U.S. patent application number 10/757525 was filed with the patent office on 2004-07-29 for novel pyridazine derivatives and medicines containing the same as effective ingredients.
This patent application is currently assigned to Kowa Co., Ltd.. Invention is credited to Habata, Yuriko, Kitamura, Takahiro, Koshi, Tomoyuki, Kotaki, Kyoko, Kumai, Natsuyo, Kyotani, Yoshinori, Matsuda, Takayuki, Ohgiya, Tadaaki, Ohkuchi, Masao, Shigyo, Hiromichi, Yamazaki, Yukiyoshi, Yoshizaki, Hideo.
Application Number | 20040147516 10/757525 |
Document ID | / |
Family ID | 26569260 |
Filed Date | 2004-07-29 |
United States Patent
Application |
20040147516 |
Kind Code |
A1 |
Ohkuchi, Masao ; et
al. |
July 29, 2004 |
Novel pyridazine derivatives and medicines containing the same as
effective ingredients
Abstract
This invention relates to pyridazine derivatives represented by
the formula (1): 1 wherein R.sup.1 represents a (substituted) aryl
group, R.sup.2 represents a phenyl group substituted at 4-position
by a lower alkoxyl group or a lower alkylthio group, R.sup.3
represents a lower alkoxyl group, a halogenated lower alkyl group,
a lower cycloalkyl group, a (subsituted) aryl group, a
(substituted) aryloxy group, a (substituted) nitrogen-containing
heterocyclic ring residue, a (substituted) aminocarbonyl group or a
lower alkylcarbonyl group, A represents a single bond, a lower
alkylene group or a lower alkenylene group, X represents O or S,
and the dashed line indicates that the carbon-carbon bond between
the 4-position and the 5-position is a single bond or a double
bond, or salts thereof; and also to medicines containing them as
effective ingredients. These compounds have excellent inhibitory
activity against interleukin-1.beta. production, and are useful as
preventives and therapeutics for immune system diseases,
inflammatory diseases, ischemic diseases and the like.
Inventors: |
Ohkuchi, Masao;
(Tokorozawa-shi, JP) ; Kyotani, Yoshinori;
(Higashiyamato-shi, JP) ; Shigyo, Hiromichi;
(Fuchu-shi, JP) ; Koshi, Tomoyuki; (Shiki-shi,
JP) ; Kitamura, Takahiro; (Higashimurayama-shi,
JP) ; Ohgiya, Tadaaki; (Tokorozawa-shi, JP) ;
Matsuda, Takayuki; (Higashimurayama-shi, JP) ;
Yamazaki, Yukiyoshi; (Higashimurayama-shi, JP) ;
Kumai, Natsuyo; (Fujimi-shi, JP) ; Kotaki, Kyoko;
(Sakado-shi, JP) ; Yoshizaki, Hideo; (Sayama-shi,
JP) ; Habata, Yuriko; (Higashiyamato-shi,
JP) |
Correspondence
Address: |
OBLON, SPIVAK, MCCLELLAND, MAIER & NEUSTADT, P.C.
1940 DUKE STREET
ALEXANDRIA
VA
22314
US
|
Assignee: |
Kowa Co., Ltd.
Nagoya-shi
JP
|
Family ID: |
26569260 |
Appl. No.: |
10/757525 |
Filed: |
January 15, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10757525 |
Jan 15, 2004 |
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09996804 |
Nov 30, 2001 |
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09996804 |
Nov 30, 2001 |
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09530949 |
May 15, 2000 |
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6348468 |
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09530949 |
May 15, 2000 |
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PCT/JP98/05023 |
Nov 9, 1998 |
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Current U.S.
Class: |
514/247 ;
514/252.01; 544/238; 544/239 |
Current CPC
Class: |
A61P 9/00 20180101; A61P
19/00 20180101; C07D 237/04 20130101; C07D 413/04 20130101; C07D
237/18 20130101; A61P 19/10 20180101; C07D 237/14 20130101; C07D
401/04 20130101; C07D 237/02 20130101; C07D 401/14 20130101; A61P
19/02 20180101; C07D 401/06 20130101; A61P 37/00 20180101; A61P
29/00 20180101 |
Class at
Publication: |
514/247 ;
514/252.01; 544/238; 544/239 |
International
Class: |
A61K 031/501; C07D
43/02 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 19, 1997 |
JP |
9-318132 |
Nov 19, 1997 |
JP |
9-318133 |
Claims
1. A pyridazine derivative represented by the following formula
(1): 9wherein R.sup.1 represents a substituted or unsubstituted
aryl group, R.sup.2 represents a phenyl group substituted at least
at 4-position by a lower alkoxyl group, a lower alkylthio group, a
lower alkylsulfinyl group or a lower alkylsulfonyl group, and
optionally has one or more substituents at the remaining positions,
R.sup.3 represents a hydrogen atom, a lower alkoxyl group, a
halogenated lower alkyl group, a lower cycloalkyl group, a
substituted or unsubstituted aryl group, a substituted or
unsubstituted aryloxy group, a substituted or unsubstituted,
nitrogen-containing heterocyclic ring residue, a substituted or
unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group,
A represents a single bond or a linear or branched lower alkylene
group or lower alkenylene group, X represents an oxygen atom or a
sulfur atom, and the dashed line indicates that the carbon-carbon
bond between the 4-position and the 5-position is a single bond or
a double bond, with the proviso that A is a single bond when
R.sup.3 is a halogenated lower alkyl group and that the following
combinations are excluded: R.sup.1 and R.sup.2 are 4-methoxyphenyl
groups, X is an oxygen atom, the carbon-carbon bond at the
4-position and the 5-position is a double bond, A is a single bond,
and R.sup.3 is a hydrogen atom or a 2-chloroethyl group; or a salt
thereof.
2. A pyridazine derivative or a salt thereof according to claim 1,
wherein R.sup.1 represents a substituted or unsubstituted phenyl or
pyridyl group.
3. A pyridazine derivative or a salt thereof according to claim 1,
wherein R.sup.1 represents a phenyl or pyridyl group which may be
substituted by 1 to 3 substituents selected from halogen atoms and
lower alkoxy groups; R.sup.2 represents a phenyl group, which may
be substituted at 4-position by a lower alkoxyl group, a lower
alkylthio group, a lower alkylsulfinyl group or a lower
alkylsulfonyl group, and at the other positions by 1 or 2
substituents selected from halogen atoms, lower alkoxyl groups,
lower alkylthio groups, lower alkylsulfinyl groups and lower
alkylsulfonyl groups; R.sup.3 represents a hydrogen atom, a lower
alkoxyl group, a halogenated lower alkyl group, a lower cycloalkyl
group, a phenyl, pyridyl or phenyloxy group which may be
substituted by 1 to 3 substituents selected from halogen atoms,
lower alkyl groups, lower alkoxyl groups, carboxyl group, lower
alkoxycarbonyl groups, nitro group, amino group, lower alkylamino
groups and lower alkylthio groups, a substituted or unsubstituted
piperidino, piperidyl, piperazino or morpholino group, a
substituted or unsubstituted aminocarbonyl group, or a lower
alkylcarbonyl group; and A represents a linear or branched lower
alkylene group having 1 to 6 carbon atoms or a linear or branched
alkenylene group having 2 to 9 carbon atoms.
4. A pyridazine derivative or a salt thereof according to claim 1,
which is a compound represented by the following formula (1A):
10wherein R.sup.4 represents a linear or branched lower alkyl or
lower alkenylene group, a lower cycloalkyl group or a lower
cycloalkylmethyl group, and X represents an oxygen atom or a sulfur
atom; or a salt thereof.
5. A pyridazine derivative or a salt thereof according to claim 1,
which is 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one,
2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione,
5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopentylmethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one,
5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, or
5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one; or a
salt thereof.
6. A medicine comprising, as an effective ingredient, a pyridazine
derivative or a salt thereof according to any one of claims
1-5.
7. A medicine according to claim 6, which is an interleukin-1.beta.
production inhibitor.
8. A medicine according to claim 6, which is a preventive or
therapeutic for a disease caused by stimulation of
interleukin-1.beta. production.
9. A medicine according to claim 6, which is a preventive or
therapeutic for an immune system disease, an inflammatory disease,
an ischemic disease, osteoporosis or ichorrhemia.
10. A medicine according to claim 6, which is a preventive or
therapeutic for rheumatism, arthritis or inflammatory colitis.
11. An interleukin-1.beta. production inhibitor comprising, as an
effective ingredient, a pyridazine derivative or a salt thereof
according to any one of claims 1-5.
12. A pharmaceutical composition comprising a pyridazine derivative
or a salt thereof according to any one of claims 1-5 and a
pharmaceutically acceptable carrier.
13. Use of a pyridazine derivative or a salt thereof according to
any one of claims 1-5 as a medicine.
14. A method for the treatment of a disease caused by stimulation
of interleukin-1.beta. production, which comprises administering a
pyridazine derivative or a salt thereof according to any one of
claims 1-5.
Description
TECHNICAL FIELD
[0001] This invention relates to novel pyridazine derivatives,
which have excellent inhibitory activity against
interleukin-1.beta. production and are useful for the prevention
and treatment of immune system diseases, inflammatory diseases,
ischemic diseases and the like, and also to medicines containing
them as effective ingredients.
BACKGROUND ART
[0002] In many diseases, for example, rheumatism, arthritis,
osteoporosis, inflammatory colitis, immune deficiency syndrome,
ichorrhemia, hepatitis, nephritis, ischemic diseases,
insulin-dependent diabetes mellitus, arterial sclerosis,
Parkinson's disease, Alzheimer's disease, leukemia and the like,
stimulation of interleukin-1.beta. production, an inflammatory
cytokine, is observed. This interleukin-1.beta. serves to induce
synthesis of an enzyme which is considered to take part in
inflammation like collagenase and PLA2 and, when intra-articularly
injected to animals, causes multi-articular destruction highly
resembling rheumatoid arthritis. On the other hand,
interleukin-1.beta. is controlled in activity by interleukin-1
receptor, soluble interleukin-1 receptor and interleukin-1 receptor
antagonist.
[0003] From research conducted making use of recombinants of these
bioactivity-inhibiting substances, anti-interleukin-1.beta.
antibodies and anti-receptor antibodies against various disease
models, interleukin-1.beta. has been found to play an important
role in the body, leading to an increasing potential of substances
having interleukin-1.beta. inhibitory activity as therapeutics for
such diseases.
[0004] For example, immunosuppressors and steroids which are used
for the treatment of rheumatism out of such many diseases have been
reported to inhibit the production of interleukin-1.beta.. Even
among medicaments currently under development, KE298, a
benzoylpropionic acid derivative [The Japanese Society of
Inflammation (11th), 1990], for example, has been reported to have
inhibitory activity against interleukin-1.beta. production although
it is an immunoregulator. Inhibitory activity against
interleukin-1.beta. production is also observed on a group of
compounds which are called "COX-2 selective inhibitors", for
example, nimesulide as a phenoxysulfonanilide derivative (DE
2333643), T-614 as a phenoxybenzopyran derivative (U.S. Pat. No.
4,954,518), and tenidap (hydroxyindole derivative) as a dual
inhibitor (COX-1/5-LO).
[0005] For all of these compounds, however, interleukin-1.beta.
production inhibitory activity is not their primary action so that
their inhibitory activity against interleukin-1.beta. production is
lower than their primary action.
[0006] In recent years, increasingly active research is under way
for the synthesis of compounds with a focus placed on inhibitory
activity against interleukin-1.beta. production. Production
inhibitors synthesized in such research can be classified into a
group of compounds which inhibit the transfer process of an
inflammatory signal to a cell nucleus and another group of
compounds which inhibit an enzyme ICE that functions in the
processing of a precursor of interleukin-1.beta.. Known examples of
compounds presumed to have the former action include SB203580
[Japanese Language Laid-Open (Kokai) Publication (PCT) No. HEI
7-503017], FR167653 (Eur. J. Pharm., 327, 169-175, 1997), E-5090
(EP 376288), CGP47969A (Gastroenterology, 109, 812-828, 1995),
hydroxyindole derivatives (Eur. J. Med. Chem. 31, 187-198, 1996),
and triarylpyrrole derivatives (WO 97/05878), while known examples
of compounds presumed to have the latter action include VE-13,045
which is a peptide compound (Cytokine, 8(5), 377-386, 1996).
[0007] None of these compounds can however exhibit sufficient
inhibitory activity against interleukin-1.beta. production.
[0008] On the other hand, a variety of 5,6-diphenylpyridazine
derivatives are known to have analgesic and anti-inflammatory
action (EUR. J. MED. CHEM., 14, 53-60, 1979). Absolutely nothing
has however been known with respect to inhibitory activity against
interleukin-1.beta. production by these 5,6-diphenylpyridazine
derivatives.
[0009] Accordingly, an object of the present invention is to
provide a compound having excellent inhibitory activity against
interleukin-1.beta. production and also a medicine containing it as
an effective ingredient.
DISCLOSURE OF THE INVENTION
[0010] Under such circumstances, the present inventors have
proceeded with an extensive investigation. As a result, it has been
found that pyridazine derivatives represented by the
below-described formula (1) have excellent inhibitory activity
against interleukin-1.beta. production and are useful as medicines
for the prevention and treatment of immune system diseases,
inflammatory diseases, ischemic diseases and the like, leading to
the completion of the present invention.
[0011] Namely, the present invention provides a pyridazine
derivative represented by the following formula (1): 2
[0012] wherein R.sup.1 represents a substituted or unsubstituted
aryl group, R.sup.2 is a phenyl group substituted at least at
4-position by a lower alkoxyl group, a lower alkylthio group, a
lower alkylsulfinyl group or a lower alkylsulfonyl group, and
optionally has one or more substituents at the remaining positions,
R.sup.3 represents a hydrogen atom, a lower alkoxyl group, a
halogenated lower alkyl group, a lower cycloalkyl group, a
substituted or unsubstituted aryl group, a substituted or.
unsubstituted aryloxy group, a substituted or unsubstituted,
nitrogen-containing heterocyclic ring residue, a substituted or
unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group,
A represents a single bond or a linear or branched lower alkylene
group or lower alkenylene group, X represents an oxygen atom or a
sulfur atom, and the dashed line indicates that the carbon-carbon
bond between the 4-position and the 5-position is a single bond or
a double bond, with the proviso that A is a single bond when
R.sup.3 is a halogenated lower alkyl group and that the following
combinations are excluded: R.sup.1 and R.sup.2 are 4-methoxyphenyl
groups, X is an oxygen atom, the carbon-carbon bond at the
4-position and the 5-position is a double bond, A is a single bond,
and R.sup.3 is a hydrogen atom or a 2-chloroethyl group; or a salt
thereof.
[0013] Further, the present invention also provides a medicine
comprising the pyridazine derivative (1) or the salt thereof as an
effective ingredient.
[0014] Furthermore, the present invention also provides a
pharmaceutical composition comprising the pyridazine derivative (1)
or the salt thereof and a pharmaceutically acceptable carrier.
[0015] Moverover, the present invention also provides use of the
pyridazine derivative (1) or the salt thereof as a medicine.
[0016] In addition, the present invention also provides a method
for treating a disease caused by stimulation of interleukin-1.beta.
production, which comprises administering the pyridazine derivative
(1) or the salt thereof.
[0017] As will be demonstrated in tests to be described
subsequently herein, the inhibitory activity against
interleukin-1.beta. production by the pyridazine derivative (1) or
the salt thereof is extremely strong and reaches 100 to 1,000 times
as high as the action of the above-described known
5,6-diphenylpyridazine derivatives (EUR. J. MED. CHEM. 14, 53-60,
1979).
BEST MODE FOR CARRYING OUT THE INVENTION
[0018] The pyridazine derivative according to the present invention
is represented by the formula (1). In the formula, illustrative of
the aryl group represented by R.sup.1 can be phenyl, naphthyl and
pyridyl, with phenyl and pyridyl being particularly preferred.
These aryl groups may contain 1 to 3 substituents. Examples of such
substituents can include halogen atoms, lower alkyl groups, lower
alkoxyl groups, lower alkylthio groups, lower alkylsulfinyl groups,
lower alkylsulfonyl groups, carboxyl group, lower alkoxycarbonyl
groups, nitro group, amino group, and lower alkylamino groups.
Here, illustrative of the halogen atoms can be fluorine, chlorine,
bromine and iodine. The lower alkyl groups are those containing 1
to 6 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl
and n-butyl. Illustrative of the lower alkoxyl groups can be those
containing 1 to 6 carbon atoms, for example, methoxy, ethoxy and
propoxy. Illustrative of the lower alkylthio groups can be those
containing 1 to 6 carbon atoms, for example, methylthio, ethylthio
and propylthio. Illustrative of the lower alkylsulfinyl groups can
be those containing 1 to 6 carbon atoms, for example,
methylsulfinyl, ethylsulfinyl and propylsulfinyl. Illustrative of
the lower alkylsulfonyl groups can be those containing 1 to 6
carbon atoms, for example, methylsulfonyl, ethylsulfonyl and
propylsulfonyl. Illustrative of the lower alkoxycarbonyl groups can
be those having alkoxyl groups each of which contains 1 to 6 carbon
atoms, for example, methoxycarbonyl, ethoxycarbonyl and
propoxycarbonyl. Illustrative of the lower alkylamino groups can be
those having one or two alkyl groups each of which contains 1 to 6
carbon atoms, for example, methylamino, dimethylamino, ethylamino
and propylamino. The lower alkyl moieties in these substituents may
be linear, branched or cyclic.
[0019] Preferred as R.sup.1 is a phenyl or pyridyl group, which may
be substituted by 1 to 3 substituents selected from halogen atoms
and lower alkoxyl groups, these substituents being preferably
present at 3-, 4- or 5-position.
[0020] Preferred as R.sup.2 is a phenyl group, which may be
substituted at 4-position by a lower alkoxyl group, a lower
alkylthio group, a lower alkylsulfinyl group or a lower
alkylsulfonyl group, and at the other position by 1 or 2
substituents selected from halogen atoms, lower alkoxyl groups,
lower alkylthio groups, lower alkylsulfinyl groups and lower
alkylsulfonyl groups. Examples of the halogen atom, lower alkoxyl
group, lower alkylthio group, lower alkylsulfinyl group and lower
alkylsulfonyl group as the substituents on the phenyl group as
R.sup.2 include the same groups as those recited as R.sup.1. These
substituents are preferably positioned at only 4-position, at 3- or
4-position, or at any of 3-, 4- or 5-position.
[0021] Illustrative of the lower alkoxyl group and the substituted
or unsubstituted aryl group out of those represented by R.sup.3 can
be similar to those exemplified above in connection with
R.sup.1.
[0022] Illustrative of the halogenated lower alkyl group can be
lower alkyl groups substituted by one or more halogen atoms as
exemplified above in connection with R.sup.1.
[0023] Examples of the lower cycloalkyl group can include those
having 3 to 8 carbon atoms, for example, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl.
[0024] Illustrative of the aryloxy group can be a phenyloxy group,
which may contain similar substituent or substituents as in the
case of R.sup.1.
[0025] Illustrative of the nitrogen-containing heterocyclic ring
residue can be saturated, nitrogen-containing heterocyclic ring
residue such as piperidino, piperidyl, piperazino and morpholino;
and nitrogen-containing aromatic heterocyclic ring residue such as
pyridyl. These residue may contain similar substituents as in the
case of R.sup.1. Further, each of them may additionally contain one
or more carbonyl groups bonded thereto.
[0026] The aminocarbonyl group may contain similar substituents as
in the case of R.sup.1 and also aralkyl groups such as benzyl and
phenethyl.
[0027] Illustrative of the lower alkylcarbonyl group can be those
containing 1 to 6 carbon atoms, for example, methylcarbonyl and
ethylcarbonyl.
[0028] Preferred examples of R.sup.3 can include a hydrogen atom;
lower alkoxyl groups; halogenated lower alkyl groups; lower
cycloalkyl groups; phenyl, pyridyl and phenyloxy groups each of
which may be substituted by 1 to 3 substituents selected from
halogen atoms, lower alkyl groups, lower alkoxyl groups, carboxyl
group, lower alkoxycarbonyl groups, nitro group, amino group, lower
alkylamino groups and lower alkylthio groups; substituted or
unsubstituted piperidino, piperidyl, piperazino and morpholino
groups; and substituted or unsubstituted aminocarbonyl groups; and
lower alkylcarbonyl groups.
[0029] Among those represented by A, the lower alkylene group can
be a linear or branched one having 1 to 6 carbon atoms, examples of
which can include methylene, ethylene and trimethylene. The lower
alkenylene group can be a linear or branched one having 2 to 9
carbon atoms, with one having 2 to 6 carbon atoms and 1 to 3 double
bonds being preferred. Illustrative can be ethenylene, propenylene,
butenylene and butadienylene.
[0030] Preferred examples of A can be linear or branched lower
alkylene groups having 1 to 6 carbon atoms and linear or branched,
lower alkenylene groups having 2 to 9 carbon atoms.
[0031] Preferred examples of the pyridazine derivative (1) can
include those containing, as R.sup.1, a phenyl or pyridyl group
substituted by 1 to 3 substituents selected from halogen atoms and
lower alkoxy groups; as R.sup.2, a phenyl group, which may be
substituted at 4-position by a lower alkoxyl group, a lower
alkylthio group, a lower alkylsulfinyl group or a lower
alkylsulfonyl group, and at the other position by 1 or 2
substituents selected from halogen atoms, lower alkoxyl groups,
lower alkylthio groups, lower alkylsulfinyl groups and lower
alkylsulfonyl groups; as R.sup.3, a hydrogen atom, a lower alkoxyl
group, a halogenated lower alkyl group, a lower cycloalkyl group,
or a phenyl, pyridyl or phenyloxy group which may be substituted by
1 to 3 substituents selected from halogen atoms, lower alkyl
groups, lower alkoxyl groups, carboxyl group, lower alkoxycarbonyl
groups, nitro group, amino group, lower alkylamino groups and lower
alkylthio groups, a substituted or unsubstituted piperidino,
piperidyl, piperazino or morpholino group, a substituted or
unsubstituted aminocarbonyl group, or a lower alkylcarbonyl group;
and as A, a linear or branched lower alkylene group having 1 to 6
carbon atoms or a linear or branched lower alkenylene group having
2 to 9 carbon atoms.
[0032] In the present invention, compounds represented by the
following formula (1A) are also preferred: 3
[0033] wherein R.sup.4 represents a linear or branched lower alkyl
or lower alkenyl group, a lower cycloalkyl group or a lower
cycloalkylmethyl group, and X represents an oxygen atom or a sulfur
atom.
