF.sub.3COOH)
Example 172
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzoic acid trifluoroacetate
[1312] 1.55 mg of the title compound was obtained by using ethyl
4-hydroxybenzoate, instead of 3-hydroxybenzoic acid, by the same
method as used in Example 171.
[1313] MS m/e (ESI) 423(MH.sup.+--CF.sub.3COOH)
Example 173
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(2-tolyloxy)-1,7-dihydropurin--
6-one trifluoroacetate
[1314] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
1-methyl-2-pyrrolidone, and then 5 mg of 2-methylphenol and 8 mg of
potassium carbonate were added thereto. The mixture was stirred at
90.degree. C. for five hours. 1N hydrochloric acid was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 4.40 mg of the
title compound.
[1315] MS m/e (ESI) 393(MH.sup.+--CF.sub.3COOH)
Example 174
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(4-tolyloxy)-1,7-dihydropurin--
6-one trifluoroacetate
[1316] 3.95 mg of the title compound was obtained by using
4-methylphenol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1317] MS m/e (ESI) 393(MH.sup.+--CF.sub.3COOH)
Example 175
7-(2-Butynyl)-2-(2-methoxyphenoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[1318] 5.24 mg of the title compound was obtained by using
2-methoxyphenol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1319] MS m/e (ESI) 409(MH.sup.+--CF.sub.3COOH)
Example 176
7-(2-Butynyl)-2-(3-methoxyphenoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[1320] 2.84 mg of the title compound was obtained by using
3-methoxyphenol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1321] MS m/e (ESI) 409(MH.sup.+--CF.sub.3COOH)
Example 177
7-(2-Butynyl)-2-(4-methoxyphenoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[1322] 5.61 mg of the title compound was obtained by using
4-methoxyphenol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1323] MS m/e (ESI) 409(MH.sup.+--CF.sub.3COOH)
Example 178
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzenesulfonamide trifluoroacetate
[1324] 4.21 mg of the title compound was obtained by using
4-hydroxybenzenesulfonamide, instead of 2-methylphenol, by the same
method as used in Example 173.
[1325] MS m/e (ESI) 458(MH.sup.+--CF.sub.3COOH)
Example 179
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]-3-methoxybenzonitrile trifluoroacetate
[1326] 4.24 mg of the title compound was obtained by using
4-hydroxy-3-methoxybenzonitrile, instead of 2-methylphenol, by the
same method as used in Example 173.
[1327] MS m/e (ESI) 434(MH.sup.+--CF.sub.3COOH)
Example 180
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzonitrile trifluoroacetate
[1328] 5.26 mg of the title compound was obtained by using
2-cyanophenol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1329] MS m/e (ESI) 404(MH.sup.+--CF.sub.3COOH)
Example 181
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzamide trifluoroacetate
[1330] 4.80 mg of the title compound was obtained by using
4-hydroxybenzamide, instead of 2-methylphenol, by the same method
as used in Example 173.
[1331] MS m/e (ESI) 422(MH.sup.+--CF.sub.3COOH)
Example 182
Ethyl
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rin-2-yloxy]benzoate trifluoroacetate
[1332] 4.38 mg of the title compound was obtained by using ethyl
2-hydroxybenzoate, instead of 2-methylphenol, by the same method as
used in Example 173.
[1333] MS m/e (ESI) 451(MH.sup.+--CF.sub.3COOH)
Example 183
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(pyrimidin-2-yloxy)-1,7-dihydr-
opurin-6-one trifluoroacetate
[1334] 1.12 mg of the title compound was obtained by using
pyrimidin-2-ol, instead of 2-methylphenol, by the same method as
used in Example 173.
[1335] MS m/e (ESI) 381(MH.sup.+--CF.sub.3COOH)
Example 184
7-(2-Butynyl)-2-(4,6-dimethylpyrimidin-2-yloxy)-1-methyl-8-(piperazin-1-yl-
)-1,7-dihydropurin-6-one trifluoroacetate
[1336] 0.66 mg of the title compound was obtained by using
4,6-dimethylpyrimidin-2-ol, instead of 2-methylphenol, by the same
method as used in Example 173.
[1337] MS m/e (ESI) 409(MH.sup.+--CF.sub.3COOH)
Example 185
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzamide trifluoroacetate
[1338] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate and 10 mg of ethyl
3-hydroxybenzoate were dissolved in 0.2 ml of N-methylpyrrolidone,
and then 10 mg of potassium carbonate was added thereto. The
mixture was stirred at 90.degree. C. for 3 hours. 1N hydrochloric
acid was added to the reaction solution, and the mixture was
extracted with ethyl acetate. The organic layer was concentrated,
and the residue was dissolved in 1.0 ml of ammonia (7N methanol
solution). The mixture was stirred at 50.degree. C. overnight. The
reaction solution was concentrated, and the residue was dissolved
in trifluoroacetic acid. The solution was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 1.91 mg of the
title compound.
[1339] MS m/e (ESI) 422(MH.sup.+--CF.sub.3COOH)
Example 186
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]-3,5-dimethylbenzoic acid trifluoroacetate
[1340] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
1-methyl-2-pyrrolidone, and then 8 mg of
4-hydroxy-3,5-dimethylbenzoic acid and 8 mg of potassium carbonate
were added thereto. The mixture was stirred at 100.degree. C. for 2
hours. 1N hydrochloric acid was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 2.71 mg of the title compound.
[1341] MS m/e (ESI) 451(MH.sup.+--CF.sub.3COOH)
Example 187
4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]-3-fluorobenzoic acid trifluoroacetate
[1342] 3.49 mg of the title compound was obtained by using
3-fluoro-4-hydroxybenzoic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
[1343] MS m/e (ESI) 441(MH.sup.+--CF.sub.3COOH)
Example 188
[4-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-yloxy]phenyl]acetic acid trifluoroacetate
[1344] 3.45 mg of the title compound was obtained by using
(4-hydroxyphenyl)acetic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
[1345] MS m/e (ESI) 437(MH.sup.+--CF.sub.3COOH)
Example 189
[2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-
-yloxy]phenyl]acetic acid trifluoroacetate
[1346] 1.34 mg of the title compound was obtained by using
(2-hydroxyphenyl)acetic acid, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
[1347] MS m/e (ESI) 437(MH.sup.+--CF.sub.3COOH)
Example 190
2-(2-Acetylphenoxy)-7-(2-butynyl)-1-methyl-8-(piperazin-1-yl)-1,7-dihydrop-
urin-6-one trifluoroacetate
[1348] 1.99 mg of the title compound was obtained by using
1-(2-hydroxyphenyl)ethanone, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
[1349] MS m/e (ESI) 421(MH.sup.+--CF.sub.3COOH)
Example 191
7-(2-Butynyl)-2-(2,6-difluorophenoxy)-1-methyl-8-(piperazin-1-yl)-1,7-dihy-
dropurin-6-one trifluoroacetate
[1350] 5.26 mg of the title compound was obtained by using
2,6-difluorophenol, instead of 4-hydroxy-3,5-dimethylbenzoic acid,
by the same method as used in Example 186.
[1351] MS m/e (ESI) 415(MH.sup.+--CF.sub.3COOH)
Example 192
7-(2-Butynyl)-1-methyl-2-pentafluorophenoxy-8-(piperazin-1-yl)-1,7-dihydro-
purin-6-one trifluoroacetate
[1352] 5.61 mg of the title compound was obtained by using
2,3,4,5,6-pentafluorophenol, instead of
4-hydroxy-3,5-dimethylbenzoic acid, by the same method as used in
Example 186.
[1353] MS m/e (ESI) 469(MH.sup.+--CF.sub.3COOH)
Example 193
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-[4-(pyrrolidine-1-carbonyl)phe-
noxy]-1,7-dihydropurin-6-one trifluoroacetate
[1354] 30 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihyd-
ro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 1 ml of
1-methyl-2-pyrrolidone, and then 15 mg of 1-(4-hydroxybenzoyl)
pyrrolidine and 11 mg of potassium carbonate were added thereto.
The mixture was stirred at 100.degree. C. for 2.5 hours. Water was
added to the reaction solution, and the mixture was extracted with
ethyl acetate. The organic layer was concentrated, and the residue
was dissolved in trifluoroacetic acid. The solution was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 23.7
mg of the title compound.
[1355] MS m/e (ESI) 476(MH.sup.+--CF.sub.3COOH)
Example 194
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]-N-[2-(piperidin-1-yl)ethyl]benzamide trifluoroacetate
[1356] 3.05 mg of the title compound was obtained by using
2-hydroxy-N-[2-(piperidin-1-yl)ethyl]benzamide by the same method
as used in Example 193.
[1357] MS m/e (ESI) 533(MH.sup.+--CF.sub.3COOH)
Example 195
5-Acetyl-2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzamide trifluoroacetate
[1358] 0.82 mg of the title compound was obtained by using 5-acetyl
salicylamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the
same method as used in Example 193.
[1359] MS m/e (ESI) 464(MH.sup.+--CF.sub.3COOH)
Example 196
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylsulfanyl]benzoic acid trifluoroacetate
[1360] 0.70 mg of the title compound was obtained by using
thiosalicylic acid, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by
the same method as used in Example 193.
[1361] MS m/e (ESI) 439(MH.sup.+--CF.sub.3COOH)
Example 197
6-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylamino]nicotinamide trifluoroacetate
[1362] 1.43 mg of the title compound was obtained by using
6-amino-nicotinamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine,
by the same method as used in Example 193.
[1363] MS m/e (ESI) 422(MH.sup.+--CF.sub.3COOH)
Example 198
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]pyridine-2-carboxylic amide trifluoroacetate
[1364] 1.44 mg of the title compound was obtained by using
3-hydroxy picolinamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine,
by the same method as used in Example 193.
[1365] MS m/e (ESI) 423(MH.sup.+--CF.sub.3COOH)
Example 199
N-t-butyl-2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1-
H-purin-2-ylamino]benzamide trifluoroacetate
[1366] 0.87 mg of the title compound was obtained by using
2-amino-N-t-butylbenzamide, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in
Example 193.
[1367] MS m/e (ESI) 477(MH.sup.+--CF.sub.3COOH)
Examples 200 and 201
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylamino]benzamide trifluoroacetate
[1368] 1.36 mg of the polar compound of the title compound and 0.39
mg of the non-polar compound of the title compound were obtained by
using 2-aminobenzamide, instead of 1-(4-hydroxybenzoyl)pyrrolidine,
by the same method as used in Example 193.
[1369] MS m/e (ESI) 477(MH.sup.+--CF.sub.3COOH)
Example 202
N-[3-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-yloxy]phenyl]acetamide trifluoroacetate
[1370] 10.79 mg of the title compound was obtained by using
3-acetamidophenol, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by
the same method as used in Example 193.
[1371] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 203
N-[4-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-yloxy]phenyl]acetamide trifluoroacetate
[1372] 11.38 mg of the title compound was obtained by using
4-acetamidophenol, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by
the same method as used in Example 193.
[1373] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 204
2-[N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-yl]methylamino]benzoic acid trifluoroacetate
[1374] 3.48 mg of the title compound was obtained by using
N-methylanthranilic acid, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in
Example 193.
[1375] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 205
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]benzoic acid trifluoroacetate
[1376] 25.75 mg of the title compound was obtained by using
salicylic acid, instead of 1-(4-hydroxybenzoyl) pyrrolidine, by the
same method as used in Example 193.
[1377] MS m/e (ESI) 423(MH.sup.+--CF.sub.3COOH)
Example 206
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
ylamino]benzenesulfonamide trifluoroacetate
[1378] 0.91 mg of the title compound was obtained by using
2-aminobenzenesulfonamide, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in
Example 193.
[1379] MS m/e (ESI) 457(MH.sup.+--CF.sub.3COOH)
Example 207
2-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yl sulfanyl]benzoic acid ethyl ester trifluoroacetate
[1380] 0.66 mg of the title compound was obtained by using ethyl
thiosalicylate, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by the
same method as used in Example 193.
[1381] MS m/e (ESI) 467(MH.sup.+--CF.sub.3COOH)
Example 208
3-[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]pyridine-2-carboxylic acid trifluoroacetate
[1382] 4.36 mg of the title compound was obtained by using
3-hydroxypicolinic acid, instead of
1-(4-hydroxybenzoyl)pyrrolidine, by the same method as used in
Example 193.
[1383] MS m/e (ESI) 424(MH.sup.+--CF.sub.3COOH)
Example 209
N-[2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-
-2-yloxy]phenyl]acetamide trifluoroacetate
[1384] 0.126 mg of the title compound was obtained by using
2-acetamidophenol, instead of 1-(4-hydroxybenzoyl)pyrrolidine, by
the same method as used in Example 193.
[1385] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 210
2-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yloxy]-N,N-dimethylbenzamide trifluoroacetate
[1386] 100 mg of salicylic acid and 0.76 ml of a 2 M
tetrahydrofuran solution of dimethylamine were dissolved in 1 ml of
N,N-dimethylformamide, and then 109 .mu.l of diethyl
cyanophosphonate and 250 .mu.l of triethylamine were added thereto.
The mixture was stirred at room temperature for 5.5 hours. Water
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was concentrated, and 20 mg
of 4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-d-
ihydro-1H-purin-8-yl]piperazine-1-carboxylic acid t-butyl ester,
potassium carbonate and 1 ml of 1-methyl-2-pyrrolidone were added
to a one-third aliquot of the residue. The mixture was stirred at
150.degree. C. for 1.5 hours. Water was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
organic layer was concentrated, and the residue was dissolved in
trifluoroacetic acid. The solution was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 1.06 mg of the
title compound.
[1387] MS m/e (ESI) 450(MH.sup.+--CF.sub.3COOH)
Example 211
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-[2-(thiazolidine-3-carbonyl)ph-
enoxy]-1,7-dihydropurin-6-one trifluoroacetate
[1388] 2.10 mg of the title compound was obtained by using
thiazolidine, instead of dimethylamine, by the same method as used
in Example 210.
[1389] MS m/e (ESI) 494(MH.sup.+--CF.sub.3COOH)
Example 212
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-[2-(pyrrolidine-1-carbonyl)phe-
noxy]-1,7-dihydropurin-6-one trifluoroacetate
[1390] 6.86 mg of the title compound was obtained by using
pyrrolidine, instead of dimethylamine, by the same method as used
in Example 210.
[1391] MS m/e (ESI) 476(MH.sup.+--CF.sub.3COOH)
Example 213
7-(2-Butynyl)-1-methyl-2-[2-(morpholine-4-carbonyl)phenoxy]-8-(piperazin-1-
-yl)-1,7-dihydropurin-6-one trifluoroacetate
[1392] 3.63 mg of the title compound was obtained by using
morpholine, instead of dimethylamine, by the same method as used in
Example 210.
[1393] MS m/e (ESI) 492(MH.sup.+--CF.sub.3COOH)
Example 214
[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yl-
]acetonitrile trifluoroacetate
Example 215
[1394]
[7-(2-butynyl)-2-cyanomethyl-1-methyl-6-oxo-8-(piperazin-1-yl)-2,3,-
6,7-tetrahydro-1H-purin-2-yl]acetonitrile trifluoroacetate
[1395] 8 mg of
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-pur-
in-8-yl]piperazine-1-carboxylic acid t-butyl ester was dissolved in
0.8 ml of acetonitrile, and then 8 mg of sodium hydride was added
thereto. The mixture was stirred at 60.degree. C. for three hours.
1N hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.85 mg and 2.20 mg of the title compounds (Examples
214 and 215), respectively.
[1396] (Example 214) MS m/e (ESI) 326(MH.sup.+--CF.sub.3COOH)
[1397] (Example 215) MS m/e (ESI) 367(MH.sup.+--CF.sub.3COOH)
Example 216
7-(2-butynyl)-1-methyl-2-(2-oxopropyl)-8-(piperazin-1-yl)-1,7-dihydropurin-
-6-one trifluoroacetate
[1398] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.8 ml of
acetone, and then 8 mg of sodium hydride was added thereto. The
mixture was stirred at 60.degree. C. for three hours. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.17 mg of the title compound.
[1399] MS m/e (ESI) 343(MH.sup.+--CF.sub.3COOH)
Example 217
7-(2-Butynyl)-2-ethynyl-1-methyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1400] 50 .mu.l of trimethylsilylacetylene was dissolved in 1.0 ml
of tetrahydrofuran, and then 0.27 ml of n-butyl lithium (1.56 M
hexane solution) was added thereto at -78.degree. C. The mixture
was stirred at 0.degree. C. for 15 minutes, and then 1.0 ml of a
tetrahydrofuran solution of 10 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-
-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was added to the
reaction solution. After the mixture had been stirred at room
temperature for 30 minutes, a saturated ammonium chloride solution
was added to the reaction solution. The mixture was extracted with
ethyl acetate. The organic layer was concentrated, and the residue
was dissolved in 1.0 ml of methanol. 10 mg of potassium carbonate
was added to the solution. After the mixture had been stirred at
room temperature for 1 hour, a saturated ammonium chloride solution
was added to the reaction solution. The mixture was extracted with
ethyl acetate. The organic layer was concentrated, and the residue
was dissolved in trifluoroacetic acid. The solution was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 1.06
mg of the title compound.
[1401] MS m/e (ESI) 311(MH.sup.+--CF.sub.3COOH)
Example 218
7-(2-Butynyl)-1-methyl-8-(piperazin-1-yl)-2-(propane-2-sulfinyl)-1,7-dihyd-
ropurin-6-one trifluoroacetate
[1402] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 20 .mu.l of 2-propanethiol and
6 mg of potassium carbonate were added thereto. The mixture was
stirred at room temperature for five hours. A saturated ammonium
chloride solution was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in 0.30 ml of
dichloromethane. The mixture was cooled to -78.degree. C. 5 mg of
m-chloroperbenzoic acid was added to the mixture, and the resulting
mixture was stirred at -78.degree. C. for 15 minutes. A saturated
sodium sulfite solution was added to the reaction solution, and the
mixture was extracted with dichloromethane. The organic layer was
concentrated, and the residue was dissolved in 0.40 ml of
trifluoroacetic acid. The solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.89
mg of the title compound.
[1403] MS m/e (ESI) 377(MH.sup.+--CF.sub.3COOH)
Example 219
N-acetyl-N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yl]acetamide trifluoroacetate
[1404] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
a 20% aqueous ammonia, and the mixture was stirred at 80.degree. C.
for 5 hours. The reaction solution was concentrated, and the
residue was dissolved in 0.4 ml of pyridine. 0.05 ml of acetic
anhydride was added to the mixture. The resulting mixture was
stirred at room temperature for 48 hours. The reaction solution was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.49 mg of the title compound.
[1405] MS m/e (ESI) 386(MH.sup.+--CF.sub.3COOH)
Example 220
N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yl]acetamide trifluoroacetate
[1406] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.2 ml of
20% aqueous ammonia, and the mixture was stirred at 80.degree. C.
for 5 hours. The reaction solution was concentrated, and the
residue was dissolved in 0.4 ml of pyridine. 0.05 ml of acetic
anhydride was added to the solution. The mixture was stirred at
room temperature for 48 hours. The reaction solution was
concentrated, and the residue was dissolved in methanol. 10 mg of
potassium carbonate was added to the solution. The mixture was
stirred at room temperature for 6 hours. The reaction solution was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 1.36 mg of the title compound.
[1407] MS m/e (ESI) 344(MH.sup.+--CF.sub.3COOH)
Example 221
[7-(2-Butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yl-
oxy]acetonitrile trifluoroacetate
[1408] 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 50 .mu.l of hydroxy
acetonitrile and 5 mg of sodium hydride were added thereto. The
mixture was stirred at room temperature for one hour. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 2.12 mg of the title compound.
[1409] MS m/e (ESI) 342(MH.sup.+--CF.sub.3COOH)
Example 222
N-[7-(2-butynyl)-1-methyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2--
yl]guanidine trifluoroacetate
[1410] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydr-
o-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in 0.15 ml
of 1-methyl-2-pyrrolidone, and then 10 mg of guanidine was added
thereto. The mixture was stirred at 90.degree. C. for 12 hours. The
reaction solution was concentrated, and the residue was dissolved
in 1.0 ml of trifluoroacetic acid. The solution was concentrated by
flushing with nitrogen gas. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.20 mg of the title compound.
[1411] MS m/e (ESI) 344(MH.sup.+--CF.sub.3COOH)
Example 223
7-(2-Butynyl)-2-methylsulfanyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1412] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-trimethylsilanylet-
hoxymethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1413] 50 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-pur-
in-8-yl]piperazine-1-carboxylate was dissolved in 1.2 ml of
N,N-dimethylformamide, and then 44 .mu.l of
(2-chloromethoxyethyl)trimeth- ylsilane and 34 mg of potassium
carbonate were added thereto. The mixture was stirred at room
temperature for 2 hours. A saturated aqueous ammonium chloride
solution was added to the reaction mixture, and the mixture was
extracted with ethyl acetate. The organic layer was concentrated,
and the residue was purified by silica gel chromatography to give
55 mg of the title compound.
[1414] .sup.1H-NMR(CDCl3) .delta. 0.07 (s, 9H) 0.97 (t, J=8.4 Hz,
2H) 1.49 (s, 9H) 1.82 (t, J=2.4 Hz, 3H) 3.40-3.44 (m, 4H) 3.58-3.62
(m, 4H) 3.71 (t, J=8.4 Hz, 2H) 4.92 (q, J=2.4 Hz, 2H) 5.67 (s,
2H)
[1415] (b)
7-(2-Butynyl)-2-methylsulfanyl-8-(piperazin-1-yl)-1,7-dihydropu-
rin-6-one trifluoroacetate
[1416] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-trimethylsilan-
ylethoxymethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and then 50
.mu.l of methyl mercaptan (30%; methanol solution) and 10 mg of
potassium carbonate were added thereto. The mixture was stirred at
room temperature for five hours. A saturated aqueous ammonium
chloride solution was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in 0.60 ml of
trifluoroacetic acid. The resulting mixture was stirred at room
temperature for 5 hours. Then, the solution was concentrated by
flushing with nitrogen gas. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.99 mg of the title compound.
[1417] MS m/e (ESI) 319(MH.sup.+--CF.sub.3COOH)
Example 224
7-(2-Butynyl)-2-isopropylsulfanyl-8-(piperazin-1-yl)-1,7-dihydropurin-6-on-
e trifluoroacetate
[1418] 2.97 mg of the title compound was obtained by using
propane-2-thiol sodium salt, instead of methyl mercaptan, according
to the method described in Example 223.
[1419] MS m/e (ESI) 347(MH.sup.+--CF.sub.3COOH)
Example 225
2-t-Butylsulfanyl-7-(2-butynyl)-8-(piperazin-1-yl)-1,7-dihydropurin-6-one
trifluoroacetate
[1420] 2.99 mg of the title compound was obtained by using
2-methyl-2-propanethiol sodium salt, instead of methyl mercaptan,
according to the method described in Example 223.
[1421] MS m/e (ESI) 361(MH.sup.+--CF.sub.3COOH)
Example 226
7-(2-Butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purine-2-carbonitril-
e trifluoroacetate
[1422] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-trimethylsilan-
ylethoxymethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and then 8 mg
of sodium cyanide and 10 mg of potassium carbonate were added
thereto. The mixture was stirred at 50.degree. C. for five hours. A
saturated aqueous ammonium chloride solution was added to the
reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in 0.60 ml of trifluoroacetic acid. The resulting mixture
was stirred at room temperature for 5 hours. Then, the solution was
concentrated by flushing with nitrogen gas. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 1.46 mg of the title compound.
[1423] MS m/e (ESI) 298(MH.sup.+--CF.sub.3COOH)
Example 227
2-[7-(2-Butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]ben-
zamide trifluoroacetate
[1424] 6 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-trimethylsilan-
ylethoxymethyl)-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
was dissolved in 0.15 ml of 1-methyl-2-pyrrolidone, and then 8 mg
of salicylamide and 8 mg of potassium carbonate were added thereto.
The mixture was stirred at 100.degree. C. for three hours. A
saturated ammonium chloride solution was added to the reaction
solution, and the mixture was extracted with ethyl acetate. The
organic layer was concentrated, and the residue was dissolved in
0.80 ml of trifluoroacetic acid. The mixture was stirred at room
temperature for 5 hours. The solution was concentrated by flushing
with nitrogen gas. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 2.45
mg of the title compound.
[1425] MS m/e (ESI) 408(MH.sup.+--CF.sub.3COOH)
Example 228
4-[7-(2-Butynyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-purin-2-yloxy]ben-
zoic acid trifluoroacetate
[1426] 1.55 mg of the title compound was obtained by using
4-hydroxybenzoic acid, instead of salicylamide, according to the
method described in Example 227.
[1427] MS m/e (ESI) 409(MH.sup.+--CF.sub.3COOH)
Example 229
7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rine-2-carbonitrile hydrochloride
[1428] (a) t-Butyl
4-[7-(2-butynyl)-2-cyano-1-(2-cyanobenzyl)-6-oxo-6,7-di-
hydro-1H-purin-8-yl]piperazine-1-carboxylate
[1429] A mixture consisting of 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-
-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
obtained in Example 96(a), 10 mg of sodium cyanide and 0.3 ml of
N,N-dimethylformamide was stirred at room temperature for 4 hours.
The reaction mixture was extracted with ethyl acetate-water, and
the organic layer was washed with water and then with saturated
brine. The organic layer was concentrated. The residue was purified
by thin layer chromatography (50% ethyl acetate/hexane) to give 6.1
mg of the title compound.