[0034] In the formula (1A), examples of the lower alkyl group out
of those represented by R.sup.4 can include linear or branched
lower alkyl groups having 1 to 6 carbon atoms, preferably 1 to 4
carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl,
n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl and
n-hexyl. Examples of the lower alkenyl group can include linear or
branched lower alkenyl groups having 2 to 6 carbon atoms,
preferably 2 to 4 carbon atoms and 1 to 2 double bonds, for
example, ethenyl, propenyl, butenyl, isobutenyl and butadienyl.
Examples of the lower cycloalkyl group can include those having 3
to 6 carbon atoms, for example, cyclopropyl, cyclobutyl,
cyclopentyl and cyclohexyl. Illustrative of the lower cycloalkyl
group in the lower cycloalkyl methyl group can be those exemplified
above.
[0035] Particularly preferred examples of R.sup.4 can include alkyl
groups having 1 to 4 carbon atoms, alkenyl groups having 2 to 4
carbon atoms, cycloalkyl groups having 3 to 6 carbon atoms, and
cycloalkylmethyl groups.
[0036] Preferred examples of the pyridazine derivative (1) can
include 5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-one,
2-allyl-5,6-bis(4-methoxy-phenyl)-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine-3-thione,
5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-cyclopentylmethyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one,
5-(4-chlorophenyl)-6-(4-methylthiophenyl)-2-benzyl-2H-pyridazin-3-one,
5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione, and
5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one.
[0037] No particular limitation is imposed on the salt of the
pyridazine (1), said salt also pertaining to the present invention,
insofar as it is a pharmacologically acceptable salt. Illustrative
can be acid addition salts of mineral acids, such as the
hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and
phosphate; and acid addition salts of organic acids, such as the
benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate,
p-toluenesulfonate, oxalate, maleate, fumarate, tartrate and
citrate.
[0038] Further, the compounds according to the present invention
may exist in the form of solvates represented by hydrates and also
in the form of keto-enol tautomers. Such solvates and isomers
should also be encompassed by the present invention.
[0039] The pyridazine derivatives (1) according to the present
invention can be prepared, for example, by the following processes.
4
[0040] wherein R.sup.5 represents a lower alkyl group, and R.sup.1,
R.sup.2, R.sup.3 and A have the same meanings as defined above.
[0041] A description will be made specifically about respective
preparation processes of compounds (1a), (2b), (1c), (1d) and (1e)
among the pyridazine derivatives (1).
[0042] (1) Preparation of 4,5-dihydro-2H-pyridazin-3-one
derivatives (1a: in the formula (1), A is a single bond, R.sup.3 is
a hydrogen atom, X is an oxygen atom, and a single bond is formed
between the 4-position and the 5-position):
[0043] A 4,5-dihydro-2H-pyridazin-3-one derivative (1a) can be
obtained by reacting a haloacetate ester with a 2-arylacetophenone
derivative (2) and then reacting hydrazine hydrate with the
resultant product.
[0044] The 2-arylacetophenone derivative (2) as the starting
material can be prepared, for example, by a known process (YAKUGAKU
ZASSHI, 74, 495-497, 1954).
[0045] The reaction between the compound (2) and the haloacetate
ester can be conducted in the presence of a base in a solvent.
Potassium tert-butoxide, lithium diisopropylamide (LDA) or the like
can be mentioned as a base usable here, and tetrahydrofuran or the
like can be mentioned as a solvent usable here. The reaction is
brought to completion at -20 to 40.degree. C. in 1 to 10 hours,
preferably at -5 to 25.degree. C. in 2 to 5 hours.
[0046] Further, the reaction between the resultant compound (3) and
hydrazine hydrate can be conducted in a solvent, and anhydrous
hydrazine may be used in place of hydrazine hydrate. As the
solvent, a lower alcohol such as ethanol, methanol, n-propanol or
isopropanol, tetrahydrofuran, 1,4-dioxane or the like can be used.
The reaction is brought to completion at 50 to 150.degree. C. in 5
to 50 hours, preferably at 80 to 100.degree. C. in 10 to 30
hours.
[0047] (2) Preparation of 4,5-dihydro-2H-pyridazin-3-one
derivatives (1d: in the formula (1), a single bond is formed
between the 4-position and the 5-position, and X is an oxygen
atom.):
[0048] A 2-substituted 4,5-dihydro-2H-pyridazin-3-one derivative
(1d) can be obtained by reacting a compound, which is represented
by the formula:
R.sup.3-A-NHNH.sub.2.2HCl
[0049] wherein R.sup.3 and A have the same meanings as defined
above, with the compound (3) in the presence of sodium acetate in a
solvent.
[0050] As a solvent usable in this reaction, methanol, ethanol,
n-propanol, isopropanol, dimethylsulfoxide, N,N-dimethylformamide,
tetrahydrofuran, 1,4-dioxane or the like can be mentioned. A lower
alcohol or a water-containing lower alcohol is particularly
preferred. The reaction is brought to completion at 40 to
150.degree. C. in 1 to 80 hours, preferably at 50 to 120.degree. C.
in 5 to 50 hours.
[0051] (3) Preparation of 2H-pyridazin-3-one derivatives (1b: in
the formula (1), A is a single bond, R.sup.3 is a hydrogen atom, X
is an oxygen atom, and a double bond is formed between the
4-position and the 5-position):
[0052] (i) Preparation by a dehydrogenating reaction:
[0053] A 2H-pyridazin-3-one derivative (1b) can be obtained by
reacting a dehydrogenating agent with the compound (1a) in acetic
acid.
[0054] As the dehydrogenating agent, bromine,
2,3-dichloro-5,6-dicyano-1,4- -benzoquinone (DDQ) or the like can
be used. As the solvent, acetic acid or the like is usable. The
reaction is brought to completion at 30 to 150.degree. C. in 5 to
50 hours, preferably at 50 to 120.degree. C. in 10 to 30 hours.
[0055] (ii) Preparation by a dehydrating reaction:
[0056] A 2H-pyridazin-3-one derivative (1b) can be obtained by
reacting glyoxalic acid--which has been formed by causing sodium
periodate to act on tartaric acid under acidic conditions--with the
2-arylacetophenone derivative (2) under basic conditions, reacting
hydrazine hydrate with the resultant 2-hydroxy-4-oxobutanoic acid
derivative (4) in a lower alcohol as a solvent to convert it into a
4,5-dihydro-4-hydroxy-2H-pyrida- zin-3-one derivative (5), and then
subjecting the derivative (5) to a dehydrating reaction in a
solvent while using para-toluenesulfonic acid hydrate as a
catalyst.
[0057] In the reaction between the compound (2) and glyoxalic acid,
commercially-available glyoxalic acid hydrate can also be used in
place of glyoxalic acid formed by causing sodium periodate to act
on tartaric acid. As an acid usable upon formation of glyoxalic
acid, an inorganic acid such as sulfuric acid, hydrochloric acid or
phosphoric acid can be mentioned. As a base usable in the reaction
between the compound (2) and glyoxalic acid, an inorganic base such
as caustic soda or caustic potash or an organic base such as
benzyltrimethylammonium hydroxide (Triton B) can be mentioned. In
these reactions, the synthesis step of glyoxalic acid is brought to
completion generally at -15 to 30.degree. C. in 20 to 180 minutes,
preferably around 0 to 25.degree. C. in 30 to 60 minutes. The
reaction with the compound (2) is conducted preferably at 0 to
120.degree. C., and is brought to completion by reacting them,
preferably at room temperature for 10 to 25 hours and then at
70.degree. C. for 0.5 to 2 hours. As the solvent, a lower alcohol
such as ethanol, methanol, n-propanol or iso-propanol,
tetrahydrofuran, 1,4-dioxane or the like can be used. Concerning
the reaction between the compound (4) and hydrazine hydrate,
anhydrous hydrazine can also be used in place of hydrazine hydrate.
The reaction is brought to completion at 50 to 150.degree. C. in 5
to 30 hours, preferably at 80 to 100.degree. C. in 10 to 20 hours.
As the solvent, a lower alcohol such as ethanol, methanol,
n-propanol or isopropanol, tetrahydrofuran, 1,4-dioxane or the like
can be used. In the dehydrating reaction of the compound (5),
para-toluenesulfonic acid hydrate or the like can be used as a
catalyst. As the solvent, toluene, benzene or the like can be used.
The reaction is brought to completion at 50 to 150.degree. C. in 3
to 50 hours, preferably at 80 to 130.degree. C. in 5 to 30
hours.
[0058] (4) Preparation of 2H-pyridazin-3-one derivatives (1c: in
the formula (1), X is an oxygen atom, and a double bond is formed
between the 4-position and the 5-position.):
[0059] (i) Preparation of the compound (1c) from the compound
(1b):
[0060] (a) Preparation by a reaction between (1b) and a halide or
reactive ester:
[0061] 2-Substituted 2H-pyridazin-3-one derivatives of a certain
type (1c) can each be obtained by reacting a compound, which is
represented by the following formula:
R.sup.3-A-Y
[0062] wherein R.sup.3 and A have the same meanings as defined
above and Y represents a halogen atom or an OH group already
converted into a reactive ester group, with the compound (1b) in
the presence of a base in a solvent.
[0063] As a base usable in this reaction, an inorganic base such as
potassium carbonate or sodium carbonate or an organic base such as
a metal alkoxide can be mentioned. As the solvent,
N,N-dimethylformamide, dimethyl sulfoxide, acetone, methyl ethyl
ketone or the like can be used. The reaction is brought to
completion at 20 to 150.degree. C. in 1 to 20 hours, preferably at
50 to 130.degree. C. in 2 to 10 hours.
[0064] Each compound (1c) in which the 2-substituent is a
piperidylalkyl group can be prepared by protecting the nitrogen
atom of the piperidyl alkanol as the starting material, converting
the hydroxyl group into a reactive ester group, reacting the
compound (1b) with the resultant compound, and then conducting
deprotection. Further, its N-lower alkylation makes it possible to
prepare an N-(lower alkyl)piperidylalkyl derivative.
[0065] As a protecting group for the nitrogen atom of the piperidyl
alkanol, a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a
dimethylphosphinothioyl group or the like is preferred. The
compound protected by such a group can be obtained by reacting
di-tert-butyl carbonate, benzyloxycarbonyl chloride or the like
with the piperidyl alkanol in the presence of a base such as
triethylamine or 4-dimethylaminopyridiene. As a solvent,
tetrahydrofuran, diethyl ether, ethyl acetate, methylene chloride,
chloroform, N,N-dimethylformamide, dimethyl sulfoxide, ethanol,
iso-propanol or the like can be used. The reaction is brought to
completion at -15 to 50.degree. C. in 5 to 50 hours, preferably at
0 to 20.degree. C. in 1 to 30 hours.
[0066] As the reactive ester group of the hydroxyl group, a
tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group or the
like is preferred. A compound which contains such a group can be
obtained by reacting para-toluenesulfonyl chloride, methanesulfonyl
chloride, methanesulfonic anhydride, benzenesulfonyl chloride or
the like with the N-protected piperidyl alkanol in the presence of
a base such as pyridine, triethylamine or collidine. As a solvent,
pyridine, tetrahydrofuran, diethyl ether, ethyl acetate, methylene
chloride, chloroform, N,N-dimethylformamide, dimethyl sulfoxide or
the like can be used. The reaction is brought to completion at -15
to 50.degree. C. in 1 to 50 hours, preferably at -5 to 30.degree.
C. in 1 to 10 hours.
[0067] The reaction between the compound (1b) and the reactive
ester derivative of the N-protected piperidyl alkanol can be
conducted in the presence of a base in a solvent. As a base usable
here, an inorganic base such as potassium carbonate or sodium
carbonate or an organic base such as a metal alkoxide can be
mentioned. As a solvent, N,N-dimethylformamide, dimethyl sulfoxide,
acetone, methyl ethyl ketone or the like can be used. The reaction
is brought to completion at 20 to 150.degree. C. in 1 to 30 hours,
preferably at 50 to 130.degree. C. in 2 to 10 hours.
[0068] The deprotection of the protecting group on the nitrogen
atom of the piperidyl group can be effected by heating the
N-protected piperidyl alkanol in the presence of an acid catalyst
in a solvent. As an acid usable here, hydrochloric acid, sulfuric
acid, acetic acid or the like can be mentioned. Such an acid may be
in a form diluted with water. Preferred is 2 to 10 N hydrochloric
acid, with 4 to 8 N hydrochloric acid being particularly preferred.
As the solvent, tetrahydrofuran, methanol, ethanol, isopropanol,
N,N-dimethylformamide or the like can be used. The reaction is
brought to completion at 40 to 150.degree. C. in 0.5 to 10 hours,
preferably at 50 to 130.degree. C. in 2 to 5 hours.
[0069] The N-lower alkylation of the thus-deprotected
piperidylalkyl derivative can be conducted by reacting a lower
alkyl sulfate, a lower alkyl halide or the like in the presence of
a base in a solvent. As a base usable here, sodium
hydrogencarbonate, potassium carbonate or the like can be
mentioned. As the solvent, acetone, dimethyl sulfoxide,
N,N-dimethylformamide, tetrahydrofuran, a mixed solvent thereof or
the like is preferred. The reaction is brought to completion at 20
to 150.degree. C. in 0.5 to 10 hours, preferably at 50 to
130.degree. C. in 1 to 5 hours.
[0070] (b) Preparation via a 2-hydroxyalkyl derivative:
[0071] A compound (1c) the 2-substituent of which is a
piperidinoalkyl, piperazinoalkyl or morpholinoalkyl group can be
prepared by converting the hydroxyl group of the 2-hydroxyalkyl
derivative, which has been obtained by reacting an alkylene
chlorohydrin or alkylene carbonate with the compound (1b), into a
reactive ester group and then reacting a corresponding amine.
[0072] The synthesis of the 2-hydroxyalkyl derivative can be
conducted by reacting the compound (1b) with an alkylene
chlorohydrin in the presence of a base, for example, in a known
manner [Eur. J. Med. Chem.-Chim. Ther., 14(1), 53-60, 1979] or by
heating the compound (1b) and the alkylene carbonate in the
presence or absence of a quaternary ammonium salt as a catalyst in
a solvent. As a quaternary ammonium salt usable here,
tetraethylammonium iodide, tetraethylammonium bromide,
tetra(n-butyl)ammonium iodide, tetra(n-butyl)ammonium bromide or
the like can be mentioned. As the solvent, N,N-dimethylformamide,
dimethyl sulfoxide, N-methylpyrrolidone or the like can be
mentioned. The reaction is brought to completion at 80 to
180.degree. C. in 0.5 to 10 hours, preferably at 120 to 160.degree.
C. in 1 to 5 hours.
[0073] As the reactive ester group of the hydroxyl group, a
tosyloxy group, a mesyloxy group, a benzenesulfonyloxy group or the
like is preferred. A compound having such a group can be obtained
by reacting para-toluenesulfonyl chloride, methanesulfonyl
chloride, methanesulfonic anhydride, benzenesulfonyl chloride or
the like with the hydroxylalkyl derivative in the presence of a
base such as pyridine, triethylamine or collidine. As a solvent,
pyridine, terahydrofuran, diethyl ether, ethyl acetate, methylene
chloride, chloroform, N,N-dimethylformamide, dimethylsulfoxide or
the like can be used. The reaction is brought to completion at -15
to 50.degree. C. in 1 to 50 hours, preferably at -5 to 30.degree.
C. in 1 to 10 hours.
[0074] The reaction between the reactive ester derivative and the
amine can be conducted by heating the reactive ester derivative in
the presence of an excess amount of the amine in a solvent or in a
solventless manner or reacting the amine in the presence of an
organic amine such as pyridine, triethylamine,
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or the like or an
inorganic base such as potassium carbonate or sodium carbonate. As
the solvent, dimethyl sulfoxide, pyridine, chloroform, methylene
chloride, toluene, benzene or the like can be used besides
N,N-dimethylformamide. The reaction is brought to completion at 0
to 150.degree. C. in 1 to 10 hours, preferably at 50 to 130.degree.
C. in 1 to 5 hours.
[0075] (c) Preparation via a 2-carboxyalkyl derivative:
[0076] A compound (1c) the 2-substituent of which is an
aminocarbonylalkyl group can be prepared by reacting a haloalkyl
carboxylate with the compound (1b), hydrolyzing the ester group of
the resultant 2-alkyl carboxylate ester derivative, converting it
into a reactive acyl derivative, and then reacting it with a
corresponding amine or condensing the carboxylic acid derivative
and a corresponding amine with a condensing agent such as
1,3-dicyclohexylcarbodiimide (DCC).
[0077] As a base usable in the reaction between the compound (1b)
and the haloalkyl carboxylate, an inorganic base such as potassium
carbonate or sodium carbonate or an organic base such as Triton B
can be mentioned. As a solvent, N,N-dimethylformamide, dimethyl
sulfoxide, acetone, methyl ethyl ketone or the like can be used.
The reaction is brought to completion at 20 to 150.degree. C. in 1
to 30 hours, preferably at 50 to 120.degree. C. in 2 to 20
hours.
[0078] The hydrolyzing reaction of the ester group can be conducted
by treating the ester derivative in the presence of a base such as
caustic soda or caustic potash in a conventional manner.
[0079] As the reactive derivative of the carboxylic acid, an acid
halide, a mixed acid anhydride or the like can be mentioned. The
acid halide can be prepared with oxalyl chloride, thionyl chloride,
thionyl bromide or the like, while the mixed acid anhydride can be
synthesized with acetic anhydride, pivalic anhydride,
methanesulfonic anhydride, para-toluenesulfonyl chloride or the
like.
[0080] The reaction between these reactive ester derivative and
amine can be conducted by reacting the reactive ester derivative
with an excess amount of the amine in a solvent or in a solventless
manner or by reacting the amine in the presence of an organic amine
such as pyridine, triethylamine or DBU or an inorganic base such as
potassium carbonate or sodium carbonate. As the solvent,
tetrahydrofuran, N,N-dimethylformamide, dimethyl sulfoxide,
pyridine, chloroform, methylene chloride, toluene, benzene or the
like can be used. The reaction is brought to completion at 0 to
150.degree. C. in 1 to 10 hours, preferably at 50 to 130.degree. C.
in 1 to 5 hours.
[0081] (d) Preparation by other processes:
[0082] Among 2-substituted derivatives (1c), each derivative in
which R.sup.3 is an aminophenyl group can be obtained by reducing
the nitro group of a compound in which R.sup.3 is a nitrophenyl
group, and its N-lower alkylation makes it possible to prepare an
N-(lower alkyl)aminophenyl compound.
[0083] The reduction of the nitro group can be effected by
conducting hydrogenation in an inert solvent such as ethyl acetate
or ethanol while using palladium on charcoal or Raney nickel as a
catalyst.
[0084] The thus-reduced product can be N-lower alkylated by
reacting it with a lower alkyl sulfate, a lower alkyl halide or the
like in the presence of a base in a solvent. The resulting
N-monoalkyl and dialkyl derivatives can be isolated, respectively,
from their mixture.
[0085] As the base employed in the N-lower alkylating reaction,
sodium hydrogencarbonate, potassium carbonate, pyridine,
triethylamine or the like can be mentioned. As the solvent,
acetone, dimethyl sulfoxide, N,N-dimethylformamide or
tetrahydrofuran, a mixed solvent of two or more of these solvents,
or the like is preferred. The reaction is brought to completion at
20 to 150.degree. C. in 0.5 to 10 hours, preferably at 50 to
130.degree. C. in 1 to 5 hours.
[0086] (ii) Preparation of the compound (1c) from the compound
(1d):
[0087] Using the compound (1d) as a starting material, the compound
(1c) can be prepared in a similar manner as in the preparation of
the compound (1b) from the compound (1a).
[0088] (iii) Preparation of compounds (1c) in each of which R.sup.1
or R.sup.2 is a lower alkylsulfinylphenyl group:
[0089] Among the compounds (1c), each derivative in which R.sup.1
or R.sup.2 is a lower alkylsulfinylphenyl group can be prepared by
selectively oxidizing a derivative (1c) in which R.sup.1 or R.sup.2
is a lower alkylthiophenyl group.
[0090] The selective oxidizing reaction can be conducted using
metha-chloroperbenzoic acid, hydrogen peroxide solution or the like
as an oxidizing agent. The reaction is brought to completion at -30
to 30.degree. C. in 10 minutes to 10 hours, preferably at -10 to
10.degree. C. in 30 minutes to 1 hour. As a solvent, methylene
chloride, chloroform or the like can be used.
[0091] (iv) Preparation of compounds (1c) in each of which R.sup.1
or R.sup.2 is a lower alkylsulfonylphenyl group:
[0092] Among the compounds (1c), each derivative in which R.sup.1
or R.sup.2 is a lower alkylsulfonylphenyl group can be prepared by
oxidizing a derivative (1c) in which R.sup.1 or R.sup.2 is a lower
alkylthiophenyl group.
[0093] The oxidizing reaction can be conducted using osmium
tetraoxide-sodium periodate, metha-chloroperbenzoic acid or the
like as an oxidizing agent. The reaction is brought to completion
at -30 to 50.degree. C. in 1 to 24 hours, preferably at 0 to
20.degree. C. in 5 to 10 hours. As a solvent,
acetone-water-chloroform or the like can be used.
[0094] (5) Preparation of 2H-pyridazin-3-thione derivatives (1e: in
the formula (1), X is a sulfur atom, and a double bond is formed
between the 4-position and the 5-position.):
[0095] Each 2H-pyridazine-3-thione derivative (1e) can be obtained
by thioketonizing its corresponding 2H-pyridazin-3-one derivative
with Lawesson's reagent
[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-
-2,4-disulfide) in a solvent.
[0096] It is preferred to use Lawesson's reagent in 0.5 to 3
equivalents, notably 1 to 1.5 equivalents relative to the
2H-pyridazin-3-one derivative. The reaction is brought to
completion at 30 to 150.degree. C. in 1 to 10 hours, preferably at
50 to 100.degree. C. in 2 to 8 hours. As a usable solvent, toluene,
xylene or the like can be mentioned.
[0097] The intermediates and target compounds obtained in the
above-described individual reactions can be separated and purified
by purification methods commonly employed in organic synthesis
chemistry, for example, by subjecting them to filtration,
extraction, washing, drying, concentration, recrystallization,
various chromatographic treatment, and the like. The intermediates
may be provided for the next reactions without purifying them
specifically. Further, they may also be obtained as solvates of
solvents such as reaction solvents or recrystallization solvents,
especially as hydrates.
[0098] The pyridazine derivatives (1) and their salts according to
the present invention, which are available as described above, have
excellent inhibitory activity against interleukin-1.beta.
production, and are useful for the prevention and treatment of
diseases caused by stimulation of interleukin-1.beta. production,
for example, immune system diseases, inflammatory diseases,
ischemic diseases, osteoporosis, ichorrhemia and the like,
especially as medicines such as preventives and therapeutics for
rheumatism, immune deficiency syndrome, arthritis, inflammatory
colitis, ischemic heart diseases, ischemic encephalopathy, ischemic
nephritis, ischemic hepatitis, insulin-dependent diabetes mellitus,
arterial sclerosis, Parkinson's disease, Alzheimer's disease,
leukemia and the like or as interleukin-1.beta. production
inhibitors.
[0099] Medicines according to the present invention contain the
pyridazine derivatives (1) or their salts as effective ingredients.
Their administration routes can include, for example, oral
administration by tablets, capsules, granules, powders, syrups or
the like and parenteral administration by intravenous injections,
intramuscular injections, suppositories, inhalants, transdermal
preparations, eye drops, nasal drops or the like. Upon formulation
of pharmaceutical compositions of these various unit dosage forms,
pharmaceutically acceptable carriers can be mixed with these
effective ingredients. As such carriers, excipients, binders,
extenders, disintegrators, surfactants, lubricants, dispersants,
buffers, preservatives, corrigents, perfumes, coating agents,
vehicles, diluents and the like can be used by combining them as
desired.
[0100] The dosage of each medicine according to the present
invention varies depending on the age, body weight, conditions,
administration form, administration frequency and the like. In
general, however, it is preferred to orally or parenterally
administer to an adult the effective ingredient in an amount of
about 0.01 to 1,000 mg, preferably 0.1 to 100 mg per day at once or
in several portions.
EXAMPLES
[0101] The present invention will next be described in further
detail by the following Examples. It should however be borne in
mind that the present invention is not limited to these
Examples.
Preparation Example 1
[0102] (1) Preparation of
3,4-bis(4-methoxyphenyl)-2-hydroxy-4-oxobutanoic acid:
[0103] To a solution of sodium periodate (11.1 g, 52.0 mmol) in
water (65 ml), concentrated sulfuric acid (1.12 ml) was added
dropwise little by little under ice-water cooling and stirring.
Subsequent to the dropwise addition, the temperature of the
resulting mixture was allowed to rise to room temperature, followed
by the addition of a solution of tartaric acid (7.81 g, 52.0 mmol)
in water (18 ml). The mixture was stirred for 50 minutes. To the
reaction mixture, an aqueous solution of sodium hydroxide and a
suspension of 2-(4-methoxyphenyl)-4'-methoxyacetophenone (13.32 g,
52.0 mmol) in ethanol (160 ml) were added. The mixture was stirred
at 40.degree. C. for 5 hours and then at room temperature for 17
hours, and a reaction was then conducted at 70.degree. C. for 1
hour. Subsequent to cooling, the ethanol was distilled off. The
liquid residue was washed with ethyl acetate, acidified with
hydrochloric acid, and then extracted with ethyl acetate. The
organic layer was washed with a saturated aqueous solution of
sodium chloride (brine) and then dried over anhydrous sodium
sulfate. The solvent was distilled off, whereby the title compound
(16.11 g, 93.8%) was obtained as a brown oil.
[0104] (2) Preparation of
5,6-bis(4-methoxyphenyl)-4,5-dihydro-4-hydroxy-2-
H-pyridazin-3-one:
[0105] Hydrazine hydrate (2.4 ml, 49.4 mmol) was added to a
solution of 3,4-bis(4-methoxyphenyl)-2-hydroxy-4-oxobutanoic acid
(16.11 g, 48.8 mmol) in ethanol (240 ml), followed by heating under
reflux for 15 hours at a bath temperature of 100.degree. C. The
ethanol was distilled off, whereby the title compound (15.82 g,
99.4%) was obtained as a crude brown oil.
[0106] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.75(3H, s), 3.78(3H, s),
4.02(1H, brs), 4.25(1H, d), 4.44(1H, d, J=3.91 Hz), 6.81(2H, d,
J=9.04 Hz), 6.82(2H, d, J=8.79 Hz), 7.10(2H, d, J=8.54 Hz),
7.58(2H, d, J=9.04 Hz), 9.03(1H, s).
[0107] (3) Preparation of
5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one:
[0108] To a solution of
5,6-bis(4-methoxyphenyl)-4,5-dihydro-4-hydroxy-2H-- pyridazin-3-one
(15.82 g, 48.5 mmol) in benzene (300 ml), para-toluenesulfonic acid
monohydrate (1.82 g, 9.6 mmol) was added. A Dean-Stark apparatus
was fitted, followed by heating under reflux for 5 hours.
Para-toluenesulfonic acid monohydrate (0.50 g) was added, followed
by heating under reflux for 18 hours. The benzene was distilled
off, and the residue was extracted with ethyl acetate (500 ml).
After the organic layer was washed with a saturated aqueous
solution of sodium hydrogencarbonate, it was washed with a brine
and then dried over anhydrous sodium sulfate. The water layers were
combined and then extracted with chloroform (200 ml.times.3). The
organic layer was washed with a brine and then dried over anhydrous
sodium sulfate. From the ethyl acetate extract and the chloroform
extract, the solvents were distilled off. The residue was separated
and purified by chromatography on a silica gel column [silica gel:
50 g, chloroform/methanol (50/1)]. An eluate was concentrated to
dryness under reduced pressure, and resulting crystals were heated
in ethanol. After the ethanol solution was cool, diethyl ether was
added and the thus-obtained solution was left over at room
temperature. A precipitate was collected by filtration and then
dried at 60.degree. C. under reduced pressure, whereby the title
compound (7.84 g, 52.4%) was obtained as pale orange crystals.
[0109] Colorless prisms (ethyl acetate-hexane)
[0110] Melting point: 240.5-242.5.degree. C.
[0111] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
6.78(2H, d, J=9.03 Hz), 6.82(2H, d, J=9.03 Hz), 6.93(1H, s),
7.06(2H, d, J=9.03 Hz), 7.13(2H, d, J=9.04 Hz), 11.42(1H, s).
[0112] IR (KBr) cm.sup.-1: 1665, 1607, 1510, 1301, 1256, 1027,
838.
Preparation Example 2
[0113] Preparation of methyl
4-(4-methoxyphenyl)-4-oxo-3-(4-pyridyl)butano- ate:
[0114] Under an argon, 2-(4-pyridyl)-4'-methoxyacetophenone (J. Am.
Chem. Soc., 112, 2163-3168, 1990: Dimitrios Stefanidis and John W.
Bunting; 9.6 g, 42.3 mmol) was suspended in tetrahydrofuran (200
ml), and under ice cooling, lithium diisopropylamide (2.0 M
solution; 25 ml, 50.0 mmol) was added. At the same temperature, the
mixture was stirred for 30 minutes. Methyl bromoacetate (6.0 ml,
63.4 mmol) was then added dropwise, and the mixture was stirred
under ice cooling for 1 hour and then at room temperature for 2
hours. The reaction mixture was diluted with toluene. The mixture
was washed successively with 2 N hydrochloric acid, water and a
brine, and was then dried over anhydrous sodium sulfate. The
solvent was distilled off and the residue was separated and
purified by chromatography on a silica gel column [silica gel: 100
g, hexane/ethyl acetate (1/2)], whereby the title compound (10.63
g, 84.1%) was obtained as a brown oil.
[0115] 1H-NMR (CDCl.sub.3) .delta.: 2.71(1H, dd, J=5.37, 16.84 Hz),
3.35(1H, dd, J=9.28, 16.84 Hz), 3.65(3H, s), 3.85(3H, s), 5.04(1H,
dd, J=5.37, 9.28 Hz), 6.88(2H, d, J=9.03 Hz), 7.23(2H, d, J=6.10
Hz), 7.93(2H, d, J=9.03 Hz), 8.52(2H, d, J=6.10 Hz).
[0116] IR (film) cm.sup.-1: 1763, 1674, 1600, 1512, 1418, 1263,
1170.
Preparation Example 3
[0117] (1) Preparation of
2-(4-chlorophenyl)-4'-(methylthio)acetophenone:
[0118] A mixture consisting of para-chlorophenyl acetic acid (17.06
g, 0.1 mol), thioanisole (24.84 g, 0.2 mol) and polyphosphoric acid
(67.59 g, 0.2 mol) was heated at 100.degree. C. for 7 hours. Water
was added to the solidified reaction product, and a white solid
insoluble in water was collected by filtration and then washed with
n-hexane. The solid was recrystallized from a mixed solvent of
ethanol and ethyl acetate, whereby the title compound (21.24 g,
76.7%) was obtained. Further, the mother liquor was separated and
purified by chromatography on a silica gel column (ethyl acetate).
Recrystallization was then conducted from ethyl acetate, whereby
the title compound (2.86 g, 10.4%) was obtained.
[0119] Colorless prisms (ethyl acetate)
[0120] Melting point: 161.1-162.1.degree. C.
[0121] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.51(3H, s), 4.21(2H, s),
7.19(2H, d, J=8.55 Hz), 7.26(2H, d, J=8.91 Hz), 7.29(2H, d, J=8.55
Hz), 7.89(2H, d, J=8.91 Hz).
[0122] (2) Preparation of ethyl
3-(4-chlorophenyl)-4-[4-(methylthio)phenyl- ]-4-oxobutanoate:
[0123] A suspension of
2-(4-chlorophenyl)-4'-(methylthio)acetophenone (34.98 g, 126.4
mmol) in tetrahydrofuran (350 ml) was ice-cooled, followed by the
addition of potassium tert-butoxide (17.01 g, 151.6 mmol) under a
nitrogen gas atmosphere. At the same temperature, the mixture was
stirred for 10 minutes. After ethyl bromoacetate (25.33 g, 151.7
mmol) was added dropwise over 10 minutes, the mixture was stirred
at the same temperature for 30 minutes. The reaction mixture was
poured into toluene (350 ml), to which ice water (350 ml) was
added, followed by extraction. The organic layer was collected.
Further, the water layer was extracted with toluene (100 ml). The
thus-obtained organic layers were combined, washed with a brine
(300 ml), and then dried over anhydrous sodium sulfate. The solvent
was distilled off, whereby the title compound (45.54 g,
quantitative) was obtained as a yellow oil.
[0124] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.19(3H, t, J=7.1 Hz),
2.47(3H, s), 2.70(1H, dd, J=5.4, 16.9 Hz), 3.31(1H, dd, J=9.4, 16.9
Hz), 4.09(2H, q, J=7.1 Hz), 5.01(1H, dd, J=5.4, 9.4 Hz),
7.16-7.28(6H, m), 7.86(2H, d, J=8.7 Hz).
[0125] IR (film) cm.sup.-1: 1738, 1733, 1683, 1590, 1252, 1233,
1178, 1094, 820.
Preparation Example 4
[0126] Preparation of methyl
3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4- -oxobutanoate:
[0127] Using 2-(4-chlorophenyl)-4'-(methylthio)acetophenone as a
starting material, the procedures of Preparation Example 2 were
repeated likewise, whereby the title compound was obtained as a
pale yellow oil in a yield of 95.8%.
[0128] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.56(3H, s), 2.61(1H, dd,
J=5.37, 16.97 Hz), 3.24(1H, dd, J=9.28, 16.97 Hz), 3.55(3H, s),
4.94(1H, dd, J=5.37, 9.28 Hz), 7.10(2H, d, J=8.55 Hz),
7.12-7.20(4H, m), 7.77(2H, d, J=8.84 Hz).
[0129] IR (film) cm.sup.-1: 1736, 1675, 1590, 1490, 1437, 1403,
1252, 1234, 1173, 1094.
Preparation Example 5
[0130] Preparation of methyl
3-(4-fluorophenyl)-4-[4-(methylthio)phenyl]-4- -oxobutanoate:
[0131] Using 2-(4-fluorophenyl)-4'-(methylthio)acetophenone as a
starting material, the procedures of Preparation Example 2 were
repeated likewise, whereby the title compound was obtained as a
pale yellow oil in a yield of 86.5%.
[0132] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45(3H, s), 2.70(1H, dd,
J=5.31, 16.91 Hz), 3.32(1H, dd, J=9.40, 16.91 Hz), 3.63(3H, s),
5.04(1H, dd, J=5.11, 9.40 Hz), 6.96(2H, t, J=8.67 Hz), 7.18(2H, d,
J=8.79 Hz), 7.25(2H, dd, J=5.25, 8.67 Hz), 7.86(2H, d, J=8.79
Hz).
Preparation Example 6
[0133] (1) Preparation of 2-phenyl-4'-(methylthio)acetophenone:
[0134] After aluminum chloride (5.61 g, 42.1 mmol) was added to
dichloroethane (25 ml), phenylacetyl chloride (5.00 g, 32.3 mmol)
and thioanisole (6.03 g, 48.5 mmol) were added under ice cooling.
The resulting mixture was stirred at room temperature for 20 hours.
Ice water was added to the reaction mixture, followed by extraction
with chloroform. The extract was washed with water and then dried
over anhydrous sodium sulfate. The solvent was distilled off, and
the residue was crystallized with hexane. The crystals were
recrystallized from ethanol, whereby the title compound (5.77 g,
73.6%) was obtained as colorless prisms. Further, the
recrystallization mother liquid was separated and purified by
chromatography on a silica gel column [hexane/ethyl acetate
(20/1)], whereby the title compound (0.57%, 7.3%) was obtained.
[0135] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.50(3H, s), 4.23(2H, s),
7.20-7.36(7H, m), 7.92(2H, d, J=8.8 Hz).
[0136] IR (KBr) cm.sup.-1: 1682, 1587, 1334, 1221, 1090, 992, 815,
706.
[0137] (2) Preparation of methyl
4-[4-(methylthio)phenyl]-4-oxo-3-phenylbu- tanoate:
[0138] Using 2-phenyl-4'-(methylthio)acetophenone as a starting
material, the procedures of Preparation Example 2 were repeated
likewise, whereby the title compound was obtained in a yield of
86.5%.
[0139] Colorless prisms (ethyl acetate-hexane).
[0140] Melting point: 82.4-83.0.degree. C.
[0141] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 2.70(1H, dd,
J=4.95, 16.91 Hz), 3.36(1H, dd, J=9.65, 16.91 Hz), 3.65(3H, s),
5.03(1H, dd, J=4.45, 9.65 Hz), 7.18(2H, d, J=8.55 Hz),
7.20-7.30(5H, m), 7.88(2H, d, J=8.55 Hz).
[0142] IR (KBr) cm.sup.-1: 1740, 1680, 1590, 1404, 1235, 1200,
1175, 1094.
Preparation Example 7
Preparation of
3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone
[0143] Thionyl chloride (3.57 g) was added to a solution of
4-methoxyphenylacetic acid (3.32 g, 19.98 mmol) in benzene (30 ml).
After the mixture was heated under reflux for 3 hours, the solvent
was distilled off. To the residue, methylene chloride (50 ml) and
2-fluoroanisole (2.10 g) were added. Under ice cooling, aluminum
chloride (13.32 g) was added, followed by stirring for 30 minutes.
The mixture was then stirred at room temperature for 2 hours. The
reaction mixture was added to ice water, followed by extraction
with methylene chloride. The extract was dried over anhydrous
sodium sulfate. The solvent was distilled off under reduced
pressure. The residue so obtained was separated and purified by
chromatography on a silica gel column and was then crystallized
form ethyl acetate-hexane, whereby the title compound (2.27 g,
49.6%) was obtained as colorless prisms.
[0144] Melting point: 141.7-142.7.degree. C.
[0145] Mass (m/Z): 274 (M.sup.+).
[0146] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 3.94(3H, s),
4.15(2H, s), 6.86(2H, d, J=8.7 Hz), 6.98(1H, dd, J=8.5 Hz, J=8.5
Hz), 7.17(2H, d, J=8.7 Hz), 7.73(1H, dd, J=12.0 Hz, J=2.2 Hz),
7.79(1H, ddd, J=8.5 Hz, J=2.2 Hz, J=1.0 Hz).
[0147] IR (KBr) cm.sup.-1: 1681, 1613, 1516, 1436, 1286, 1254,
1223, 1177, 1132, 1034, 1014, 889, 809, 787.
Preparation Example 8
Preparation of ethyl
3-(3-fluoro-4-methoxyphenyl)-4-(4-methoxyphenyl)-4-ox-
obutanoate
[0148] (1) Preparation of
2-(3-fluoro-4-methoxyphenyl)-4'-methoxyacetophen- one:
[0149] Using 3-fluoro-4-methoxyphenylacetic acid and anisole as
starting materials, the procedures of Preparation Example 7 were
repeated likewise, whereby the title compound was obtained in a
yield of 57.0%.
[0150] Colorless needles (ethyl acetate-hexane).
[0151] Melting point: 117.0-117.7.degree. C.
[0152] Mass (m/Z): 274 (M.sup.+).
[0153] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.82(3H, s), 3.83(3H, s),
4.13(2H, s), 6.85-7.01(5H, m), 7.96(2H, d, J=9.0 Hz).
[0154] IR (KBr) cm.sup.-1: 1682, 1600, 1524, 1278, 1263, 1214,
1178, 1127, 1025.
[0155] (2) Preparation of ethyl
3-(3-fluoro-4-methoxyphenyl)-4-(4-methoxyp-
henyl)-4-oxobutanoate:
[0156] Using 2-(3-fluoro-4-methoxyphenyl)-4'-methoxyacetophenone as
a starting material, the procedures of Preparation Example 2 were
repeated likewise, whereby the title compound was obtained in a
yield of 85.5%. Yellow oil.
[0157] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.14(3H, t, J=7.1 Hz),
2.71(1H, dd, J=16.3 Hz, J=5.1 Hz), 3.33(1H, dd, J=16.3 Hz, J=9.5
Hz), 3.695(3H, s), 3.703(3H, s), 4.06(2H, q, J=7.1 Hz), 5.07(1H,
dd, J=9.5 Hz, J=5.1 Hz), 6.77-6.91(3H, m), 7.03(1H, d, J=8.3 Hz),
7.10(1H, dd, J=12.0 Hz, J=2.0 Hz), 7.99(2H, d, J=8.8 Hz).
Preparation Example 9
Preparation of ethyl
3,4-bis(3-fluoro-4-methoxyphenyl)-4-oxobutanoate
[0158] (1) Preparation of
3'-fluoro-2-(3-fluoro-4-methoxyphenyl)-4'-methox-
yacetophenone:
[0159] Using 3-fluoro-4-methoxyphenylacetic acid and
2-fluoroanisole as starting materials, the procedures of
Preparation Example 7 were repeated likewise, whereby the title
compound was obtained in a yield of 77.5%.
[0160] Colorless needles (ethyl acetate-hexane).
[0161] Melting point: 150.6-151.7.degree. C.
[0162] Mass (m/Z): 292 (M.sup.+).
[0163] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.87(3H, s), 3.95(3H, s),
4.14(2H, s), 6.88-7.03(4H, m), 7.73(1H, dd, J=12.0 Hz, J=2.2 Hz),
7.78(1H, ddd, J=8.5 Hz, J=2.2 Hz, J=1.0 Hz).
[0164] IR (KBr) cm.sup.-1: 1677, 1613, 1520, 1436, 1282, 1265,
1224, 1180, 1124.
[0165] (2) Preparation of ethyl
3,4-bis(3-fluoro-4-methoxyphenyl)-4-oxobut- anoate:
[0166] Using
3'-fluoro-2-(3-fluoro-4-methoxyphenyl)-4'-methoxyacetophenone as a
starting material, the procedures of Preparation Example 2 were
repeated likewise, whereby the title compound was obtained in a
yield of 62.3%.
[0167] Yellow oil.
[0168] Mass (m/Z): 378 (M.sup.+).
[0169] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.18(3H, t, J=7.1 Hz),
2.69(1H, dd, J=17.0 Hz, J=5.1 Hz), 3.30(1H, dd, J=17.0 Hz, J=9.5
Hz), 3.81(3H, s), 3.89(3H, s), 4.09(2H, q, J=7.1 Hz), 4.94(1H, dd,
J=9.5 Hz, J=5.1 Hz), 6.88(1H, dd, J=8.5 Hz, J=8.5 Hz), 6.93(1H, dd,
J=8.5 Hz, J=8.5 Hz), 6.96-7.06(2H, m), 7.70(1H, dd, J=12.0 Hz,
J=2.0 Hz), 7.77(1H, d, J=8.5 Hz).
[0170] HRMS: Calcd. for C.sub.20H.sub.20F.sub.2O.sub.5:
378.12785.
[0171] Found: 378.12759.
Example 1
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-4,5-dihydro-2H--
pyridazin-3-one
[0172] Hydrazine hydrate (10.56 g, 210.9 mmol) was added to a
solution of ethyl
3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate (42.54
g, 117.2 mmol) in ethanol (85 ml), followed by heating under reflux
for 15 hours at a bath temperature of 100.degree. C. A 4 N aqueous
solution of sodium hydroxide (40 ml) was added to the reaction
mixture. After the mixture was ice-cooled, precipitated crystals
were collected by filtration, washed with water (3.times.100 ml),
dried in air, and then dried under reduced pressure (100.degree.
C., 2 hours), whereby the title compound (31.49 g, 81.2%) was
obtained as pale yellow crystalline powder.
[0173] Melting point: 170.5-172.8.degree. C.
Example 2
Preparation of
4,5-dihydro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H--
pyridazin-3-one
[0174] Using methyl
3-(4-fluorophenyl)-4-[(4-methylthio)phenyl]-4-oxobutan- oate as a
starting material, the procedures of Example 1 were repeated
likewise, whereby the title compound was obtained in a yield of
33.1%.
[0175] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 2.77(1H, d,
J=17.01 Hz), 2.99(1H, dd, J=7.73, 17.01 Hz), 4.41(1H, d, J=7.73
Hz), 7.00(2H, t, J=8.67 Hz), 7.12-7.29(4H, m), 7.59(2H, d, J=8.55
Hz).