[1430] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.83 (s, 3H)
3.50 (s, 4H) 3.58-3.64 (m, 4H) 4.99 (s, 2H) 5.74 (s, 2H) 7.02 (d,
J=8 Hz, 1H) 7.44 (t, J=8 Hz, 1H) 7.55 (t, J=8 Hz, 1H) 7.74 (d, J=8
Hz, 1H)
[1431] (b)
7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-di-
hydro-1H-purine-2-carbonitrile hydrochloride
[1432] A mixture consisting of 6.1 mg of t-butyl
4-[7-(2-butynyl)-2-cyano--
1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
and 0.2 ml of trifluoroacetic acid was stirred at room temperature
for 20 minutes. The reaction solution was concentrated, and the
residue was purified by reverse-phase column chromatography using a
20% to 60% methanol/water (0.1% concentrated hydrochloric acid)
solvent to give 5.0 mg of the title compound.
[1433] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 3.30 (s, 4H)
3.60-3.70 (m, 4H) 5.09 (s, 2H) 5.60 (s, 2H) 7.27 (d, J=8 Hz, 1H)
7.54 (t, J=8 Hz, 1H) 7.68 (t, J=8 Hz, 1H) 7.94 (d, J=8 Hz, 1H) 9.36
(br.s, 2H)
Example 230
3-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]pyridine-2-carboxylic amide trifluoroacetate
[1434] 7 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6-
,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.2 ml of 1-methyl-2-pyrrolidone, and then 8 mg of
3-hydroxypyridine-2-carboxyli- c amide and 8 mg of potassium
carbonate were added thereto. The mixture was stirred at
100.degree. C. for 2 hours. 1N hydrochloric acid was added to the
reaction mixture, and the mixture was extracted with ethyl acetate.
The organic layer was concentrated, and the residue was dissolved
in trifluoroacetic acid. The solution was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 2.93 mg of the
title compound.
[1435] MS m/e (ESI) 524(MH.sup.+--CF.sub.3COOH)
Example 231
4-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzenesulfonamide trifluoroacetate
[1436] 1.90 mg of the title compound was obtained by using
4-hydroxybenzenesulfonamide, instead of
3-hydroxypyridine-2-carboxylic amide, according to the method
described in Example 230.
[1437] MS m/e (ESI) 559(MH.sup.+--CF.sub.3COOH)
Example 232
2-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzonitrile trifluoroacetate
[1438] 2.15 mg of the title compound was obtained by using
2-cyanophenol, instead of 3-hydroxypyridine-2-carboxylic amide,
according to the method described in Example 230.
[1439] MS m/e (ESI) 505(MH.sup.+--CF.sub.3COOH)
Example 233
4-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzoic acid trifluoroacetate
[1440] 3.74 mg of the title compound was obtained by using
4-hydroxybenzoic acid, instead of 3-hydroxypyridine-2-carboxylic
amide, according to the method described in Example 230.
[1441] MS m/e (ESI) 524(MH.sup.+--CF.sub.3COOH)
Example 234
2-[7-(2-Butynyl)-1-(2-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzamide trifluoroacetate
[1442] 3.74 mg of the title compound was obtained by using
salicylamide, instead of 3-hydroxypyridine-2-carboxylic amide,
according to the method described in Example 230.
[1443] MS m/e (ESI) 523(MH.sup.+--CF.sub.3COOH)
Example 235
2-[7-(2-Butynyl)-1-(4-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzamide trifluoroacetate
[1444] (a) t-Butyl
4-[7-(2-Butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7-d-
ihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1445] 100 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-pu-
rin-8-yl]piperazine-1-carboxylate was dissolved in 1.2 ml of
N,N-dimethylformamide, and then 97 mg of 4-cyanobenzyl bromide and
68 mg of potassium carbonate were added thereto. The mixture was
stirred at room temperature for 4 hours. A saturated aqueous
ammonium chloride solution was added to the reaction mixture, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was purified by silica gel
chromatography to give 71 mg of the title compound.
[1446] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.84 (t, J=2.5
Hz, 3H) 3.43-3.47 (m, 4H) 3.59-3.63 (m, 4H) 4.94 (q, 2.5 Hz, 2H)
5.53 (s, 2H) 7.42 (d, J=8.0 Hz, 2H) 7.62 (d, J=8.0 Hz, 2H)
[1447] (b)
2-[7-(2-Butynyl)-1-(4-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-
-dihydro-1H-purin-2-yloxy]benzamide trifluoroacetate
[1448] 12 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo--
6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.3 ml of 1-methyl-2-pyrrolidone, and then 10 mg of salicylamide
and 10 mg of potassium carbonate were added thereto. The mixture
was stirred at 100.degree. C. for 12 hours. 1N hydrochloric acid
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was concentrated, and the
residue was dissolved in trifluoroacetic acid. The solution was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 6.69
mg of the title compound.
[1449] MS m/e (ESI) 523(MH.sup.+--CF.sub.3COOH)
Example 236
7-(2-Butynyl)-1-(4-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rine-2-carbonitrile trifluoroacetate
[1450] 12 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo--
6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.3 ml of 1-methyl-2-pyrrolidone, and then 10 mg of sodium cyanide
was added thereto. The mixture was stirred at 50.degree. C. for 2
hours. 1N hydrochloric acid was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.87 mg of the title compound.
[1451] MS m/e (ESI) 413(MH.sup.+--CF.sub.3COOH)
Example 237
4-[7-(2-Butynyl)-2-methylsulfanyl-6-oxo-8-(piperazin-1-yl)-6,7-dihydropuri-
n-1-ylmethyl]benzonitrile trifluoroacetate
[1452] 12 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo--
6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.3 ml of 1-methyl-2-pyrrolidone, and then 20 .mu.l of methyl
mercaptan (30%; methanol solution) and 10 mg of potassium carbonate
were added thereto. The mixture was stirred at 50.degree. C. for 2
hours. 1N hydrochloric acid was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 6.69 mg of the title compound.
[1453] MS m/e (ESI) 434(MH.sup.+--CF.sub.3COOH)
Example 238
2-[7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-
-purin-2-yloxy]benzamide trifluoroacetate
[1454] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-1-(3-cyanobenzyl)-6-oxo-6,7-d-
ihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1455] 100 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-pu-
rin-8-yl]piperazine-1-carboxylate was dissolved in 1.2 ml of
N,N-dimethylformamide, and then 97 mg of 3-cyanobenzyl bromide and
68 mg of potassium carbonate were added thereto. The mixture was
stirred at room temperature for 12 hours. Then, a saturated
ammonium chloride solution was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was purified by silica gel
chromatography to give 71 mg of the title compound.
[1456] .sup.1H-NMR(CDCl3) .delta. 1.49 (s, 9H) 1.84 (t, J=2.5 Hz,
3H) 3.43-3.47 (m, 4H) 3.59-3.63 (m, 4H) 4.94 (q, 2.5 Hz, 2H) 5.53
(s, 2H) 7.42 (d, J=8.0 Hz, 2H) 7.62 (d, J=8.0 Hz, 2H)
[1457] (b)
2-[7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-
-dihydro-1H-purin-2-yloxy]benzamide trifluoroacetate
[1458] 12 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(3-cyanobenzyl)-6-oxo6-
,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.3 ml of 1-methyl-2-pyrrolidone, and then 10 mg of salicylamide
and 10 mg of potassium carbonate were added thereto. The mixture
was stirred at 100.degree. C. for five hours. 1N hydrochloric acid
was added to the reaction solution, and the mixture was extracted
with ethyl acetate. The organic layer was concentrated, and the
residue was dissolved in trifluoroacetic acid. The solution was
concentrated, and the residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 8.76
mg of the title compound.
[1459] MS m/e (ESI) 523(MH.sup.+--CF.sub.3COOH)
Example 239
7-(2-Butynyl)-1-(3-cyanobenzyl)-6-oxo-8-(piperazin-1-yl)-6,7-dihydro-1H-pu-
rine-2-carbonitrile trifluoroacetate
[1460] 12 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-1-(3-cyanobenzyl)-6-oxo--
6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate was dissolved in
0.3 ml of 1-methyl-2-pyrrolidone, and then 10 mg of sodium cyanide
was added thereto. The mixture was stirred at 50.degree. C. for 1
hour. 1N hydrochloric acid was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 4.96 mg of the title compound.
[1461] MS m/e (ESI) 413(MH.sup.+--CF.sub.3COOH)
Example 240
1-(2-Butynyl)-2-(piperazin-1-yl)-7,8-dihydro-1H,6H-5-oxa-1,3,4,8a-tetraaza-
cyclopenta[b]naphthalen-9-one hydrochloride
[1462] (a) t-Butyl
4-[7-(2-butynyl)-2-chloro-6-oxo-1-[3-(tetrahydropyran-2-
-yloxy)propyl]-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate
[1463] A mixture consisting of 20 mg of t-butyl
4-[7-(2-butynyl)-2chloro-6-
-oxo-6,7-dihydro-1H-purin-8-yl]piperazine-1-carboxylate obtained in
Example 95(a), 20 .mu.l of 2-(3-bromopropoxy) tetrahydropyran, 20
mg of anhydrous potassium carbonate and 0.2 ml of
N,N-dimethylformamide was stirred at room temperature overnight.
The reaction solution was extracted with ethyl acetate-water, and
the organic layer was washed with water and then with saturated
brine. The organic layer was then concentrated, and the residue was
purified by thin layer chromatography (70% ethyl acetate/hexane) to
give 8 mg of the title compound.
[1464] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.50-1.81 (m,
6H) 1.83(t, J=2 Hz, 3H) 2.06 (quint, J=7 Hz, 2H) 3.38-3.62 (m, 10H)
3.80-3.90 (m, 2H) 4.34-4.47 (m, 2H) 4.59 (t, J=3 Hz, 1H) 4.92 (q,
J=2 Hz, 2H)
[1465] (b) t-Butyl
4-[1-(2-butynyl)-9-oxo-1,7,8,9-tetraazacyclopenta[b]nap-
hthalen-2-yl]piperazine-1-carboxylate
[1466] A mixture consisting of 8 mg of t-butyl
4-[7-(2-butynyl)-2-chloro-6-
-oxo-1-[3-(tetrahydropyran-2-yloxy)propyl]-6,7-dihydro-1H-purin-8-yl]piper-
azine-1-carboxylate, 0.2 ml of ethanol and a catalytic amount of
para-toluenesulfonic acid monohydrate was stirred at room
temperature for 4 hours, and then 40 mg of anhydrous potassium
carbonate was added thereto. The mixture was further stirred
overnight. The reaction solution was extracted with ethyl
acetate-water, and the organic layer was washed with water and then
with saturated brine. The organic layer was then concentrated, and
the residue was purified by thin layer chromatography (20%
methanol/ethyl acetate) to give 3 mg of the title compound.
[1467] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.82 (t, J=2 Hz
3H) 2.18-2.26 (m, 2H) 3.37-3.43 (m, 4H) 3.56-3.62 (m, 4H) 4.07 (t,
J=6 Hz, 2H) 4.43 (t, J=5 Hz, 2H) 4.88 (q, J=2 Hz, 2H)
[1468] (c)
1-(2-Butynyl)-2-(piperazin-1-yl)-7,8-dihydro-1H,6H-5-oxa-1
3,4,8a-tetraazacyclopenta[b]naphthalen-9-one hydrochloride
[1469] A mixture consisting of 3 mg of t-butyl
4-[1-(2-butynyl)-9-oxo-1,7,-
8,9-tetraazacyclopenta[b]naphthalen-2-yl]piperazine-1-carboxylate
and 0.5 ml of trifluoroacetic acid was stirred at room temperature
for 20 minutes. Then, the solution was concentrated, and the
residue was purified by reverse-phase column chromatography using
20% to 50% methanol/water (0.1% concentrated hydrochloric acid)
solvent to give 2.1 mg of the title compound.
[1470] .sup.1H-NMR(DMSO-d6) .delta. 1.79 (s, 3H) 2.08-2.16 (m, 2H)
3.27 (br.s, 4H) 3.44-3.54 (m, 4H) 3.90 (t, J=6 Hz, 2H) 4.38 (t, J=5
Hz, 2H) 4.94 (s, 2H) 9.02 (br.s, 2H)
Example 241
1-(2-Butynyl)-2-(piperazin-1-yl)-6,7-dihydro-1H-5-oxa-1,3,4,7a-tetraaza-s--
indacen-8-one hydrochloride
[1471] In Example 240, the title compound was obtained by using
2-(2-bromoethoxy)tetrahydropyran, instead of
2-(3-bromopropoxy)tetrahydro- pyran, according to the method
described in Example 240.
[1472] .sup.1H-NMR(DMSO-d6) .delta. 1.80 (s, 3H) 3.27 (br.s, 4H)
4.19 (t, J=8 Hz, 2H) 4.70 (t, J=8 Hz, 2H) 4.94 (s, 2H) 9.06 (br.s,
2H)
Example 242
8-(3-amino
piperidin-1-yl)-7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-6,7-dihyd-
ro-1H-purine-2-carbonitrile hydrochloride
[1473] (a) Benzyl
3-t-butoxycarbonylaminopiperidine-1-carboxylate
[1474] 88 g of benzyl chloroformate (30% toluene solution) was
added dropwise to a mixture consisting of 24.3 g of ethyl
piperidine-3-carboxylate, 26 ml of triethylamine and 300 ml of
ethyl acetate over 30 minutes while the mixture was being cooled
with ice. The reaction mixture was filtered to remove insoluble
material. The filtrate was again filtered through a small amount of
silica gel. The filtrate was concentrated.
[1475] 200 ml of ethanol and 40 ml of a 5 M aqueous sodium
hydroxide solution were added to the residue. The mixture was
stirred at room temperature overnight. The reaction solution was
concentrated, and 200 ml of water was added to the residue. The
mixture was extracted with t-butyl methyl ether. 5 M aqueous
hydrochloric acid was added to the aqueous layer, and the mixture
was extracted with ethyl acetate. The organic layer was washed with
water and then with saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, and then concentrated to give an
oily residue (30.9 g).
[1476] A mixture consisting of 30 g of this residue, 24.5 ml of
diphenyl phosphoryl azide, 15.9 ml of triethylamine and 250 ml of
t-butanol was stirred at room temperature for 1.5 hours. The
mixture was further stirred in an oil bath at 100.degree. C. for 20
hours. The reaction solution was concentrated, and the residue was
extracted with ethyl acetate-water. The organic layer was washed
with dilute aqueous sodium bicarbonate solution and. then with
saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, and then concentrated. The residue was purified
by silica gel column chromatography using 10% to 20% ethyl
acetate/hexane, followed by recrystallization from ethyl
acetate-hexane to give 21.4 g of the title compound.
[1477] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (s, 9H) 1.48-1.92 (m,
4H) 3.20-3.80 (m, 5H) 4.58 (br.s, 1H) 5.13 (s, 2H) 7.26-7.40(m,
5H)
[1478] (b) t-Butyl piperidin-3-ylcarbamate
[1479] A mixture consisting of 10 g of benzyl
3-t-butoxycarbonylaminopiper- idine-1-carboxylate, 500 mg of 10%
palladium carbon and 100 ml of ethanol was stirred at room
temperature under a hydrogen atmosphere overnight. The catalyst was
removed by filtration. The filtrate was concentrated and dried to
give 6.0 g of the title compound.
[1480] .sup.1H-NMR(CDCl.sub.3) .delta.1.44 (s, 9H) 1.47-1.80 (m,
4H) 2.45-2.60 (m, 1H) 2.60-2.75 (m, 1H) 2.75-2.90 (m, 1H) 3.05 (dd,
J=3 Hz, 1.2 Hz, 1H) 3.57 (br.s, 1H) 4.83 (br.s, 1H)
[1481] (c) t-Butyl
[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidin--
3-yl]carbamate
[1482] A mixture consisting of 1.25 g of
7-(2-butynyl)-2,6,8-trichloro-7H-- purine, 1.0 g of t-butyl
piperidin-3-ylcarbamate and 10 ml of acetonitrile was stirred at
room temperature for 10 minutes. 0.63 ml of triethylamine was added
dropwise over 10 minutes, and then the mixture was continuously
stirred at room temperature for 30 minutes. The reaction solution
was partitioned between ethyl acetate and water, and the organic
layer was washed with saturated brine. The organic layer was dried
over anhydrous magnesium sulfate, and then concentrated. The
residue was crystallized with t-butyl methyl ether-hexane to give
1.79 g of the title compound.
[1483] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (s, 9H) 1.60-2.02 (m,
4H) 1.83 (t, J=2 Hz, 3H) 3.32-3.41 (m, 1H) 3.42-3.52 (m, 1H)
3.67-3.76 (m, 1H) 3.80-3.91 (m, 1H) 4.76-4.90 (m, 3H)
[1484] (d) t-Butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-
-yl]piperidin-3-yl]carbamate
[1485] A mixture consisting of 1.79 g of t-butyl
[1-[7-(2-butynyl)-2,6-dic-
hloro-7H-purin-8-yl]piperidin-3-yl]carbamate, 1.0 g of sodium
acetate and 18 ml of dimethyl sulfoxide was stirred in an oil bath
at 120.degree. C. for three hours. The mixture was removed from the
oil bath, and 18 ml of water was added to the reaction solution.
The mixture was cooled to room temperature. The crystals were
collected by filtration, and washed with water and then with
t-butyl methyl ether. The crystals were then dried to give 1.59 g
of the title compound.
[1486] .sup.1H-NMR(DMSO-d6) .delta. 1.39 (s, 9H) 1.34-1.88 (m, 4H)
1.78 (s, 3H) 2.81 (t, J=11 Hz, 1H) 2.95 (t, J=11 Hz, 1H) 3.48-3.60
(m, 2H) 3.64 (d, J=6 Hz, 1H) 4.90 (s, 2H) 6.94 (d, J=8 Hz, 1H)
[1487] (e) t-Butyl
[1-[7-(2-butynyl)-2-chloro-1-(2-cyanobenzyl)-6-oxo-6,7--
dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate
[1488] A mixture consisting of 100 mg of t-butyl
[1-[7-(2-butynyl)-2-chlor-
o-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate, 66 mg
of anhydrous potassium carbonate, 70 mg of 2-cyanobenzyl bromide
and 1 ml of N,N-dimethylformamide was stirred at room temperature
for five hours. The reaction solution was partitioned between ethyl
acetate and water, and the organic layer was washed with water and
then with saturated brine. The organic layer was dried over
anhydrous magnesium sulfate, and then concentrated. The residue was
purified by silica gel column chromatography using 50% ethyl
acetate/hexane to give 44.7 mg of the title compound.
[1489] .sup.1H-NMR(CDCl.sub.3) .delta. 1.44 (s, 9H) 1.59-1.81 (m,
2H) 1.83 (t, J=2 Hz, 3H) 1.86-1.94 (m, 2H) 3.20-3.50 (m, 3H) 3.66
(d, J=7 Hz, 1H) 3.86 (br.s, 1H) 4.88-5.06 (m, 3H) 5.72 (s, 2H) 7.06
(d, J=8 Hz, 1H) 7.38 (t, J=8 Hz, 1H) 7.51 (t, J=8 Hz, 1H) 7.70 (d,
J=8 Hz, 1H)
[1490] (f) t-Butyl
[1-[7-(2-butynyl)-2-cyano-1-(2-cyanobenzyl)-6-oxo-6,7-d-
ihydro-1purin-8-yl]piperidin-3-yl]carbamate
[1491] A mixture consisting of 15 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-
-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamat-
e, 20 mg of sodium cyanide and 0.2 ml of N,N-dimethylformamide was
stirred at room temperature for three hours. The reaction solution
was partitioned between ethyl acetate and water, and the organic
layer was washed with water and then with saturated brine. Then,
the organic layer was concentrated, and the residue was purified by
thin layer chromatography using 50% ethyl acetate/hexane solvent
(developed three times) to give 10.3 mg of the title compound.
[1492] .sup.1H-NMR(CDCl.sub.3) .delta. 1.44 (s, 9H) 1.52-1.98 (m,
4H) 1.81 (t, J=2 Hz 3H) 3.24 (dd, J=7 Hz, 12 Hz, 1H) 3.30-3.40 (m,
1H) 3.46-3.56 (m, 1H), 3.72 (d, J=12 Hz, 1H) 3.86 (br.s, 1H)
4.86-5.10 (m, 3H) 5.73 (s, 2H) 7.00 (d, J=8 Hz, 1H) 7.42 (t, J=8
Hz, 1H) 7.54 (dt, J=2 Hz, 8 Hz, 1H) 7.73 (dd, J=2 Hz, 8 Hz, 1H)
[1493] (g)
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-(2-cyanobenzyl)-6-oxo-
6,7-dihydro-1H-purine-2-carbonitrile hydrochloride
[1494] A mixture consisting of 10.3 mg of t-butyl
[1-[7-(2-butynyl)-2-cyan-
o-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]
piperidin-3-yl]carbamate and 0.2 ml of trifluoroacetic acid was
stirred for 20 minutes. The reaction solution was concentrated, and
the residue was purified by reverse-phase column chromatography
using 20% to 80% methanol/water (0.1% concentrated hydrochloric
acid) solvent to give 8.0 mg of the title compound.
[1495] .sup.1H-NMR(DMSO-d6) .delta. 1.60-1.74 (m, 2H) 1.79 (t, J=2
Hz, 3H) 1.88-2.03 (m, 2H) 3.14-3.28 (m, 2H) 3.42 (br.s, 1H)
3.52-3.82 (m, 2H) 4.98-5.12 (m, 2H) 5.58 (s, 2H) 7.26 (d, J=8 Hz,
1H) 7.53 (t, J=8 Hz, 1H) 7.66 (t, J=8 Hz, 1H) 7.93 (d, J=8 Hz, 1H)
8.16 (br.s, 3H)
Example 243
2-[8-(3-Amino
piperidin-1-yl)-7-(2-butynyl)-2-methoxy-6-oxo-6,7-dihydropur-
in-1-ylmethyl]benzonitrile hydrochloride
[1496] A mixture consisting of 15 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-
-1-(2-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]carbamat-
e, 20 mg of anhydrous potassium carbonate and 0.2 ml of methanol
was stirred for three hours. Subsequent steps were carried out
according to the same procedure as used in Examples 242 (f) and
(g). Thus, the title compound was synthesized.
[1497] .sup.1H-NMR(DMSO-d6) .delta. 1.58-1.72 (m, 2H) 1.84-1.94 (m,
1H) 1.96-2.04 (m, 1H) 3.08-3.20 (m, 2H) 3.36-3.70 (m, 3H) 3.90 (s,
3H) 4.90-5.02 (m, 2H) 5.32 (s, 2H) 7.20 (d, J=8 Hz, 1H) 7.47 (t,
J=8 Hz, 1H) 7.63 (t, J=8 Hz, 1H) 7.87 (d, J=8 Hz, 1H) 8.12 (br.s,
3H)
Example 244
8-(3-Amino
piperidin-1-yl)-7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-6,7-dihyd-
ro-1H-purine-2-carbonitrile hydrochloride
[1498] (a) t-Butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7--
dihydro-1H-purin-8-yl]piperidin-3-yl] carbamate
[1499] The title compound was obtained using 2-bromoethyl benzene,
instead of 2-cyanobenzyl bromide, according to the method described
in Example 242(e).
[1500] .sup.1H-NMR(CDCl.sub.3) .delta. 1.44 (s, 9H) 1.58-1.80 (m,
2H) 1.83 (t, J=2 Hz, 3H) 1.86-1.94 (m, 2H) 3.00-3.06 (m, 2H)
3.20-3.50 (m, 3H) 3.60 (d, J=12 Hz, 1H) 3.85 (b.s, 1H) 4.42-4.48
(m, 2H) 4.88-5.04 (m, 3H) 7.02-7.34 (m, 5H)
[1501] (b)
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-6-oxo-1-(2-phenylethyl)-
-6,7-dihydro-1H-purine-2-carbonitrile hydrochloride
[1502] The title compound was synthesized by using t-butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purin-8-
-yl]piperidin-3-yl]carbamate according to the method described in
Example 242 (f) and (g).
[1503] .sup.1H-NMR(DMSO-d6) .delta. 1.60-1.72 (m, 2H) 1.83 (s, 3H)
1.88-2.06 (m, 3H) 3.04 (t, J=7 Hz, 2H) 3.35-3.60 (m, 2H) 3.75 (d,
J=12 Hz, 1H) 4.35 (t, J=7 Hz, 2H) 5.09 (s, 2H) 7.18 (d, J=7 Hz, 2H)
7.22-7.34 (m, 3H) 8.16 (br.s, 3H)
Example 245
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-2-methoxy-1-(2-phenylethyl)-1,7-di-
hydropurin-6-one hydrochloride
[1504] The title compound was synthesized by using t-butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-1-(2-phenylethyl)-6,7-dihydro-1H-purin-8-
-yl]piperidin-3-yl]carbamate, according to the method described in
Example 243.
[1505] .sup.1H-NMR(DMSO-d6) .delta. 1.56-1.72 (m, 2H) 1.80 (t, J=2
Hz, 3H) 1.84-2.04 (m, 2H) 2.85 (t, J=7 Hz, 2H) 3.08-3.18 (m, 2H)
3.34-3.54 (m, 2H) 3.64 (d, J=12 Hz, 1H) 3.83 (s, 3H) 4.15 (t, J=7
Hz, 2H) 4.88-5.02 (m, 2H) 7.16-7.24 (m, 3H) 7.29 (t, J=7 Hz, 2H)
8.09 (br.s, 3H)
Example 246
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-(4-cyanobenzyl)-6-oxo6,7-dihydro-
-1H-purine-2-carbonitrile hydrochloride
[1506] (a) t-Butyl
[1-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7--
dihydro-1H-purin-8-yl]piperidin-3-yl]carbamate
[1507] The title compound was obtained by using 4-cyanobenzyl
bromide, instead of 2-cyanobenzyl bromide, according to the method
described in Example 242(e).
[1508] .sup.1H-NMR(CDCl.sub.3) .delta. 1.44 (s, 9H) 1.58-1.80 (m,
2H) 1.82 (t, J=2 Hz, 3H), 1.85-1.95 (m, 2H) 3.18-3.26 (m, 1H)
3.29-3.37 (m, 1H) 3.40-3.48 (m, 1H) 3.65 (d, J=12 Hz, 1H) 3.86
(br.s, 1H) 4.86-5.04 (m, 3H) 5.22 (s, 2H) 7.41 (d, J=8 Hz, 2H) 7.62
(d, J=8 Hz, 2H)
[1509] (b)
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-(4-cyanobenzyl)-6-oxo-
6,7-dihydro-1H-purine-2-carbonitrile hydrochloride
[1510] The title compound was synthesized by using t-butyl
[1-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-
-yl]piperidin-3-yl]carbamate according to the method described in
Examples 242 (f) and (g).
[1511] .sup.1H-NMR(DMSO-d6) .delta. 1.62-1.72 (m, 2H) 1.80 (s, 3H)
1.88-1.96 (m, 1H) 1.98-2.06 (m, 1H) 3.16-3.26 (m, 2H) 3.41 (br.s,
1H) 3.50-3.80 (m, 2H) 5.07 (s, 2H) 5.49 (s, 2H) 7.49 (d, J=8 Hz,
2H) 7.85 (d, J=8 Hz, 2H) 8.16 (br.s, 3H)
Example 247
4-[8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-2-methoxy-6-oxo-6,7-dihydropuri-
n-1-ylmethyl]benzonitrile hydrochloride
[1512] The title compound was synthesized by using t-butyl
[1-[7-(2-butynyl)-2-chloro-1-(4-cyanobenzyl)-6-oxo-6,7-dihydro-1H-purin-8-
-yl]piperidin-3-yl]carbamate according to the method described in
Example 243.
[1513] .sup.1H-NMR(DMSO-d6) .delta. 1.58-1.70 (m, 2H) 1.79 (s, 3H)
1.84-2.04 (m, 2H) 3.08-3.20 (m, 2H) 3.36-3.70 (m, 3H) 3.89 (s, 3H)
4.88-5.02 (m, 2H) 5.22 (s, 2H) 7.39 (d, J=8 Hz, 2H) 7.79 (d, J=8
Hz, 2H) 8.14 (br.s, 3H)
Example 248
2-[8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-dihydro-1H-p-
urin-2-yloxy]benzamide trifluoroacetic acid salt
[1514] (a) t-Butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1-
H-purin-8-yl]piperidin-3-yl]carbamate
[1515] 700 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-p-
urin-8-yl]piperidin-3-yl]carbamate was dissolved in 7.0 ml of
dimethyl sulfoxide, and then 114 .mu.l of methyl iodide and 299 mg
of potassium carbonate were added thereto. The mixture was stirred
at room temperature for 30 minutes, and 40 ml of water was added to
the reaction solution. The mixture was stirred at room temperature
for 30 minutes, and the white precipitate was collected by
filtration. The resulting white solid was washed with water and
then with hexane to give 540 mg of the title compound.
[1516] .sup.1H-NMR(CDCl3) .delta. 1.44 (s, 9H) 1.72-1.94 (m, 4H)
1.81 (t, J=2.4 Hz, 3H) 3.16-3.92 (m, 5H) 3.72 (s, 3H) 4.91 (dd,
J=17.6, 2.4 Hz, 1H) 5.01 (d, J=17.6 Hz, 1H)
[1517] (b)
2-[8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-d-
ihydro-1H-purin-2-yloxy]benzamide trifluoroacetate
[1518] 10 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 0.3 ml
of 1-methyl-2-pyrrolidone, and then 10 mg of salicylamide and 10 mg
of potassium carbonate were added thereto. The mixture was stirred
at 100.degree. C. for 2 hours. 1N hydrochloric acid was added to
the reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 5.54 mg of the
title compound.
[1519] MS m/e (ESI) 436(MH.sup.+--CF.sub.3COOH)
Example 249
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-dihydro-1H-puri-
ne-2-carbonitrile trifluoroacetate
[1520] 10 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperidin-3-yl]carbamate dissolved in 0.3 ml of
1-methyl-2-pyrrolidone, and then 10 mg of sodium cyanide was added
thereto. The mixture was stirred at 60.degree. C. for 2 hours. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 3.67 mg of the title compound.
[1521] MS m/e (ESI) 326(MH.sup.+--CF.sub.3COOH)
Example 250
8-(3-Aminopiperidin-1-yl)-2-t-butylsulfanyl-7-(2-butynyl)-1-methyl-1,7-dih-
ydropurin-6-one trifluoroacetate
[1522] 10 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 0.3 ml
of 1-methyl-2-pyrrolidone, and then 10 mg of the sodium salt of
2-methyl-2-propanethiol was added thereto. The mixture was stirred
at room temperature for 2 hours. 1N hydrochloric acid was added to
the reaction solution, and the mixture was extracted with ethyl
acetate. The organic layer was concentrated, and the residue was
dissolved in trifluoroacetic acid. The solution was concentrated,
and the residue was purified by reverse-phase high performance
liquid chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 5.00 mg of the
title compound.
[1523] MS m/e (ESI) 389(MH.sup.+--CF.sub.3COOH)
Example 251
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-2-methoxy-1-methyl-1,7-dihydropuri-
n-6-one trifluoroacetate
[1524] 10 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 0.6 ml
of methanol, and then 8 mg of sodium hydride was added thereto. The
mixture was stirred at room temperature for one hour. 1N
hydrochloric acid was added to the reaction solution, and the
mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the residue was dissolved in trifluoroacetic
acid. The solution was concentrated, and the residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 2.14 mg of the title compound.
[1525] MS m/e (ESI) 331(MH.sup.+--CF.sub.3COOH)
Example 252
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-2-diethylamino-1-methyl-1,7-dihydr-
opurin-6-one trifluoroacetate
[1526] 10 mg of t-butyl
[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihy-
dro-1H-purin-8-yl]piperidin-3-yl]carbamate was dissolved in 0.3 ml
of 1-methyl-2-pyrrolidone, and then 50 .mu.l of diethylamine was
added thereto. The mixture was stirred at 60.degree. C. for 4
hours. 1N hydrochloric acid was added to the reaction solution, and
the mixture was extracted with ethyl acetate. The organic layer was
concentrated, and the resulting residue was dissolved in
trifluoroacetic acid. The solution was concentrated, and the
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 2.17 mg of the
title compound.
[1527] MS m/e (ESI) 372(MH.sup.+--CF.sub.3COOH)
Example 253
8-(3-Aminopiperidin-1-yl)-7-(2-butynyl)-1-methyl-2-(pyrrolidin-1-yl)-1,7-d-
ihydropurin-6-one trifluoroaceate
[1528] 1.94 mg of the title compound was obtained by using
pyrrolidine, instead of diethylamine, according to the method
described in Example 252.
[1529] MS m/e (ESI) 370(MH.sup.+--CF.sub.3COOH)
Example 254
8-(3-Methylaminopiperidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-dihydro-1-
H-purine-2-carbonitrile hydrochloride
[1530] (a) t-Butyl N-methyl-N-(piperidin-3-yl)carbamate
[1531] 0.4 g of sodium hydride (60%; in oil) was added to a mixture
consisting of 3.3 g of benzyl
3-t-butoxycarbonylaminopiperidine-1-carboxy- late, 0.75 ml of
methyl iodide and 20 ml of N,N-dimethylformamide in a water bath at
room temperature. The mixture was stirred at room temperature for 4
hours. The reaction solution was partitioned between ethyl acetate
and water, and the organic layer was washed with water and then
with saturated brine. The organic layer was dried over anhydrous
magnesium sulfate, and then concentrated. The residue was purified
by silica gel column chromatography using 10% to 20% ethyl
acetate/hexane to give an oily material (3.04 g). This whole
ammount was combined with 20 ml of ethanol and 10% palladium
carbon. This mixture was stirred at room temperature under a
hydrogen atmosphere for five hours. After the catalyst was removed
by filtration, the filtrate was concentrated to give 1.82 g of the
title compound.
[1532] .sup.1H-NMR(CDCl.sub.3) .delta. 1.46 (s, 9H) 1.48-1.64 (m,
2H) 1.72-1.84 (m, 2H) 2.43 (dt, J=3 Hz, 12 Hz, 1H) 2.60 (t, J=12
Hz, 1H) 2.75 (s, 3H) 2.74-3.02 (m, 2H) 3.86 (br.s, 1H)
[1533] (b) t-Butyl
N-[1-[7-(2-butynyl)-2,6-dichloro-7H-purin-8-yl]piperidi-
n-3-yl]-N-methylcarbamate
[1534] The title compound was synthesized by using
7-(2-butynyl)-2,6,8-tri- chloro-7H-purine and t-butyl
piperidin-3-ylcarbamate according to the method described in
Example 242 (c).
[1535] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.70-2.02 (m,
7H) 2.83 (s, 3H) 3.00 (t, J=12 Hz, 1H) 3.14 (t, J=12 Hz, 1H)
3.96-4.25 (m, 3H) 4.80 (s, 2H)
[1536] (c) t-Butyl
N-[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-
-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate
[1537] A mixture consisting of 580 mg of t-butyl
N-[1-[7-(2-butynyl)-2,6-d-
ichloro-7H-purin-8-yl]piperidin-3-yl]-N-methylcarbamate, 315 mg of
sodium acetate and 6 ml of dimethyl sulfoxide was stirred in an oil
bath at120.degree. C. for 7 hours. The reaction solution was
partitioned between ethyl acetate and water, and the organic layer
was washed with water and then with saturated brine. The organic
layer was dried over anhydrous magnesium sulfate, was filtered
through a small amount of silica gel. The filtrate was
concentrated, and the residue was crystallized with ethyl
acetate-hexane to give 420 mg of t-butyl
N-[1-[7-(2-butynyl)-2-chloro-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3--
yl]-N-methylcarbamate. A mixture consisting of an 100 mg aliquot of
the compound obtained above, 0.17 ml of methyl iodide, 48 mg of
anhydrous potassium carbonate and 0.5 ml of N,N-dimethylformamide
was stirred at room temperature for 4 hours. The reaction solution
was partitioned between ethyl acetate and water, and the organic
layer was washed with water and then with saturated brine. Then,
the organic layer was concentrated, and the residue was purified by
silica gel column chromatography using 50% ethyl acetate/hexane to
give 104 mg of the title compound.
[1538] .sup.1H-NMR(CDCl.sub.3) .delta. 1.47 (s, 9H) 1.62-1.74 (m,
1H) 1.81 (t, J=2 Hz, 3H) 1.82-1.96 (m, 3H) 2.82 (s, 3H) 2.86 (t,
J=12 Hz, 1H) 3.02 (t, J=12 Hz, 1H) 3.68-3.82 (m, 2H) 3.72 (s, 3H)
4.20 (br. s, 1H) 4.90 (s, 2H)
[1539] (d)
7-(2-Butynyl)-1-methyl-8-(3-methylaminopiperidin-1-yl)-6-oxo-6,-
7-dihydro-1H-purine-2-carbonitrile hydrochloride
[1540] The title compound was synthesized by using t-butyl
N-[1-[7-(2-butynyl)-2-chloro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]pip-
eridin-3-yl]-N-methylcarbamate according to the method described in
Example 242 (f) and (g).
[1541] .sup.1H-NMR(DMSO-d6) .delta. 1.60-1.77 (m, 2H) 1.81 (s, 3H)
1.84-2.00 (m, 1H) 2.02-2.12 (m, 1H) 2.60 (t, J=5 Hz, 3H) 3.17-3.40
(m, 3H) 3.46-3.56 (m, 1H) 3.79 (d, J=12 Hz, 1H) 5.00-5.15 (m, 2H)
9.01 (br.s, 2H)
Example 255
2-[7-(2-Butynyl)-1-methyl-8-(3-methylaminopiperidin-1-yl)-6-oxo6,7-dihydro-
-1H-purin-2-yloxy]benzamide hydrochloride
[1542] A mixture consisting of 20 mg of t-butyl
N-[1-[7-(2-butynyl)-2-chlo-
ro-1-methyl-6-oxo-6,7-dihydro-1H-purin-8-yl]piperidin-3-yl]-N-methylcarbam-
ate, 20 mg of 2-hydroxybenzamide, 20 mg of anhydrous potassium
carbonate, and 0.3 ml of N-methyl-2-pyrrolidone was stirred in an
oil bath at 80.degree. C. for 4 hours. Subsequent synthesis steps
were carried out according to the same procedure as used in
Examples 242(f) and (g) to give the title compound.
[1543] .sup.1H-NMR(DMSO-d6) .delta. 1.69 (br.s, 2H) 1.82 (s, 3H)
1.92 (br.s, 1H) 2.07 (br.s, 1H) 2.62 (s, 3H) 3.10-3.40 (m, 4H) 3.48
(s, 3H) 3.76 (br.s, 1H) 5.02 (br.s, 2H) 6.96 (br.s, 2H) 7.44 (br.s,
1H) 7.91 (br.s, 1H) 8.81 (br.s, 2H)
Example 256
8-(3-Aminopyrrolidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-dihydro-1H-pur-
ine-2-carbonitrile hydrochloride
[1544] In Example 254, the title compound was synthesized by using
t-butyl pyrrolidin-3-ylcarbamate, instead of t-butyl
N-methyl-N-(piperidin-3-yl)c- arbamate, according to the method
described in Examples 254(b), (c), and (d).
[1545] .sup.1H-NMR(DMSO-d6) .delta. 1.81 (s, 3H) 2.13 (br.s, 1H)
2.32 (br.s, 1H) 3.64 (s, 3H) 3.74-3.86 (m, 2H) 3.93 (br.s, 3H) 5.19
(d, J=18 Hz, 1H) 5.28 (d, J=18 Hz, 1H) 8.32 (br.s, 3H)
Example 257
2-[8-(3-Aminopyrrolidin-1-yl)-7-(2-butynyl)-1-methyl-6-oxo-6,7-dihydro-1H--
purin-2-yloxy]benzamide hydrochloride
[1546] The title compound was synthesized by using
2-hydroxybenzamide according to the method described in Examples
255 and 256.
[1547] .sup.1H-NMR(DMSO-d6) .delta. 1.82 (s, 3H) 2.11 (br.s, 1H)
2.32 (br.s, 1H) 3.46 (s, 3H) 3.72-4.00 (m, 5H) 5.15 (d, J=19 Hz,
1H) 5.23 (d, J=19 Hz, 1H) 6.90-7.02 (m, 2H) 7.42-7.50 (m, 1H)
7.90-7.99 (m, 1H) 8.22 (br.s, 3H)
Example 258
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimidazo[4,5-d]p-
yridazin-4-one trifluoroacetate
[1548] (a) t-Butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyr-
idazin-2-yl]piperazine-1-carboxylate
[1549] 0.299 g of triethylamine, 0.023 g of 4-dimethylaminopyridine
and 0.645 g of di-t-butyl dicarbonate were added to 20 ml of an
N,N-dimethylformamide solution of 0.448 g of
3-(2-butynyl)-2-(piperazin-1-
-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate at
room temperature, and the mixture was stirred for five hours. Then,
2 ml of a 5N aqueous sodium hydroxide solution was added to this
solution, and the mixture was stirred for one hour. The reaction
solution was poured into a mixture of 200 ml of ethyl acetate and
100 ml of a saturated aqueous ammonium chloride solution. The
organic layer was washed twice with 100 ml of water and then with
100 ml of a saturated sodium chloride solution. The organic liquid
was dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.298 g of the title compound was obtained
from the fraction eluted with ethyl acetate.
[1550] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.84 (t, J=2.3
Hz, 3H) 3.41 (m, 4H) 3.63 (m, 4H) 5.06 (q, J=2.3 Hz, 2H) 8.17 (s,
1H) 9.92 (br.s, 1H)
[1551] (b)
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimid-
azo[4,5-d]pyridazin-4-one trifluoroacetate
[1552] 0.005 g of potassium carbonate and 0.003 ml of
3-bromo-1-propyne were added to 0.5 ml of an N,N-dimethylformamide
solution of 0.010 g of t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-y-
l]piperazine-1-carboxylate, and the mixture was stirred at room
temperature for 10 hours. 1 ml of ethyl acetate and 1 ml of water
were added to the reaction solution, and the layers were separated.
The organic layer was concentrated, and the resulting residue was
dissolved in a mixture consisting of 0.5 ml of dichloromethane and
0.5 ml of trifluoroacetic acid. The mixture was stirred for 1 hour,
and then concentrated. The residue was purified by reverse-phase
high performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.011
g of the title compound.
[1553] MS m/e (ESI) 311.29(MH.sup.+--CF.sub.3COOH)
Example 259
[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-
-5-yl]acetonitrile trifluoroacetate
[1554] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and bromoacetonitrile according to the method
described in Example 258(b).
[1555] MS m/e (ESI) 312.28(MH.sup.+--CF.sub.3COOH)
Example 260
3-(2-Butynyl)-5-(2-hydroxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-
-d]pyridazin-4-one trifluoroacetate
[1556] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromoethanol according to the method
described in Example 258(b).
[1557] MS m/e (ESI) 317.30(MH.sup.+--CF.sub.3COOH)
Example 261
3-(2-Butynyl)-5-(2-methoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-
-d]pyridazin-4-one trifluoroacetate
[1558] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and bromoethyl methyl ether according to the
method described in Example 258(b).
[1559] MS m/e (ESI) 331.32(MH.sup.+--CF.sub.3COOH)
Example 262
Ethyl
[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyr-
idazin-5-yl]acetate trifluoroacetate
[1560] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and ethyl bromoacetate according to the method
described in Example 258(b).
[1561] MS m/e (ESI) 359.13(MH.sup.+--CF.sub.3COOH)
Example 263
3-(2-Butynyl)-5-(2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5--
d]pyridazin-4-one trifluoroacetate
[1562] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and (2-bromoethyl)benzene according to the
method described in Example 258(b).
[1563] MS m/e (ESI) 377.34(MH.sup.+--CF.sub.3COOH)
Example 264
3-(2-Butynyl)-5-(2-phenoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-
-d]pyridazin-4-one trifluoroacetate
[1564] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromoethyl phenyl ether according to the
method described in Example 258(b).
[1565] MS m/e (ESI) 393.32(MH.sup.+--CF.sub.3COOH)
Example 265
3-(2-Butynyl)-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidaz-
o[4,5-d]pyridazin-4-one trifluoroacetate
[1566] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromoacetophenone according to the method
described in Example 258(b).
[1567] MS m/e (ESI) 391.32(MH.sup.+--CF.sub.3COOH)
Example 266
3-(2-Butynyl)-5-[2-(3-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3,5-di-
hydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1568] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-3'-methoxy acetophenone according to
the method described in Example 258(b).
[1569] MS m/e (ESI) 421.33(MH.sup.+--CF.sub.3COOH)
Example 267
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzonitrile trifluoroacetate
[1570] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromomethylbenzonitrile according to the
method described in Example 258(b).
[1571] .sup.1H-NMR(CD.sub.3OD) .delta. 1.81 (t, J=2.5 Hz, 3H)
3.45-3.49 (m, 4H) 3.66-3.70 (m, 4H) 5.15 (q, J=2.5 Hz, 2H) 5.62 (s,
2H) 7.34 (dd, J=7.6,1.5 Hz, 1H) 7.45 (td, J=7.6, 1.5 Hz, 1H) 7.59
(td, J=7.6, 1.7 Hz, 1H) 7.75 (dd, J=7.6, 1.7 Hz, 1H) 8.25 (s,
1H)
[1572] MS m/e (ESI) 388.32(MH.sup.+--CF.sub.3COOH)
Example 268
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(2-trifluoromethylbenzyl)-3,5-dihydroim-
idazo[4,5-d]pyridazin-4-one trifluoroacetate
[1573] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-(trifluoromethyl)benzyl bromide according
to the method described in Example 258(b).
[1574] MS m/e (ESI) 431.21(MH.sup.+--CF.sub.3COOH)
Example 269
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(3-trifluoromethylbenzyl)-3,5-dihydroim-
idazo[4,5-d]pyridazin-4-one trifluoroacetate
[1575] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-(trifluoromethyl)benzyl bromide according
to the method described in Example 258(b).
[1576] MS m/e (ESI) 431.23(MH.sup.+--CF.sub.3COOH)
Example 270
3-(2-Butynyl)-5-(2-nitrobenzyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5--
d]pyridazin-4-one trifluoroacetate
[1577] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-nitrobenzyl bromide according to the
method described in Example 258(b).
[1578] MS m/e (ESI) 408.25(MH.sup.+--CF.sub.3COOH)
Example 271
3-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzonitrile trifluoroacetate
[1579] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-bromomethylbenzonitrile according to the
method described in Example 258(b).
[1580] MS m/e (ESI) 388.27(MH.sup.+--CF.sub.3COOH)
Example 272
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzonitrile trifluoroacetate
[1581] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-bromomethylbenzonitrile according to the
method described in Example 258(b).
[1582] MS m/e (ESI) 388.29(MH.sup.+--CF.sub.3COOH)
Example 273
Methyl
3-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]-
pyridazin-5-ylmethyl]benzoate trifluoroacetate
[1583] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and methyl 3-(bromomethyl)benzoate according to
the method described in Example 258(b).
[1584] MS m/e (ESI) 421.29(MH.sup.+--CF.sub.3COOH)
Example 274
Methyl
4-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]-
pyridazin-5-ylmethyl]benzoate trifluoroacetate
[1585] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and methyl 4-(bromomethyl)benzoate according to
the method described in Example 258(b).
[1586] MS m/e (ESI) 421.31(MH.sup.+--CF.sub.3COOH)
Example 275
Ethyl
5-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]p-
yridazin-5-ylmethyl]furan-2-carboxylate trifluoroacetate
[1587] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and ethyl 5-(bromomethyl)furan-2-carboxylate
according to the method described in Example 258(b).
[1588] MS m/e (ESI) 425.30(MH.sup.+--CF.sub.3COOH)
Example 276
3-(2-Butynyl)-5-[2-(2-nitrophenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3,5-dihy-
droimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1589] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-2'-nitroacetophenone according to
the method described in Example 258(b).
[1590] MS m/e (ESI) 436.28(MH.sup.+--CF.sub.3COOH)
Example 277
4-[2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyri-
dazin-5-yl]acetyl]benzonitrile trifluoroacetate
[1591] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-4'-cyanoacetophenone according to
the method described in Example 258(b).
[1592] MS m/e (ESI) 416.31(MH.sup.+--CF.sub.3COOH)
Example 278
3-(2-Butynyl)-5-[2-(4-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3,5-di-
hydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1593] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-4'-methoxyacetophenone according to
the method described in Example 258(b).
[1594] MS m/e (ESI) 421.32(MH.sup.+--CF.sub.3COOH)
Example 279
3-(2-Butynyl)-5-[2-(2-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3,5-di-
hydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1595] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-2'-methoxyacetophenone according to
the method described in Example 258(b).
[1596] MS m/e (ESI) 421.33(MH.sup.+--CF.sub.3COOH)
Example 280
4-[2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyri-
dazin-5-yl]ethyl]benzoic acid trifluoroacetate
[1597] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and t-butyl 4-(2-bromoethyl)benzoate according
to the method described in Example 258(b).
[1598] MS m/e (ESI) 421.33(MH.sup.+--CF.sub.3COOH)
Example 281
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-2-ylmethyl)-3,5-dihydroimidazo-
[4,5-d]pyridazin-4-one bis trifluoroacetate
[1599] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxyate and 2-(chloromethyl)pyridine hydrochloride
according to the method described in Example 258(b).
[1600] MS m/e (ESI) 364.24(MH.sup.+--2CF.sub.3COOH)
Example 282
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-3-ylmethyl)-3,5-dihydroimidazo-
[4,5-d]pyridazin-4-one bis trifluoroacetate
[1601] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-(chloromethyl)pyridine hydrochloride
according to the method described in Example 258(b).
[1602] MS m/e (ESI) 364.30(MH.sup.+--2CF.sub.3COOH)
Example 283
3-(2-Butynyl)-2-(piperazin-1-yl)-5-(pyridin-4-ylmethyl)-3,5-dihydroimidazo-
[4,5-d]pyridazin-4-one bis trifluoroacetate
[1603] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-(chloromethyl)pyridine hydrochloride
according to the method described in Example 258(b).
[1604] MS m/e (ESI) 364.26(MH.sup.+--2CF.sub.3COOH)
Example 284
3-(2-Butynyl)-5-[2-oxo-2-(pyridin-2-yl)ethyl]-2-(piperazin-1-yl)-3,5-dihyd-
roimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
[1605] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-(2-bromoacetyl)pyridine hydrobromide
according to the method described in Example 258(b).
[1606] MS m/e (ESI) 392.27(MH.sup.+--2CF.sub.3COOH)
Example 285
3-(2-Butynyl)-5-[2-oxo-2-(pyridin-3-yl)ethyl]-2-(piperazin-1-yl)-3,5-dihyd-
roimidazo[4,5-d]pyridazin-4-one bis trifluoroacetate
[1607] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-(2-bromoacetyl)pyridine hydrobromide
according to the method described in Example 258(b).