Example 3
Preparation of
4,5-dihydro-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin--
3-one
[0176] Methyl 4-(4-methoxyphenyl)-4-oxo-3-(4-pyridyl)butanoate
(10.63 g, 35.6 mmol) was dissolved in ethanol (200 ml), followed by
the addition of hydrazine hydrate (1.77 g, 35.26 mmol). The mixture
was heated under reflux for 17 hours. The reaction mixture was
concentrated under reduced pressure. The residue so obtained was
separated and purified by chromatography on a silica gel column
[silica gel: 100 g, chloroform/methanol (10/1)] and was then
recrystallized from ethanol-hexane, whereby the title compound
(5.92 g, 59.3%) was obtained as pale yellow crystalline powder.
[0177] Melting point: 100.1-102.3.degree. C.
[0178] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.80(1H, dd, J=1.71, 17.09
Hz), 3.04(1H, dd, J=7.81, 17.09 Hz), 3.82(3H, s), 4.46(1H, dd,
J=1.71, 7.81 Hz), 6.89(2H, d, J=9.03 Hz), 7.15(2H, d, J=6.10 Hz),
7.62(2H, d, J=9.03 Hz), 8.56(2H, d, J=6.10 Hz), 8.68(1H, brs).
[0179] IR (KBr) cm.sup.-1: 1679, 1611, 1597, 1515, 1355, 1330,
1259, 1167.
Example 4
Preparation of
6-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3--
one
[0180] Using 2-(4-methoxyphenyl)-3',4'-dimethoxyacetophenone as a
starting material, the procedures of Preparation Example 1 were
repeated likewise. The reaction product was then recrystallized
from ethyl acetate-hexane, whereby the title compound was obtained
as pale orange crystals in a yield of 29%.
[0181] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.66(3H, s), 3.81(3H, s),
3.87(3H, s), 6.70(1H, d, J=1.65 Hz), 6.75(1H, d, J=8.24 Hz),
6.79(1H, dd, J=1.65, 8.25 Hz), 6.94(2H, d, J=8.91 Hz), 7.07(2H, d,
J=8.90 Hz).
Example 5
Preparation of 6-(4-methoxyphenyl)-5-phenyl-2H-pyridazin-3-one
[0182] Using 2-phenyl-4'-methoxyacetophenone (J. Med. Chem., 25,
1070-1077, 1982: Martin R. Schneider, Erwin von Angerer, Helmut
Schonenberger, Ralf Th Michel, and H. F. Fortmeyer) as a starting
material, the procedures of Preparation Example 1 were repeated
likewise, whereby the title compound was obtained as colorless
crystals in a yield of 56.1%.
[0183] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.57-1.69(1H, br),
3.78(3H, s), 6.76(2H, d, J=8.79 Hz), 6.97(1H, s), 7.07-7.18(4H, m),
7.24-7.40(3H, m),
Example 6
Preparation of
5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one
[0184] Using 2-(4-chlorophenyl)-4'-methoxyacetophenone as a
starting material, the procedures of Preparation Example 1 were
repeated likewise, whereby the title compound was obtained as pale
brown crystals in a yield of 11%.
[0185] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 6.79(2H, d,
J=8.90 Hz), 6.95(1H, s), 7.07(2H, d, J=8.90 Hz), 7.10(2H, d, J=8.91
Hz), 7.29(2H, d, J=8.58 Hz), 11.73(1H, br).
Example 7
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3--
one
[0186] A solution of
5-(4-chlorophenyl)-4,5-dihydro-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one (31.49 g, 95.2 mmol) in acetic acid (160 ml)
was stirred under heating at 70.degree. C. After a solution of
bromine (15.21 g, 95.2 mmol) in acetic acid (60 ml) was added
dropwise over 20 minutes, the mixture was continuously stirred
under heating for 30 minutes. The reaction mixture was cooled with
ice water, followed by the successive gradual addition of a 10%
aqueous solution of sodium hydrogensulfite (50 ml) and water (1.1
l). A precipitate was collected by filtration, washed with water,
and then dried in air, whereby pale yellow crystalline powder
(33.88 g) was obtained. The powder was suspended in ethyl acetate
(120 ml). The suspension was heated under reflux at 90.degree. C.
for 30 minutes, and hexane (120 ml) was then added. The mixture was
cooled with ice water. Precipitated crystals were collected by
filtration and then dried in air, whereby title compound (29.84 g,
95.3%) was obtained as pale brown crystalline powder.
[0187] Colorless needles (chloroform-hexane)
[0188] Melting point: 201.7-203.7.degree. C.
[0189] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 6.95(1H, s),
7.05-7.16(6H, m), 7.27(2H, d, J=7.3 Hz), 11.40(1H, brs).
[0190] IR (KBr) cm.sup.-1: 1656, 1584, 1490, 1282, 1092.
Example 8
Preparation of
6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
[0191]
4,5-Dihydro-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
(5.4 g, 19.2 mmol) was dissolved in acetic acid (180 ml), followed
by the addition of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (5.0
g, 22.0 mmol). The interior of the reaction system was purged with
argon, and the contents were stirred at 70.degree. C. for 18 hours.
The reaction mixture was concentrated under reduced pressure. The
residue was separated and purified by chromatography on a silica
gel column [silica gel: 100 g, chloroform/methanol
(10/1).fwdarw.chloroform/methanol (with 10% (W/W) ammonia) (20/1)],
followed by further separation and purification by chromatography
on a silica gel column [silica gel: 200 g, chloroform/methanol
(with 10% (W/W) ammonia) (20/1)]. The crude crystals were
recrystallized from chloroform-ethyl acetate-diethyl ether, whereby
the title compound (4.61 g, 86.0%) was obtained as pale yellow
crystals.
[0192] Melting point: 236.0-267.6.degree. C.
[0193] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 6.78(2H, d,
J=8.79 Hz), 7.03(1H, s), 7.08(2H, d, J=6, 10 Hz), 7.09(2H, d,
J=8.79 Hz), 8.60(2H, d, J=6.10 Hz).
[0194] IR (KBr) cm.sup.-1: 3236, 1672, 1605, 1515, 1254, 1176.
Example 9
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3--
one
[0195] Using
4,5-dihydro-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-py-
ridazin-3-one as a starting material, the procedures of Example 8
were repeated likewise, whereby the title compound was obtained in
a yield of 92.6%.
[0196] Pale yellow prisms (ethyl acetate-hexane).
[0197] Melting point: 197.4-198.2.degree. C.
[0198] Mass (m/e): 312 (M.sup.+).
[0199] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 6.96(1H, s),
7.02(2H, t, J=8.59 Hz), 7.07-7.13(6H, m).
[0200] IR (KBr) cm.sup.-1: 3122, 1660, 1597, 1511, 1225, 1171,
1026, 852, 818, 759, 699.
Example 10
Preparation of
4,5-dihydro-5-phenyl-6-[4-(methylthio)phenyl]-2H-pyridazin--
3-one
[0201] Using methyl
4-[4-(methylthio)phenyl]-4-oxo-3-phenylbutanoate as a starting
material, the procedures of Example 1 were repeated likewise,
whereby the title compound was obtained in a yield of 47.5%.
[0202] Colorless needles (ethyl acetate-hexane).
[0203] Melting point: 212.6-213.8.degree. C.
[0204] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 2.81(1H, dd,
J=1.65, 16.97 Hz), 3.01(1H, dd, J=7.88, 16.97 Hz), 4.45(1H, dd,
J=1.65, 7.88 Hz), 7.14-7.43(7H, m), 7.61(2H, d, J=8.79 Hz).
Example 11
Preparation of
6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one
[0205] Using
4,5-dihydro-6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-- one
as a starting material, the procedures of Example 8 were repeated
likewise, whereby the title compound was obtained in a yield of
95.7%.
[0206] Colorless needles (ethyl acetate-hexane).
[0207] Melting point: 185.8-186.1.degree. C.
[0208] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45(3H, s), 7.04(1H, s),
7.05-7.17(6H, m), 7.27-7.40(3H, m).
[0209] IR (KBr) cm.sup.-1: 1656, 1588, 1574, 1491, 1020, 894, 827,
774, 755, 701.
Example 12
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin--
3-one
[0210] 4-Chlorocinnamyl chloride (898 mg, 4.8 mmol) was added to a
suspension of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (802 mg,
2.4 mmol) and potassium carbonate (663 mg, 4.8 mmol) in
N,N-dimethylformamide (8 ml), followed by stirring at 70.degree. C.
for 6 hours. After water (50 ml) was added to the reaction mixture,
the resulting mixture was extracted with ethyl acetate. The organic
layer was washed successively with water and a saturated aqueous
solution of sodium chloride, and then dried over anhydrous sodium
sulfate. The solvent was distilled off. An orange oil (1.73 g) so
obtained was separated and purified by chromatography on a silica
gel column [silica gel: 40 g, hexane/ethyl acetate (1/1)], whereby
pale yellow crystalline powder (1.22 g) was obtained. The powder
was recrystallized from chloroform-diethyl ether-hexane, whereby
the title compound (1.09 g, 91.3%) was obtained as pale yellow
prisms (dried at 70.degree. C. for 3 hours under reduced
pressure).
[0211] Melting point: 155.0-156.7.degree. C.
[0212] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 3.80(3H, s),
5.01(2H, dd, J=1.22, 6.59 Hz), 6.45(1H, dt, J=15.87, 6.59 Hz),
6.69(1H, d, J=15.87 Hz), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.78
Hz), 6.91(1H, s), 7.04(2H, d, J=8.78 Hz), 7.13(2H, d, J=8.79 Hz),
7.26(2H, d, J=8.54 Hz), 7.33(2H, d, J=8.79 Hz).
[0213] IR (KBr) cm.sup.-1: 1665, 1609, 1513, 1246, 965, 837,
700.
Example 13
Preparation of
5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazin-3-one
[0214] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
74.4%.
[0215] Colorless prisms (chloroform-hexane).
[0216] Melting point: 145.0-145.7.degree. C.
[0217] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.41(2H, s), 6.78(2H, d, J=9.04 Hz), 6.80(2H, d, J=8.79 Hz),
6.89(1H, s), 7.02(2H, d, J=8.79 Hz), 7.11(2H, d, J=8.79 Hz),
7.11(2H, d, J=8.78 Hz), 7.27-7.40(3H, m), 7.50-7.60(2H, m).
[0218] IR (KBr) cm.sup.-1: 1659, 1608, 1515, 1293, 1249, 1186,
1177, 1029, 841, 702.
Example 14
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-methoxybenzyl)-2H-pyridazin-3-
-one
[0219] Using 5,6-bis(4methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
54.54%.
[0220] Colorless prisms (methanol-diethyl ether).
[0221] Melting point: 171-172.degree. C.
[0222] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(9H, s), 5.35(2H, s),
6.78(2H, d, J=8.79 Hz), 6.83(2H, d, J=8.79 Hz), 6.87(1H, s),
6.88(2H, d, J=8.79 Hz), 7.01(2H, d, J=8.79 Hz), 7.11(2H, d, J=9.04
Hz), 7.69(2H, d, J=8.79 Hz).
[0223] IR (KBr) cm.sup.-1: 1664, 1609, 1512, 1247, 1185, 1173,
1023, 951.
Example 15
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4-dimethoxybenzyl)-2H-pyridaz-
in-3-one
[0224] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
17.4%.
[0225] Pale yellow amorphous.
[0226] Mass (m/e): 458 (M.sup.+).
[0227] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(6H, s), 3.87(3H, s),
3.90(3H, s), 5.32(2H, s), 6.78(2H, d, J=8.79 Hz), 6.80(2H, d,
J=8.79 Hz), 6.85(1H, d, J=8.30 Hz), 6.88(1H, s), 6.96(2H, d, J=8.79
Hz), 7.10-7.14(1H, m), 7.11(2H, d, J=8.79 Hz), 7.17(1H, d, J=1.95
Hz).
[0228] IR (film) cm.sup.-1: 1660, 1609, 1515, 1250, 1028, 834.
Example 16
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyri-
dazin-3-one
[0229] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
73.6%.
[0230] Pale yellow prisms (chloroform-diethyl ether).
[0231] Melting point: 138.0-139.0.degree. C.
[0232] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(6H, s), 3.84(3H, s),
3.87(3H, s), 5.33(2H, s), 6.78(2H, d, J=8.79 Hz), 6.80(2H, d,
J=8.79 Hz), 6.82(2H, s), 6.89(1H, s), 7.02(2H, d, J=8.79 Hz),
7.11(2H, d, J=8.76 Hz).
[0233] IR (KBr) cm.sup.-1: 1658, 1607, 1590, 1511, 1250, 1130,
1118, 840.
Example 17
Preparation of
5,6-bis(4-methoxyphenyl)-2-phenethyl-2H-pyridazin-3-one
[0234] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
80.0%.
[0235] Pale yellow needles (chloroform-hexane).
[0236] Melting point: 139.8-140.4.degree. C.
[0237] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17-3.23(2H, m), 3.79(3H,
s), 3.81(3H, s), 4.46-4.52(2H, m), 6.77(2H, d, J=8.79 Hz), 6.81(2H,
d, J=9.03 Hz), 6.90(1H, s), 7.02(2H, d, J=9.03 Hz), 7.03(2H, d,
J=9.03 Hz), 7.24-7.33(5H, m).
[0238] IR (KBr) cm.sup.-1: 1654, 1608, 1512, 1245, 1177, 1029, 843,
743.
Example 18
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4-dimethoxyphenethyl)-2H-pyri-
dazin-3-one
[0239] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
77.0%.
[0240] Pale yellow needles (ethyl acetate-hexane).
[0241] Melting point: 130.9-131.4.degree. C.
[0242] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.12-3.17(2H, m), 3.79(3H,
s), 3.81(3H, s), 3.84(3H, s), 3.87(3H, s), 4.44-4.50(2H, m),
6.76-6.85(7H, m), 6.91(1H, s), 7.02(2H, d, J=9.03 Hz), 7.04(1H, s),
7.05(2H, d, J=9.04 Hz).
[0243] IR (KBr) cm.sup.-1: 1655, 1608, 1516, 1266, 1242, 1028,
842.
Example 19
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-phenylpropyl)-2H-pyridazin-3--
one
[0244] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
81.3%.
[0245] Brown amorphous.
[0246] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.18-2.30(2H, m), 2.76(2H,
t, J=8.30 Hz), 3.79(3H, s), 3.80(3H, s), 4.31(2H, t, J=8.32 Hz),
6.78(2H, d, J=9.04 Hz), 6.81(2H, d, J=8.79 Hz), 6.86(1H, s),
7.03(2H, d, J=8.79 Hz), 7.12(2H, d, J=9.03 Hz), 7.15-7.30(5H,
m).
[0247] IR (film) cm.sup.-1: 1652, 1608, 1515, 1295, 1247, 1177,
1031, 833, 750, 700.
Example 20
Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(phenoxy)propyl]-2H-pyridazin-
-3-one
[0248] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
75.5%.
[0249] Pale yellow crystalline powder (diethyl ether).
[0250] Melting point: 110.0-111.0.degree. C.
[0251] Mass (m/e): 442 (M.sup.+).
[0252] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.37-2.42(2H, m), 3.78(3H,
s), 3.81(3H, s), 4.12(2H, t, J=6.35 Hz), 4.47(2H, t, J=7.08 Hz),
6.74(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz), 6.88-6.97(4H, m),
7.03(4H, d, J=9.04 Hz), 7.24-7.30(2H, m).
[0253] IR (KBr) cm.sup.-1: 1660, 1609, 1513, 1295, 1250, 1176,
1027, 838, 753.
Example 21
Preparation of
5,6-bis(4-methoxyphenyl)-2-cinnamyl-2H-pyridazin-3-one
[0254] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
50.4%.
[0255] Yellow amorphous.
[0256] Mass (m/e): 424 (M.sup.+).
[0257] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.01(2H, dd, J=0.98, 6.59 Hz), 6.48(1H, dt, J=15.87, 6.59 Hz),
6.74(1H, d, J=15.87 Hz), 6.78(2H, d, J=9.03 Hz), 6.81(2H, d, J=8.79
Hz), 6.91(1H, s), 7.04(2H, d, J=8.78 Hz), 7.13(2H, d, J=9.03 Hz),
7.20-7.33(3H, m), 7.37-7.42(2H, m).
[0258] IR (KBr) cm.sup.-1: 1660, 1609, 1511, 1295, 1248, 1177,
1027, 950, 833.
Example 22
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-methoxycinnamyl)-2H-pyridazin-
-3-one
[0259] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
16.1%.
[0260] Pale yellow oil.
[0261] Mass (m/e): 454 (M.sup.+).
[0262] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
4.98(2H, d, J=6.59 Hz), 6.35(1H, dt, J=15.87, 6.59 Hz), 6.70(1H, d,
J=15.8 Hz), 6.78(2H, d, J=9.03 Hz), 6.81(2H, d, J=9.03 Hz),
6.84(2H, d, J=9.03 Hz), 6.91(1H, s), 7.04(2H, d, J=9.04 Hz),
7.13(2H, d, J=8.79 Hz), 7.34(2H, d, J=8.79 Hz).
[0263] IR (film) cm.sup.-1: 1652, 1608, 1514, 1297, 1248, 1177,
1031, 834, 754.
Example 23
Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(4-methoxyphenyl)propyl]-2H-p-
yridazin-3-one
[0264] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
59.4%.
[0265] Pale yellow amorphous.
[0266] Mass (m/e): 456 (M.sup.+).
[0267] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.16-2.27(2H, m), 2.70(2H,
t, J=7.32 Hz), 3.77(3H, s), 3.80(3H, s), 3.81(3H, s), 4.29(2H, t,
J=7.32 Hz), 6.79(2H, d, J=8.79 Hz), 6.81(4H, d, J=8.79 Hz),
6.87(1H, s), 7.03(2H, d, J=9.03 Hz), 7.12(2H, d, J=8.79 Hz),
7.15(2H, d, J=7.81 Hz).
[0268] IR (film) cm.sup.-1: 1661, 1609, 1514, 1297, 1247, 1179,
1034, 833, 754.
Example 24
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-methylcinnamyl)-2H-pyridazin--
3-one
[0269] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
71.6%.
[0270] Pale brown oil.
[0271] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33(3H, s), 3.79(3H, s),
3.80(3H, s), 5.00(2H, d, J=6.59 Hz), 6.42(1H, dt, J=15.87, 6.60
Hz), 6.72(1H, d, J=15.87 Hz), 6.78(2H, d, J=8.78 Hz), 6.81(2H, d,
J=8.79 Hz), 6.91(1H, s), 7.04(2H, d, J=8.78 Hz), 7.11(2H, d, J=7.32
Hz), 7.13(2H, d, J=9.04 Hz), 7.30(2H, d, J=8.06 Hz).
[0272] IR (film) cm.sup.-1: 1652, 1610, 1514, 1296, 1251, 1180,
1034, 834, 756.
Example 25
Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(4-methylphenyl)propyl]-2H-py-
ridazin-3-one
[0273] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
30.4%.
[0274] Pale yellow oil.
[0275] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.22(2H, quintet, J=7.32
Hz), 2.30(3H, s), 2.72(2H, t, J=7.33 Hz), 3.79(3H, s), 3.80(3H, s),
4.30(2H, t, J=7.32 Hz), 6.78(2H, d, J=8.78 Hz), 6.80(2H, d, J=8.79
Hz), 6.86(1H, s), 7.23(2H, d, J=8.79 Hz), 7.09(2H, d, J=5.86 Hz),
7.11(2H, d, J=9.03 Hz).
[0276] IR (film) cm.sup.-1: 1652, 1610, 1514, 1296, 1247, 1179,
1033, 833, 807, 755.
Example 26
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-fluorobenzyl)-2H-pyridazin-3--
one
[0277] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
56.8%.
[0278] Pale yellow needles (diethyl ether-hexane).
[0279] Melting point: 132.3-132.9.degree. C.
[0280] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.37(2H, s), 6.78(2H, d, J=8.78 Hz), 6.80(2H, d, J=9.03 Hz),
7.02(2H, d, J=9.03 Hz).
[0281] IR (KBr) cm.sup.-1: 1665, 1609, 1515, 1294, 1247, 1184,
1177, 1027, 839.
Example 27
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorobenzyl)-2H-pyridazi-
n-3-one
[0282] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
88.4%.
[0283] Pale yellow needles (ethyl acetate-hexane).
[0284] Melting point: 150.1-150.9.degree. C.
[0285] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
5.44(2H, s), 6.77(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz),
6.83-6.88(2H, m), 6.89(1H, s), 7.04(2H, d, J=8.78 Hz), 7.09(2H, d,
J=9.03 Hz), 7.42-7.51(1H, m).
[0286] IR (KBr) cm.sup.-1: 1667, 1608, 1512, 1502, 1292, 1252,
1243, 1181, 840, 831.
Example 28
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-fluoro-4-methoxybenzyl)-2H-py-
ridazin-3-one
[0287] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
84.3%.
[0288] Pale yellow scales (ethyl acetate-diethyl ether).
[0289] Melting point: 166.5-167.5.degree. C.
[0290] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(6H, s), 3.87(3H, s),
5.32(2H, s), 6.77-6.82(1H, m), 6.78(2H, d, J=9.03 Hz), 6.79(2H, d,
J=8.79 Hz), 6.88(1H, s), 6.90-6.96(1H, m), 7.02(2H, d, J=8.79 Hz),
7.11(2H, d, J=8.78 Hz), 7.27-7.32(1H, m).
[0291] IR (KBr) cm.sup.-1: 1662, 1609, 1516, 1275, 1248, 1183,
837.
Example 29
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4-difluorobenzyl)-2H-pyridazi-
n-3-one
[0292] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
51.6%.
[0293] Pale yellow prisms (ethyl acetate-diethyl ether).
[0294] Melting point: 155.4-156.1.degree. C.
[0295] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.34(2H, s), 6.79(2H, d, J=8.79 Hz), 6.80(2H, d, J=8.79 Hz),
6.89(1H, s), 7.03(2H, d, J=9.03 Hz), 7.08-7.18(1H, m), 7.10(2H, d,
J=8.79 Hz), 7.23-7.31(1H, m), 7.33-7.40(1H, m).
[0296] IR (KBr) cm.sup.-1: 1660, 1610, 1516, 1293, 1286, 1251,
1241, 1134, 1030, 847.
Example 30
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-fluorocinnamyl)-2H-pyridazin--
3-one
[0297] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
41.0%.
[0298] Pale yellow amorphous.
[0299] Mass (m/e): 442 (M.sup.+).
[0300] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.00(2H, d, J=6.84 Hz), 6.40(1H, dt, J=15.87, 6.60 Hz), 6.71(1H, d,
J=15.86 Hz), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=9.03 Hz),
6.91(1H, s), 6.96-7.06(4H, m), 7.14(2H, d, J=9.04 Hz),
7.34-7.39(2H, m).