[1608] MS m/e (ESI) 392.27(MH.sup.+--2CF.sub.3COOH)
Example 286
3-(2-Butynyl)-5-[2-oxo-2-(pyridin-4-yl)ethyl]-2-oxoethyl]]-2-(piperazin-1--
yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bis
trifluoroacetate
[1609] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-(2-bromoacetyl)pyridine hydrobromide
according to the method described in Example 258(b).
[1610] MS m/e (ESI) 392.28(MH.sup.+--2CF.sub.3COOH)
Example 287
3-(2-Butynyl)-5-(2-methoxypyridin-3-ylmethyl)-2-(piperazin-1-yl)-3,5-dihyd-
roimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1611] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-(chloromethyl)-2-methoxypyridine according
to the method described in Example 258(b).
[1612] MS m/e (ESI) 394.30(MH.sup.+--CF.sub.3COOH)
Example 288
Methyl
6-[3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]-
pyridazin-5-ylmethyl]nicotinate bis trifluoroacetate
[1613] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and methyl 6-(chloromethyl)nicotinate according
to the method described in Example 258(b).
[1614] MS m/e (ESI) 422.31(MH.sup.+--CF.sub.3COOH)
Example 289
5-(6-Aminopyridin-3-ylmethyl)-3-(2-butynyl)-2-(piperazin-1-yl)-3,5-dihydro-
imidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1615] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-(t-butoxycarbonylamino)-5-(bromomethyl)
pyridine according to the method described in Example 258(b).
[1616] MS m/e (ESI) 379.31(MH.sup.+--CF.sub.3COOH)
Example 290
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-3-cyano-5-ethoxy-N-methylbenzamide
trifluoroacetate
[1617] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and
4-bromomethyl-3-cyano-5-ethoxy-N-methylbenzamide according to the
method described in Example 258(b).
[1618] MS m/e (ESI) 489.35(MH.sup.+--CF.sub.3COOH)
Example 291
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-3,5-dicyano-N-methylbenzamide trifluoroacetate
[1619] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-bromomethyl-3,5-dicyano-N-methylbenzamide
according to the method described in Example 258(b).
[1620] MS m/e (ESI) 470.33(MH.sup.+--CF.sub.3COOH)
Example 292
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-3-cyano-5-fluoro-N-methylbenzamide
trifluoroacetate
[1621] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and
4-bromomethyl-3-cyano-5-fluoro-N-methylbenzamide according to the
method described in Example 258(b).
[1622] MS m/e (ESI) 463.33(MH.sup.+--CF.sub.3COOH)
Example 293
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-5-cyano-2-ethoxy-N-methylbenzamide
trifluoroacetate
[1623] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and
4-bromomethyl-5-cyano-2-ethoxy-N-methylbenzamide according to the
method described in Example 258(b).
[1624] MS m/e (ESI) 489.35(MH.sup.+--CF.sub.3COOH)
Example 294
5-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-2-fluorobenzonitrile trifluoroacetate
[1625] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 5-bromomethyl-2-fluorobenzonitrile according
to the method described in Example 258(b).
[1626] MS m/e (ESI) 406.15(MH.sup.+--CF.sub.3COOH)
Example 295
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-5-fluorobenzonitrile trifluoroacetate
[1627] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromomethyl-5-fluorobenzonitrile according
to the method described in Example 258(b).
[1628] MS m/e (ESI) 406.16(MH.sup.+--CF.sub.3COOH)
Example 296
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-3-fluorobenzonitrile trifluoroacetate
[1629] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-bromomethyl-3-fluorobenzonitrile according
to the method described in Example 258(b).
[1630] MS m/e (ESI) 406.23(MH.sup.+--CF.sub.3COOH)
Example 297
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]-3-fluorobenzonitrile trifluoroacetate
[1631] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromomethyl-3-fluorobenzonitrile according
to the method described in Example 258(b).
[1632] MS m/e (ESI) 406.25(MH.sup.+--CF.sub.3COOH)
Example 298
3-(2-Butynyl)-5-(isoquinolin-1-ylmethyl)-2-(piperazin-1-yl)-3,5-dihydroimi-
dazo[4,5-d]pyridazin-4-one trifluoroacetate
[1633] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 1-bromomethylisoquinoline according to the
method described in Example 258(b).
[1634] .sup.1H-NMR(CDCl.sub.3) .delta. 1.80 (t, J=2.4 Hz, 3H) 3.46
(m, 4H) 3.68 (m, 4H) 5.17 (q, J=2.4 Hz, 2H) 6.22 (s, 2H) 7.94 (dd,
J=8.2, 8.0 Hz, 1H) 8.08 (t, J=8.2 Hz, 1H) 8.21 (d, J=8.0 Hz, 1H)
8.24 (d, J=6.4 Hz, 1) 8.27 (s, 1H) 8.46 (d, J=6.4 Hz, 1H) 8.68 (d,
J=8.2 Hz, 1H)
[1635] MS m/e (ESI) 414.32(MH.sup.+--CF.sub.3COOH)
Example 299
3-(2-Butynyl)-5-(2-fluoropyridin-3-ylmethyl)-2-(piperazin-1-yl)-3,5-dihydr-
oimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1636] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-(bromomethyl)-2-fluoropyridine
hydrochloride according to the method described in Example
258(b).
[1637] MS m/e (ESI) 384.22(MH.sup.+--CF.sub.3COOH)
Example 300
3-(2-Butynyl)-5-(2-fluoropyridin-4-ylmethyl)-2-(piperazin-1-yl)-3,5-dihydr-
oimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1638] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-(bromomethyl)-2-fluoropyridine
hydrochloride according to the method described in Example
258(b).
[1639] MS m/e (ESI) 384.20(MH.sup.+--CF.sub.3COOH)
Example 301
3-(2-Butynyl)-5-(6-fluoropyridin-2-ylmethyl)-2-(piperazin-1-yl)-3,5-dihydr-
oimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1640] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-(bromomethyl)-6-fluoropyridine
hydrochloride according to the method described in Example
258(b).
[1641] MS m/e (ESI) 384.22(MH.sup.+--CF.sub.3COOH)
Example 302
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzamide trifluoroacetate
[1642] 0.005 g of potassium carbonate and 0.007 g of
2-bromomethylbenzonitrile were added to a 0.5 ml
N,N-dimethylformamide solution containing 0.010 g of t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-
-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the
mixture was stirred at room temperature for 20 hours. 1 ml of ethyl
acetate and 1 ml of water were added to the reaction solution, and
the layers were separated. The organic layer was concentrated, and
the residue was dissolved in 1.0 ml of methanol. 0.2 ml of aqueous
ammonia solution and 0.2 ml of 31% aqueous hydrogen peroxide were
added to the solution, and the mixture was stirred at 5.degree. C.
for 20 hours. 1 ml of ethyl acetate and 1 ml of water were added to
the reaction solution, and the layers were separated. The organic
layer was concentrated, and the resulting residue was dissolved in
a mixture consisting of 0.5 ml of dichloromethane and 0.5 ml of
trifluoroacetic acid. The mixture was stirred for 1 hour, and then
concentrated. The residue was purified by reverse-phase high
performance liquid chromatography (using an acetonitrile-water
mobile phase (containing 0.1% trifluoroacetic acid)) to give 0.009
g the title compound.
[1643] MS m/e (ESI) 406.28(MH.sup.+--CF.sub.3COOH)
Example 303
3-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzamide trifluoroacetate
[1644] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 3-bromomethylbenzonitrile according to the
method described in Example 302.
[1645] MS m/e (ESI) 406.30(MH.sup.+--CF.sub.3COOH)
Example 304
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzamide trifluoroacetate
[1646] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 4-bromomethylbenzonitrile according to the
method described in Example 302.
[1647] MS m/e (ESI) 406.31(MH.sup.+--CF.sub.3COOH)
Example 305
3-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzoic acid trifluoroacetate
[1648] 0.005 g of potassium carbonate and 0.008 g of methyl
3-(bromomethyl)benzoate were added to a 0.5 ml
N,N-dimethylformamide solution of 0.010 g of t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imid-
azo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the mixture
was stirred at room temperature for 20 hours. 1 ml of ethyl acetate
and 1 ml of water were added to the reaction mixture, and the
layers were separated. The organic layer was concentrated, and the
residue was dissolved in 1.0 ml of methanol. 0.1 ml of a 5N aqueous
sodium hydroxide solution was added to this solution, and the
mixture was stirred at room temperature for 20 hours. 1 ml of ethyl
acetate and 1 ml of water were added to the reaction solution. The
solution was acidified using concentrated hydrochloric acid, and
the layers were separated. The organic layer was concentrated, and
the residue was dissolved in a mixture consisting of 0.5 ml of
dichloromethane and 0.5 ml of trifluoroacetic acid. The mixture was
stirred for one hour and then concentrated. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.008 g of the title compound.
[1649] MS m/e (ESI) 407.29(MH.sup.+--CF.sub.3COOH)
Example 306
4-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]benzoic acid trifluoroacetate
[1650] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and methyl 4-(bromomethyl)benzoate according to
the method described in Example 305.
[1651] MS m/e (ESI) 407.30(MH.sup.+--CF.sub.3COOH)
Example 307
5-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridaz-
in-5-ylmethyl]furan-2-carboxylic acid trifluoroacetate
[1652] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and ethyl 5-(bromomethyl)furan-2-carboxylate
according to the method described in Example 305.
[1653] MS m/e (ESI) 397.28(MH.sup.+--CF.sub.3COOH)
Example 308
3-Benzyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one
trifluoroacetate
[1654] (a) t-Butyl
4-(1-benzyl-6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imid-
azo[4,5-d]pyridazin-2-yl)piperazine-1-carboxylate
[1655] The title compound was obtained by using t-butyl
4-(6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)pi-
perazine-1-carboxylate and benzyl bromide according to the method
described in Example 116(d).
[1656] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 3.13-3.18 (m,
4H) 3.50-3.54 (m, 4H) 4.72 (s, 2H) 5.61 (s, 2H) 5.65 (s, 2H)
7.20-7.35(m, 10H) 8.22 (s, 1H)
[1657] (b)
3-Benzyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin--
4-one trifluoroacetate
[1658] The title compound was obtained by treating t-butyl
4-(1-benzyl-6-benzyloxymethyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazi-
n-2-yl)piperazine-1-carboxylate according to the method described
in Example 117.
[1659] .sup.1H-NMR(CD.sub.3OD) .delta. 3.31-3.37 (m, 4H) 3.40-3.46
(m, 4H) 5.68 (s, 2H) 7.22-7.36(m, 5H) 8.25 (s, 1H)
[1660] MS m/e (ESI) 311.24(MH.sup.+--CF.sub.3COOH)
Example 309
3-Benzyl-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridazin-4--
one trifluoroacetate
[1661] (a) t-Butyl
4-(1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazi-
n-2-yl)piperazine-1-carboxylate
[1662] The title compound was obtained by using
3-benzyl-2-(piperazin-1-yl- )-3,5-dihydroimidazo [4,5-d]
pyridazin-4-one trifluoroacetate according to the method described
in Example 258(a).
[1663] .sup.1H-NMR(CDCl.sub.3) .delta. 1.47 (s, 9H) 3.12-3.16 (m,
4H) 3.47-3.52 (m, 4H) 5.58 (s, 2H) 7.20-7.34(m, 5H) 8.20 (s, 1H)
10.04 (br.s, 1H)
[1664] (b)
3-Benzyl-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]p-
yridazin-4-one trifluoroacetate
[1665] The title compound was obtained by using t-butyl
4-(1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxylate and methyl iodide according to the method described
in Example 258(b).
[1666] .sup.1H-NMR(CD.sub.3OD) .delta. 3.29-3.35 (m, 4H) 3.36-3.41
(m, 4H) 3.83 (s, 3H) 5.68 (s, 2H) 7.21-7.34(m, 5H) 8.20 (s, 1H)
[1667] MS m/e (ESI) 325.01(MH.sup.+--CF.sub.3COOH)
Example 310
3-Benzyl-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-
-d]pyridazin-4-one trifluoroacetate
[1668] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 2-bromoacetophenone according to the method
described in Example 258(b).
[1669] .sup.1H-NMR(CD.sub.3OD) .delta. 3.31-3.36 (m, 4H) 3.44-3.49
(m, 4H) 5.69 (s, 2H) 5.77 (s, 2H) 7.22-7.52(m, 8H) 8.06 (d, J=9.3
Hz, 2H) 8.32 (s, 1H)
[1670] MS m/e (ESI) 429.39(MH.sup.+--CF.sub.3COOH)
Example 311
3-Benzyl-5-(2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyr-
idazin-4-one trifluoroacetate
[1671] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]
piperazine-1-carboxylate and (2-bromoethyl)benzene according to the
method described in Example 258(b).
[1672] .sup.1H-NMR(CDCl.sub.3) .delta. 3.11 (t, J=8.1 Hz, 2H)
3.24-3.29 (m, 4H) 3.37-3.42 (m, 4H) 4.46 (t, J=8.1 Hz, 2H) 5.58 (s,
2H) 7.09-7.34 (m, 10H) 8.20 (s, 1H) MS m/e (ESI)
415.54(MH.sup.+--CF.sub.3COOH)
Example 312
3-Benzyl-5-(2-phenoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]py-
ridazin-4-one trifluoroacetate
[1673] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 2-bromoethyl phenyl ether according to the method
described in Example 258(b).
[1674] .sup.1H-NMR(CDCl.sub.3) .delta. 3.21-3.24 (m, 4H) 3.37-3.42
(m, 4H) 4.37 (t, J=5.8 Hz, 2H) 4.64 (t, J=5.8 Hz, 2H) 5.58 (s, 2H)
6.86-6.94 (m, 3H) 7.07-7.34 (m, 7H) 8.21 (s, 1H)
[1675] MS m/e (ESI) 431.57(MH.sup.+--CF.sub.3COOH)
Example 313
3-benzyl-2-(piperazin-1-yl)-5-(2-propynyl)-3,5-dihydroimidazo[4,5-d]pyrida-
zin-4-one trifluoroacetate
[1676] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 3-bromo-1-propyne according to the method
described in Example 258(b).
[1677] MS m/e (ESI) 349.31(MH.sup.+--CF.sub.3COOH)
Example 314
[3-Benzyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-5-yl-
]acetonitrile trifluoroacetate
[1678] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and bromoacetonitrile according to the method
described in Example 258(b).
[1679] MS m/e (ESI) 350.30(MH.sup.+--CF.sub.3COOH)
Example 315
3-Benzyl-5-(2-hydroxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]py-
ridazin-4-one trifluoroacetate
[1680] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 2-bromoethanol according to the method described
in Example 258(b).
[1681] MS m/e (ESI) 355.32(MH.sup.+--CF.sub.3COOH)
Example 316
3-Benzyl-5-(2-methoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]py-
ridazin-4-one trifluoroacetate
[1682] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and bromoethyl methyl ether according to the method
described in Example 258(b).
[1683] MS m/e (ESI) 369.35(MH.sup.+--CF.sub.3COOH)
Example 317
Ethyl
[3-benzyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazi-
n-5-yl]acetate trifluoroacetate
[1684] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and ethyl bromoacetate according to the method
described in Example 258(b).
[1685] MS m/e (ESI) 397.33(MH.sup.+--CF.sub.3COOH)
Example 318
3-Benzyl-5-[2-(3-methoxyphenyl)-2-oxoethyl]-2-(piperazin-1-yl)-3,5-dihydro-
imidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1686] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 2-bromo-3'-methoxyacetophenone according to the
method described in Example 258(b).
[1687] MS m/e (ESI) 459.34(MH.sup.+--CF.sub.3COOH)
Example 319
2-[3-Benzyl-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]pyridazin-5--
ylmethyl]benzonitrile trifluoroacetate
[1688] The title compound was obtained by using t-butyl
4-[1-benzyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine--
1-carboxylate and 2-bromomethylbenzonitrile according to the method
described in Example 258(b).
[1689] MS m/e (ESI) 326.33(MH.sup.+--CF.sub.3COOH)
Example 320
5-Methyl-2-(piperazin-1-yl)-3-(2-propynyl)-3,5-dihydroimidazo[4,5-d]pyrida-
zin-4-one trifluoroacetate
[1690] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxylate and 3-bromo-1-propyne according to the method
described in Example 258(b).
[1691] .sup.1H-NMR(CD.sub.3OD) .delta. 2.99 (t, J=3.3 Hz, 1H)
3.45-3.49 (m, 4H) 3.65-3.69 (m, 4H) 3.83 (s, 3H) 5.75 (d, J=3.3 Hz,
2H) 8.20 (s, 1H)
[1692] MS m/e (ESI) 273.1(MH.sup.+--CF.sub.3COOH)
Example 321
3-(2-Butenyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one trifluoroacetate
[1693] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxylate and 1-bromo-2-butene according to the method
described in Example 258(b).
[1694] .sup.1H-NMR(CD.sub.3OD) .delta. 1.69 and 1.84 (dd, J=6.3,
1.3 Hz and dd, J=6.3, 1.3 Hz, 3H) 3.43-3.48 (m, 4H) 3.54-3.58 (m,
4H) 3.82 and 3.84 (s, 3H) 4.94 and 5.07 (d, J=6.5 Hz and d, J=6.5
Hz, 2H) 5.63-5.80 and 6.11-6.20 (m, 2H) 8.19 and 8.22 (s, 1H)
[1695] MS m/e (ESI) 289.2(MH.sup.+--CF.sub.3COOH)
Example 322
5-Methyl-3-(2-pentenyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyrida-
zin-4-one trifluoroacetate
[1696] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxylate and 1-bromo-2-pentene according to the method
described in Example 258(b).
[1697] .sup.1H-NMR(CD.sub.3OD) .delta. 0.97 and 1.08 (t, J=7.7 Hz
and t, J=7.7 Hz, 3H) 2.04-2.27 (m, 2H) 3.42-3.46 (m, 4H) 3.54-3.58
(m, 4H) 3.81 and 3.84 (s, 3H) 4.91-4.96 (m, 2H) 5.59-5.81 and
6.14-6.22 (m, 2H) 8.19 and 8.22 (s, 1H)
[1698] MS m/e (ESI) 303.25(MH.sup.+--CF.sub.3COOH)
Example 323
5-Methyl-3-(3-methyl-2-butenyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5--
d]pyridazin-4-one trifluoroacetate
[1699] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxylate and 1-bromo-3-methyl-2-butene according to the method
described in Example 258(b).
[1700] .sup.1H-NMR(CD.sub.3OD) .delta. 1.75 (s, 3H) 1.83 (s, 3H)
3.43-3.47 (m, 4H) 3.52-3.57 (m, 4H) 3.84 (s, 3H) 5.00 (d, J=6.8 Hz,
2H) 5.40-5.45 (m, 1H) 8.17 (s, 1H)
[1701] MS m/e (ESI) 303.27(MH.sup.+--CF.sub.3COOH)
Example 324
3-Cyclopropylmethyl-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]p-
yridazin-4-one trifluoroacetate
[1702] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperazine--
1-carboxyate and cyclopropylmethyl bromide according to the method
described in Example 258(b).
[1703] .sup.1H-NMR(CD.sub.3OD) .delta. 0.44-0.55 (m, 4H) 0.81-0.85
(m, 1H) 3.42-3.46 (m, 4H) 3.54-3.58 (m, 4H) 3.83 (s, 3H) 4.39 (d,
J=6.6 Hz, 2H) 8.21 (s, 1H)
[1704] MS m/e (ESI) 289.25(MH.sup.+--CF.sub.3COOH)
Example 325
5-[2-(2-Aminophenyl)-2-oxoethyl]-3-(2-butynyl)-2-(piperazin-1-yl)-3,5-dihy-
droimidazo[4,5-d]pyridazin-4-one bistrifluoroacetate
[1705] (a) t-Butyl
4-[1-(2-butynyl)-6-[2-(2-nitrophenyl)-2-oxoethyl]-7-oxo-
-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1706] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl]pipera-
zine-1-carboxylate and 2-bromo-2'-nitroacetophenone according to
the method described in Example 258(b).
[1707] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.37-3.44 (m, 4H) 3.50-3.55 (m, 4H) 5.04 (q, J=2.3 Hz, 2H)
5.44 (s, 2H) 7.62 (m, 1H) 7.71-7.74 (m, 2H) 8.13 (d, J=7.9 Hz, 1H)
8.21 (s, 1H)
[1708] (b)
5-[2-(2-Aminophenyl)-2-oxoethyl]-3-(2-butynyl)-2-(piperazin-1-y-
l)-3,5-dihydroimidazo[4,5-d]pyridazin-4-one bistrifluoroacetate
[1709] 2 ml of water, 0.070 g of iron and 0.007 g of ammonium
chloride were added to a 5 ml ethanol solution of 0.058 g of
t-butyl
4-[1-(2-butynyl)-6-[2-(2-nitrophenyl)-2-oxoethyl]-7-oxo-6,7-dihydro-1H-im-
idazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the
mixture was heated under reflux for three hours. The reaction
mixture was filtered, and the filtrate was concentrated under
reduced pressure. The residue was dissolved in 4 ml of
dichloromethane, and 4 ml of trifluoroacetic acid was added
thereto. After the mixture had been stirred for two hours, the
solvent was concentrated under reduced pressure. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.051 g of the title compound.
[1710] .sup.1H-NMR(CD.sub.3OD) .delta. 1.82 (t, J=2.3 Hz, 3H)
3.45-3.50 (m, 4H) 3.68-3.72 (m, 4H) 5.16 (q, J=2.3 Hz, 2H) 5.68 (s,
2H) 6.56 (t, J=7.2 Hz, 1H) 6.67 (d, J=7.2 Hz, 1H) 7.30 (t, J=7.2
Hz, 1H) 7.85 (d, J=7.2 Hz, 1H) 8.25 (s, 1H)
[1711] MS m/e (ESI) 406.22(MH.sup.+--2CF.sub.3COOH)
Example 326
3-(2-Butynyl)-5,7-dimethyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]pyr-
idazin-4-one trifluoroacetate
[1712] (a) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(1-hydroxyethyl)-1H-
-imidazol-2-yl]piperazine-1-carboxylate
[1713] 0.5 ml of a 0.3 M tetrahydrofuran solution of methyl
magnesium bromide was added to a 3 ml tetrahydrofuran solution of
0.050 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piper-
azine-1-carboxylate at -70.degree. C. under a nitrogen atmosphere,
and the mixture was allowed to warm to room temperature. 10 ml of a
5% aqueous ammonium chloride solution was added to this solution,
and the mixture was extracted with 30 ml of ethyl acetate. The
organic layer was washed successively with 10 ml of water and 10 ml
of a saturated sodium chloride solution, and then dried over
magnesium sulfate. The organic layer was concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.049 g of the title compound was obtained
from the fraction eluted with ethyl acetate-hexane (1:1).
[1714] .sup.1H-NMR(CDCl.sub.3) .delta. 1.37 (t, J=7.1 Hz, 3H) 1.47
(d, J=6.9 Hz, 3H) 1.48 (s, 9H) 1.81 (t, J=2.3 Hz, 3H) 3.17-3.22 (m,
4H) 3.55-3.59 (m, 4H) 3.84 (d, J=6.9 Hz, 1H) 4.38 (q, J=7.1 Hz, 2H)
4.78 (q, J=2.3 Hz, 2H) 5.12 (quint, J=6.9 Hz, 1H)
[1715] (b) t-Butyl
4-[4-acetyl-1-(2-butynyl)-5-ethoxycarbonyl-1H-imidazol--
2-yl]piperazine-1-carboxylate
[1716] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(1-hydroxyethyl)-1H-imidazol-2-yl]
piperazine-1-carboxylate according to the method described in
Example 115(g).
[1717] .sup.1H-NMR(CDCl.sub.3) .delta. 1.38 (t, J=7.1 Hz, 3H) 1.48
(s, 9H) 1.79 (t, J=2.3 Hz, 3H) 2.53 (s, 3H) 3.14-3.18 (m, 4H)
3.56-3.60 (m, 4H) 4.38 (q, J=7.1 Hz, 2H) 4.77 (q, J=2.3 Hz, 2H)
[1718] (c)
3-(2-Butynyl)-5,7-dimethyl-2-(piperazin-1-yl)-3,5-dihydroimidaz- o
[4,5-d]pyridazin-4-one trifluoroacetate
[1719] 0.15 ml of methylhydrazine was added to a 3 ml ethanol
solution of 0.019 g of t-butyl
4-[4-acetyl-1-(2-butynyl)-5-ethoxycarbonyl-1H-imidazol-
-2-yl]piperazine-1-carboxylate, and the mixture was heated at
110.degree. C. for 25 hours. The solvent was concentrated under
reduced pressure. The residue was dissolved in 0.5 ml of
dichloromethane, and 0.5 ml of trifluoroacetic acid was added
thereto. The solvent was concentrated under reduced pressure. The
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 0.017 g of the
title compound.
[1720] MS m/e (ESI) 301.33(MH.sup.+--CF.sub.3COOH)
Example 327
3-(2-Butynyl)-7-phenyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-d]
pyridazin-4-one trifluoroacetate
[1721] (a) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(1-hydroxyphenylmet-
hyl)-1H-imidazol-2-yl]piperazine-1-carboxylate
[1722] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-1H-imidazol-2-yl]piperazine-1--
carboxylate and phenylmagnesium bromide according to the method
described in Example 326(a).