[0301] IR (KBr) cm.sup.-1: 1660, 1609, 1509, 1296, 1249, 1178,
1027, 833.
Example 31
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyrida-
zin-3-one
[0302] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
34.8%.
[0303] Colorless needles(ethyl acetate-diethyl ether).
[0304] Melting point: 107.3-108.1.degree. C.
[0305] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
5.01(2H, d, J=6.35 Hz), 6.49(1H, dt, J=15.86, 6.60 Hz),
6.74-6.84(3H, m), 6.79(2H, d, J=8.78 Hz), 6.81(2H, d, J=8.79 Hz),
6.91(1H, s), 7.04(2H, d, J=8.78 Hz), 7.14(2H, d, J=8.78 Hz),
7.39-7.48(1H, m).
[0306] IR (KBr) cm.sup.-1: 1664, 1608, 1508, 1252, 1244, 1180,
1034, 973, 925, 833.
Example 32
Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(2,4-difluorophenyl)propyl]-2-
H-pyridazin-3-one
[0307] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
83.7%.
[0308] Yellow amorphous.
[0309] Mass (m/e): 462 (M.sup.+).
[0310] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.22(2H, q, J=7.57 Hz),
2.57(2H, t, J=7.56 Hz), 3.80(3H, s), 3.81(3H, s), 4.30(2H, t,
J=7.57 Hz), 6.72-6.83(2H, m), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d,
J=8.79 Hz), 6.87(1H, s), 7.03(2H, d, J=8.79 Hz), 7.12(2H, d, J=8.79
Hz), 7.16-7.22(1H, m).
[0311] IR (film) cm.sup.-1: 1660, 1608, 1512, 1296, 1250, 1178,
834.
Example 33
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-chlorobenzyl)-2H-pyridazin-3--
one
[0312] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
89.2%.
[0313] Pale yellow powder (chloroform-diethyl ether).
[0314] Melting point: 124.2-127.3.degree. C.
[0315] Mass (m/e): 432 (M.sup.+).
[0316] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.36(2H, s), 6.78(2H, d, J=8.79 Hz), 6.80(2H, d, J=9.03 Hz),
6.88(1H, s), 7.02(2H, d, J=8.79 Hz), 7.06(2H, d, J=9.04 Hz),
7.31(2H, d, J=8.30 Hz), 7.47(2H, d, J=8.30 Hz).
[0317] IR (KBr) cm.sup.-1: 1667, 1609, 1513, 1249, 1184, 1176,
835.
Example 34
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazi-
n-3-one
[0318] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
67.7%.
[0319] Slightly yellowish needles (chloroform-diethyl ether).
[0320] Melting point: 140.7-141.2.degree. C.
[0321] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 3.81(3H, s),
5.31(2H, s), 6.76(2H, d, J=8.79 Hz), 6.82(2H, d, J=8.79 Hz),
6.93(1H, s), 7.06(2H, d, J=8.79 Hz), 7.09(2H, d, J=9.03 Hz),
7.22-7.23(2H, m), 7.43(1H, d, J=1.71 Hz).
[0322] IR (KBr) cm.sup.-1: 1664, 1608, 1587, 1512, 1468, 1252,
1181, 1032, 834, 696.
Example 35
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4-dichlorobenzyl)-2H-pyridazi-
n-3-one
[0323] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
56.4%.
[0324] Colorless scales (ethyl acetate-hexane).
[0325] Melting point: 107.8-109.5.degree. C.
[0326] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.34(2H, s), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz),
6.89(1H, s), 7.03(2H, d, J=9.03 Hz), 7.10(2H, d, J=9.04 Hz),
7.37(1H, dd, J=1.95, 8.30 Hz), 7.42(1H, d, J=8.06 Hhz), 7.63(1H, d,
J=1.71 Hz).
[0327] IR (KBr) cm.sup.-1: 1661, 1609, 1514, 1471, 1293, 1248,
1182, 1024, 834.
Example 36
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,6-dichlorobenzyl)-2H-pyridazi-
n-3-one
[0328] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
70.0%.
[0329] Yellow needles (diethyl ether).
[0330] Melting point: 144.0-144.5.degree. C.
[0331] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.75(3H, s), 3.80(3H, s),
5.70(2H, s), 6.67(2H, d, J=8.78 Hz), 6.81(2H, d, J=9.28 Hz),
6.92(2H, d, J=9.28 Hz), 7.04(2H, d, J=8.79 Hz), 7.21(1H, dd,
J=7.32, 8.79 Hz).
[0332] IR (KBr) cm.sup.-1: 1664, 1608, 1513, 1290, 1254, 1182,
1027, 834, 786.
Example 37
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4,6-trichlorobenzyl)-2H-pyrid-
azin-3-one
[0333] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
28.5%.
[0334] Slight yellow needles (diethyl ether-hexane).
[0335] Melting point: 142.1-142.7.degree. C.
[0336] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.76(3H, s), 3.81(3H, s),
5.65(2H, s), 6.70(2H, d, J=9.03 Hz), 6.81(2H, d, J=9.03 Hz),
6.89(1H, s), 6.94(2H, d, J=9.04 Hz), 6.94(2H, d, J=9.03 Hz),
7.37(2H, s).
[0337] IR (KBr) cm.sup.-1: 1663, 1609, 1512, 1248, 1177, 1026, 838,
787.
Example 38
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-chlorophenethyl)-2H-pyridazin-
-3-one
[0338] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
67.4%.
[0339] Pale yellow needles (ethyl acetate-hexane).
[0340] Melting point: 133.0-134.0.degree. C.
[0341] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.17(2H, t, J=7.81 Hz),
3.80(3H, s), 3.81(3H, s), 4.46(2H, t, J=7.81 Hz), 6.78(2H, d,
J=8.79 Hz), 6.81(2H, d, J=8.79 Hz), 6.89(1H, s), 7.01(2H, d, J=8.79
Hz), 7.02(2H, d, J=8.79 Hz), 7.22(2H, d, J=8.79 Hz), 7.28(2H, d,
J=8.54 Hz).
[0342] IR (KBr) cm.sup.-1: 1648, 1608, 1514, 1297, 1252, 1175,
836.
Example 39
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorophenethyl)-2H-pyrid-
azin-3-one
[0343] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
80.2%.
[0344] Pale yellow prisms (diethyl ether-hexane).
[0345] Melting point: 119.4-120.1.degree. C.
[0346] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.30(2H, t, J=7.08 Hz),
3.79(3H, s), 3.81(3H, s), 4.51(2H, t, J=7.08 Hz), 6.76(2H, d,
J=9.03 Hz), 6.81(2H, d, J=9.03 Hz), 6.87(1H, s), 6.96(2H, d, J=8.79
Hz), 7.02(2H, d, J=8.79 Hz), 7.18(2H, d, J=1.71 Hz), 7.40(1H, d,
J=1.71 Hz).
[0347] IR (KBr) cm.sup.-1: 1660, 1607, 1513, 1294, 1249, 1185,
832.
Example 40
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorocinnamyl)-2H-pyrida-
zin-3-one
[0348] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
74.5%.
[0349] Pale yellow amorphous.
[0350] Mass (m/e): 492, 494(M.sup.+).
[0351] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
5.04(2H, dd, J=1.46, 6.59 Hz), 6.46(1H, dt, J=15.87, 6.59 Hz),
6.78(2H, d, J=8.78 Hz), 6.81(2H, d, J=8.79 Hz), 6.92(1H, s),
7.04(1H, d, J=15.87 Hz), 7.05(2H, d, J=9.03 Hz), 7.19(1H, dd,
J=2.19, 8.55 Hz), 7.37(1H, d, J=2.20 Hz), 7.84(1H, d, J=8.54
Hz).
[0352] IR (KBr) cm.sup.-1: 1664, 1609, 1512, 1469, 1248, 950, 833,
746.
Example 41
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-o- ne
[0353] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
86.2%.
[0354] Pale brown crystals.
[0355] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 3.81(3H, s),
5.49(2H, s), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz),
6.91(1H, s), 7.03(2H, d, J=8.79 Hz), 7.10(2H, d, J=8.79 Hz),
8.21(2H, d, J=8.79 Hz).
[0356] IR (KBr) cm.sup.-1: 1664, 1609, 1522, 1347, 1247, 1185,
1025, 835.
Example 42
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-methoxycarbonylbenzyl)-2H-pyr-
idazin-3-one
[0357] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
78.8%.
[0358] Colorless needles (ethyl acetate-hexane).
[0359] Melting point: 185.5-186.6.degree. C.
[0360] Mass (m/e): 456 (M.sup.+).
[0361] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
3.91(3H, s), 5.45(2H, s), 6.78(2H, d, J=8.79 Hz), 6.80(2H, d,
J=9.04 Hz), 6.90(1H, s), 7.03(2H, d, J=8.79 Hz), 7.09(2H, d, J=9.03
Hz), 7.56(2H, d, J=8.06 Hz), 8.06(2H, d, J=8.54 Hz).
[0362] IR (KBr) cm.sup.-1: 1722, 1659, 1608, 1565, 1514, 1249,
1183, 1113, 1021, 835.
Example 43
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2-pyridylmethyl)-2H-pyridazin-3-
-one
[0363] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
63.1%.
[0364] Slight yellow prisms (chloroform-diethyl ether-hexane).
[0365] Melting point: 116.0-117.0.degree. C.
[0366] Mass (m/e): 399 (M.sup.+).
[0367] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 3.81(3H, s),
5.58(2H, s), 6.76(2H, d, J=8.79 Hz), 6.82(2H, d, J=9.04 Hz),
6.95(1H, s), 7.06(2H, d, J=8.79 Hz), 7.12(2H, d, J=8.79 Hz),
7.20(1H, dd, J=4.87, 7.56 Hz), 7.30(1H, d, J=7.81 Hz), 7.66(1H, dt,
J=1.71, 7.81 Hz), 8.59(1H, d, J=4.88 Hz).
[0368] IR (KBr) cm.sup.-1: 1656, 1608, 1514, 1246, 1176, 1027,
843.
[0369] In a manner known per se in the art, the hydrochloride of
the title compound was obtained in a yield of 96.4%.
[0370] Pale yellow amorphous.
[0371] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.73(3H, s), 3.76(3H, s),
5.54(2H, s), 6.84(2H, d, J=8.79 Hz), 6.90(2H, d, J=8.79 Hz),
6.95(1H, s), 7.08(2H, d, J=8.79 Hz), 7.14(2H, d, J=8.79 Hz),
7.54(1H, d, J=7.82 Hz), 8.06(1H, m), 8.66(1H, d, J=4.64 Hz).
[0372] IR (KBr) cm.sup.-1: 1661, 1609, 1512, 1297, 1250, 1177,
1026, 835.
Example 44
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-
-one
[0373] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
71.4%.
[0374] Pale yellow prisms (chloroform-diethyl ether).
[0375] Melting point: 167.4-168.4.degree. C.
[0376] Mass (m/e): 399 (M.sup.+).
[0377] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 5.42(2H, s),
6.78(2H, d, J=8.79 Hz), 6.80(2H, d, J=9.03 Hz), 6.89(1H, s),
7.02(2H, d, J=8.79 Hz), 7.11(2H, d, J=8.79 Hz), 7.29(1H, dd,
J=4.88, 7.81 Hz), 7.88(1H, td, J=1.71, 7.81 Hz), 8.56(1H, dd,
J=1.71, 4.88 Hz), 8.79(1H, d, J=1.47 Hz).
[0378] IR (KBr) cm.sup.-1: 1669, 1608, 1514, 1294, 1249, 1183,
839.
[0379] In a manner known per se in the art, the methanesulfonate of
the title compound was obtained in a yield of 89.1%.
[0380] Colorless prisms (methanol-diethyl ether)
[0381] Melting point: 214.2-214.8.degree. C.
[0382] .sup.1H-NMR (CDCl.sub.3+CD.sub.3OD) .delta.: 2.89(3H, s),
3.81(6H, s), 5.55(2H, s), 6.80(2H, d, J=9.03 Hz), 6.82(2H, d,
J=8.79 Hz), 6.91(1H, s), 7.04(2H, d, J=9.03 Hz), 7.11(2H, d, J=8.79
Hz), 7.92(2H, dd, J=5.86, 8.05 Hz), 8.63(1H, d, J=8.31 Hz),
8.93(1H, d, J=5.61 Hz), 8.98(1H, brs).
[0383] IR (KBr) cm.sup.-1: 1655, 1603, 1515, 1243, 1156, 1034,
840.
Example 45
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-pyridylmethyl)-2H-pyridazin-3-
-one
[0384] Using 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
76.0%.
[0385] Orange prisms (chloroform-diethyl ether).
[0386] Melting point: 182.1-183.1.degree. C.
[0387] Mass (m/e): 399 (M.sup.+).
[0388] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
5.40(2H, s), 6.78(2H, d, J=8.78 Hz), 6.81(2H, d, J=8.06 Hz),
6.92(1H, s), 7.04(2H, dd, J=2.20, 9.03 Hz), 7.10(2H, dd, J=2.20,
8.79 Hz), 7.36(2H, dd, J=1.71, 6.10 Hz), 8.59(2H, dd, J=1.71, 6.10
Hz).
[0389] IR (KBr) cm.sup.-1: 1660, 1610, 1513, 1294, 1247, 1174,
1028, 845.
[0390] In a manner known per se in the art, the methanesulfonate of
the title compound was obtained in a yield of 86.0%.
[0391] Slight yellow prisms (methanol-diethyl ether).
[0392] Melting point: 219.0-221.0.degree. C. (decomposed)
[0393] .sup.1H-NMR (CD.sub.3OD) .delta.: 2.70(3H, s), 3.77(3H, s),
3.79(3H, s), 5.73(2H, s), 6.82(2H, d, J=8.79 Hz), 6.88(2H, d,
J=8.79 Hz), 7.00(1H, s), 7.13(2H, d, J=9.03 Hz), 7.15(2H, d, J=8.79
Hz), 8.07(2H, d, J=6.84 Hz), 8.83(2H, d, J=6.83 Hz).
[0394] IR (KBr) cm.sup.-1: 1656, 1603, 1514, 1298, 1245, 1178,
1163, 1035, 840.
Example 46
Preparation of
6-(4-methoxyphenyl)-5-phenyl-2-cinnamyl-2H-pyridazin-3-one
[0395] Using 6-(4-methoxyphenyl)-5-phenyl-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
73.9%.
[0396] Orange prisms (ethyl acetate-hexane).
[0397] Melting point: 135.8-137.1.degree. C.
[0398] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 5.02(2H, dd,
J=0.98, 6.67 Hz), 6.50(1H, dt, J=15.86, 6.67 Hz), 6.71-6.80(3H, m),
6.94(1H, s), 7.06-7.15(4H, m), 7.20-7.34(6H, m), 7.36-7.44(2H,
m).
[0399] IR (KBr) cm.sup.-1: 1664, 1609, 1517, 1250, 1182, 1023, 965,
840.
Example 47
Preparation of
6-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)-2-(2,4-dichloro-
benzyl)-2H-pyridazin-3-one
[0400] Using
6-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
69.5%.
[0401] Colorless needles (ethyl acetate-hexane).
[0402] Melting point: 118.6-119.8.degree. C.
[0403] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.18(2H, t, J=7.32 Hz),
3.63(3H, s), 3.80(3H, s), 3.87(3H, s), 4.48(2H, t, J=7.32 Hz),
6.52(1H, d, J=1.95 Hz), 6.67(1H, dd, J=1.95, 8.30 Hz), 6.76(1H, d,
J=8.30 Hz), 6.81(2H, d, J=9.03 Hz), 6.91(1H, s), 7.03(2H, d, J=8.79
Hz), 7.21(2H, d, J=8.55 Hz), 7.28(2H, d, J=8.54 Hz).
[0404] IR (KBr) cm.sup.-1: 1668, 1519, 1513, 1469, 1270, 1253,
1175, 1140.
Example 48
Preparation of
6-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)-2-(4-chlorophen-
ethyl)-2H-pyridazin-3-one:
[0405] Using
6-(3,4-dimethoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
87.0%.
[0406] Pale yellow amorphous.
[0407] Mass (m/e): 476 (M.sup.+).
[0408] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.62(3H, s), 3.81(3H, s),
3.86(3H, s), 5.52(2H, s), 6.65(1H, s), 6.73(2H, d, J=1.22 Hz),
6.83(2H, d, J=8.79 Hz), 6.94(1H, s), 7.07(2H, d, J=8.79 Hz),
7.22(1H, dd, J=1.95, 8.30 Hz), 7.30(1H, d, J=8.30 Hz), 7.44(1H, d,
J=2.20 Hz).
[0409] IR (KBr) cm.sup.-1: 1660, 1608, 1512, 1267, 1251, 1218,
1175, 1027, 834.
Example 49
Preparation of
5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2-benzyl-2H-pyridazi-
n-3-one
[0410] Using
5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
65.5%.
[0411] Pale yellow prisms (diethyl ether-hexane).
[0412] Melting point: 165.0-167.0.degree. C.
[0413] Mass (m/e): 402, 404 (M.sup.+).
[0414] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 5.42(2H, s),
6.79(2H, d, J=8.79 Hz), 6.89(1H, s), 7.03(2H, d, J=8.79 Hz),
7.08(2H, d, J=9.04 Hz), 7.27(2H, d, J=8.79 Hz), 7.29-7.40(3H, m),
7.52(2H, dd, J=1.71, 8.06 Hz).
[0415] IR (KBr) cm.sup.-1: 1672, 1608, 1515, 1248, 1184, 833.
Example 50
Preparation of
5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2-(4-pyridylmethyl)--
2H-pyridazin-3-one
[0416] Using
5-(4-chlorophenyl)-6-(4-methoxyphenyl)-2H-pyridazin-3-one as a
starting material, the procedures of Example 12 were repeated
likewise, whereby the title compound was obtained in a yield of
73.2%.
[0417] Slightly pale yellow prisms (diethyl ether).
[0418] Melting point: 142.0-143.0.degree. C.
[0419] Mass (m/e): 403, 405 (M.sup.+).
[0420] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 5.41(2H, s),
6.79(2H, dd, J=2.20, 8.79 Hz), 6.95(1H, s), 7.06(2H, dd, J=1.95,
8.54 Hz), 7.07(2H, dd, J=2.20, 9.03 Hz), 7.29(2H, dd, J=1.95, 8.55
Hz), 7.36(2H, dd, J=1.71, 6.11 Hz), 8.60(2H, dd, J=1.71, 6.11
Hz).
[0421] IR (KBr) cm.sup.-1: 1660, 1601, 1587, 1514, 1247, 1174,
1091, 953, 844, 789.
[0422] In a manner known per se in the art, the methanesulfonate of
the title compound was obtained in a yield of 66.8%.
[0423] Colorless prisms (methanol-ethyl acetate).
[0424] Melting point: 201.5-203.0.degree. C.
[0425] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.89(3H, s), 3.81(3H, s),
5.60(2H, s), 6.80(2H, d, J=8.79 Hz), 6.97(1H, s), 7.06(2H, d,
J=9.04 Hz), 7.07(2H, d, J=8.79 Hz), 7.31(2H, d, J=8.79 Hz),
7.95(2H, d, J=6.83 Hz), 8.88(2H, d, J=6.83 Hz).
[0426] IR (KBr) cm.sup.-1: 1662, 1609, 1515, 1247, 1209, 1192,
1179, 1036, 842, 785.
Example 51
Preparation of
2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyr-
idazin-3-one
[0427]
5-(4-Chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one (500
mg, 1.52 mmol) was dissolved in anhydrous N,N-dimethylformamide (20
ml), followed by the addition of potassium carbonate (420 mg, 3.04
mmol). Benzyl bromide (286 mg, 1.67 mmol) was then added at
50.degree. C., and the mixture was stirred at 70.degree. C. for 40
minutes. After the temperature of the reaction mixture was allowed
to cool down to room temperature, the reaction mixture was diluted
with ethyl acetate. The mixture was washed with water and then with
a brine, and was then dried over anhydrous sodium sulfate. The
solvent was distilled off. The residue so obtained was separated
and purified by chromatography on a silica gel column [hexane/ethyl
acetate (3/1)], whereby pale yellow crystals were obtained. The
crystals were recrystallized from ethyl acetate-hexane, whereby the
title compound (552.6 mg, 86.8%) was obtained as pale yellow
prisms.
[0428] Melting point: 155.0-155.6.degree. C.
[0429] Mass (m/e): 418, 420 (M.sup.+).
[0430] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.42(2H, s),
6.90(1H, s), 7.04(2H, d, J=8.40 Hz), 7.06(2H, d, J=8.40 Hz),
7.11(2H, d, J=8.59 Hz), 7.27(2H, d, J=8.40 Hz), 7.31-7.38(3H, m),
7.53(2H, d, J=6.83 Hz).
[0431] IR (KBr) cm.sup.-1: 3032, 2925, 1669, 1581, 1493, 1095, 950,
829, 695.
Example 52
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-cyclopropylme-
thyl-2H-pyridazin-3-one
[0432] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
84.0%.
[0433] Pale yellow crystalline powder (diethyl ether).
[0434] Melting point: 142.0-143.0.degree. C.
[0435] Mass (m/e): 382, 384 (M.sup.+).
[0436] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.61(4H, m),
1.42-1.48(1H, m), 2.47(3H, s), 4.12(2H, d, J=7.42 Hz), 6.91(1H, s),
7.08(2H, d, J=8.40 Hz), 7.10(2H, d, J=7.62 Hz), 7.13(2H, d, J=8.79
Hz), 7.29(2H, d, J=8.40 Hz).
[0437] IR (KBr) cm.sup.-1: 1664, 1598, 1583, 1493, 1092, 952,
829.
Example 53
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(2,4-difluoro-
benzyl)-2H-pyridazin-3-one
[0438] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
79.0%.
[0439] Pale yellow prisms (ethyl acetate-hexane).
[0440] Melting point: 157.4-157.5.degree. C.
[0441] Mass (m/e): 454, 456 (M.sup.+).
[0442] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.45(2H, s),
6.82(2H, m), 6.91(1H, s), 7.03-7.07(4H, m), 7.12(2H, d, J=8.40 Hz),
7.29(2H, d, J=8.40 Hz), 7.45-7.51(1H, m).
[0443] IR (KBr) cm.sup.-1: 1672, 1600, 1506, 1274, 1140, 1093, 972,
829.
Example 54
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(2,4-dichloro-
benzyl)-2H-pyridazin-3-one
[0444] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
97.1%.
[0445] Colorless prisms (ethyl acetate-hexane).
[0446] Melting point: 154.5-155.0.degree. C.
[0447] Mass (m/e): 486, 488, 490 (M.sup.+).
[0448] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.51(2H, s),
6.94(1H, s), 7.04(2H, d, J=8.55 Hz), 7.09(2H, d, J=8.55 Hz),
7.08(2H, d, J=8.79 Hz), 7.22(1H, dd, J=8.30, 1.83 Hz),
7.24-7.33(3H, m), 7.43(1H, d, J=1.83 Hz).
[0449] IR (KBr) cm.sup.-1: 1660, 1585, 1484, 1095, 829, 819.
Example 55
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmet-
hyl)-2H-pyridazin-3-one
[0450] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
65.6%.
[0451] Pale yellow prisms (ethyl acetate-hexane).
[0452] Melting point: 148.4-148.5.degree. C.
[0453] Mass (m/e): 419 (M.sup.+).
[0454] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 5.42(2H, s),
6.91(1H, s), 7.03-7.13(6H, m), 7.27-7.32(3H, m), 7.88(1H, tt,
J=7.81, 1.95 Hz), 8.57(1H, dd, J=4.88, 1.71 Hz), 8.79(1H, d, J=1.95
Hz).
[0455] IR (KBr) cm.sup.-1: 1665, 1580, 1490, 1428, 1311, 1093,
834.
Example 56
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-cinnamyl-2H-p-
yridazin-3-one
[0456] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
73.9%.
[0457] Colorless prisms (chloroform-hexane).
[0458] Melting point: 109.3-110.2.degree. C.
[0459] Mass (m/e): 444, 446 (M.sup.+).
[0460] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 5.01(2H, dd,
J=6.71, 1.10 Hz), 6.48(1H, dt, J=15.75, 6.71 Hz), 6.75(1H, d,
J=15.75 Hz), 6.93(1H, s), 7.00-7.14(6H, m), 7.20-7.33(5H, m),
7.34-7.42(2H, m).
[0461] IR (KBr) cm.sup.-1: 1665, 1598, 1582, 1493, 1095, 967,
948.
Example 57
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-phenylprop-
yl)-2H-pyridazin-3-one
[0462] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
97.5%.
[0463] Pale yellow oil.
[0464] Mass (m/e): 446, 448 (M.sup.+).
[0465] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.23(2H, q, J=7.48 Hz),
2.47(3H, s), 2.76(2H, t, J=7.48 Hz), 4.32(2H, t, J=7.48 Hz),
6.87(1H, s), 7.02-7.31(13H, m).
[0466] IR (KBr) cm.sup.-1: 1665, 1598, 1582, 1493, 1095, 967,
948.
Example 58
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-cyclopropylme-
thyl-2H-pyridazin-3-one
[0467] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
99.7%.
[0468] Yellow amorphous.
[0469] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.60(4H, m),
1.43-1.49(1H, m), 2.73(3H, s), 4.14(2H, d, J=7.32 Hz), 6.92(1H, s),
7.01(2H, t, J=8.54 Hz), 7.09-7.12(2H, m), 7.36(2H, d, J=8.05 Hz),
7.56(2H, d, J=8.29 Hz).
[0470] IR (KBr) cm.sup.-1: 1664, 1599, 1578, 1510, 1229, 1093,
840.
Example 59
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-cyclopentylme-
thyl-2H-pyridazin-3-one
[0471] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
76.6%.
[0472] Colorless amorphous.
[0473] Mass (m/e): 394 (M.sup.+).
[0474] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.36-1.45(2H, m),
1.54-1.60(2H, m), 1.66-1.80(4H, m), 2.46(3H, s), 2.53-2.64(1H, m),
4.21(2H, d, J=7.56 Hz), 6.90(1H, s), 7.00(2H, t, J=8.54 Hz),
7.07-7.13(6H, m).
[0475] IR (KBr) cm.sup.-1: 1669, 1598, 1578, 1510, 1228, 1160,
1096, 840, 680.
Example 60
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(2,2,2-triflu-
oroethyl)-2H-pyridazin-3-one
[0476] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
72.3%.
[0477] Colorless amorphous.
[0478] Mass (m/e): 394, 395 (M.sup.+).
[0479] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 4.88(2H, q,
J=8.40 Hz), 6.95(1H, s), 6.99-7.14(8H, m).
[0480] IR (KBr) cm.sup.-1: 1678, 1597, 1513, 1335, 1263, 1088, 843,
827.
Example 61
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-benzyl-2H-pyr-
idazin-3-one
[0481] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
82.0%.
[0482] Colorless needles (ethyl acetate-hexane).
[0483] Melting point: 140.6-140.7.degree. C.
[0484] Mass (m/e): 402 (M.sup.+).
[0485] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.42(2H, s),
6.90(1H, s), 6.95-7.12(8H, m), 7.31-7.39(3H, m), 7.52-7.55(2H,
m).
[0486] IR (KBr) cm.sup.-1: 1664, 1601, 1509, 1232, 1098, 841,
699.
Example 62
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(4-methoxyben-
zyl)-2H-pyridazin-3-one
[0487] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
96.2%.
[0488] Colorless needles (ethyl acetate-hexane).
[0489] Melting point: 165.3-165.7.degree. C.
[0490] Mass (m/e): 432 (M.sup.+).
[0491] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 3.80(3H, s),
5.35(2H, s), 6.87(1H, s), 6.88(2H, d, J=6.83 Hz), 6.98(2H, t,
J=8.66 Hz), 7.01-7.16(6H, m), 7.50(2H, d, J=8.78 Hz).
[0492] IR (KBr) cm.sup.-1: 1663, 1511, 1246, 1233, 842.
Example 63
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-[4-(methylthi-
o)benzyl]-2H-pyridazin-3-one
[0493] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
80.3%.
[0494] Colorless plate crystals (ethyl acetate-hexane).
[0495] Melting point: 116.0-116.1.degree. C.
[0496] Mass (m/e): 448 (M.sup.+).
[0497] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(6H, s), 5.36(2H, s),
6.89(1H, s), 6.99(2H, t, J=8.69 Hz), 7.04-7.12(6H, m), 7.24(2H, d,
J=8.40 Hz), 7.47(2H, d, J=8.40 Hz).
[0498] IR (KBr) cm.sup.-1: 1660, 1599, 1576, 1511, 1495, 1233,
1161, 1093, 950, 841, 678.
Example 64
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(4-fluorobenz-
yl)-2H-pyridazin-3-one
[0499] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
89.8%.
[0500] Colorless needles (ethyl acetate-hexane).
[0501] Melting point: 155.9-156.2.degree. C.
[0502] Mass (m/e): 448, 449 (M.sup.+).
[0503] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.37(2H, s),
6.89(1H, s), 6.95-7.13(9H, m), 7.30-7.35(1H, m), 7.52(2H, dd,
J=8.54, 5.37 Hz).
[0504] IR (KBr) cm.sup.-1: 1664, 1602, 1510, 1225, 847, 812.
Example 65
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(2,4-dichloro-
benzyl)-2H-pyridazin-3-one
[0505] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
61.7%.
[0506] Colorless needles (ethyl acetate-hexane).
[0507] Melting point: 139.3-139.5.degree. C.
[0508] Mass (m/e): 470, 472 (M.sup.+).
[0509] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.44(3H, s), 5.51(2H, s),
6.94(1H, s), 6.97-7.43(11H, m).
[0510] IR (KBr) cm.sup.-1: 1665, 1583, 1510, 1233, 1098, 828.
Example 66
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(2,4-difluoro-
benzyl)-2H-pyridazin-3-one
[0511] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
21.0%.
[0512] Colorless oil.
[0513] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.45(2H, s),
6.78-6.88(2H, m), 6.91(1H, s), 6.98-7.12(8H, m), 7.37-7.49(1H,
m).
[0514] IR (KBr) cm.sup.-1: 1652, 1605, 1575, 1507, 1235, 1091, 972,
842.
Example 67
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmet-
hyl)-2H-pyridazin-3-one
[0515] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
31.7%.
[0516] Colorless needles (acetone-water).
[0517] Melting point: 159.8-160.7.degree. C.
[0518] Mass (m/e): 403 (M.sup.+).
[0519] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.43(2H, s),
6.91(1H, s), 6.96-7.13(8H, m), 7.30(1H, dd, J=8.30, 5.37 Hz),
7.89(1H, dt, J=7.80, 1.96 Hz), 8.58(1H, dd, J=4.77, 1.51 Hz),
8.79(1H, d, J=1.71 Hz).
[0520] IR (KBr) cm.sup.-1: 1661, 1580, 1509, 1216, 1095, 955, 852,
832, 680.
Example 68
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(4-pyridylmet-
hyl)-2H-pyridazin-3-one
[0521] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
23.5%.
[0522] Colorless crystals.
[0523] Melting point: 223.4-224.3%.
[0524] Mass (m/e): 403 (M.sup.+).
[0525] .sup.1H-NMR (DMSO-D.sub.6) .delta.: 2.44(3H, s), 5.39(2H,
s), 7.04(1H, s), 7.08(2H, d, J=8.29 Hz), 7.16(2H, d, J=8.54 Hz),
7.19-7.29(4H, m), 7.34(2H, d, J=5.61 Hz), 8.35(2H, d, J=5.85
Hz).
[0526] IR (KBr) cm.sup.-1: 1664, 1601, 1582, 1562, 1510, 1417,
1219, 852, 683.
Example 69
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(2,4-difluoro-
cinnamyl)-2H-pyridazin-3-one
[0527] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
49.5%.
[0528] Colorless amorphous.
[0529] Mass (m/e): 464 (M.sup.+).
[0530] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.02(2H, d,
J=6.34 Hz), 6.48(1H, dt, J=16.11, 6.59 Hz), 6.74-6.85(3H, m),
6.93(1H, s), 6.97-7.14(8H, m), 7.39-7.45(1H, m).
[0531] IR (KBr) cm.sup.-1: 1664, 1554, 1502, 1273, 1232, 1094, 966,
841.
Example 70
Preparation of
2-(4-chlorocinnamyl)-5-(4-fluorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one
[0532] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 58 were repeated
likewise, whereby the title compound was obtained in a yield of
67.5%.
[0533] Colorless needles (ethyl acetate-hexane).
[0534] Melting point: 118.6-118.9.degree. C.
[0535] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.00(2H, d,
J=5.62 Hz), 6.44(1H, dt, J=15.87, 6.59 Hz), 6.70(1H, d, J=16.12
Hz), 6.93(1H, s), 6.97-7.13(8H, m), 7.26(2H, d, J=5.79 Hz),
7.33(2H, d, J=8.55 Hz).
[0536] IR (KBr) cm.sup.-1: 1669, 1605, 1575, 1509, 1492, 1095, 841,
830.
Example 71
Preparation of
2-benzyl-6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-o- ne
[0537] Using 6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one
as a starting material, the procedures of Example 51 were repeated
likewise, whereby the title compound was obtained in a yield of
55.3%.
[0538] Colorless needles (ethyl acetate).
[0539] Melting point: 157.3-158.4.degree. C.
[0540] Mass (m/e): 384, 386 (M.sup.+).
[0541] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45(3H, s), 5.43(2H, s),
6.92(1H, s), 7.05-7.12(6H, m), 7.25-7.40(6H, m), 7.51-7.57(2H,
m).
[0542] IR (KBr) cm.sup.-1: 1665, 1597, 1585, 1493, 775, 711.
Example 72
Preparation of
2-acetonyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-
-one
[0543] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, propargyl chloride was treated in a similar
manner as in Example 12, whereby the title compound was obtained in
a yield of 29.3%.
[0544] Colorless crystalline powder (diethyl ether-hexane).
[0545] Melting point: 68.3-70.6.degree. C.
[0546] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.30(3H, s), 3.78(3H, s),
5.07(2H, s), 6.77(2H, d, J=8.54 Hz), 6.98(1H, s), 7.04-7.10(4H, m),
8.58(2H, td, J=0.85, 4.39 Hz).
[0547] IR (KBr) cm.sup.-1: 1734, 1669, 1610, 1517, 1250, 1170.
Example 73
Preparation of
2-cyclopropylmethyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-py-
ridazin-3-one
[0548] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
70.8%.
[0549] Colorless needles (ethyl acetate-hexane).
[0550] Melting point: 128.3-130.1.degree. C.
[0551] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.47-0.54(2H, m),
0.55-0.62(2H, m), 1.40-1.52(1H, m), 3.79(3H, s), 4.14(2H, d, J=7.08
Hz), 6.79(2H, d, J=8.92 Hz), 6.95(1H, s), 7.07(2H, dd, J=1.65, 4.91
Hz), 7.09(2H, d, J=8.92 Hz), 8.58(2H, dd, J=1.65, 4.91 Hz).
[0552] IR (KBr) cm.sup.-1: 1664, 1610, 1582, 1572, 1517, 1254,
1024, 834.
Example 74
Preparation of
2-cyclopentylmethyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-py-
ridazin-3-one
[0553] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
32.0%.
[0554] Colorless prisms (methylene chloride-hexane).
[0555] Melting point: 119.3-120.2.degree. C.
[0556] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.33-1.49(2H, m),
1.52-1.64(2H, m), 1.65-1.84(4H, m), 2.59(1H, septet, J=7.61 Hz),
3.79(3H, s), 4.22(2H, d, J=7.61 Hz), 6.79(2H, d, J=8.85 Hz),
6.94(1H, s), 7.07(2H, dd, J=1.71, 4.44 Hz), 7.09(2H, d, J=8.88 Hz),
8.57(2H, dd, J=1.71, 4.44 Hz).
[0557] IR (KBr) cm.sup.-1: 1668, 1610, 1601, 1572, 1517, 1250,
1180, 827.
Example 75
Preparation of
2-benzyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-o- ne
[0558] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
43.1%.
[0559] Pale yellow needles (ethyl acetate-hexane).
[0560] Melting point: 153.9-155.1.degree. C.
[0561] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 5.42(2H, s),
6.78(2H, d, J=8.66 Hz), 6.93(1H, s), 7.03(2H, d, J=5.73 Hz),
7.06(2H, d, J=8.66 Hz), 7.35-7.39(3H, m), 7.54(2H, d, J=7.07 Hz),
8.56(2H, d, J=5.73 Hz).
[0562] IR (KBr) cm.sup.-1: 1668, 1601, 1517, 1251, 1182, 826,
761.
Example 76
Preparation of
2-(4-methoxybenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-py-
ridazin-3-one
[0563] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
37.2%.
[0564] Colorless prisms (ethyl acetate-hexane).
[0565] Melting point: 142.6-143.3.degree. C.
[0566] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(6H, s), 5.36(2H, s),
6.78(2H, d, J=8.66 Hz), 6.88(2H, d, J=8.42 Hz), 6.92(1H, d, J=1.46
Hz), 7.02(2H, d, J=4.64 Hz), 7.07(2H, d, J=8.66 Hz), 7.50(2H, d,
J=8.42 Hz), 8.56(2H, d, J=3.64 Hz).
[0567] IR (KBr) cm.sup.-1: 1665, 1609, 1598, 1570, 1514, 1296,
1250, 1179, 1025, 844, 829.
Example 77
Preparation of
2-(4-fluorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyr-
idazin-3-one
[0568] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
42.2%.
[0569] Colorless prisms (ethyl acetate-hexane).
[0570] Melting point: 154.3-155.2.degree. C.
[0571] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 5.38(2H, s),
6.79(2H, d, J=8.78 Hz), 6.93(1H, s), 6.98-7.04(4H, m), 7.07(2H, d,
J=8.78 Hz), 7.53(2H, dd. J=8.54, 5.61 Hz), 7.56(2H, d, J=5.86
Hz).
[0572] IR (KBr) cm.sup.-1: 1666, 1609, 1601, 1572, 1517, 1509,
1297, 1253, 1226, 1182, 1158, 1028, 842, 826.
Example 78
Preparation of
2-(4-chlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyr-
idazin-3-one
[0573] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
81.2%.
[0574] Orange prisms (ethyl acetate-hexane).
[0575] Melting point: 175.4-176.1.degree. C.
[0576] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.38(2H, s),
6.79(2H, d, J=8.90 Hz), 6.93(1H, s), 7.03(2H, dd, J=1.70, 4.37 Hz),
7.05(2H, d, J=8.90 Hz), 7.33(2H, d, J=8.42 Hz), 7.48(2H, d, J=8.42
Hz), 8.56(2H, dd, J=1.70, 4.37 Hz).
[0577] IR (KBr) cm.sup.-1: 1665, 1608, 1598, 1571, 1517, 1492,
1252, 1181, 843, 827.
Example 79
Preparation of
2-(2,4-dichlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-
-pyridazin-3-one
[0578] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
47.2%.
[0579] Pale yellowish-brown prisms (methanol-diethyl ether).
[0580] Melting point: 151.3-153.0.degree. C.
[0581] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.78(3H, s), 5.53(2H, s),
6.77(2H, d, J=8.79 Hz), 6.98(1H, s), 7.04(2H, d, J=8.79 Hz),
7.07(2H, d, J=6.10 Hz), 7.22(1H, dd, J=1.96, 8.31 Hz), 7.29(2H, d,
J=8.31 Hz), 7.44(1H, d, J=1.96 Hz), 8.59(2H, d, J=6.10 Hz).
[0582] IR (KBr) cm.sup.-1: 1658, 1610, 1596, 1517, 1490, 1250,
1185.
Example 80
Preparation of
6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(3-pyridylmethyl)-2H-py-
ridazin-3-one
[0583] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
55.1%.
[0584] Colorless prisms (ethyl acetate-hexane).
[0585] Melting point: 161.7-162.3.degree. C.
[0586] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.44(2H, s),
6.79(2H, d, J=8.78 Hz), 6.95(1H, s), 7.04(2H, dd, J=1.71, 4.39 Hz),
7.06(2H, d, J=8.78 Hz), 7.31(1H, ddd, J=0.73, 4.88, 7.81 Hz),
7.91(1H, td, J=1.95, 7.81 Hz), 8.56-8.60(3H, m), 8.81(1H, d, J=1.95
Hz).
[0587] IR (KBr) cm.sup.-1: 1665, 1610, 1599, 1587, 1574, 1518,
1264, 1252, 1181, 1023, 839, 829, 716.
Example 81
Preparation of
6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(4-pyridylmethyl)-2H-py-
ridazin-3-one
[0588] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
45.4%.
[0589] Colorless prisms (chloroform-hexane).
[0590] Melting point: 192.8-194.4.degree. C.
[0591] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.42(2H, s),
6.79(2H, d, J=8.90 Hz), 6.98(1H, s), 7.06(2H, dd, J=1.71, 4.39 Hz),
7.06(2H, d, J=8.90 Hz), 7.38(2H, dd, J=1.71, 4.39 Hz), 8.58(2H, dd,
J=1.71, 4.39 Hz), 8.60(2H, dd, J=1.71, 4.39 Hz).
[0592] IR (KBr) cm.sup.-1: 1665, 1602, 1585, 1516, 1417, 1301,
1250, 1174, 838, 720.
Example 82
Preparation of
2-cinnamyl-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-
-one
[0593] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
29.9%.
[0594] Pale yellow amorphous.
[0595] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.02(2H, dd,
J=0.98, 6.59 Hz), 6.47(1H, td, J=6.59, 15.86 Hz), 6.77(1H, dd,
J=0.98, 15.86 Hz), 6.79(2H, d, J=8.79 Hz), 6.96(1H, s), 7.05(2H, d,
J=6.11 Hz), 7.09(2H, d, J=8.79 Hz), 7.21-7.31(3H, m), 7.33-7.40(2H,
m), 8.57(2H, d, J=6.11 Hz).
[0596] IR (KBr) cm.sup.-1: 1668, 1609, 1516, 1485, 1482, 1251,
1178.
Example 83
Preparation of
6-(4-methoxyphenyl)-5-(4-pyridyl)-2-(3-phenylpropyl)-2H-pyr-
idazin-3-one
[0597] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
70.7%.
[0598] Reddish brown prisms (ethyl acetate-diethyl
ether-hexane).
[0599] Melting point: 67.7-68.3.degree. C.
[0600] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.26(2H, quintet, J=7.33
Hz), 2.77(2H, t, J=7.33 Hz), 3.79(3H, s), 4.33(2H, t, J=7.33 Hz),
6.79(2H, d, J=8.79 Hz), 6.90(1H, s), 7.01(2H, d, J=6.11 Hz),
7.06(2H, d, J=8.79 Hz), 7.15-7.30(5H, m), 8.57(2H, d, J=6.11
Hz).
[0601] IR (KBr) cm.sup.-1: 1665, 1608, 1517, 1496, 1298, 1252,
1181.
Example 84
Preparation of
2-(2,4-difluorocinnamyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)--
2H-pyridazin-3-one
[0602] Using 6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyridazin-3-one
as a starting material, the procedures of Example 72 were repeated
likewise, whereby the title compound was obtained in a yield of
30.7%.
[0603] Colorless crystalline powder (ethyl acetate-diethyl
ether).
[0604] Melting point: 55.4-56.9.degree. C.
[0605] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.03(2H, d,
J=6.59 Hz), 6.49(1H, td, J=6.59, 16.03 Hz), 6.73-6.88(5H, m),
6.98(1H, s), 7.02-7.15(4H, m), 7.43(1H, dd, J=8.67, 15.02 Hz),
8.58(2H, brs).
[0606] IR (KBr) cm.sup.-1: 1668, 1610, 1516, 1502, 1297, 1251,
1178, 965, 829.
Example 85
Preparation of
2-benzyl-5-(4-chlorophenyl)-6-[4-(methylsulfinyl)phenyl]-2H-
-pyridazin-3-one
[0607]
2-Benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-
-one (100 mg, 0.239 mmol) was dissolved in dichloromethane (5 ml).
Under cooling at -20.degree. C., methachloroperbenzoic acid (60%)
(68.7 mg, 0.239 mmol) was added. The resulting mixture was stirred
through the night until its temperature arose to room temperature.
A saturated aqueous solution of sodium hydrogencarbonate was added.
After the resulting mixture was extracted with chloroform, the
extract was washed with water and then dried over anhydrous sodium
sulfate. The solvent was distilled off, and the residue so obtained
was then separated and purified by silica gel preparative
chromatography [hexane/ethyl acetate (1/2)], whereby the title
compound (91.8 mg, 88.4%) was obtained.
[0608] Colorless crystalline powder (hexane-diethyl ether)
[0609] Melting point: 143.7-144.7.degree. C.