[1723] .sup.1H-NMR(CDCl.sub.3) .delta. 1.33 (t, J=7.3 Hz, 3H) 1.48
(s, 9H) 1.81 (t, J=2.2 Hz, 3H) 3.16-3.27 (m, 4H) 3.55-3.59 (m, 4H)
4.24-4.34 (m, 2H) 4.39 (d, J=8.3 Hz, 1H) 4.78 (q, J=2.2 Hz, 2H)
6.09 (d, J=8.3 Hz, 1H) 7.22 (t, J=8.0 Hz, 1H) 7.30 (t, J=8.0 Hz,
2H) 7.41 (d, J=8.0 Hz, 2H)
[1724] (b) t-Butyl
4-[4-benzoyl-1-(2-butynyl)-5-ethoxycarbonyl-1H-imidazol-
-2-yl]piperazine-1-carboxylate
[1725] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(1-hydroxyphenylmethyl)-1H-imidazol-2-
-yl]piperazine-1-carboxylate according to the method described in
Example 115(g).
[1726] .sup.1H-NMR(CDCl.sub.3) .delta. 0.92 (t, J=7.1 Hz, 3H) 1.48
(s, 9H) 1.83 (t, J=2.3 Hz, 3H) 3.22-3.28 (m, 4H) 3.57-3.62 (m, 4H)
4.03 (q, J=7.1 Hz, 2H) 4.88 (q, J=2.3 Hz, 2H) 7.43 (t, J=8.1 Hz,
2H) 7.55 (t, J=8.1 Hz, 1H) 7.92 (d, J=8.1 Hz, 2H)
[1727] (c) t-Butyl
4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl] piperazine-1-carboxylate
[1728] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(1-hydroxyphenylmethyl)-1H-imidazol-2-
-yl]piperazine-1-carboxylate and hydrazine according to the method
described in Example 115(h).
[1729] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.44-3.48 (m, 4H) 3.63-3.67 (m, 4H) 5.15 (q, J=2.3 Hz, 2H)
7.40-7.50 (m, 3H) 8.34 (d, J=8.1 Hz, 2H) 10.70 (s, 1H)
[1730] (d)
3-(2-Butynyl)-7-phenyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,-
5-d]pyridazin-4-one trifluoroacetate
[1731] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate according to the method described in
Example 115(i).
[1732] MS m/e (ESI) 349.30(MH.sup.+--CF.sub.3COOH)
Example 328
3-(2-Butynyl)-5-methyl-7-phenyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5--
d]pyridazin-4-one trifluoroacetate
[1733] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate and methyl iodide according to the
method described in Example 258(b).
[1734] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.4 Hz, 3H)
3.47-3.51 (m, 4H) 3.71-3.75 (m, 4H) 3.92 (s, 3H) 5.22 (q, J=2.4 Hz,
2H) 7.43-7.48 (m, 3H) 8.35 (d, J=8.1 Hz, 2H)
[1735] MS m/e (ESI) 363.31(MH.sup.+--CF.sub.3COOH)
Example 329
[3-(2-Butynyl)-4-oxo-7-phenyl-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-d]-
pyridazin-5-yl]acetic acid trifluoroacetate
[1736] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate and t-butyl bromoacetate according to
the method described in Example 258(b).
[1737] MS m/e (ESI) 407.29(MH.sup.+--CF.sub.3COOH)
Example 330
2-[3-(2-Butynyl)-4-oxo-7-phenyl-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5--
d]pyridazin-5-ylmethyl]benzonitrile trifluoroacetate
[1738] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-4-phenyl-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate and 2-bromomethylbenzonitrile according
to the method described in Example 258(b).
[1739] MS m/e (ESI) 464.33(MH.sup.+--CF.sub.3COOH)
Example 331
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-7-trifluoromethyl-3,5-dihydroimi-
dazo[4,5-d]pyridazin-4-one trifluoroacetate
[1740] (a) t-Butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(2,2,2-trifluoro-1--
hydroxyethyl)-1H-imidazol-2-yl]piperazine-1-carboxylate
[1741] 0.065 g of zinc and a 2 ml N,N-dimethylformamide solution of
0.200 g of trifluoromethyl iodide were added to a 3 ml
N,N-dimethylformamide solution of 0.155 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-formyl-
-1H-imidazol-2-yl]piperazine-1-carboxylate under a nitrogen
atmosphere, and the mixture was stirred under sonication for 30
minutes. 30 ml of ethyl acetate and 30 ml of a 5% ammmonium
chloride solution were added to the mixture. The organic layer was
washed twice with 20 ml of water and then with 20 ml of a saturated
sodium chloride solution, and dried over magnesium sulfate. The
organic liquid was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography. Thus, 0.013 g of
the title compound was obtained from the fraction eluted with ethyl
acetate-hexane (1:9).
[1742] .sup.1H-NMR(CDCl.sub.3) .delta. 1.39 (t, J=6.9 Hz, 3H) 1.48
(s, 9H) 1.83 (t, J=2.4 Hz, 3H) 3.15-3.26 (m, 4H) 3.55-3.60 (m, 4H)
4.34 (qq, J=10.2, 6.9 Hz, 2H) 4.53-4.64 (br.s, 1H) 4.83 (qq,
J=17.6, 2.4 Hz, 2H) 5.39-5.47 (br.s, 1H)
[1743] (b)
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-7-trifluoromethyl-3,5-
-dihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1744] 0.060 g of Dess-Martin reagent was added to a 4 ml
dichloromethane solution of 0.013 g of t-butyl
4-[1-(2-butynyl)-5-ethoxycarbonyl-4-(2,2,2-
-trifluoro-1-hydroxyethyl)-1H-imidazol-2-yl]piperazine-1-carboxylate,
and the mixture was stirred at room temperature for 15 hours. 5 ml
of dichloromethane, 10 ml of a saturated aqueous sodium bicarbonate
solution and 0.100 g of sodium hydrogen sulfite were added to the
solution. The organic layer was dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was dissolved in 4
ml of ethanol, and 0.2 ml of methylhydrazine was added to the
solution. The mixture was heated at 110.degree. C. for 20 hours.
The solvent was concentrated under reduced pressure. The residue
was dissolved in 0.5 ml of dichloromethane, and 0.5 ml of
trifluoroacetic acid was added thereto. The solvent was
concentrated under reduced pressure. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 0.008 g of the title compound.
[1745] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.71-3.75 (m, 4H) 3.87 (s, 3H) 5.18 (q, J=2.3 Hz,
2H)
[1746] MS m/e (ESI) 355.16(MH.sup.+--CF.sub.3COOH)
Example 332
1-(2-Butynyl)-6-methyl-7-oxo-2-(piperazin-1-yl)-6,7-dihydroimidazo
[4,5-d] pyridazine-4-carboxamide trifluoroacetate
[1747] (a) t-Butyl
4-[1-(2-butynyl)-4-(cyano-hydroxymethyl)-5-methoxycarbo-
nyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1748] 0.200 g of sodium cyanide and 0.010 ml of acetic acid were
added to a 15 ml acetonitrile solution of t-butyl
4-[1-(2-butynyl)-5-methoxycarbon-
yl-4-formyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the
mixture was stirred at room temperature for 16 hours. 100 ml of
ethyl acetate was added to the solution, and the mixture was washed
twice with 50 ml of water and then with 50 ml of a saturated sodium
chloride solution. The organic layer was dried over magnesium
sulfate, and the solvent was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography. Thus,
0.274 g of the title compound was obtained from the fraction eluted
with ethyl acetate-hexane (2:3).
[1749] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2.5
Hz, 3H) 3.19-3.23 (m, 4H) 3.56-3.60 (m, 4H) 3.95 (s, 3H) 4.68 (d,
J=9.0 Hz, 1H) 4.82 (q, J=2.5 Hz, 2H) 5.72 (d, J=9.0 Hz, 1H)
[1750] (b) t-Butyl
4-[1-(2-butynyl)-4-(carbamoyl-hydroxymethyl)-5-methoxyc-
arbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1751] 3.2 ml of 30% aqueous hydrogen peroxide and 3.2 ml of 28%
aqueous ammonia solution were added to an 8 ml methanol solution of
0.274 g of t-butyl
4-[1-(2-butynyl)-4-(cyano-hydroxymethyl)-5-methoxycarbonyl-1H-imi-
dazol-2-yl]piperazine-1-carboxylate at 5.degree. C., and the
mixture was stirred for 15 hours. 100 ml of a saturated sodium
hydrogen sulfite solution was added to the solution, and the
mixture was extracted twice with 100 ml of ethyl acetate. The
organic layers were combined together. The conbined organic layers
were dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.039 g of the title compound was obtained
from the fraction eluted with methanol-ethyl acetate (1:9).
[1752] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.83 (t, J=2.5
Hz, 3H) 3.13-3.25 (m, 4H) 3.54-3.57 (m, 4H) 3.91 (s, 3H) 4.33-4.37
(br.s, 1H) 4.77 (q, J=2.5 Hz, 2H) 5.54 (s, 1H) 5.63 (s, 1H) 6.82
(s, 1H)
[1753] (c) t-Butyl
4-[4-aminooxalyl-1-(2-butynyl)-5-methoxycarbonyl-1H-imi-
dazol-2-yl]piperazine-1-carboxylate
[1754] 0.051 ml of triethylamine and a 1 ml dimethyl sulfoxide
solution of 0.058 g of sulfur trioxide pyridine were added to a 2
ml dichloromethane solution of 0.038 g of t-butyl
4-[1-(2-butynyl)-4-(carbamoyl-hydroxymethy-
l)-5-methoxycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate at
0.degree. C., and the mixture was stirred at room temperature for
15 hours. Then, 0.102 ml of triethylamine and a 1 ml dimethyl
sulfoxide solution of 0.116 g of sulfur trioxide pyridine were
added, and the mixture was stirred at room temperature for 8 hours.
50 ml of ethyl acetate was added to the solution, and the organic
layer was washed successively with 20 ml of an aqueous solution of
1% sulfuric acid, 20 ml of a saturated sodium bicarbonate solution,
and 20 ml of a saturated sodium chloride solution. The organic
layer was dried over magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography. Thus, 0.021 g of the title compound was obtained
from the fraction eluted with ethyl acetate-hexane (2:1).
[1755] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.82 (t, J=2.5
Hz, 3H) 3.19-3.23 (m, 4H) 3.56-3.59 (m, 4H) 3.84 (s, 3H) 4.84 (q,
J=2.5 Hz, 2H) 5.62 (br.s, 1H) 7.02 (br.s, 1H)
[1756] (d) t-Butyl
4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-
-1H-dihydroimidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1757] The title compound was obtained by using t-butyl
4-[4-aminooxalyl-1-(2-butynyl)-5-methoxycarbonyl-1H-imidazol-2-yl]piperaz-
ine-1-carboxylate according to the method described in Example
115(h).
[1758] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.84 (t, J=2.3
Hz, 3H) 3.46-3.50 (m, 4H) 3.63-3.66 (m, 4H) 3.99 (s, 3H) 5.12 (q,
J=2.3 Hz, 2H) 6.16 (s, 1H) 8.85 (s, 1H)
[1759] (e)
1-(2-Butynyl)-6-methyl-7-oxo-2-(piperazin-1-yl)-6,7-dihydroimid-
azo[4,5-d]pyridazine-4-carboxamide trifluoroaceate
[1760] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-dihydroimidazo-
[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate according to the
method described in Example 115(i).
[1761] MS m/e (ESI) 330.18(MH.sup.+--CF.sub.3COOH)
Example 333
1-(2-Butynyl)-6-methyl-7-oxo-2-(piperazin-1-yl)-6,7-dihydroimidazo[4,5-d]p-
yridazine-4-carbonitrile trifluoroacetate
[1762] 0.030 ml of triethylamine and 0.015 ml of phosphorus
oxychloride were added to a 1 ml dichloromethane solution of 0.015
g of t-butyl
4-[1-(2-butynyl)-4-carbamoyl-6-methyl-7-oxo-6,7-dihydro-1H-dihydroimidazo-
[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate, and the mixture was
stirred at room temperature for 15 hours. 1 ml of dichloromethane
and 1 ml of trifluoroacetic acid were added to the solution. After
one hour, the solvent was concentrated under reduced pressure. The
residue was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 0.001 g of the
title compound.
[1763] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.74-3.78 (m, 4H) 3.88 (s, 3H) 5.18 (q, J=2.3 Hz,
2H)
[1764] MS m/e (ESI) 312.25(MH.sup.+--CF.sub.3COOH)
Example 334
3-(2-Butynyl)-7-dimethylamino-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimida-
zo[4,5-d]pyridazin-4-one trifluoroacetate
[1765] (a)
1-Benzyl-7-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-
one
[1766] 0.604 g of potassium carbonate and 0.297 ml of methyl iodide
were added to a 30 ml N,N-dimethylformamide solution of 1.035 g of
1-benzyl-7-chloro-1,5-dihydroimidazo[4,5-d]pyridazin-4-one (J. A.
Carbon Journal of the American Chemical Society, 80, pp. 6083,
1958), and the mixture was stirred at room temperature for 15
hours. 300 ml of ethyl acetate and 100 ml of water were added to
the solution, and the organic layer was washed twice with 100 ml of
water and then with 100 ml of a saturated sodium chloride solution.
The organic layer was dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography. Thus, 0.280 g of the title
compound was obtained from the fraction eluted with ethyl
acetate.
[1767] .sup.1H-NMR(CDCl.sub.3) .delta. 3.86 (s, 3H) 5.64 (s, 2H)
7.11-7.16 (m, 2H) 7.35-7.43 (m, 3H) 7.90 (s, 1H)
[1768] (b)
1-Benzyl-7-dimethylamino-5-methyl-1,5-dihydroimidazo[4,5-d]pyri-
dazin-4-one
[1769] A 2 ml aqueous solution of 50% dimethylamine was added to a
2 ml ethanol solution of 0.138 g of
1-benzyl-7-chloro-5-methyl-1,5-dihydroimid-
azo[4,5-d]pyridazin-4one, and the mixture was heated at 130.degree.
C. for 72 hours. The reaction solution was cooled to room
temperature, and concentrated under reduced pressure. The residue
was purified by silica gel column chromatography. Thus, 0.139 g of
the title compound was obtained from the fraction eluted with
methanol-ethyl acetate (1:19).
[1770] .sup.1H-NMR(CDCl.sub.3) .delta. 2.73 (s, 6H) 3.79 (s, 3H)
5.59 (s, 2H) 7.12-7.16 (m, 2H) 7.30-7.39 (m, 3H) 7.79 (s, 1H)
[1771] (c)
1-Benzyl-2-chloro-7-dimethylamino-5-methyl-1,5-dihydroimidazo[4-
,5-d]pyridazin-4-one
[1772] 1.15 ml of a 1 M tetrahydrofuran solution of
dibutylmagnesium was added to a 2 ml tetrahydrofuran solution of
0.320 ml of diisopropylamine at room temperature under a nitrogen
atmosphere, and the mixture was stirred for 8 hours. This solution
was added to a 4 ml tetrahydrofuran solution of 0.162 g of
1-benzyl-7-dimethylamino-5-methyl-1,5-dihydroimida-
zo[4,5-d]pyridazin-4-one at room temperature under a nitrogen
atmosphere, and the mixture was stirred at room temperature for 15
hours. Then, a 5 ml tetrahydrofuran solution of 0.540 g of
hexachloroethane was added dropwise to the solution. After the
mixture had been stirred for 4 hours, 30 ml of a 5% aqueous
ammonium chloride solution was added thereto. The mixture was
extracted with 100 ml of ethyl acetate. The organic layer was
washed successively with 30 ml of water and 30 ml of a saturated
sodium chloride solution, and dried over magnesium sulfate. The
organic layer was concentrated under reduced pressure. The residue
was purified by silica gel column chromatography. Thus, 0.094 g of
the title compound was obtained from the fraction eluted with ethyl
acetate-hexane (2:1).
[1773] .sup.1H-NMR(CDCl.sub.3) .delta. 2.68 (s, 6H) 3.78 (s, 3H)
5.60 (s, 2H) 7.05-7.08 (m, 2H) 7.29-7.37 (m, 3H)
[1774] (d) t-Butyl
4-[1-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro--
1H-imidazo[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1775] The title compound was obtained by using
1-benzyl-2-chloro-7-dimeth-
ylamino-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one according
to the method described in Example 116(c).
[1776] .sup.1H-NMR(CDCl.sub.3) .delta. 1.47 (s, 9H) 2.68 (s, 6H)
3.19-3.22 (m, 4H) 3.41-3.46 (m, 4H) 3.76 (s, 3H) 5.40 (s, 2H) 6.88
(m, 2H) 7.20-7.25 (m, 3H)
[1777] (e) t-Butyl
4-[7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidaz-
o[4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1778] A 5 ml tetrahydrofuran solution of 0.117 g of t-butyl
4-[1-benzyl-7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo[4,5-d]p-
yridazin-2-yl]piperazine-1-carboxylate was added to 15 ml of liquid
ammonia, and 0.009 g of lithium was added to the mixture under
reflux. 1 ml of a 5% aqueous ammonium chloride solution was added
to the solution, and the solvent was evaporated off. The residue
was purified by reverse-phase high performance liquid
chromatography (using an acetonitrile-water mobile phase
(containing 0.1% trifluoroacetic acid)) to give 0.007 g of the
title compound.
[1779] .sup.1H-NMR(CD.sub.3OD) .delta. 1.48 (s, 9H) 3.11 (s, 6H)
3.55-3.58 (m, 8H) 3.69 (s, 3H)
[1780] (f)
3-(2-Butynyl)-7-dimethylamino-5-methyl-2-(piperazin-1-yl)-3,5-d-
ihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1781] The title compound was obtained by using t-butyl
4-[7-dimethylamino-5-methyl-4-oxo-4,5-dihydro-1H-imidazo[4,5-d]pyridazin--
2-yl]piperazine-1-carboxylate and 1-bromo-2-butyne according to the
method described in Example 258(b).
[1782] .sup.1H-NMR(CD.sub.3OD) .delta. 1.80 (t, J=2.3 Hz, 3H) 2.75
(s, 6H) 3.44-3.48 (m, 4H) 3.62-3.65 (m, 4H) 3.68 (s, 3H) 5.16 (q,
J=2.3 Hz, 2H)
[1783] MS m/e (ESI) 330.16(MH.sup.+--CF.sub.3COOH)
Example 335
3-(2-Butynyl)-5-methyl-2-(piperidin-4-yl)-3,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one trifluoroacetate
[1784] (a)
5-Methyl-2-(piperidin-4-yl)-3,5-dihydroimidazo[4,5-d]pyridazin--
4-one trifluoroacetate
[1785] 2.71 g of iron (III) chloride was added to a 16 ml ethanol
solution of 0.292 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one [CAS
No. 4725-76-2] (Martine Beljean-Leymarie, Michel Pays and
Jean-Claude Richer, Canadian Journal of Chemistry 61, pp. 2563,
1983) and 0.426 g of t-butyl 4-formylpiperidine-1-carboxylate, and
the mixture was heated under reflux for 6 hours. The reaction
solution was cooled to room temperature. The solution was filtered,
and concentrated under reduced pressure. The residue was purified
by reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 0.061 g of the title compound.
[1786] .sup.1H-NMR(CD.sub.3OD) .delta. 2.06-2.17 (m, 2H) 2.28-2.35
(m, 2H) 3.15-3.24 (m, 2H) 3.29-3.35 (m, 1H) 3.50-3.56 (m, 2H) 3.85
(s, 3H) 8.28 (s, 1H)
[1787] (b) t-Butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazi-
n-2-yl)piperidine-1-carboxylate
[1788] The title compound was obtained by using
5-methyl-2-(piperidin-4-yl- )-3,5-dihydroimidazo [4,5-d]
pyridazin-4-one trifluoroacetate according to the method described
in Example 258(a).
[1789] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 2.00-2.16 (m,
4H) 2.85-2.99 (br.s, 2H) 3.23 (tt, J=11.9, 4.0 Hz, 1H) 3.95 (s, 3H)
4.11-4.40 (br.s, 2H) 8.39 (s, 1H) 13.90 (s, 1H)
[1790] (c) t-Butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl]piperidine-1-carboxylate
[1791] The title compound was obtained by using t-butyl
4-(6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2-yl)piperidine--
1-carboxylate according to the method described in Example
119(d).
[1792] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.81 (t, J=2.3
Hz, 3H) 1.93-2.00 (m, 4H) 2.85-2.96 (br.s, 2H) 3.14 (quint, J=7.9
Hz, 1H) 3.85 (s, 3H) 4.16-4.37 (br.s, 2H) 5.39 (q, J=2.3 Hz, 2H)
8.24 (s, 1H)
[1793] (d)
3-(2-Butynyl)-5-methyl-2-(piperidin-4-yl)-3,5-dihydroimidazo[4,-
5-d]pyridazin-4-one trifluoroacetate
[1794] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperidine-1-carboxylate according to the method described in
Example 115(i).
[1795] .sup.1H-NMR(CD.sub.3OD) .delta. 1.80 (t, J=2.3 Hz, 3H)
2.10-2.11 (m, 2H) 2.25-2.32 (m, 2H) 3.18-3.41 (m, 3H) 3.56-3.61 (m,
2H) 3.83 (s, 3H) 5.47 (t, J=2.3 Hz, 2H) 8.27 (s, 1H)
[1796] MS m/e (ESI) 286.27(MH.sup.+--CF.sub.3COOH)
Example 336
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-
-4-one trifluoroacetate
[1797] (a) 3-(2-Butynyl)-4-chloro-3H-imidazo[4,5-c]pyridine
[1798] 2.0 g of 4-chloro-1H-imidazo[4,5-c]pyridine, 1.37 ml of
1-bromo-2-butyne, and 1.98 g of potassium carbonate were suspended
in 15 ml of N,N-dimethylformamide, and the suspension was stirred
at room temperature for 18 hours. The reaction solution was diluted
with ethyl acetate, and washed with water. The organic layer was
dried over anhydrous magnesium sulfate, then filtered. The filtrate
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography. Thus, 1.79 g of a 1:1 mixture
consisting of the title compound and the compound alkylated at the
1-position was obtained from the fraction eluted with hexane-ethyl
acetate (1:2).
[1799] (b) 3-(2-Butynyl)-2,4-dichloro-3H-imidazo[4,5-c]pyridine
[1800] 2.22 ml of a tetrahydrofuran solution of lithium
diisopropylamide was added dropwise to a 5 ml tetrahydrofuran
solution of 490 mg of 3-(2-butynyl)-4-chloro-3H-imidazo [4,5-c]
pyridine in a dry ice-methanol bath, and the mixture was stirred
below -66.degree. C. for 20 minutes. The resulting reaction mixture
was added dropwise to a 2 ml tetrahydrofuran solution of 1.13 g of
hexachloroethane while the temperature of the mixture was
controlled to be -63.degree. C. or lower. The mixture was stirred
for one hour and 40 minutes in the same bath, and then a saturated
aqueous ammonium chloride solution was added thereto. The resulting
mixture was extracted twice with ethyl acetate, and the organic
layer was dried over anhydrous magnesium sulfate, then filtered.
The filtrate was concentrated under reduced pressure. Then, the
resulting residue was purified by silica gel column chromatography.
Thus, 120 mg of brown oily material was obtained from the fraction
eluted with hexane-ethyl acetate (2:1).
[1801] .sup.1H-NMR(d6-DMSO) .delta.: 1.78 (s, 3H) 5.29 (s, 2H) 7.70
(d, J=5.6 Hz, 1H) 8.21 (d, J=5.6 Hz, 1H)
[1802] (c) t-Butyl
4-[3-(2-butynyl)-4-chloro-3H-imidazo[4,5-c]pyridin-2-yl-
]piperazine-1-carboxylate
[1803] 211 mg of t-butyl
3-(2-butynyl)-2,4-dichloro-3H-imidazo[4,5-c]pyrid- ine, 197 mg of
piperazine-1-carboxylate, and 222 mg of sodium bicarbonate were
dissolved in ethanol, and the mixture was stirred at 80.degree. C.
for 30 minutes and then at room temperature for three hours and 20
minutes. The reaction solution was diluted with ethyl acetate, and
the solution was washed with water. The organic layer was dried
over anhydrous magnesium sulfate, then filtered. The filtrate was
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography. Thus, 244 mg of the title
compound was obtained from the fraction eluted with hexane-ethyl
acetate (3:1).
[1804] .sup.1H-NMR(CDCl.sub.3) .delta.: 1.52 (s, 9H) 1.87 (s, 3H)
3.47-3.49 (m, 4H) 3.65-3.68 (m, 4H) 4.94 (s, 2H) 7.41 (d, J=5.2 Hz,
1H) 8.15 (d, J=5.2 Hz, 1H)
[1805] (d)
3-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,-
5-c]pyridin-4-one trifluoroacetate
[1806] 98 mg of sodium acetate was dissolved in 2 ml of dimethyl
sulfoxide containing 0.3 mmol of t-butyl
4-[3-(2-butynyl)-4-chloro-3H-imidazo[4,5-c-
]pyridin-2-yl]piperazine-1-carboxylate, and the mixture was stirred
at 120.degree. C. for 4 hours. Then, 100 mg of potassium carbonate
and 1 ml of methyl iodide were added to the reaction solution. The
mixture was stirred at room temperature. The reaction solution was
diluted with ethyl acetate, and the solution was washed with water.