[0610] Mass (m/e): 434, 436 (M.sup.+).
[0611] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72(3H, s), 5.43(2H, s),
6.94(1H, s), 7.02(2H, d, J=8.59 Hz), 7.27(2H, d, J=8.30 Hz),
7.29-7.40(5H, m), 7.49-7.52(2H, m), 7.55(2H, d, J=8.54 Hz).
[0612] IR (KBr) cm.sup.-1: 1665, 1583, 1494, 1091, 1050, 1015, 951,
833.
Example 86
Preparation of
5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylsulfinyl-
)phenyl]-2H-pyridazin-3-one
[0613] Using
5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 77.0%.
[0614] Colorless prisms (ethyl acetate-hexane).
[0615] Melting point: 152.2-152.3.degree. C.
[0616] Mass (m/e): 398, 400 (M.sup.+).
[0617] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.62(4H, m),
1.42-1.49(1H, m), 2.73(3H, s), 4.14(2H, d, J=7.42 Hz), 6.95(1H, s),
7.05(2H, d, J=8.40 Hz), 7.29(2H, d, J=8.40 Hz), 7.36(2H, d, J=8.40
Hz), 7.56(2H, d, J=8.40 Hz).
[0618] IR (KBr) cm.sup.-1: 1661, 1584, 1494, 1317, 1090, 1051,
838.
Example 87
Preparation of
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylsulfinyl-
)phenyl]-2H-pyridazin-3-one
[0619] Using
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 72.1%.
[0620] Colorless prisms (ethyl acetate-hexane).
[0621] Melting point: 133.3-133.5.degree. C.
[0622] Mass (m/e): 382 (M.sup.+).
[0623] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.49-0.62(4H, m),
1.42-1.48(1H, m), 3.05(3H, s), 4.14(2H, d, J=7.42 Hz), 6.96(1H, s),
7.03(2H, t, J=8.50 Hz), 7.08-7.11(2H, m), 7.40(2H, d, J=8.40 Hz),
7.85(2H, d, J=8.20 Hz).
[0624] IR (KBr) cm.sup.-1: 1664, 1582, 1511, 1220, 1055, 840,
612.
Example 88
Preparation of
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfinyl)phenyl]-2H-
-pyridazin-3-one
[0625] Using
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyrid-
azin-3-one as a starting material, the procedures of Example 85
were repeated likewise, whereby the title compound was obtained in
a yield of 24.2%.
[0626] Colorless needles (ethyl acetate-hexane).
[0627] Melting point: 197.7-198.2.degree. C.
[0628] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72(3H, s), 5.44(2H, s),
6.99(1H, s), 6.97-7.07(4H, m), 7.31-7.39(5H, m), 7.52-7.56(4H,
m).
[0629] IR (KBr) cm.sup.-1: 1665, 1511, 1231, 1049, 954, 840.
Example 89
Preparation of
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylsulfinyl-
)phenyl]-2H-pyridazin-3-one
[0630] Using
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 94.3%.
[0631] Colorless powder (ethyl acetate-hexane).
[0632] Melting point: 81.3-81.5.degree. C.
[0633] Mass (m/e): 448 (M.sup.+).
[0634] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.73(3H, s), 3.79(3H, s),
5.37(2H, s), 6.89(2H, d, J=8.54 Hz), 6.92(1H, s), 6.99(2H, t,
J=8.66 Hz), 7.03-7.07(2H, m), 7.33(2H, d, J=8.54 Hz), 7.50(2H, d,
J=8.78 Hz), 7.55(2H, d, J=8.54 Hz).
[0635] IR (KBr) cm.sup.-1: 1664, 1512, 1248, 1047, 840.
Example 90
Preparation of
2-(4-fluorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylsulfinyl)-
phenyl]-2H-pyridazin-3-one
[0636] Using
2-(4-fluorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl-
]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 80.6%.
[0637] Colorless needles (ethyl acetate-hexane).
[0638] Melting point: 198.1-198.3.degree. C.
[0639] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.73(3H, s), 5.39(2H, s),
6.94(1H, s), 6.94-7.08(6H, m), 7.32(2H, d, J=8.06 Hz),
7.50-7.57(2H, m).
[0640] IR (KBr) cm.sup.-1: 1665, 1511, 1225, 1157, 1051, 850,
842.
Example 91
Preparation of
2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylsulfi-
nyl)phenyl]-2H-pyridazin-3-one
[0641] Using
2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 81.1%.
[0642] Colorless prisms (ethyl acetate-hexane).
[0643] Melting point: 155.6-155.7.degree. C.
[0644] Mass (m/e): 470, 472 (M.sup.+).
[0645] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72(3H, s), 5.46 (2H, s)
6.83-6.90(2H, m), 6.95(1H, s), 7.03(2H, d, J=8.59 Hz), 7.29(2H, d,
J=8.40 Hz), 7.31(2H, d, J=8.20 Hz), 7.50-7.52(1H, m), 7.55(2H, d,
J=8.20 Hz).
[0646] IR (KBr) cm.sup.-1: 1667, 1604, 1506, 1272, 1052, 971, 951,
838.
Example 92
Preparation of
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylsulfi-
nyl)phenyl]-2H-pyridazin-3-one
[0647] Using
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 71.6%.
[0648] Colorless needles (chloroform-hexane).
[0649] Melting point: 236.5-237.3.degree. C.
[0650] Mass (m/e): 502, 504 (M.sup.+).
[0651] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.72(3H, s), 5.53(2H, s),
6.98(1H, s), 7.05(2H, d, J=8.55 Hz), 7.24(1H, dd, J=8.30, 2.03 Hz),
7.27-7.34(5H, m), 7.45(1H, d, J=8.03 Hz), 7.54(2H, d, J=8.79
Hz).
[0652] IR (KBr) cm.sup.-1: 1665, 1588, 1492, 1473, 1091, 1051,
1016, 954, 835.
Example 93
Preparation of
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylsulfi-
nyl)phenyl]-2H-pyridazin-3-one
[0653] Using
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 86.5%.
[0654] Colorless needles (ethyl acetate-hexane).
[0655] Melting point: 214.4-214.5.degree. C.
[0656] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.71(3H, s), 5.53(2H, s),
6.98(1H, s), 6.99-7.12(4H, m), 7.22-7.31(4H, m), 7.44(1H, d, J=1.95
Hz), 7.54(2H, d, J=8.05 Hz).
[0657] IR (KBr) cm.sup.-1: 1668, 1510, 1235, 1047, 840, 609.
Example 94
Preparation of
5-(4-chlorophenyl)-6-[4-(methylsulfinyl)phenyl]-2-(3-pyridy-
lmethyl)-2H-pyridazin-3-one
[0658] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmethy-
l)-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained in a yield of 98.5%.
[0659] Colorless prisms (ethyl acetate-hexane).
[0660] Melting point: 154.6-154.7.degree. C.
[0661] Mass (m/e): 435, 437 (M.sup.+).
[0662] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.74(3H, s), 5.45(2H, s),
6.96(1H, s), 7.03(2H, d, J=8.59 Hz), 7.23-7.34(5H, m), 7.57(2H, d,
J=8.40 Hz), 7.89(1H, tt, J=7.81, 1.95 Hz), 8.58(1H, dd, J=4.88,
1.66 Hz), 8.79(1H, d, J=1.56 Hz).
[0663] IR (KBr) cm.sup.-1: 1664, 1584, 1494, 1090, 1050, 837.
Example 95
Preparation of
5-(4-fluorophenyl)-6-[4-(methylsulfinyl)phenyl]-2-(4-pyridy-
lmethyl)-2H-pyridazin-3-one
[0664] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(4-pyridylmethy-
l)-2H-pyridazin-3-one as a starting material, the procedures of
Example 85 were repeated likewise, whereby the title compound was
obtained. The title compound was then converted into its
methanesulfonate (yield: 88.1%).
[0665] Colorless needles (methanol-diethyl ether).
[0666] Melting point: 212.8-218.5.degree. C. (decomposed).
[0667] .sup.1H-NMR (CDCl.sub.3-CD.sub.3OD) .delta.: 2.45(3H, s),
2.69(3H, s), 5.73(2H, s), 7.06(1H, s), 7.08(2H, d, J=8.77 Hz),
7.14(4H, s), 7.25(2H, dd, J=8.79, 5.12 Hz), 8.05(2H, d, J=6.10 Hz),
8.82(2H, d, J=6.83 Hz).
[0668] IR (KBr) cm.sup.-1: 1664, 1601, 1510, 1210, 1192, 1050,
843.
Example 96
Preparation of
2-(2,4-difluorocinnamyl)-5-(4-fluorophenyl)-6-[4-(methylsul-
finyl)phenyl]-2H-pyridazin-3-one
[0669] Using
2-(2,4-difluorocinnamyl)-5-(4-fluorophenyl)-6-[4-(methylthio)-
phenyl]-2H-pyridazin-3-one as a starting material, the procedures
of Example 85 were repeated likewise, whereby the title compound
was obtained in a yield of 58.1%.
[0670] Colorless amorphous.
[0671] .sup.1H-NMR (CDCl.sub.3-CD.sub.3OD) .delta.: 2.72(3H, s),
5.03(2H, d, J=6.59 Hz), 6.49(1H, dt, J=15.87, 6.65 Hz),
6.77-6.85(3H, m), 6.96(1H, s), 6.99-7.10(4H, m), 7.35(2H, d, J=8.30
Hz), 7.44(1H, dd, J=15.01, 8.42 Hz), 7.56(2H, d, J=8.06 Hz).
[0672] IR (KBr) cm.sup.-1: 1665, 1502, 1274, 1230, 1050, 966,
841.
Example 97
Preparation of
2-benzyl-5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-
-pyridazin-3-one
[0673]
2-Benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-
-one (159.2 mg, 0.380 mmol) and sodium periodate (325.2 mg, 1.402
mmol) were dissolved in a mixed solvent of acetone (40 ml)-water
(20 ml)-chloroform (5 ml). Under ice cooling, osmium
tetraoxide/tert-butanol (1 g/25 ml) (0.24 ml) was added, and the
mixture was stirred through the night until its temperature arose
to room temperature. The reaction mixture was concentrated, and the
residue was extracted with chloroform. The extract was dried over
anhydrous sodium sulfate and then concentrated. The residue was
separated and purified by silica gel preparative chromatography
[hexane/ethyl acetate (1/1)], whereby the title compound (151.1 mg,
88.2%) was obtained.
[0674] Colorless crystalline powder (ethyl acetate-hexane)
[0675] Melting point: 103.2-105.7.degree. C.
[0676] Mass (m/e): 450, 452 (M.sup.+).
[0677] .sup.1H-NMR (CDCl.sub.3-CD.sub.3OD) .delta.: 3.06(3H, s),
5.43(2H, s), 6.95(1H, s), 7.01(2H, d, J=8.59 Hz), 7.30(2H, d,
J=8.59 Hz), 7.33-7.41(5H, m), 7.49-7.55(2H, m), 7.84(2H, d, J=8.79
Hz).
[0678] IR (KBr) cm.sup.-1: 1668, 1316, 1153, 1091, 951.
Example 98
Preparation of
5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-pyridazi-
n-3-one
[0679] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 97 were repeated
likewise, whereby the title compound was obtained in a yield of
60.9%.
[0680] Colorless prisms (methylene chloride-methanol-hexane).
[0681] Melting point: 254.0-254.7.degree. C.
[0682] Mass (m/e): 360, 362 (M.sup.+).
[0683] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.07(3H, s), 7.02(1H, s),
7.06(2H, d, J=8.55 Hz), 7.33(2H, d, J=8.55 Hz), 7.42(2H, d, J=8.55
Hz), 7.86(2H, d, J=8.55 Hz), 12.40(1H, brs).
[0684] IR (KBr) cm.sup.-1: 1661, 1587, 1316, 1153, 1095.
Example 99
Preparation of
5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylsulfonyl-
)phenyl]-2H-pyridazin-3-one
[0685] Using
5-(4-chlorophenyl)-2-cyclopropylmethyl-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 20.6%.
[0686] Colorless needles (ethyl acetate-hexane).
[0687] Melting point: 139.7-139.8.degree. C.
[0688] Mass (m/e): 414, 416 (M.sup.+).
[0689] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.49-0.63(4H, m),
1.41-1.49(1H, m), 3.06(3H, s), 4.14(2H, d, J=7.22 Hz), 6.96(1H, s),
7.05(2H, d, J=8.59 Hz), 7.31(2H, d, J=8.59 Hz), 7.41(2H, d, J=8.59
Hz), 7.86(2H, d, J=8.59 Hz).
[0690] IR (KBr) cm.sup.-1: 1664, 1584, 1313, 1303, 1151.
Example 100
Preparation of
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl-
)phenyl]-2H-pyridazin-3-one
[0691] Using
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 87.1%.
[0692] Colorless prisms (ethyl acetate-hexane).
[0693] Melting point: 123.8-123.9.degree. C.
[0694] Mass (m/e): 398 (M.sup.+).
[0695] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.48-0.63(4H, m),
1.42-1.48(1H, m), 3.05(3H, s), 4.14(2H, d, J=7.42 Hz), 6.96(1H, s),
7.03(2H, t, J=8.50 Hz), 7.08-7.11(2H, m), 7.40(2H, d, J=8.40 Hz),
7.85(2H, d, J=8.20 Hz).
[0696] IR (KBr) cm.sup.-1: 1664, 1511, 1316, 1229, 1153, 954, 852,
613.
Example 101
Preparation of
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-
-pyridazin-3-one
[0697] Using
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl)-2H-pyrid-
azin-3-one as a starting material, the procedures of Example 97
were repeated likewise, whereby the title compound was obtained in
a yield of 99.0%.
[0698] Pale yellow needles (ethyl acetate-hexane).
[0699] Melting point: 187.6-188.0.degree. C.
[0700] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05(3H, s), 5.43(2H, s),
6.95(1H, s), 7.01-7.07(4H, m), 7.33-7.40(5H, m), 7.53(2H, dd,
J=7.69, 1.83 Hz), 7.84(2H, d, J=8.55 Hz).
[0701] IR (KBr) cm.sup.-1: 1668, 1595, 1582, 1510, 1313, 1154, 955,
849, 779.
Example 102
Preparation of
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylsulfonyl-
)phenyl]-2H-pyridazin-3-one
[0702] Using
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 99.0%.
[0703] Colorless amorphous.
[0704] Mass (m/e): 464 (M.sup.+).
[0705] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05(3H, s), 3.80(3H, s),
5.37(2H, s), 6.89(2H, d, J=8.01 Hz), 6.93(1H, s), 7.01-7.05(4H, m),
7.36(2H, d, J=8.20 Hz), 7.48(2H, d, J=8.01 Hz), 7.83(2H, d, J=8.01
Hz).
[0706] IR (KBr) cm.sup.-1: 1668, 1512, 1315, 1248, 1153, 842.
Example 103
Preparation of
2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylsulfo-
nyl)phenyl]-2H-pyridazin-3-one
[0707] Using
2-(2,4-difluorobenzyl)-5-(4-chlorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 94.5%.
[0708] Colorless needles (ethyl acetate-hexane).
[0709] Melting point: 173.8-173.9.degree. C.
[0710] Mass (m/e): 486, 488 (M.sup.+).
[0711] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05(3H, s), 5.46(2H, s),
6.83-6.90(2H, m), 6.96(1H, s), 7.03(2H, d, J=8.40 Hz), 7.31(2H, d,
J=8.40 Hz), 7.35(2H, d, J=8.20 Hz), 7.48-7.54(1H, m), 7.84(2H, d,
J=8.20 Hz).
[0712] IR (KBr) cm.sup.-1: 1668, 1507, 1316, 1153, 1093, 972,
837.
Example 104
Preparation of
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylsulfo-
nyl)phenyl]-2H-pyridazin-3-one
[0713] Using
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 53.3%.
[0714] Colorless scales (chloroform-hexane).
[0715] Melting point: 232.7-234.5.degree. C.
[0716] Mass (m/e): 518, 520 (M.sup.+).
[0717] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05(3H, s), 5.54(2H, s),
6.99(1H, s), 7.03(2H, d, J=8.30 Hz), 7.25(1H, dd, J=8.30, 2.12 Hz),
7.28-7.40(5H, m), 7.45(1H, d, J=2.12 Hz), 7.83(2H, d, J=8.30
Hz).
[0718] IR (KBr) cm.sup.-1: 1665, 1324, 1314, 1158, 1093.
Example 105
Preparation of
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylsulfo-
nyl)phenyl]-2H-pyridazin-3-one
[0719] Using
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 10.3%.
[0720] Colorless needles (ethyl acetate-hexane)
[0721] Melting point: 211.8-212.2.degree. C.
[0722] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.04(3H, s), 5.54(2H, s),
6.99(1H, s), 7.01-7.11(4H, m), 7.23-7.35(5H, m), 7.45(1H, d, J=2.20
Hz), 7.82(2H, d, J=6.59 Hz).
[0723] IR (KBr) cm.sup.-1: 1669, 1590, 1510, 1314, 1236, 1156, 954,
842, 554.
Example 106
Preparation of
5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(3-pyridy-
lmethyl)-2H-pyridazin-3-one
[0724] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmethy-
l)-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 57.5%.
[0725] Colorless crystalline powder (ethyl acetate-hexane)
[0726] Melting point: 248.0-248.1.degree. C.
[0727] Mass (m/e): 451 (M.sup.+).
[0728] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.08(3H, s), 5.37(2H, s),
6.98(1H, s), 7.03(2H, d, J=8.40 Hz), 7.30-7.33(1H, m), 7.32(2H, d,
J=8.40 Hz), 7.49(1H, d, J=7.81 Hz), 7.86(2H, d, J=8.40 Hz),
8.17(2H, d, J=6.44 Hz), 8.34(1H, s).
[0729] IR (KBr) cm.sup.-1: 1664, 1555, 1314, 1278, 1153, 1091.
Example 107
Preparation of
5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(4-pyridy-
lmethyl)-2H-pyridazin-3-one
[0730] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2-(4-pyridylmethy-
l)-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 89.1%.
[0731] Pale yellow prisms (ethyl acetate-hexane)
[0732] Melting point: 253.3-254.5.degree. C.
[0733] Mass (m/e): 435 (M.sup.+).
[0734] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.05(3H, s), 5.42(2H, d,
J=4.15 Hz), 7.00(1H, s), 7.03-7.10(4H, m), 7.35-7.38(4H, m),
7.85(2H, d, J=8.30 Hz), 8.61(2H, d, J=5.81 Hz).
[0735] IR (KBr) cm.sup.-1: 1666, 1602, 1582, 1511, 1315, 1237,
1154, 944, 848.
Example 108
Preparation of
5-(4-chlorophenyl)-6-[4-(methylsulfonyl)phenyl]-2-(3-phenyl-
propyl)-2H-pyridazin-3-one
[0736] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-phenylpropyl-
)-2H-pyridazin-3-one as a starting material, the procedures of
Example 97 were repeated likewise, whereby the title compound was
obtained in a yield of 72.5%.
[0737] Colorless crystalline powder (ethyl acetate-hexane)
[0738] Melting point: 70.2-71.6.degree. C.
[0739] Mass (m/e): 478, 480 (M.sup.+).
[0740] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.26(2H, q, J=7.45 Hz),
2.77(2H, t, J=7.45 Hz), 3.06(3H, s), 4.34(2H, t, J=7.45 Hz),
6.91(1H, s), 7.02(2H, d, J=8.79 Hz), 7.14-7.33(7H, m), 7.38(2H, d,
J=8.54 Hz), 7.85(2H, d, J=8.54 Hz).
[0741] IR (KBr) cm.sup.-1: 1664, 1584, 1494, 1314, 1152, 1091, 835,
540.
Example 109
Preparation of
2-benzyl-6-[4-(methylsulfonyl)phenyl]-5-phenyl-2H-pyridazin-
-3-one
[0742] Using
2-benzyl-6-[4-(methylthio)phenyl]-5-phenyl-2H-pyridazin-3-one as a
starting material, the procedures of Example 97 were repeated
likewise, whereby the title compound was obtained in a yield of
72.4%.
[0743] Colorless needles (chloroform-hexane)
[0744] Melting point: 211.0-212.0.degree. C.
[0745] Mass (m/e): 416, 418 (M.sup.+).
[0746] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.04(3H, s), 5.44(2H, s),
6.97(1H, s), 7.04-7.09(2H, m), 7.24-7.41(8H, m), 7.50-7.56(2H, m),
7.81(2H, d, J=8.54 Hz).
[0747] IR (KBr) cm.sup.1: 1663, 1590, 1497, 1320, 1311, 1304, 1154,
957, 779, 720, 707.
Example 110
Preparation of
2-(4-aminobenzyl)-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-o- ne
[0748] 10% palladium on charcoal (200 mg) was added to a solution
of 5,6-bis(4-methoxyphenyl)-2-(4-nitrobenzyl)-2H-pyridazin-3-one
(300 mg, 0.68 mmol) in ethyl acetate (30 ml), followed by catalytic
reduction at room temperature and atmospheric pressure. Ninety
minutes later, the reaction mixture was filtered. After the
catalyst was washed with ethyl acetate, the filtrate and the
washing were combined. The solvent was distilled off, whereby a
pale yellow oil (253 mg) was obtained. The oil (253 mg) was
separated and purified by silica gel preparative chromatography
[developer: chloroform/methanol (20/1)], whereby the title compound
(250 mg, 89.2%) was obtained as pale yellow amorphous.
[0749] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.70(2H, brs), 3.79(6H,
s), 5.29(2H, d, J=8.30 Hz), 6.77(2H, d, J=9.03 Hz), 6.79(2H, d,
J=8.79 Hz), 6.85(1H, s), 7.00(2H, d, J=9.03 Hz), 7.10(2H, d, J=8.79
Hz), 7.37(2H, d, J=8.54 Hz).
[0750] Melting point: 171.0-173.0.degree. C. (decomposed).
[0751] IR (KBr) cm.sup.-1: 3668, 3419, 2906, 2835, 1641, 1606,
1510, 1257, 1176, 1025, 834.