The organic layer was dried over anhydrous magnesium sulfate, then
filtered. The filtrate was concentrated under reduced pressure. The
residue was purified by silica gel column chromatography. 5 mg of
the product obtained from the fraction eluted with methanol-ethyl
acetate (1:10) was dissolved in 0.5 ml of trifluoroacetic acid, and
the mixture was concentrated. The residue was purified by
reverse-phase high performance liquid chromatography (using an
acetonitrile-water mobile phase (containing 0.1% trifluoroacetic
acid)) to give 0.55 mg of the title compound.
[1807] MS m/e (ESI) 286(MH.sup.+--CF.sub.3COOH)
Example 337
3-Benzyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one
trifluoroacetate
[1808] (a) Allyl-(3-nitropyridin-4-yl)amine
[1809] 40 ml of allylamine was added to a 400 ml ethanol solution
of 18.0 g of 4-ethoxy-3-nitropyridine hydrochloride, and the
mixture was heated under reflux for 8 hours. The reaction solution
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography. Thus, 13.6 g of the title
compound was obtained from the fraction eluted with ethyl
acetate-hexane (1:1).
[1810] .sup.1H-NMR(CDCl.sub.3) .delta. 4.00 (m, 2H) 5.29-5.35 (m,
2H) 5.87-5.98 (m, 1H) 6.63 (d, J=6.5 Hz, 1H) 8.30 (d, J=6.5 Hz, 1H)
8.31 (br.s, 1H) 9.23 (s, 1H)
[1811] (b) N*4*-allyl-2-chloropyridine-3,4-diamine
[1812] 55 ml of 35% hydrochloric acid was added to 3.02 g of
allyl-(3-nitropyridin-4-yl) amine, and the mixture was heated to
90.degree. C. 19.1 g of tin chloride was added to the solution, and
the mixture was kept at 90.degree. C. for 30 minutes. The reaction
solution was cooled in an ice-water bath, and then 250 ml ice/water
was added thereto. The reaction solution was concentrated under
reduced pressure, and then 250 ml of ammonia-saturated methanol was
added thereto. The mixture was stirred for 20 hours. 750 ml of
ethyl acetate was added to the solution, and the mixture was
filtered through celite. The filtrate was concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography. Thus, 2.88 g of the title compound was obtained
from the fraction eluted with ethyl acetate-hexane (1:1).
[1813] .sup.1H-NMR(CDCl.sub.3) .delta. 3.29-3.58 (br.s, 2H) 3.84
(d, J=6.3 Hz, 2H) 4.26-4.37 (br.s, 1H) 5.24 (d, J=11.0 Hz, 1H) 5.29
(d, J=16.0 Hz, 1H) 5.85-5.98 (ddt, J=16.0, 11.0, 6.5 Hz, 1H) 6.43
(d, J=6.5 Hz, 1H) 7.66 (d, J=6.5 Hz, 1H)
[1814] (c)
1-Allyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one
[1815] A 400 ml acetonitrile solution of 4.46 g of
N,N'-disuccinimidyl carbonate was added to an acetonitrile solution
containing 2.88 g of N*4*-allyl-2-chloropyridine-3,4-diamine, and
the mixture was heated under reflux for 70 hours. The solvent was
concentrated under reduced pressure, and the residue was dissolved
in a mixture consisting of 500 ml of ethyl acetate and 300 ml of
water. The organic layer was washed twice with 100 ml of 1N
hydrochloric acid and then with 100 ml of a saturated sodium
chloride solution. The organic layer was dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography. Thus, 2.30 g of the
title compound was obtained from the fraction eluted with ethyl
acetate-dichloromethane (1:1).
[1816] .sup.1H-NMR(CDCl.sub.3) .delta. 4.51 (d, J=5.7 Hz, 1H) 5.25
(d, J=16.0 Hz, 1H) 5.30 (d, J=10.9 Hz, 1H) 5.85-5.95 (ddt, J=16.0,
10.9, 5.7 Hz, 1H) 6.91 (d, J=6.9 Hz, 1H) 8.10 (d, J=6.9 Hz, 1H)
8.99 (br.s, 1H)
[1817] (d)
1-Allyl-3-benzyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-on-
e
[1818] 0.76 g of potassium carbonate and 0.94 g of benzyl bromide
were added to a 50 ml N,N-dimethylformamide solution of 1.05 g of
1-allyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one, and the
mixture was stirred at room temperature for 14 hours. 300 ml of
water, and 300 ml of ethyl acetate were added to the solution, and
the organic layer was washed three times with 100 ml of water and
then with 100 ml of a saturated sodium chloride solution. The
organic layer was dried over magnesium sulfate, and concentrated
under reduced pressure to give 1.57 g of the title compound.
[1819] .sup.1H-NMR(CDCl.sub.3) .delta. 4.56 (d, J=5.7 Hz, 1H) 5.23
(d, J=16.0 Hz, 1H) 5.30 (d, J=10.9 Hz, 1H) 5.44 (s, 2H) 5.85-5.95
(ddt, J=16.0, 10.9, 5.7 Hz, 1H) 6.91 (d, J=6.9 Hz, 1H) 7.25-7.34
(m, 5H) 8.08 (d, J=6.9 Hz, 1H) 8.99 (br.s, 1H)
[1820] (e)
3-Benzyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one
[1821] 1.5 ml of water, 1.06 g of 4-methyl morpholine N-oxide, 3 ml
of an aqueous solution of 2% osmic acid, and a 6 ml aqueous
solution of 1.94 g of sodium periodate were added to a 15 ml
1,4-dioxane solution of 0.75 g of
1-allyl-3-benzyl-4-chloro-1,3-dihydroimidazo[4,5-c]pyridin-2-one,
and the mixture was heated at 60.degree. C. for 18 hours. 200 ml of
water was added to the solution, and the mixture was extracted with
100 ml of ethyl acetate. The organic layer was washed twice with 50
ml of water and then washed with 50 ml of a saturated sodium
chloride solution. The organic layer was dried over magnesium
sulfate, and concentrated under reduced pressure. The residue was
purified by silica gel column chromatography. Thus, 0.38 g of the
title compound was obtained from the fraction eluted with ethyl
acetate-hexane (1:1).
[1822] .sup.1H-NMR(CDCl.sub.3) .delta. 5.44 (s, 2H) 7.01 (d, J=6.5
Hz, 1H) 7.30-7.38 (m, 5H) 8.08 (d, J=6.5 Hz, 1H) 9.18 (s, 1H)
[1823] (f) 3-Benzyl-2,
4-dichloro-1,3-dihydroimidazo[4,5-c]pyridine
[1824] 5 ml of phosphorus oxychloride and 0.338 g of phosphorus
pentachloride were added to 0.383 g of
3-benzyl-4-chloro-1,3-dihydroimida- zo[4,5-c]pyridin-2-one, and the
mixture was heated under reflux for 24 hours. The solvent was
concentrated under reduced pressure, and the residue was poured
into 50 g of ice/water. The mixture was extracted with 100 ml of
ethyl acetate. The organic layer was dried over magnesium sulfate,
and concentrated under reduced pressure. The residue was purified
by silica gel column chromatography. Thus, 0.13 g of the title
compound was obtained from the fraction eluted with ethyl
acetate-hexane (2:1).
[1825] .sup.1H-NMR(CDCl.sub.3) .delta. 5.43 (s, 2H) 7.12 (d, J=6.5
Hz, 1H) 7.30-7.38 (m, 5H) 8.18 (d, J=6.5 Hz, 1H)
[1826] (g) t-Butyl
4-(3-benzyl-4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)pipe-
razine-1carboxylate
[1827] 0.094 g of t-butyl piperazine-1-carboxylate was added to a 1
ml N,N-dimethylformamide solution of 0.127 g of
3-benzyl-2,4-dichloro-1,3-di- hydroimidazo[4,5-c]pyridine, and the
mixture was heated at 150.degree. C. for two hours. 25 ml of ethyl
acetate was added to the mixture, and the organic layer was washed
three times with 10 ml of water and then with 10 ml of an aqueous
solution saturated with sodium chloride. The organic liquid was
dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.029 g of the title compound was obtained
from the fraction eluted with ethyl acetate-hexane (3:2).
[1828] .sup.1H-NMR(CDCl.sub.3) .delta. 1.44 (s, 9H) 3.21-3.25 (m,
4H) 3.49-3.53 (m, 4H) 5.53 (s, 2H) 7.08 (d, J=6.5 Hz, 1H) 7.30-7.38
(m, 5H) 8.14 (d, J=6.5 Hz, 1H)
[1829] (h)
3-Benzyl-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-4--
one trifluoroacetate
[1830] 1 ml of water and 1 ml of 35% hydrochloric acid were added
to a 2 ml N,N-dimethylformamide solution of 0.029 g of t-butyl
4-(3-benzyl-4-chloro-3H-imidazo[4,5-c]pyridin-2-yl)piperazine-1carboxylat-
e, and the mixture was heated under reflux for 36 hours. The
solvent was concentrated under reduced pressure. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.006 g of the title compound.
[1831] MS m/e (ESI) 310.29(MH.sup.+--CF.sub.3COOH)
Example 338
3-(2-Butynyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one
trifluoroacetate
[1832] (a)
2-bromo-1-(2-butynyl)-1H-imidazole-4,5-dicarbonitrile
[1833] 69.8 g of potassium carbonate and 50 ml
N,N-dimethylformamide solution of 74 ml of 1-bromo-2-butyne were
added to a 520 ml N,N-dimethylformamide solution of 90.6 g of
2-bromo-1H-imidazole-4,5-dica- rbonitrile [CAS No 50847-09-1], and
the mixture was heated at 50.degree. C. for 8 hours. 1 L of ethyl
acetate and 500 ml of water were added to the solution, and the
organic layer was washed twice with 500 ml of water and then with
500 ml of a saturated sodium chloride solution. The organic layer
was dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 48.0 g of the title compound was obtained
from the fraction eluted with ethyl acetate-hexane (1:4).
[1834] .sup.1H-NMR(CDCl.sub.3) .delta. 1.87 (t, J=2.3 Hz, 3H) 4.85
(q, J=2.3 Hz, 2H)
[1835] (b) Ethyl
2-bromo-1-(2-butynyl)-5-cyano-1H-imidazole-4-carboxylate
[1836] 25 ml of concentrated sulfuric acid was added to a 500 ml
ethanol solution of 48.0 g of
2-bromo-1-(2-butynyl)-1H-imidazole-4,5-dicarbonitri- le, and the
mixture was heated under reflux for 110 hours. The reaction
solution was cooled to room temperature, and then concentrated
under reduced pressure. The residue was dissolved in a mixture
consisting of 500 ml of ethyl acetate and 500 ml of water, and the
pH of the solution was adjusted to 8 using potassium hydroxide. The
aqueous layer was extracted with 500 ml of ethyl acetate, and the
organic layers were combined together. The organic layer was dried
over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography. Thus,
21.7 g of the title compound was obtained from the fraction eluted
with ethyl acetate-hexane (1:3).
[1837] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.0 Hz, 3H) 1.87
(t, J=2.3 Hz, 3H) 4.46 (q, J=7.0 Hz, 2H) 4.85 (q, J=2.3 Hz, 2H)
[1838] (c) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-ethoxycarbonyl-1H-imidazol-2- -yl]
piperazine-1-carboxylate
[1839] 25.1 g of the title compound was obtained by using 21.7 g of
ethyl 2-bromo-1-(2-butynyl)-5-cyano-1H-imidazole-4-carboxylate
according to the method described in Example 115(b).
[1840] .sup.1H-NMR(CDCl.sub.3) .delta. 1.43 (t, J=7.0 Hz, 3H) 1.49
(s, 9H) 1.87 (t, J=2.3 Hz, 3H) 3.22-3.26 (m, 4H) 3.56-3.61 (m, 4H)
4.44 (q, J=7.0 Hz, 2H) 4.68 (q, J=2.3 Hz, 2H)
[1841] (d) t-Butyl
4-[1-(2-butynyl)-4-carboxy-5-cyano-1H-imidazol-2-yl]
piperazine-1-carboxylate
[1842] 16 ml of a 5N aqueous sodium hydroxide solution was added to
a 500 ml ethanol solution of 25.1 g of t-butyl
4-[1-(2-butynyl)-5-cyano-4-ethox-
ycarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the
mixture was stirred at room temperature for two hours. Then, the
solvent was concentrated under reduced pressure. The residue was
dissolved in a mixture consisting of 1L of ethyl acetate and 500 ml
of water. 50 ml of 2N hydrochloric acid was added to the solution.
The organic layer was washed with 200 ml of a saturated sodium
chloride solution, and dried over magnesium sulfate. The organic
liquid was concentrated under reduced pressure to give 23.2 g of
the title compound.
[1843] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.87 (t, J=2.3
Hz, 3H) 3.22-3.26 (m, 4H) 3.56-3.61 (m, 4H) 4.68 (q, J=2.3 Hz,
2H)
[1844] (e) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-1H-imidazol-2-- yl]
piperazine-1-carboxylate
[1845] 6.9 g of triethylamine and then 100 ml tetrahydrofuran
solution of 10.19 g of isobutyl chloroformate were added dropwise
to 600 ml of tetrahydrofuran containing 22.9 g of t-butyl
4-[1-(2-butynyl)-4-carboxy-5- -cyano-1H-imidazol-2-yl]
piperazine-1-carboxylate at -10.degree. C. After the precipitate
had been removed by filtration, the solution was again cooled to
-10.degree. C. A 100 ml aqueous solution of 9.45 g of sodium
borohydride was added dropwise to the solution. After one hour, 500
ml of ethyl acetate and 500 ml of water were added to the solution.
The pH of the solution was adjusted to 5 using 1 N hydrochloric
acid, and then adjusted to 10 using a saturated sodium bicarbonate
solution. The organic layer was washed successively with 500 ml of
water and 500 ml of a saturated sodium chloride solution. The
organic layer was dried over magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography. Thus, 19.1 g of the title compound was
obtained from the fraction eluted with ethyl acetate-hexane
(4:1).
[1846] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.84 (t, J=2.3
Hz, 3H) 2.26 (t, J=6.3 Hz, 1H) 3.13-3.17 (m, 4H) 3.53-3.57 (m, 4H)
4.58 (q, J=2.3 Hz, 2H) 4.64 (d, J=6.3 Hz, 2H)
[1847] (f) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-formyl-1H-imidazol-2-yl]pipe-
razine-1carboxylate
[1848] 3.28 g of manganese dioxide was added to a 5 ml
dichloromethane solution of 1.35 g of t-butyl
4-[1-(2-butynyl)-5-cyano-4-hydroxymethyl-1H-
-imidazol-2-yl]piperazine-1-carboxylate. The reaction solution was
stirred at room temperature for 15 hours, then stirred and heated
under reflux for five hours. The solution was filtered, and then
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography. Thus, 1.11 g of the title
compound was obtained from the fraction eluted with ethyl
acetate-hexane (2:3).
[1849] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.88 (t, J=2.3
Hz, 3H) 3.24-3.28 (m, 4H) 3.59-3.63 (m, 4H) 4.70 (q, J=2.3 Hz, 2H)
9.87 (s, 1H)
[1850] (g) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-(2-ethoxycarbonylvinyl)-1H-i-
midazol-2-yl]piperazine-1-carboxylate
[1851] 0.038 g of sodium hydride was added to a 5 ml
tetrahydrofuran solution of 0.243 g of ethyl
diethylphosphonoacetate at 5.degree. C. under a nitrogen
atmosphere. 0.310 g of t-butyl 4-[1-(2-butynyl)-5-cyano--
4-formyl-1H-imidazol-2-yl] piperazine-1-carboxylate dissolved in 5
ml of tetrahydrofuran was added, and the mixture was stirred for 30
minutes. 50 ml of ethyl acetate and 25 ml of 0.1N sodium hydroxide
were added to the solution. The organic layer was dried over
magnesium sulfate, and concentrated under reduced pressure. The
residue was purified by silica gel column chromatography. Thus,
0.380 g of the title compound was obtained from the fraction eluted
with ethyl acetate-hexane (3:7).
[1852] .sup.1H-NMR(CDCl.sub.3) .delta. 1.33 (t, J=7.4 Hz, 3H) 1.50
(s, 9H) 1.86 (t, J=2.3 Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4H)
4.25 (q, J=7.4 Hz, 2H) 4.59 (q, J=2.3 Hz, 2H) 6.70 (d, J=15.8 Hz,
1H) 7.50 (d, J=15.8 Hz, 1H)
[1853] (h) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-(2-carboxyvinyl)-1H-imidazol-
-2-yl]piperazine-1-carboxylate
[1854] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-5-cyano-4-(2-ethoxycarbonylvinyl)-1H-imidazol-2-yl]piper-
azine-1-carboxylate according to the method described in Example
338(d).
[1855] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.86 (t, J=2.3
Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4H) 4.59 (q, J=2.3 Hz, 2H)
6.70 (d, J=15.8 Hz, 1H) 7.50 (d, J=15.8 Hz, 1H)
[1856] (i) t-Butyl
4-[1-(2-butynyl)-5-cyano-4-(2-azidecarbonylvinyl)-1H-im-
idazol-2-yl] piperazine-1-carboxylate
[1857] A mixture consisting of 0.200 g of t-butyl.
4-[1-(2-butynyl)-5-cyan-
o-4-(2-carboxyvinyl)-1H-imidazol-2-yl]piperazine-1-carboxylate,
0.073 ml of triethylamine, and a 2 ml t-butanol solution of 0.108
ml of diphenylphosphoryl azide was heated at 50.degree. C. under a
nitrogen atmosphere for 4 hours. 50 ml of ethyl acetate was added
to the solution, and the mixture was washed with 20 ml of water.
The organic layer was dried over magnesium sulfate, and
concentrated under reduced pressure. The residue was purified by
silica gel column chromatography. Thus, 0.178 g of the title
compound was obtained from the fraction eluted with ethyl
acetate-hexane (2:3).
[1858] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.86 (t, J=2.2
Hz, 3H) 3.19-3.23 (m, 4H) 3.55-3.59 (m, 4.H) 4.59 (q, J=2.2 Hz, 2H)
6.67 (d, J=15.4 Hz, 1H) 7.56 (d, J=15.4 Hz, 1H)
[1859] (j) t-Butyl
4-[4-(2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-cya-
no-1H-imidazol-2-yl] piperazine-1-carboxylate
[1860] A 10 ml t-butanol solution of 0.178 g of t-butyl
4-[1-(2-butynyl)-5-cyano-4-(2-azide
carbonylvinyl)-1H-imidazol-2-yl] piperazine-1-carboxylate was
heated under reflux under a nitrogen atmosphere for 15 hours. The
solvent was concentrated under reduced pressure. The residue was
purified by silica gel column chromatography. Thus, 0.169 g of the
title compound was obtained from the fraction eluted with ethyl
acetate-hexane (9:11).
[1861] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.84 (t, J=2.2
Hz, 3H) 3.16-3.19 (m, 4H) 3.54-3.58 (m, 4H) 4.51 (q, J=2.2 Hz, 2H)
5.83 (d, J=15.0 Hz, 1H) 6.43-6.53 (m, 1H) 7.55-7.66 (m, 1H)
[1862] (k) t-Butyl
4-[4-(2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-car-
bamoyl-1H-imidazol-2-yl] piperazine-1-carboxylate
[1863] The title compound was obtained by using t-butyl
4-[4-(2-t-butoxycarbonylaminovinyl)-1-(2-butynyl)-5-cyano-1H-imidazol-2-y-
l]piperazine-1-carboxylate according to the method described in
Example 332(b).
[1864] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.84 (t, J=2.2
Hz, 3H) 3.21-3.25 (m, 4H) 3.54-3.58 (m, 4H) 4.68 (q, J=2.2 Hz, 2H)
5.90 (br.s, 1H) 6.36 (br.d, J=14.8 Hz, 1H) 6.92 (br.d, J=8.4 Hz,
1H) 7.45 (br.s, 1H) 7.52 (m, 1H)
[1865] (l)
3-(2-Butynyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-c]pyrid-
in-4-one trifluoroacetate
[1866] 0.1 ml of 5N hydrochloric acid was added to a 0.3 ml ethanol
solution of 0.0075 g of t-butyl
4-[4-(2-t-butoxycarbonylaminovinyl)-1-(2--
butynyl)-5-carbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and
the mixture was stirred at room temperature for 15 hours. The
solvent was concentrated under reduced pressure. The residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.0043 g of the title compound.
[1867] .sup.1H-NMR(CD.sub.3OD) .delta. 1.81 (t, J=2.4 Hz, 3H)
3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 5.15 (q, J=2.4 Hz, 2H) 6.60 (d,
J=7.1 Hz, 1H) 7.18 (d, J=7.1 Hz, 1H)
[1868] MS m/e (ESI) 272.32(MH.sup.+--CF.sub.3COOH)
Example 339
3-(2-Butynyl)-5-(2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5--
c]pyridin-4-one trifluoroacetate
[1869] (a) t-Butyl
4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyr-
idin-2-yl]piperazine-1-carboxylate
[1870] The title compound was obtained by using
3-(2-butynyl)-2-(piperazin-
-1-yl)-3,5-dihydroimidazo[4,5-c]pyridin-4-one trifluoroacetate
according to the method described in Example 258(a).
[1871] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.35-3.39 (m, 4H) 3.60-3.64 (m, 4H) 5.07 (q, J=2.3 Hz, 2H)
6.55 (d, J=7.1 Hz, 1H) 6.97 (d, J=7.1 Hz, 1H)
[1872] (b)
3-(2-Butynyl)-5-(2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroi-
midazo[4,5-c]pyridin-4-one trifluoroacetate
[1873] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperazi-
ne-1-carboxylate and (2-bromoethyl)benzene according to the method
described in Example 258(b).
[1874] .sup.1H-NMR(CD.sub.3OD) .delta. 1.83 (t, J=2.4 Hz, 3H) 3.05
(t, J=7.3 Hz, 2H) 3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 4.26 (t,
J=7.3 Hz, 2H) 5.18 (q, J=2.4 Hz, 2H) 6.46 (d, J=7.3 Hz, 1H) 7.15
(d, J=7.3 Hz, 1H) 7.16-7.30 (m, 5H)
[1875] MS m/e (ESI) 376.36(MH.sup.+--CF.sub.3COOH)
Example 340
3-(2-Butynyl)-5-(2-phenoxyethyl)-2-(piperazin-1-yl)-3,5-dihydroimidazo[4,5-
-c]pyridin-4-one trifluoroacetate
[1876] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperazi-
ne-1-carboxylate and 2-bromoethyl phenyl ether according to the
method described in Example 258(b).
[1877] .sup.1H-NMR(CD.sub.3OD) .delta. 1.80 (t, J=2.4 Hz, 3H)
3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 4.30 (t, J=5.5 Hz, 2H) 4.44 (t,
J=5.5 Hz, 2H) 5.16 (q, J=2.4 Hz, 2H) 6.59 (d, J=6.1 Hz, 1H)
6.87-6.91 (m, 3H) 7.20-7.24 (m, 2H) 7.50 (d, J=6.1 Hz, 1H)
[1878] MS m/e (ESI) 392.34(MH.sup.+--CF.sub.3COOH)
Example 341
3-(2-Butynyl)-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl)-3,5-dihydroimidaz-
o[4,5-c]pyridin-4-one trifluoroacetate
[1879] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperazi-
ne-1-carboxylate and 2-bromoacetophenone according to the method
described in Example 258(b).
[1880] .sup.1H-NMR(CD.sub.3OD) .delta. 1.79 (t, J=2.3 Hz, 3H)
3.46-3.50 (m, 4H) 3.64-3.68 (m, 4H) 5.16 (q, J=2.3 Hz, 2H) 5.61 (s,
2H) 6.65 (d, J=7.3 Hz, 1H) 7.37 (d, J=7.3 Hz, 1H) 7.57 (t, J=8.0
Hz, 2H) 7.69 (t, J=8.0 Hz, 1H) 8.10 (d, J=8.0 Hz, 2H)
[1881] MS m/e (ESI) 392.34(MH.sup.+--CF.sub.3COOH)
Example 342
2-[3-(2-Butynyl)-4-oxo-2-(piperazin-1-yl)-3,4-dihydroimidazo[4,5-c]pyridin-
-5-ylmethyl]benzonitrile trifluoroacetate
[1882] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-7-oxo-6,7-dihydro-1H-imidazo[4,5-d]pyridin-2-yl]piperazi-
ne-1-carboxylate and 2-bromomethylbenzonitrile according to the
method described in Example 258(b).
[1883] .sup.1H-NMR(CD.sub.3OD) .delta. 1.78 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.64-3.67 (m, 4H) 5.14 (q, J=2.3 Hz, 2H) 5.47 (s,
2H) 6.67 (d, J=7.0 Hz, 1H) 7.20 (dd, J=7.2, 1.0 Hz, 1H) 7.46 (td,
J=7.2, 1.0 Hz, 1H) 7.50 (d, J=7.0 Hz, 1H) 7.60 (td, J=7.2, 1.0 Hz,
1H) 7.80 (dd, J=7.2, 1.0 Hz, 1H)
[1884] MS m/e (ESI) 387.34(MH.sup.+--CF.sub.3COOH)
Example 343
Methyl
3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidazo[4,5-c]pyr-
idine-6-carboxylate trifluoroacetate
[1885] (a) t-Butyl
4-[1-(2-butynyl)-4-hydroxymethyl-5-thiocarbamoyl-1H-imi-
dazol-2-yl]piperazine-1-carboxylate
[1886] 10 ml of a 50% aqueous solution of ammonium sulfide was
added to a 50 ml ethanol solution of 3.596 g of t-butyl
4-[1-(2-butynyl)-5-cyano-4-h-
ydroxymethyl-1H-imidazol-2-yl]piperazine-1-carboxylate, and the
mixture was stirred at room temperature for 16 hours. 400 ml of
ethyl acetate was added to the solution, and the mixture was washed
three times with 100 ml of water and then with 100 ml of a
saturated sodium chloride solution. The organic layer was dried
over magnesium sulfate, and concentrated under reduced pressure.
The residue was purified by silica gel column chromatography. Thus,
3.221 g of the title compound was obtained from the fraction eluted
with ethyl acetate-hexane(4:1).
[1887] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.84 (t, J=2.4
Hz, 3H) 3.17-3.21 (m, 4H) 3.54-3.60 (m, 4H) 3.62 (t, J=5.8 Hz, 1H)
4.68 (d, J=5.8 Hz, 2H) 5.05 (q, J=2.4 Hz, 2H) 7.35 (br.s, 1H) 8.46
(br.s, 1H)
[1888] (b) t-Butyl
4-[4-(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5--
thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1889] 0.668 g of imidazole and 2.70 g of
t-butylchlorodiphenylsilane were added to a 25 ml
N,N-dimethylformamide solution of 3.221 g of t-butyl
4-[1-(2-butynyl)-4-hydroxymethyl-5-thiocarbamoyl-1H-imidazol-2-yl]piperaz-
ine-1-carboxylate, and the mixture was stirred at room temperature
for 16 hours. 300 ml of ethyl acetate was added to the solution,
and the organic layer was washed three times with 100 ml of water
and then with 100 ml of a saturated sodium chloride solution. The
organic layer was dried over magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography. Thus, 4.357 g of the title compound was
obtained from the fraction eluted with ethyl acetate-hexane
(2:3).
[1890] .sup.1H-NMR(CDCl.sub.3) .delta. 1.05 (s, 9H) 1.49 (s, 9H)
1.84 (t, J=2.4 Hz, 3H) 3.06-3.11 (m, 4H) 3.53-3.57 (m, 4H) 4.74 (s,
2H) 5.19 (q, J=2.4 Hz, 2H) 7.31 (br.d, J=4.1 Hz, 1H) 7.37 (t, J=7.2
Hz, 4H) 7.44 (d, J=7.2 Hz, 2H) 7.63 (d, J=7.2 Hz, 4H) 9.28 (br.d,
J=4.1 Hz, 1H)
[1891] (c) t-Butyl
4-[4-(t-butyldiphenylsilanyloxymethyl)-1-(2-butynyl)-5--
methylsulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1892] 1.23 g of trimethyloxonium tetrafluoroborate was added to a
100 ml dichloromethane solution of 4.351 g of t-butyl
4-[4-(t-butyldiphenylsilan-
yloxymethyl)-1-(2-butynyl)-5-thiocarbamoyl-1H-imidazol-2-yl]piperazine-1-c-
arboxylate, and the mixture was stirred at room temperature for 15
hours. 300 ml of ethyl acetate was added to the solution, and the
organic layer was washed successively with 100 ml of a saturated
sodium bicarbonate solution and 100 ml a saturated ammonium
chloride solution. The organic layer was dried over magnesium
sulfate, and concentrated under reduced pressure to give 4.439 g of
the title compound.
[1893] .sup.1H-NMR(CDCl.sub.3) .delta. 1.05 (s, 9H) 1.49 (s, 9H)
1.84 (br.s, 3H) 2.36 (br.s, 3H) 3.11-3.15 (m, 4H) 3.54-3.58 (m, 4H)
4.63 (br.s, 2H) 4.66 (br.s, 2H) 7.37 (t, J=7.2 Hz, 4H) 7.44 (d,
J=7.2 Hz, 2H) 7.63 (d, J=7.2 Hz, 4H)
[1894] (d) t-Butyl
4-[1-(2-butynyl)-4-hydroxymethyl-5-methylsulfanylcarbon-
yl-1H-imidazol-2-yl]piperazine-1-carboxylate
[1895] 30 ml of 5N hydrochloric acid was added to a 100 ml
tetrahydrofuran solution of 5.05 g of t-butyl 4-[4-(t-butyl
diphenylsilanyloxymethyl)-1-(-
2-butynyl)-5-methylsulfanylcarbonimidoyl-1H-imidazol-2-yl]piperazine-1-car-
boxylate, and the mixture was stirred at room temperature for 22
hours. The solvent was concentrated under reduced pressure. The
residue was dissolved in 100 ml of dichloromethane, and 2.05 g of
di-t-butyl dicarbonate was added thereto. The solution was made
alkaline with 5N sodium hydroxide, and stirred for 2 hours. The
organic layer was dried over magnesium sulfate, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography. Thus, 2.24 g of the title compound was
obtained from the fraction eluted with ethyl acetate-hexane
(2:3).
[1896] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s 9H) 1.84 (t, J=2.3
Hz, 3H) 2.47 (s, 3H) 3.21-3.25 (m, 4H) 3.27 (t, J=5.6 Hz, 1H)
3.56-3.60 (m, 4H) 4.81 (q, J=2.4 Hz, 2H) 4.89 (d, J=5.6 Hz, 2H)
[1897] (e) t-Butyl
4-[1-(2-butynyl)-4-formyl-5-methylsulfanylcarbonyl-1H-i-
midazol-2-yl] piperazine-1-carboxylate
[1898] The title compound was obtained by using t-butyl
4-[1-(2-butynyl)-4-hydroxymethyl-5-methylsulfanylcarbonyl-1H-imidazol-2-y-
l]piperazine-1-carboxylate according to the method described in
Example 115(g).
[1899] .sup.1H-NMR(CDCl.sub.3) .delta. 1.48 (s, 9H) 1.84 (t, J=2.3
Hz, 3H) 2.58 (s, 3H) 3.22-3.26 (m, 4H) 3.56-3.60 (m, 4H) 4.80 (q,
J=2.4 Hz, 2H) 9.88 (s, 1H)
[1900] (f)
2-(4-t-Butoxycarbonylpiperazin-1-yl)-3-(2-butynyl)-4-oxo-3,4-di-
hydroimidazo[4,5-c]pyridine-5,6-dicarboxylic acid 5-benzyl ester
6-methyl ester
[1901] 0.079 g of 1,8-diazabicyclo[5.4.0]-7-undecene and then 5 ml
of dichloromethane containing 0.194 g of t-butyl
4-[1-(2-butynyl)-4-formyl-5-
-methylsulfanylcarbonyl-1H-imidazol-2-yl]piperazine-1-carboxylate
were added to a 2 ml dichloromethane solution of 0.174 g of methyl
benzyloxycarbonylamino-(dimethoxyphosphoryl)-acetate, and the
mixture was stirred at room temperature for 16 hours. The solvent
was concentrated under reduced pressure. The residue was purified
by silica gel column chromatography. Thus, 0.147 g of the title
compound was obtained from the fraction eluted with ethyl
acetate-hexane (3:2).
[1902] .sup.1H-NMR(CDCl.sub.3) .delta. 1.49 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.37-3.41 (m, 4H) 3.59-3.64 (m, 4H) 3.83 (s, 3H) 5.04 (q,
J=2.3 Hz, 2H) 5.46 (s, 2H) 7.33-7.38 (m, 3H) 7.41 (s, 1H) 7.45-7.48
(m, 2H)
[1903] (g) t-Butyl 4-[3-(2-butynyl)-4-oxo-6-trimethoxy
methyl-4,5-dihydro-3H-imidazo[4,5-c]pyridin-2-yl]piperazine-1-carboxylate
[1904] 0.023 g of sodium was added to 2 ml of methanol under a
nitrogen atmosphere. After hydrogen generation stopped, a 2 ml
methanol solution of 0.147 g of
2-(4-t-butoxycarbonypiperazin-1-yl)-3-(2-butynyl)-4-oxo-3,4-
-dihydroimidazo[4,5-c]pyridine-5,6-dicarboxylic acid 5-benzyl ester
6-methyl ester was added to the solution. The mixture was stirred
at room temperature for 16 hours. Then, 40 ml of ethyl acetate, 20
ml of 5% aqueous ammonium chloride solution, and 1 ml of 1 N
hydrochloric acid were added to the solution. The organic layer was
dried over magnesium sulfate, and concentrated under reduced
pressure. The residue was purified by silica gel column
chromatography. Thus, 0.108 g of the title compound was obtained
from the fraction eluted with ethyl acetate.
[1905] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.83 (t, J=2.3
Hz, 3H) 3.20 (s, 9H) 3.37-3.41 (m, 4H) 3.59-3.64 (m, 4H) 5.07 (q,
J=2.3 Hz, 2H) 6.82 (s, 1H) 8.60 (br.s, 1H)
[1906] (h) Methyl
3-(2-butynyl)-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidaz- o
[4,5-c]pyridine-6-carboxylate trifluoroacetate
[1907] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo
[4,5-c]pyridin-2-yl]piperazin-1-carboxylate according to the method
described in Example 338(l).
[1908] .sup.1H-NMR(CD.sub.3OD) .delta. 1.81 (t, J=2.3 Hz, 3H)
3.45-3.49 (m, 4H) 3.64-3.67 (m, 4H) 3.95 (s, 3H) 5.17 (q, J=2.3 Hz,
2H) 7.35 (s, 1H) MS m/e (ESI) 330.16(MH.sup.+--CF.sub.3COOH)
Example 344
Methyl
3-(2-butynyl)-5-methyl-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidazo[-
4,5-c]pyridine-6-carboxylate trifluoroacetate
[1909] 0.024 g of potassium carbonate and 0.027 ml of methyl iodide
were added to a 2 ml N,N-dimethylformamide solution of 0.030 g of
t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo
[4,5-c]pyridin-2-yl]piperazine-1-carboxylate, and the mixture was
heated at 50.degree. C. for 48 hours. 2 ml of ethyl acetate and 2
ml of water were added to the solution. The aqueous layer was
extracted with 1 ml of ethyl acetate. The organic layers were
combined together, and then divided into equal halves. One of the
halves was concentrated by flushing with nitrogen gas, and the
residue was dissolved in 0.5 ml of methanol. The solution was
combined with 0.1 ml of 5N hydrochloric acid, and the mixture was
left for 1 hour. The solvent was removed, and the residue was
purified by reverse-phase high performance liquid chromatography
(using an acetonitrile-water mobile phase (containing 0.1%
trifluoroacetic acid)) to give 0.007 g of the title compound.
[1910] .sup.1H-NMR(CD.sub.3OD) .delta. 1.81 (t, J=2.4 Hz, 3H)
3.45-3.48 (m, 4H) 3.62-3.65 (m, 4H) 3.74 (s, 3H) 3.94. (s, 3H) 5.17
(q, J=2.4 Hz, 2H) 7.25 (s, 1H)
[1911] MS m/e (ESI) 344.30(MH.sup.+--CF.sub.3COOH)
Example 345
3-(2-Butynyl)-5-methyl-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidazo[4,5-c]p-
yridine-6-carboxylic amide trifluoroacetate
[1912] The other half of the solution prepared in Example 344 was
concentrated by flushing with nitrogen gas. The residue was treated
with 1 ml of 28% ammonia water. The solution was heated under
reflux in a sealed tube for 48 hours. The solvent was concentrated
under reduced pressure. Subsequent synthetic steps were carried out
according to the same procedure as used in Example 115(i). Thus,
0.010 g of the title compound was synthesized.
[1913] MS m/e (ESI) 329.32(MH.sup.+--CF.sub.3COOH)
Example 346
Methyl
3-(2-butynyl)-4-oxo-5-(2-oxo-2-phenylethyl)-2-(piperazin-1-yl)-4,5--
dihydroimidazo[4,5-c]pyridine-6-carboxylate trifluoroacetate
[1914] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo
[4,5-c]pyridin-2-yl]piperazine-1-carboxylate and
2-bromoacetophenone according to the method described in Example
344.
[1915] MS m/e (ESI) 448.31(MH.sup.+--CF.sub.3COOH)
Example 347
Methyl
3-(2-butynyl)-5-(2-cyanobenzyl)-4-oxo-2-(piperazin-1-yl)-4,5-dihydr-
oimidazo[4,5-c]pyridine-6-carboxylate trifluoroacetate
[1916] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxy
methyl-4,5-dihydro-3H-imidazo[4,5-c]p-
yridin-2-yl]piperazine-1-carboxylate and 2-bromomethylbenzonitrile
according to the method described in Example 344.
[1917] MS m/e (ESI) 445.32(MH.sup.+--CF.sub.3COOH)
Example 348
3-(2-Butynyl)-5-(2-cyanobenzyl)-4-oxo-2-(piperazin-1-yl)-4,5-dihydroimidaz-
o[4,5-c]pyridine-6-carboxylic amide trifluoroacetate
[1918] The title compound was obtained by using t-butyl
4-[3-(2-butynyl)-4-oxo-6-trimethoxymethyl-4,5-dihydro-3H-imidazo
[4,5-c]pyridin-2-yl]piperazine-1-carboxylate and
2-bromomethylbenzonitril- e according to the method described in
Example 345.
[1919] MS m/e (ESI) 430.34(MH.sup.+--CF.sub.3COOH)
Example 349
1-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-1,5-dihydroimidazo[4,5-d]pyridaz-
in-4-one trifluoroacetate
[1920] (a)-1
3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyri-
dazin-4-one and
[1921] (a) -2
1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyr-
idazin-4-one
[1922] 0.166 g of potassium carbonate and 0.106 .mu.l of 2-butynyl
bromide were added to a 10 ml N,N-dimethylformamide solution of
0.184 g of
2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one, and the
mixture was stirred at room temperature for 18 hours. 50 ml of
ethyl acetate was added to the solution, and the mixture was washed
three times with 20 ml of water and then with 20 ml of a saturated
sodium chloride solution. The organic liquid was dried over
magnesium sulfate, and concentrated under reduced pressure. Then,
the residue was purified by silica gel column chromatography. Thus,
0.175 g of
3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one
was obtained from the fraction eluted with hexane-ethyl acetate
(4:1), and 0.033 g of
1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo[4,5-d]p-
yridazin-4-one was obtained from the fraction eluted with
hexane-ethyl acetate (2:3).
[1923]
3-(2-butynyl)-2-chloro-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin--
4-one
[1924] .sup.1H-NMR(CDCl.sub.3) .delta. 1.82 (t, J=2.3 Hz, 3H) 3.87
(s, 3H) 5.32 (q, J=2.3 Hz, 2H) 8.19 (s, 1H)
[1925] 1-(2-butynyl)-2-chloro-5-methyl-1,5-dihydroimidazo [4,5-d]
pyridazin-4-one
[1926] .sup.1H-NMR(CDCl.sub.3) .delta. 1.87 (t, J=2.3 Hz, 3H) 3.91
(s, 3H) 4.90 (q, J=2.3 Hz, 2H) 8.20 (s, 1H)
[1927] (b) t-Butyl
4-[1-(2-butynyl)-5-methyl-4-oxo-4,5-dihydro-1H-imidazo[-
4,5-d]pyridazin-2-yl]piperazine-1-carboxylate
[1928] The title compound was obtained by using
1-(2-butynyl)-2-chloro-5-m-
ethyl-1,5-dihydroimidazo[4,5-d]pyridazin-4-one and t-butyl
piperazine-1-carboxylate according to the method described in
Example 119(c).
[1929] .sup.1H-NMR(CDCl.sub.3) .delta. 1.50 (s, 9H) 1.87 (t, J=2.3
Hz, 3H) 3.30-3.34 (m, 4H) 3.59-3.63 (m, 4H) 3.90 (s, 3H) 4.70 (q,
J=2.3 Hz, 2H) 8.11 (s, 1H)
[1930] (c)
1-(2-Butynyl)-5-methyl-2-(piperazin-1-yl)-1,5-dihydroimidazo[4,-
5-d]pyridazin-4-one trifluoroacetate
[1931] The title compound was obtained by using t-butyl
4-[5-methyl-1-(2-butynyl)-4-oxo-4,5-dihydro-1H-imidazo[4,5-d]pyridazin-2--
yl]piperazine-1-carboxylate according to the method described in
Example 115(i).
[1932] .sup.1H-NMR(CD.sub.3OD) .delta. 1.84 (t, J=2.4 Hz, 3H)
3.44-3.48 (m, 4H) 3.58-3.62 (m, 4H) 3.86 (s, 3H) 4.96 (q, J=2.4 Hz,
2H) 8.39 (s, 1H)
[1933] MS m/e (ESI) 287.17(MH.sup.+--CF.sub.3COOH)
Example 350
2-[(1R*,2R*)2-aminocyclohexylamino]-3-(2-butynyl)-5-methyl-3,5-dihydroimid-
azo[4,5-d]pyridazin-4-one trifluoroacetate
[1934] The title compound was obtained by reacting
3-(2-butynyl)-2-chloro--
5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one and
trans-1,2-cyclohexanediamine by the method as used in Example
119(c) and purifying the product by reverse-phase high performance
liquid chromatography.
[1935] .sup.1H-NMR(CD.sub.3OD) .delta. 1.39-1.49 (m, 2H) 1.50-1.61
(m, 2H) 1.80 (t, J=2.3 Hz, 3H) 1.85-1.92 (m, 2H) 2.11-2.18 (m, 2H)
3.19 (td, J=11.0, 4.1 Hz, 1H) 3.80 (s, 3H) 3.93 (td, J=11.0, 4.2
Hz, 1H) 4.91 (dq, J=18.0, 2.3 Hz, 1H) 5.44 (dq, J=18.0, 2.3 Hz, 1H)
8.07 (s, 1H)
[1936] MS m/e (ESI) 315.19(MH.sup.+--CF.sub.3COOH)
Example 351
2-[(1R*,2S*)2-aminocyclohexylamino]-3-(2-butynyl)-5-methyl-3,5-dihydroimid-
azo[4,5-d]pyridazin-4-one trifluoroacetate
[1937] The title compound was obtained by reacting
3-(2-butynyl)-2-chloro--
5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one and
cis-1,2-cyclohexanediamine by the method as used in Example 119(c)
and purifying the product by reverse-phase high performance liquid
chromatography.
[1938] .sup.1H-NMR(CD.sub.3OD) .delta. 1.54-1.68 (m, 3H) 1.71-1.81
(m, 2H) 1.83 (t, J=2.4 Hz, 3H) 1.85-1.91 (m, 2H) 1.91-2.01 (m, 1H)
3.69 (m, 1H) 3.80 (s, 3H) 4.37 (m, 1H) 5.04 (dq, J=18.3, 2.4 Hz,
1H) 5.55 (dq, J=18.3, 2.4 Hz, 1H) 8.09 (s, 1H)
[1939] MS m/e (ESI) 315.27(MH.sup.+--CF.sub.3COOH)
Example 352
3-(2-Butynyl)-5-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)-3,5-dihydroimida-
zo[4,5-d]pyridazin-4-one trifluoroacetate
[1940] (a)
5-Methyl-2-(pyridin-4-yl)-1,5-dihydroimidazo[4,5-d]pyridazin-4--
one
[1941] 0.560 g of 4,5-diamino-2-methyl-2H-pyridazin-3-one and 0.535
g of 4-pyridinecarbaldehyde were added to 10 ml of nitrobenzene,
and the mixture was heated at 190.degree. C. under a nitrogen
atmosphere for three hours. The reaction solution was cooled down,
and the precipitate was collected by filtration to give 0.381 g of
the title compound.
[1942] .sup.1H-NMR(d.sub.6DMSO) .delta. 3.78 (s, 3H) 8.14 (d, J=6.0
Hz, 2H) 8.48 (s, 1H) 8.76 (d, J=6.0 Hz, 2H)
[1943] MS m/e (ESI) 228.1(MH.sup.+)
[1944] (b)
3-(2-Butynyl)-5-methyl-2-(pyridin-4-yl)-3,5-dihydroimidazo[4,5--
d]pyridazin-4-one
[1945] The title compound was obtained by using
5-methyl-2-(pyridin-4-yl)--
1,5-dihydro-imidazo[4,5-d]pyridazin-4one and 2-butynyl bromide
according to the method described in Example 119(d).
[1946] .sup.1H-NMR(CDCl.sub.3) .delta. 1.84 (t, J=2.3 Hz, 3H) 3.91
(s, 3H) 5.37 (q, J=2.3 Hz, 2H) 7.89 (d, J=6.1 Hz, 2H) 8.32 (s, 1H)
8.85 (d, J=2.3 Hz, 2H)
[1947] (c) 4-[1-(2-Butynyl)-6-methyl-7-oxo-6,7-dihydro-1H
imidazo[4,5-d]pyridazin-2-yl]-1-(4-methoxybenzyl)pyridinium
chloride
[1948] 0.045 g of
3-(2-butynyl)-5-methyl-2-(pyridin-4-yl)-3,5-dihydroimida-
zo[4,5-d]pyridazin-4-one and 0.060 .mu.l of p-methoxybenzyl
chloride were added to 0.100 ml of N,N-dimethylformamide, and the
mixture was stirred at 65.degree. C. under a nitrogen atmosphere
for 4 hours. The reaction solution was cooled down, and 1 ml of
acetone and 1 ml of diethyl ether were added thereto. The
precipitate was collected by filtration to give 0.060 g of the
title compound.
[1949] .sup.1H-NMR(CD.sub.3OD) .delta. 1.75 (t, J=2.3 Hz, 3H) 3.74
(s, 3H) 3.77 (s, 3H) 5.64 (q, J=2.3 Hz, 2H) 5.86 (s, 2H) 7.05 (d,
J=8.3 Hz, 2H) 7.54 (d, J=8.3 Hz, 2H) 8.43 (s, 1H) 8.70 (d, J=6.3
Hz, 2H) 9.24 (d, J=6.3 Hz, 2H)
[1950] (d)
3-(2-Butynyl)-2-[1-(4-methoxybenzyl)-1,2,3,6-tetrahydropyridin--
4-yl]-5-methyl-3,5-dihydroimidazo[4,5-d]pyridazin-4-one
[1951] 0.020 g of sodium borohydride was added to a 5 ml methanol
solution of 0.060 g of
4-[1-(2-butynyl)-6-methyl-7-oxo-6,7-dihydro-1H-imidazo[4,5--
d]pyridazin-2-yl]-1-(4-methoxybenzyl)pyridinium chloride, and the
mixture was stirred for one hour. 15 ml of water and 0.1 ml of 5N
hydrochloric acid were added to the solution to quench the reducing
agent. Then, the solution was made alkaline with 1 ml of 5N sodium
hydroxide, and extracted with 30 ml of ethyl acetate. The organic
layer was dried over magnesium sulfate, and concentrated under
reduced pressure. The residue was purified by silica gel column
chromatography. Thus, 0.033 g of the title compound was obtained
from the fraction eluted with methanol-ethyl acetate (1:19).
[1952] .sup.1H-NMR(CDCl.sub.3) .delta. 1.80 (t, J=2.4 Hz, 3H)
2.71-2.78 (m, 4H) 3.25-3.28 (m, 2H) 3.62 (s, 2H) 3.82 (s, 3H) 3.87
(s, 3H) 5.30 (q, J=2.4 Hz, 2H) 6.61 (m, 1H) 6.89 (d, J=9.1 Hz, 2H)
7.30 (d, J=9.1 Hz, 2H) 8.22 (s, 1H)
[1953] (e)
3-(2-Butynyl)-5-methyl-2-(1,2,3,6-tetrahydropyridin-4-yl)-3,5-d-
ihydroimidazo[4,5-d]pyridazin-4-one trifluoroacetate
[1954] 0.10 ml of 1-chloroethyl chloroformate was added to a 2 ml
1,2-dichloroethane solution of 0.033 g of
3-(2-butynyl)-2-[1-(4-methoxybe-
nzyl)-1,2,3,6-tetrahydropyridin-4-yl]-5-methyl-3,5-dihydroimidazo[4,5-d]py-
ridazin-4-one, and the mixture was heated under reflux for 90
minutes. 5 ml of methanol was added to the solution, and the
mixture was further heated under reflux for 4 hours. The solvent
was then concentrated under reduced pressure. The residue was
purified by reverse-phase high performance liquid chromatography to
give 0.010 g of the title compound.
[1955] .sup.1H-NMR(CD.sub.3OD) .delta. 1.81 (t, J=2.4 Hz, 3H)
2.89-2.94 (m, 2H) 3.52 (t, J=6.2 Hz, 2H) 3.84 (s, 3H) 4.01 (q,
J=2.8 Hz, 2H) 5.27 (q, J=2.4 Hz, 2H) 6.67 (m, 1H) 8.30 (s, 1H)
[1956] MS m/e (ESI) 284.22(MH.sup.+--CF.sub.3COOH)
Assay Example 1
DPPIV-Inhibiting Activity Assay
[1957] Porcine kidney-derived DPP-IV was dissolved in a reaction
buffer (50 mM Tris-HCl (pH 7.4)/0.1% BSA) at a concentration of 10
m.mu./ml. After 110 .mu.l of this solution had been combined with
15 .mu.l of an agent, the mixture was incubated at room temperature
for 20 minutes. 25 .mu.l of 2 mM Gly-Pro-p-nitroanilide was added
(to a final concentration of 0.33 mM) to the solution to initiate
the enzyme reaction. The reaction time was 20 minutes. 25 .mu.l of
1N phosphoric acid solution was added to the reaction solution to
quench the reaction. Absorbance of this solution at 405 nm was
determined, and then the inhibition rate for the enzyme reaction
was calculated to determine the IC.sub.50.
2 TABLE 1 Example No. IC.sub.50 (.mu.M) Example 1 0.287 Example 4
0.211 Example 7 0.401 Example 9 0.141 Example 12 0.183 Example 13
0.125 Example 16 0.272 Example 20 0.152 Example 22 0.170 Example 29
0.310 Example 53 0.0469 Example 64 0.126 Example 73 0.0334 Example
76 0.0865 Example 79 0.0357 Example 82 0.161 Example 83 0.0274
Example 86 0.00408 Example 88 0.00289 Example 98 0.00969 Example
109 1.48 Example 119 0.154 Example 120 0.116 Example 122 0.0153
Example 129 0.115 Example 142 0.0685 Example 146 0.0817 Example 159
0.0377 Example 229 0.00897 Example 230 0.000890 Example 234 0.00174
Example 235 0.00144 Example 238 0.00119 Example 243 0.00215 Example
248 0.00640 Example 266 0.00155 Example 267 0.00722 Example 297
0.00622 Example 311 0.0775 Example 341 0.00732
Assay Example 2
Effect on the Glucose Tolerance of Normal Mice (in Vivo Test)
[1958] Animal: male C57BL/6N mice (purchased from Charles River
Japan, Inc.)
[1959] Method:
[1960] [Preparation and Administration of Test Compounds]
[1961] Each test compound was suspended in a 0.5% methyl cellulose
(MC) solution at the concentration indicated below in Table. The
suspension of a test compound, and of NVP DPP728 (U.S. Pat. No.
6,011,155), or a 0.5% MC solution that was used as a medium control
group was given orally at a dose of 10 mL/kg. After 30 minutes, a
glucose solution was given orally at a dose of 10 mL/kg. The dose
of glucose given orally was 2 g/kg.
[1962] [Blood Collection and Determination of Blood Glucose
Levels]
[1963] Immediately before administering the test compound and NVP
DPP728, immediately before administering the glucose solution, and
30, 60, and 120 minutes after the administration, without
anesthetic the caudal vein was lightly cut with a razor blade to
let blood out. 10 .mu.l of blood was collected and immediately
combined with 140 .mu.l of 0.6 M perchloric acid. The sample was
centrifuged at 1500 g at 4.degree. C. for 10 minutes in a
refrigerated centrifuge GS-6KR (Beckman Corp.). The glucose
concentration in the resulting supernatant was determined using
Glucose CII TEST WAKO (Wako Pure Chemical Industries).
[1964] Result:
[1965] The area under the blood glucose level time curve
(AUC.sub.0-120; Area Under the Curve) obtained from the curve of
time vs. blood glucose level between the start of glucose
administration and 120 minutes after administration was determined
for each of the 0.5% MC solution-treated group, NVP DPP728-treated
group and test compound-treated group. The improvement factor for
glucose tolerance of a test compound was determined by taking the
AUC.sub.0-120 of the 0.5% MC solution-treated group as 100% and the
AUC.sub.0-120 of the NVP DPP728 (10 mg/kg)-treated group as 0%
according to the formula indicated below.
[1966] Improvement factor for glucose tolerance (%)=(AUC.sub.0-120
of the group treated with a test compound-AUC.sub.0-120 of the
group treated with NVP DPP728 (10 mg/kg))/AUC.sub.0-120 of the
group treated with 0.5% MC solution-AUC.sub.0-120 of the group
treated with NVP DPP728 (10 mg/kg)).times.100
[1967] The lower the % value, the grater the improvement in the
glucose tolerance.
[1968] Some of the novel condensed imidazole derivatives of the
present invention were found to have significant effects on the
glucose tolerance of normal mice through the in vivo experiment
described above which comprised oral administration of the
compounds at doses of 0.1-10 (mg/kg).
Assay Example 3
[1969] Acceptable Timing of Administration in in Vivo Test
[1970] A drug for treating postprandial hyperglycemia is ideally
required to have comparable effectiveness in treating postprandial
hyperglycemia when it is given immediately before meals as well as
1 hour before meals. Thus, an excellent drug exhibiting higher
efficacy can be achieved by widening the range of acceptable timing
of administration
[1971] Method:
[1972] The respective tests described below were carried out in
combination with the in vivo test (administration before 0.5 hour)
as described in Assay Example 2:
[1973] 1. A test compound is administered simultaneously with
glucose loading (2 g/kg) (the test compound is suspended in an
aqueous solution of 0.5% methyl cellulose; the solution is combined
with an equal volume of a glucose solution; and the mixture is
administered orally at a dose of 10 ml/kg);
[1974] 2. A test compound is administered one hour before glucose
loading (2 g/kg) (the test compound suspended in an aqueous
solution of 0.5% methyl cellulose is administered orally one hour
before the oral administration of the glucose solution; each is
given orally at a dose of 10 ml/kg).
[1975] The improvement factor for glucose tolerance is estimated in
each test. The range of acceptable timing of administration can be
assessed by estimating whether comparable degrees of improvement
are obtained by the two types of administrations, preferably when
the dose difference is 3 times or lower, and most preferably
estimating whether comparable degrees of improvement are obtained
by the two types of administrations when the doses are identical.
Such representative compounds of the present invention (in
particular, compounds selected from the group consisting of those
shown in Examples 82, 119, 120, 122, 229, and 267) were shown to
have sufficiently wide ranges of acceptable timing of
administration as defined above.
Assay Example 4
Purpose: Effect of a Test Compound on the Blood Glucose Level of
Fasted Male Wistar Rats (in Vivo Test)
[1976] Animal: male Wistar rats (purchased from Charles River
Japan, Inc.)
[1977] Method:
[1978] [Preparation and Administration of Test Compounds]
[1979] A test compound was suspended in 0.5% methyl cellulose (MC)
solution and administered orally at a dose of 5 mL/kg. The control
group was treated with a 0.5% MC solution. The solution was
administered orally at a dose of 5 mL/kg.
[1980] [Blood Collection and Determination of Blood Glucose
Levels]
[1981] Immediately before administering a test compound or 0.5% MC
solution, and 0.5, 1, and 3 hours after the administration, without
anesthetic the caudal vein was lightly cut with a razor blade to
let the blood out. 10 .mu.L of blood was collected and combined
with 140 .mu.L of 0.6 M perchloric acid solution. The sample was
centrifuged at 3000 g at 4.degree. C. for 10 minutes and the
resultant supernatant was assayed with the Glucose CII TEST WAKO
(Wako Pure Chemical Industries).
[1982] Result:
[1983] Some of the novel condensed imidazole derivatives of the
present invention (in particular, compounds selected from the group
consisting of those shown in Examples 82, 119, 120, 122, 229, and
267) showed no significant change in the blood glucose level in
blood samples collected at any sampling time, as compared with the
control group treated with the medium alone in the in vivo
experiment as described above, where each compound was administered
orally at a dose of 10-30 (mg/kg).
Assay Example 5
Effect of a Test Compound on the Glucose Tolerance of Male Zucker
fa/fa Rat (Obesity Type II Diabetes Mellitus Model Animal) (in Vivo
Test)
[1984] Animal: male Zucker fa/fa rats (purchased from Charles River
Japan, Inc.)
[1985] Method:
[1986] [Preparation and Administration of Test Compounds]
[1987] The test compound was suspended in 0.5% methyl cellulose
(MC) solution. The suspension of the test compound or a 0.5% MC
solution that was used as a medium-control group was given orally
at a dose of 5 mL/kg. After 0.5 hr, a glucose solution was given
orally at a dose of 5 mL/kg. The dose of glucose given orally was 2
g/kg.
[1988] [Blood Collection Method and Determination of Blood Glucose,
Insulin, and GLP-1 Levels]
[1989] Immediately before administering a test compound or 0.5% MC
solution, immediately before the glucose loading, and 0.5, 1, 2,
and 3 hours after the glucose loading, without anesthetic the
caudal vein was slightly cut with a razor blade to let blood out.
250 .mu.l of blood was collected using a heparin-coated capillary,
and transferred into a centrifuge tube. The sample was centrifuged
at 10000 g at 4.degree. C. for 2 minutes. The levels of insulin and
GLP-1 in the resultant supernatant were determined with an insulin
assay kit (Morinaga Biochemical Institute) and Active GLP-1 ELISA
kit (Linco), respectively. At the same time, 10 .mu.l of blood was
collected and combined with 140 .mu.l of 0.6 M perchloric acid
solution. The sample was centrifuged at 3000 g at 4.degree. C. for
10 minutes, and the resultant supernatant was assayed with the
Glucose CII TEST WAKO (Wako Pure Chemical Industries). Only the
blood glucose level was determined three hours after glucose
loading.
[1990] Result:
[1991] The area under the blood glucose level (AUC.sub.Glu(0-3 h))
between the start of glucose administration and 3 hours after
administration, the area under insulin level time curve
(AUC.sub.ins(0-2 h)), and the area under GLP-1 level time curve
(AUC.sub.GLP-1(0-2 h)) were determined for each of the 0.5% MC
solution-treated group and eath of the test compound-treated
groups. The variation in glucose tolerance, variations in the
insulin level, and GLP-1 level due to the test compound were
determined by taking the AUC of the 0.5% MC solution-treated group
as 100% according to the following formula.
[1992] The rate of change in glucose tolerance (%)=AUC.sub.0-3 h of
the group treated with a test compound/(AUC.sub.0-3 h of the group
treated with 0.5% MC solution).times.100
[1993] The rate of change in insulin and GLP-1 level
(%)=AUC.sub.0-2 h of the group treated with a test
compound/(AUC.sub.0-2 h of the group treated with 0.5% MC
solution).times.100
[1994] Some of the novel condensed imidazole derivatives of the
present invention (in particular, compounds selected from the group
consisting of those shown in Examples 82, 119, 120, 122, 229, and
267) were shown to change the insulin and GLP-1 levels at rates
higher than 100% and exhibit glucose tolerance at a rate of change
lower than 100% in the in vivo experiment as described above, where
each compound was administered orally at a dose of 0.1-10
(mg/kg).
Assay Example 6
Assessment for Drug-Metabolizing Enzyme (Cytochrome P450)
[1995] The inhibitory activity IC.sub.50 was determined using an
expression system for recombinant P450 and the fluorescent
substrates (GENTEST Corp.) indicated in Tables 2 and 3 according to
the Assay Procedure (WWW.gentest.com) prepared by GENTEST Corp.
P450 molecular species assessed were the five molecular species,
CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The experimental
conditions used are shown below. The fluorescence intensity was
determined using a plate reader (CYTO FLUOR Multi-Well Plate Reader
Series 4000; PerSeptive Biosystems Corp.). The degree of inhibition
was determined as a mean value from nine independent assays per
second using as an index the intensity fluorescence emitted from
the metabolite of the fluorescent substrate.
[1996] The substrates, metabolites, inhibitors, excitation
wavelengths, and fluorescence wavelengths used in the assay are
shown in Table 2.
3TABLE 2 Fluo- Excitation rescence Molecular wave- wave- species of
Sub- Me- length length p450 strate tabolite Inhibitor (nm) (nm)
CYP1A2 CEC CHC .alpha.- 409 460 Naphthoflavone CYP2C9 MFC HFC
Sulfaphenazole 409 530 CYP2C19 CEC CHC Tranylcypromine 409 460
CYP2D6 AMMC AHMC Quinidine 390 460 CYP3A4 BFC HFC Ketoconazole 409
530
[1997] The abbreviations for the substrates and metabolites are
listed in Table 3.
4TABLE 3 CEC 3-Cyano-7-ethoxycoumarin CHC 3-Cyano-7-hydroxycoumarin
MFC 7-Methoxy-4-trifluoromethylcoumarin HFC
7-Hydroxy-4-trifluoromethylcoumarin CEC 7-Ethoxy-3-cyanocoumarin
CHC 7-Hydroxy-3-cyanocoumarin AMMC
3-[2-(N,N-diethyl-N-methylamino)ethyl]-7-methoxy-4- methylcoumarin
AHMC 3-[2-(N,N-diethylamino)ethyl]-7-hydroxy-4-meth- ylcoumarin BFC
7-Benzyloxy-4-(trifluoromethyl)-coumarin HFC
7-hydroxy-4-(trifluoromethyl)-coumarin
[1998] <Assay Result>
[1999] The compounds of the present invention were evaluated for
their ability to inhibit metabolic reactions due to P450 in Assay
Example 6. This experiment showed that representative compounds of
the present invention (in particular, compounds selected from the
group consisting of those shown in Examples 82, 119, 120, 122, 229,
and 267) exhibited 10 .mu.M or higher IC.sub.50 values with respect
to five out of the P450 group of molecules, namely the molecular
species, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4.
Assay Example 7
Suppression of hERG Channel Current
[2000] (1) Activity towards inhibiting the hERG channel current was
evaluated according to the report Zhou, Z et al, Biophysical
Journal, 74(1), 230-241 (1998).
[2001] (2) This experiment was carried out using HEK-293 cells into
which the hERG channel gene (subtype 1) had been introduced (the
cell line was established by the inventors).
[2002] (3) One to several days before the experiment, cells were
plated on a poly-lysine-coated glass plate. The cells were cultured
until the day of the experiment. At the start of the experiment,
the cell-seeded glass plate was transferred into a bath for current
measurement. The hERG channel current was measured by the voltage
clamp method using the patch clamp technique. The current was
measured using a current amplifier (Axon Instruments). The current
was recorded and analyzed using pCLAMP software (Axon
Instruments).
[2003] (4) The hERG channel current was induced by applying to the
cells a depolarizing pulse from a holding potential of -80 mV to
+20 mV for 5 seconds and to -50 mV for 4 seconds, at 20 second
intervals. After the current became stable in a control solution,
the cells were perfused with solutions containing various
concentrations of test compounds.
[2004] (5) The amplitude of the hERG channel current was defined as
the peak value of the tail current observed upon restoring the
potential to -50 mV. The inhibiting effect of a test compound on
the hERG channel current (IC.sub.50) was estimated based on the
change in the peak value of tail current upon addition of the test
compound at various concentrations. The peak value of tail current
recorded for a normal solution was taken as 100%.
[2005] <Test result>
[2006] Representative compounds of the present invention (in
particular, compounds selected from the group consisting of those
shown in Examples 82, 119,120, 122, 229, and 267) were evaluated
for their ability to inhibit the hERG channel current in Assay
Example 7. The IC.sub.50 values of the compounds were 30 .mu.M or
higher.
[2007] The structural formulae for the compounds in Production
examples and Examples described above are shown below.
5 Production Example 1. a) 75 Production Example 1. b) 76
Production Example 1. c) 77 Production Example 1. d) 78 Production
Example 2. a) 79 Production Example 2. b) 80 Production Example 2.
c) 81 Production Example 2. d) 82 Example 1. a) 83 Example 1. b) 84
Example 1. c) 85 Example 1. d) 86 Example 1. e) 87 Example 1. f) 88
Example 1. g)-1 89 Example 1. g)-2 90 Example 1. h) 91 Example 2.
92 Example 3. a) 93 Example 3. b) 94 Example 3. c) 95 Example 3. d)
96 Example 3. e) 97 Example 3. f) 98 Example 4. a) 99 Example 4. b)
100 Example 4. c) 101 Example 4. d) 102 Example 5. 103 Example 6.
104 Example 7. 105 Example 8. 106 Example 9. 107 Example 10. 108
Example 11. a)-1 109 Example 11. a)-2 110 Example 11. b) 111
Example 12. 112 Example 13. 113 Example 14. 114 Example 15. 115
Example 16. 116 Example 17. 117 Example 18. 118 Example 19. 119
Example 20. 120 Example 21. 121 Example 22. 122 Example 23. 123
Example 24. 124 Example 25. 125 Example 26. 126 Example 27. 127
Example 28. 128 Example 29. 129 Example 30. 130 Example 31. 131
Example 32. 132 Example 33. 133 Example 34. 134 Example 35. 135
Example 36. 136 Example 37. 137 Example 38. 138 Example 39. 139
Example 40. 140 Example 41. 141 Example 42. 142 Example 43. 143
Example 44. 144 Example 45. 145 Example 46. 146 Example 47. 147
Example 48. 148 Example 49. 149 Example 50. 150 Example 51. 151
Example 52. 152 Example 53. 153 Example 54. 154 Example 55. 155
Example 56. 156 Example 57. 157 Example 58. 158 Example 59. 159
Example 60. 160 Example 61. 161 Example 62. 162 Example 63. 163
Example 64. 164 Example 65. 165 Example 66. 166 Example 67. 167
Example 68. 168 Example 69. 169 Example 70. 170 Example 71. 171
Example 72. 172 Example 73. 173 Example 74. 174 Example 75. 175
Example 76. 176 Example 77. 177 Example 78. 178 Example 79. 179
Example 80. 180 Example 81. 181 Example 82. 182 Example 83. a) 183
Example 83. b) 184 Example 84. 185 Example 85. 186 Example 86. a)
187 Example 86. b) 188 Example 86. c) 189 Example 86. d) 190
Example 86. e) 191 Example 87. 192 Example 88. 193 Example 89. 194
Example 90. 195 Example 91. 196 Example 92. 197 Example 93. 198
Example 94. 199 Example 95. a) 200 Example 95. b) 201 Example 96.
a) 202 Example 96. b) 203 Example 96. c) 204 Example 97. 205
Example 98. 206 Example 99. a) 207 Example 99. b) 208 Example 100.
a) 209 Example 100. b) 210 Example 101. 211 Example 102. 212
Example 103. a) 213 Example 103. b) 214 Example 104. 215 Example
105. 216 Example 106. a) 217 Example 106. b) 218 Example 107. 219
Example 108. 220 Example 109. a) 221 Example 109. b) 222 Example
109. c) 223 Example 110. 224 Example 111. 225 Example 112. 226
Example 113. 227 Example 114. 228 Example 115. a) 229 Example 115.
b) 230 Example 115. c) 231 Example 115. d) 232 Example 115. e) 233
Example 115. f) 234 Example 115. g) 235 Example 115. h) 236 Example
115. i) 237 Example 116. a) 238 Example 116. b) 239 Example 116. c)
240 Example 116. d) 241 Example 116. e) 242 Example 117. 243
Example 118. a) 244 Example 118. b) 245 Example 119. a) 246 Example
119. b) 247 Example 119. c) 248 Example 119. d) 249 Example 119. e)
250 Example 120. a) 251 Example 120. b) 252 Example 120. c) 253
Example 121 254 Example 122. 255 Example 123. 256 Example 124. 257
Example 125. 258 Example 126. 259 Example 127. 260 Example 128. 261
Example 129. 262 Example 130. 263 Example 131. 264 Example 132. 265
Example 133. 266 Example 134. 267 Example 135. 268 Example 136. 269
Example 137. 270 Example 138. 271 Example 139. 272 Example 140. 273
Example 141. 274 Example 142. 275 Example 143. 276 Example 144. 277
Example 145. 278 Example 146. 279 Example 147. 280 Example 148. 281
Example 149. 282 Example 150. 283 Example 151. 284 Example 152. 285
Example 153. 286 Example 154. 287 Example 155. 288 Example 156. 289
Example 157. 290 Example 158. 291 Example 159. 292 Example 160. 293
Example 161. 294 Example 162. 295 Example 163. 296 Example 164. 297
Example 165. 298 Example 166. 299 Example 167. 300 Example 168. 301
Example 169. 302 Example 170. 303 Example 171. 304 Example 172. 305
Example 173. 306 Example 174. 307 Example 175. 308 Example 176. 309
Example 177. 310 Example 178. 311 Example 179. 312 Example 180. 313
Example 181. 314 Example 182. 315 Example 183. 316 Example 184. 317
Example 185. 318 Example 186. 319 Example 187. 320 Example 188. 321
Example 189. 322 Example 190. 323 Example 191. 324 Example 192. 325
Example 193. 326 Example 194. 327 Example 195. 328 Example 196. 329
Example 197. 330 Example 198. 331 Example 199. 332 Example 200,
201. 333 Example 202. 334 Example 203. 335 Example 204. 336 Example
205. 337 Example 206. 338 Example 207. 339 Example 208. 340 Example
209. 341 Example 210. 342 Example 211. 343 Example 212. 344 Example
213. 345 Example 214. 346 Example 215. 347 Example 216. 348 Example
217. 349 Example 218. 350 Example 219. 351 Example 220. 352 Example
221. 353 Example 222. 354 Example 223. a) 355 Example 223. b) 356
Example 224. 357 Example 225. 358 Example 226. 359 Example 227. 360
Example 228. 361 Example 229. a) 362 Example 229. b) 363 Example
230. 364 Example 231. 365 Example 232. 366 Example 233. 367 Example
234. 368 Example 235. a) 369 Example 235. b) 370 Example 236. 371
Example 237. 372 Example 238. a) 373 Example 238. b) 374 Example
239. 375 Example 240. a) 376 Example 240. b) 377 Example 240. c)
378 Example 241. 379 Example 242. a) 380 Example 242. b) 381
Example 242. c) 382 Example 242. d) 383 Example 242. e) 384 Example
242. f) 385 Example 242. g) 386 Example 243. 387 Example 244. a)
388 Example 244. b) 389 Example 245. 390 Example 246. a) 391
Example 246. b) 392 Example 247. 393 Example 248. a) 394 Example
248. b) 395 Example 249. 396 Example 250. 397 Example 251. 398
Example 252. 399 Example 253. 400 Example 254. a) 401 Example 254.
b) 402 Example 254. c) 403 Example 254. d) 404 Example 255. 405
Example 256. 406 Example 257. 407 Example 258. a) 408 Example 258.
b) 409 Example 259. 410 Example 260. 411 Example 261. 412 Example
262. 413 Example 263. 414 Example 264. 415 Example 265. 416 Example
266. 417 Example 267. 418 Example 268. 419 Example 269. 420 Example
270. 421 Example 271. 422 Example 272. 423 Example 273. 424 Example
274. 425 Example 275. 426 Example 276. 427 Example 277. 428 Example
278. 429 Example 279. 430 Example 280. 431 Example 281. 432 Example
282. 433 Example 283. 434 Example 284. 435 Example 285. 436 Example
286. 437 Example 287. 438 Example 288. 439 Example 289. 440 Example
290. 441 Example 291. 442 Example 292. 443 Example 293. 444 Example
294.
445 Example 295. 446 Example 296. 447 Example 297. 448 Example 298.
449 Example 299. 450 Example 300. 451 Example 301. 452 Example 302.
453 Example 303. 454 Example 304. 455 Example 305. 456 Example 306.
457 Example 307. 458 Example 308. a) 459 Example 308. b) 460
Example 309. a) 461 Example 309. b) 462 Example 310. 463 Example
311. 464 Example 312. 465 Example 313. 466 Example 314. 467 Example
315. 468 Example 316. 469 Example 317. 470 Example 318. 471 Example
319. 472 Example 320. 473 Example 321. 474 Example 322. 475 Example
323. 476 Example 324. 477 Example 325. a) 478 Example 325. b) 479
Example 326. a) 480 Example 326. b) 481 Example 326. c) 482 Example
327. a) 483 Example 327. b) 484 Example 327. c) 485 Example 327. d)
486 Example 328. 487 Example 329. 488 Example 330. 489 Example 331.
a) 490 Example 331. b) 491 Example 332. a) 492 Example 332. b) 493
Example 332. c) 494 Example 332. d) 495 Example 332. e) 496 Example
333. 497 Example 334. a) 498 Example 334. b) 499 Example 334. c)
500 Example 334. d) 501 Example 334. e) 502 Example 334. f) 503
Example 335. a) 504 Example 335. b) 505 Example 335. c) 506 Example
335. d) 507 Example 336. a) 508 Example 336. b) 509 Example 336. c)
510 Example 336. d) 511 Example 337. a) 512 Example 337. b) 513
Example 337. c) 514 Example 337. d) 515 Example 337. e) 516 Example
337. f) 517 Example 337. g) 518 Example 337. h) 519 Example 338. a)
520 Example 338. b) 521 Example 338. c) 522 Example 338. d) 523
Example 338. e) 524 Example 338. f) 525 Example 338. g) 526 Example
338. h) 527 Example 338. i) 528 Example 338. j) 529 Example 338. k)
530 Example 338. l) 531 Example 339. a) 532 Example 339. b) 533
Example 340. 534 Example 341. 535 Example 342. 536 Example 343. a)
537 Example 343. b) 538 Example 343. c) 539 Example 343. d) 540
Example 343. e) 541 Example 343. f) 542 Example 343. g) 543 Example
343. h) 544 Example 344. 545 Example 345. 546 Example 346. 547
Example 347. 548 Example 348. 549 Example 349. a)-1 550 Example
349. a)-2 551 Example 349. b) 552 Example 349. c) 553 Example 350.
554 Example 351. 555 Example 352. a) 556 Example 352. b) 557
Example 352. c) 558 Example 352. d) 559 Example 352. e) 560
INDUSTRIAL APPLICABILITY
[2008] The present invention provides condensed imidazole
derivatives having a DPPIV-inhibiting activity.
[2009] Accordingly, the condensed imidazole derivatives of the
present invention are useful as therapeutic and preventive agents,
for example, for diabetes mellitus, obesity, hyperlipidemia, AIDS,
osteoporosis, gastrointestinal disorders, angiogenesis,
infertility, as anti-inflammatory agents, anti-allergy agents,
immunomodulators, hormone regulators, anti-rheumatic drugs, and
anti-cancer agents.
[2010] Furthermore, using their glucose tolerance improving action
as an index, these compounds were tested to assess their efficacy
after oral administration. In result, it was confirmed that these
compounds were sufficiently effective, thereby demonstrating their
usefulness as pharmaceuticals.
* * * * *