Example 111
Preparation of
5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyr-
idazin-3-one and
5,6-bis(4-methoxyphenyl)-2-[4-(methylamino)benzyl]-2H-pyr-
idazin-3-one
[0752] To a solution of
2-(4-aminobenzyl)-5,6-bis(4-methoxyphenyl)-2H-pyri- dazin-3-one
(245 mg, 0.6 mmol) in acetone/N,N-dimethylformamide (5/1) (6 ml),
sodium hydrogencarbonate (378 mg, 4.5 mmol) and a solution of
dimethyl sulfate in acetone [an acetone solution of dimethyl
sulfate (631 mg) (total volume: 5 ml); 3.0 ml, 3.0 mmol)] was
added, followed by stirring under heat at 60.degree. C. for 90
minutes. After the acetone was distilled off, the residue was
extracted with ethyl acetate. The organic layer was washed
successively with water and a brine, and was then dried over
anhydrous sodium sulfate. The solvent was distilled off. The pale
orange oil (238 mg) was separated and purified by silica gel
preparative chromatography [developer: chloroform/methanol (20/1)],
whereby
5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-
-3-one (80.6 mg, 30.8%) was obtained as a reddish brown oil from
fractions having large Rf values.
[0753] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.94(6H, s), 3.79(6H, s),
5.32(2H, s), 6.71(2H, d, J=8.79 Hz), 6.78(2H, d, J=8.79 Hz),
6.79(2H, d, J=9.03 Hz), 6.85(1H, s), 7.07(2H, d, J=8.79 Hz),
7.11(2H, d, J=9.03 Hz), 7.48(2H, d, J=8.79 Hz).
[0754] In a manner known per se in the art, the hydrochloride of
5,6-bis(4-methoxyphenyl)-2-[4-(dimethylamino)benzyl]-2H-pyridazin-3-one
was obtained in a yield of 67.7%.
[0755] Yellow needles (methanol-diethyl ether).
[0756] Melting point: 122-126.degree. C.
[0757] .sup.1H-NMR (DMSO-D.sub.6+D.sub.2O) .delta.: 3.06(6H, s),
3.74(3H, s), 3.75(3H, s), 5.33(2H, s), 6.86(2H, d, J=8.79 Hz),
6.89(2H, d, J=8.30 Hz), 6.91(1H, s), 7.11(4H, d, J=8.79 Hz),
7.30(2H, d, J=8.79 Hz), 7.46(2H, d, J=8.79 Hz).
[0758] IR (KBr) cm.sup.-1: 3668, 3383, 1655, 1609, 1513, 1298,
1247, 1182, 1174, 837, 827.
[0759] From fractions having small Rf values,
5,6-bis(4-methoxyphenyl)-2-[-
4-(methylamino)benzyl]-2H-pyridazin-3-one (47.4 mg, 18.7%) was
obtained as a pale brown oil.
[0760] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.82(3H, s), 3.79(6H, s),
5.30(2H, s), 6.58(2H, d, J=8.54 Hz), 6.77(2H, d, J=9.03 Hz),
6.79(2H, d, J=8.79 Hz), 6.85(1H, s), 7.00(2H, d, J=8.79 Hz),
7.11(2H, d, J=8.78 Hz), 7.42(2H, d, J=8.54 Hz).
[0761] IR (film) cm.sup.-1: 3410, 3373, 1652, 1610, 1515, 1296,
1249, 1181, 1029, 833, 754.
Example 112
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-carboxybenzyl)-2H-pyridazin-3-
-one
[0762] To a solution of
5,6-bis(4-methoxyphenyl)-2-(4-methoxycarbonylbenzy-
l)-2H-pyridazin-3-one (168 mg, 0.37 mmol) in methanol (4 ml), a 1 N
aqueous solution of sodium hydroxide (1.84 ml) was added, followed
by stirring under heat at 40.degree. C. for 4 hours. The methanol
was distilled off, and to the residue, a 2 N aqueous solution of
hydrochloric acid was added to acidify the residue (pH<1). The
thus-acidified mixture was extracted with ethyl acetate. The
organic layer was washed successively with water and a brine, and
was then dried over anhydrous sodium sulfate. The solvent was
distilled off and the thus-obtained residue (161 mg) was
recrystallized from chloroform-methanol, whereby the title compound
(138 mg, 84.7%) was obtained as colorless needles.
[0763] Melting point: 241.0-242.0.degree. C.
[0764] Mass (m/e): 442 (M.sup.+).
[0765] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
5.48(2H, s), 6.78(2H, d, J=8.79 Hz), 6.80(2H, d, J=8.79 Hz),
6.93(1H, s), 7.04(2H, d, J=8.79 Hz), 7.10(2H, d, J=8.79 Hz),
7.59(2H, d, J=8.55 Hz), 8.08(2H, d, J=8.30 Hz).
[0766] IR (KBr) cm.sup.-1: 1706, 1632, 1611, 1553, 1254, 1180,
1025, 829.
Example 113
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2-(4-methylpiperadinocarbonyl)e-
thyl]-[2H-pyridazin-3-one
[0767] (1) Preparation of
5,6-bis(4-methoxyphenyl)-2-(2-ethoxycarbonylethy-
l)-2H-pyridazin-3-one:
[0768] To a solution of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one
(308 mg, 1 mmol) in N,N-dimethylformamide (3 ml), potassium
carbonate (276 mg, 2 mmol) and ethyl 3-chloropropionate (273 mg, 2
mmol) were added, followed by stirring at 80.degree. C. for 16
hours. After the reaction mixture was allowed to cool down, water
was added to the reaction mixture and the mixture was extracted
with ethyl acetate. The organic layer was washed successively with
water and a brine, and was then dried over anhydrous sodium
sulfate. The solvent was distilled off and the residue (416 mg) was
separated and purified by chromatography on a silica gel column
[silica gel: 11 g, chloroform/ methanol (20/1)], whereby the title
compound (390 mg, 97%) was obtained as a pale yellow oil.
[0769] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.22(3H, t, J=7.08 Hz),
2.91(2H, t, J=7.32 Hz), 3.79(3H, s), 3.81(3H, s), 4.14(2H, q,
J=7.08 Hz), 4.55(2H, t, J=7.32 Hz), 6.78(2H, d, J=8.79 Hz),
6.81(2H, d, J=8.79 Hz), 6.88(1H, s), 7.04(2H, d, J=8.79 Hz),
7.11(2H, d, J=8.79 Hz).
[0770] IR (KBr) cm.sup.-1: 1733, 1659, 1607, 1515, 1297, 1250,
1179, 1029, 845.
[0771] (2) Preparation of
5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-p-
yridazin-3-one:
[0772] A 2 N aqueous solution of sodium hydroxide was added to a
solution of
5,6-bis(4-methoxyphenyl)-2-(2-ethoxycarbonylethyl)-2H-pyridazin-3-one
(390 mg, 0.97 mmol) in methanol (7 ml). The mixture was heated to
dissolve precipitated crystals, followed by stirring at room
temperature for 25 hours. After the methanol was distilled off, the
residue was dissolved in water. A 2 N aqueous solution of
hydrochloric acid was added to the resulting mixture to acidify the
same. The mixture was extracted with ethyl acetate. The organic
layer was washed successively with water and a brine, and was then
dried over anhydrous sodium sulfate. The solvent was distilled off,
and the residue (377 mg) was separated and purified by
chromatography on a silica gel column [silica gel: 2 g,
chloroform/methanol (10/1)], whereby the title compound (356 mg,
96.5%) was obtained as a pale yellow amorphous.
[0773] Mass (m/e): 380 (M.sup.+).
[0774] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.97(2H, t, J=7.08 Hz),
3.78(3H, s), 3.80(3H, s), 4.57(2H, t, J=7.08 Hz), 6.77(2H, d,
J=8.79 Hz), 6.80(2H, d, J=8.79 Hz), 6.93(1H, s), 7.03(2H, d, J=8.79
Hz), 7.11(2H, d, J=8.79 Hz).
[0775] IR (KBr) cm.sup.-1: 3427, 1637, 1609, 1511, 1297, 1249,
1178, 834.
[0776] (3) Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperadin-
ocarbonyl)ethyl]-2H-pyridazin-3-one:
[0777] To a solution of
5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyr- idazin-3-one
(266 mg, 0.7 mmol) in tetrahydrofuran (1.3 ml), oxalyl chloride
(133 mg, 1.5 eq) was gradually added dropwise under ice cooling.
The mixture was stirred at room temperature for 90 minutes. A
solution of triethylamine (283 mg, 4.0 eq) and N-methylpiperazine
(102 mg, 1.5 eq) in tetrahydrofuran (2 ml) was then added, followed
by stirring at room temperature for 4 hours. The tetrahydrofuran
was distilled off and the residue was extracted with ethyl acetate.
The organic layer was washed successively with a saturated aqueous
solution of sodium hydrogencarbonate, water and a brine, and was
then dried over anhydrous sodium sulfate. The solvent was distilled
off, and the residue (293 mg) was separated and purified by
chromatography on a silica gel column [silica gel: 9 g,
chloroform/methanol (50/1)], whereby the title compound (272 mg,
84.0%) was obtained as a pale yellow amorphous.
[0778] Mass (m/e): 462 (M.sup.+).
[0779] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.28(3H, s), 2.36-2.38(4H,
m), 2.94(2H, t, J=7.81 Hz), 3.48-3.52(2H, m), 3.63-3.66(2H, m),
3.79(3H, s), 3.81(3H, s), 4.56(2H, t, J=7.81 Hz), 6.78(2H, d,
J=9.04 Hz), 6.81(2H, d, J=7.89 Hz), 6.88(1H, s), 7.04(2H, d, J=8.79
Hz), 7.12(2H, d, J=8.78 Hz).
[0780] IR (KBr) cm.sup.-1: 1652, 1609, 1513, 1460, 1259, 1249,
1175, 1028, 834.
Example 114
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-methylpiperazinocarbonylmethy-
l)-2H-pyridazin-3-one
[0781] After
5,6-bis(4-methoxyphenyl)-2-carboxymethyl)-2H-pyridazin-3-one (Eur.
J. Med. Chem., 14, 53, 1979) was reacted with oxalyl chloride in a
similar manner as in Example 113-(3), a further reaction was
conducted with 4-methylpiperazine, whereby the title compound was
obtained in a yield of 20.7%. Orange amorphous.
[0782] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.30(3H, s), 2.45(4H, m),
3.66-3.71(4H, m), 3.79(3H, s), 3.81(3H, s), 5.32(2H, s), 6.78(2H,
d, J=8.79 Hz), 6.82(2H, d, J=8.79 Hz), 6.90(1H, s), 7.06(2H, d,
J=8.79 Hz), 7.13(2H, d, J=8.79 Hz).
[0783] IR (KBr) cm.sup.-1: 1659, 1609, 1513, 1463, 1294, 1259,
1176, 1028, 834.
Example 115
Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(benzylaminocarbonyl)ethyl]-2-
H-pyridazin-3-one
[0784] After
5,6-bis(4-methoxyphenyl)-2-(2-carboxyethyl)-2H-pyridazin-3-on- e
was reacted with oxalyl chloride in a similar manner as in Example
113-(3), a further reaction was conducted with benzylamine, whereby
the title compound was obtained in a yield of 52.2%.
[0785] Colorless fine needles (ethyl acetate-hexane).
[0786] Melting point: 135.0-137.0.degree. C.
[0787] Mass (m/e): 469 (M.sup.+).
[0788] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.88(2H, t, J=6.83 Hz),
3.79(3H, s), 3.81(3H, s), 4.43(2H, d, J=5.85 Hz), 4.57(2H, t,
J=6.83 Hz), 6.71(1H, m), 6.76(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79
Hz), 6.85(1H, s), 7.01(2H, d, J=8.79 Hz), 7.10(2H, d, J=8.79 Hz),
7.24-7.38(5H, m).
[0789] IR (KBr) cm.sup.-1: 3434, 3297, 1642, 1609, 1510, 1247,
1177, 1029, 831.
Example 116
Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperazino)ethyl]-2H-
-pyridazin-3-one
[0790] (1) Preparation of
5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-p-
yridazin-3-one:
[0791] To a solution of 5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one
(154 mg, 0.5 mmol) in N,N-dimethylformamide (0.03 ml),
tetraethylammonium iodide (413 mg, 1.5 mmol) and ethylene carbonate
(132 mg, 1.5 mmol) were added, followed by stirring at
145-150.degree. C. for 2 hours. After the reaction mixture was
allowed to cool down, water was added to the reaction mixture and
the mixture was extracted with ethyl acetate. The organic layer was
washed successively with water and a brine, and was then dried over
anhydrous sodium sulfate. The solvent was distilled off and the
residue (100 mg) was separated and purified twice by chromatography
on a silica gel column (silica gel: 4 g, ethyl acetate), whereby
the title compound (165 mg, 94%) was obtained as a pale brown
oil.
[0792] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.58(1H, t, J=5.86 Hz),
3.80(3H, s), 3.81(3H, s), 4.05-4.15(2H, m), 4.48(2H, dd, J=4.88,
4.88 Hz), 6.79(2H, d, J=8.79 Hz), 6.82(2H, d, J=8.79 Hz), 6.94(1H,
s), 7.05(2H, d, J=8.79 Hz), 7.12(2H, d, J=9.28 Hz).
[0793] (2) Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(4-methylpiperazin-
o)ethyl]-2H-pyridazin-3-one:
[0794] To a solution of para-toluenesulfonyl chloride (357 mg, 4
eq) in pyridine (0.5 ml), a solution of
5,6-bis(4-methoxyphenyl)-2-(2-hydroxyeth- yl)-2H-pyridazin-3-one
(165 mg, 0.47 mmol) in pyridine (1.0 ml) was added, followed by
stirring at room temperature for 2 hours. The reaction mixture was
poured into ice water, followed by extraction with ethyl acetate.
The organic layer was washed successively with water and a brine,
and was then dried over anhydrous sodium sulfate. The solvent was
distilled off, and N-methylpiperazine (0.15 ml, 3 eq) was added to
the residue. The resulting mixture was stirred at 90-100.degree. C.
for 2 hours. After water was added to the reaction mixture, the
mixture was extracted with ethyl acetate. The organic layer was
washed successively with water and a brine, and then dried over
anhydrous sodium sulfate. The solvent was distilled off, and
ethanol was added to the residue. The resulting mixture was
azeotropically boiled three times with ethanol to drive off water.
The thus-obtained residue (256 mg) was separated and purified by
chromatography on a silica gel column [silica gel: 8 g,
chloroform/methanol (20/1)], whereby a yellow oil (165 mg, 81%) was
obtained. The oil was left over in a refrigerator. Precipitated
crystals were washed with a mixed solvent of methanol and diethyl
ether, whereby the title compound (65 mg, 32%) was obtained as pale
yellow prisms.
[0795] Melting point: 109.7-110.8.degree. C.
[0796] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.29(3H, s), 2.46(4H,
brs), 2.64(4H, brs), 2.87(2H, t, J=6.83 Hz), 3.80(3H, s), 3.81(3H,
s), 4.40(2H, t, J=6.84 Hz), 6.79(2H, d, J=9.03 Hz), 6.81(2H, d,
J=8.78 Hz), 6.87(1H, s), 7.02(2H, d, J=8.79 Hz), 7.12(2H, d, J=9.03
Hz).
[0797] IR (KBr) cm.sup.-1: 1659, 1608, 1513, 1295, 1250, 1177,
1013.
Example 117
Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(morpholino)ethyl]-2H-pyridaz-
in-3-one
[0798] After
5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-on- e
was reacted with para-toluenesulfonyl chloride in a similar manner
as in Example 116-(2), a further reaction was conducted with
morpholine, whereby the title compound was obtained in a yield of
42.6%.
[0799] Pale yellow needles (methanol-diethyl ether).
[0800] Melting point: 145.1-145.8.degree. C.
[0801] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.59(4H, t, J=4.64 Hz),
2.86(2H, t, J=6.83 Hz), 3.75(4H, t, J=4.64 Hz), 3.81(3H, s),
3.81(3H, s), 4.40(2H, t, J=7.08 Hz), 6.79(2H, d, J=8.79 Hz),
6.81(2H, d, J=8.79 Hz), 6.88(1H, s), 7.05(2H, d, J=8.79 Hz),
7.12(2H, d, J=8.78 Hz).
[0802] IR (KBr) cm.sup.-1: 1664, 1608, 1513, 1247, 1181, 1119,
834.
Example 118
Preparation of
5,6-bis(4-methoxyphenyl)-2-[2-(piperidino)ethyl]-2H-pyridaz-
in-3-one
[0803] After
5,6-bis(4-methoxyphenyl)-2-(2-hydroxyethyl)-2H-pyridazin-3-on- e
was reacted with para-toluenesulfonyl chloride in a similar manner
as in Example 116-(2), a further reaction was conducted with
piperidine, whereby the title compound was obtained in a yield of
38.1%.
[0804] Yellow oil.
[0805] Mass (m/e): 419 (M.sup.+).
[0806] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44-1.46(2H, m),
1.56-1.64(4H, m), 2.52-2.56(4H, m), 2.84(2H, t, J=7.33 Hz),
3.79(3H, s), 3.80(3H, s), 4.40(2H, t, J=7.33 Hz), 6.78(2H, d,
J=8.79 Hz), 6.81(2H, d, J=8.30 Hz), 6.87(1H, s), 7.04(2H, d, J=8.79
Hz), 7.13(2H, d, J=8.79 Hz).
[0807] IR (film) cm.sup.-1: 1660, 1609, 1514, 1296, 1250, 1177,
1033, 834.
Example 119
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2H-pyridazin-
-3-one
[0808] (1) Preparation of
3-(hydroxymethyl)-1-(tert-butoxycarbony)piperidi- ne:
[0809] Triethylamine (2.8 ml, 20 mmol) was added to a solution of
3-(hydroxymethyl)piperidine (1.15 g, 10 mmol) in tetrahydrofuran
(15 ml), followed by the addition of a solution of di-tert-butyl
carbonate (2.62 g, 10 mmol) in tetrahydrofuran (5 ml) at room
temperature under stirring. The mixture was stirred at room
temperature for 20 hours. The solvent was distilled off, and the
residue was dissolved in ethyl acetate (50 ml). The solution was
washed successively with water and a brine, and was then dried over
anhydrous sodium sulfate. The solvent was then distilled off,
whereby the title compound (2.15 g, 100%) was obtained as colorless
crystals.
[0810] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.2-1.4(2H, m), 1.46(9H,
s), 1.5-1.9(4H, m), 2.8-3.3(2H, m), 3.51(2H, t, J=6.10 Hz),
3.6-3.9(2H, m).
[0811] IR (KBr) cm.sup.-1: 3491, 1742, 1674, 1428, 1269, 1177,
1153, 858, 769.
[0812] (2) Preparation of
1-(tert-butoxycarbonyl)-3-(tosyloxymethyl)piperi- dine:
[0813] To a solution of
3-(hydroxymethyl)-1-(tert-butoxycarbonyl)piperidin- e (200 mg, 0.9
mmol) in anhydrous pyridine (4 ml), para-toluenesulfonic acid (890
mg) was added in small portions while stirring the solution under
cooling with ice water. Five minutes later, the resultant mixture
was heated to room temperature, at which stirring was continued for
2 hours. The reaction mixture was poured into ice water, followed
by extraction with ethyl acetate. The organic layer was washed
successively with water and a brine, and was then dried over
anhydrous sodium sulfate. The solvent was distilled off, whereby
the title compound (343 mg, 100%) was obtained as a colorless
oil.
[0814] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.1-1.3(2H, m), 1.44(9H,
m), 1.4-1.9(2H, m), 2.46(3H, s), 2.7-2.9(1H, m), 3.8-4.1(4H, m),
3.89(2H, d, J=6.11 Hz), 7.35(2H, d, J=8.54 Hz), 7.78(2H, d, J=8.30
Hz).
[0815] (3) Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(1-tert-butoxycarb-
onyl)piperidyl)methyl]-2H-pyridazin-3-one:
[0816] To a solution of
1-(tert-butoxycarbonyl)-3-(tosyloxymethyl)piperidi- ne (200 mg,
0.65 mmol) in N,N-dimethylformamide (4 ml),
5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (343 mg, 0.93 mmol) and
potassium carbonate (276 mg, 2.0 mmol) were added, followed by
stirring at 80.degree. C. for 8 hours. After the reaction mixture
was allowed to cool down, water was added to the reaction mixture.
The mixture was extracted with ethyl acetate. The organic layer was
washed successively with water (twice) and a brine, and was then
dried over anhydrous sodium sulfate. The solvent was distilled off
and the resulting reddish brown oil (405 mg) was then purified by
silica gel preparative chromatography [chloroform/methanol (20/1)],
whereby the title compound (383 mg, quantitative) was obtained as a
pale brown oil.
[0817] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.40(2H, m), 1.41(9H,
s), 1.60-1.90(2H, m), 2.15-2.35(1H, m), 2.65-2.90(2H, m), 3.80(3H,
s), 3.81(3H, s), 3.85-4.25(4H, m), 6.79(2H, d, J=8.79 Hz), 6.80(2H,
d, J=8.78 Hz), 7.04(2H, d, J=8.79 Hz), 7.13(2H, d, J=8.79 Hz).
[0818] (4) Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2-
H-pyridazin-3-one:
[0819] A 6 N aqueous solution of hydrochloric acid (0.2 ml, 1.2
mmol) was added to a solution of
5,6-bis(4-methoxyphenyl)-2-[3-(1-tert-butoxycarbon-
yl)piperidyl)methyl]-2H-pyridazin-3-one (69 mg; content: 59 mg,
0.12 mmol) in tetrahydrofuran (2 ml), followed by stirring at
70.degree. C. for 1 hour. After the reaction mixture was allowed to
cool down, the solvent was distilled off and ethanol was added to
the residue. The thus-obtained mixture was azeotropically boiled
three times with ethanol to drive off water. The residue (oil, 94
mg) was separated and purified by silica gel preparative
chromatography [chloroform/methanol (with 10% (W/W) ammonia)
(30:1)], whereby the title compound (46 mg, 97.0%) was obtained as
a pale yellow oil.
[0820] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.20-1.40(1H, m),
1.40-1.58(1H, m), 1.65-1.80(1H, m), 2.10-2.20(1H, m), 2.45-2.68(2H,
m), 2.94-3.12(2H, m), 3.79(3H, s), 3.81(3H, s), 4.04-5.04(2H, m),
6.78(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz), 6.88(1H, s),
7.04(2H, d, J=8.54 Hz), 7.12(2H, d, J=8.55 Hz).
[0821] IR (KBr) cm.sup.-1: 3313, 3003, 2935, 2840, 1668, 1652,
1609, 1296, 1251, 1178, 1030, 834.
Example 120
Preparation of
5,6-bis(4-methoxyphenyl)-2-[3-(1-methylpiperidyl)methyl]-2H-
-pyridazin-3-one
[0822] To a solution of
5,6-bis(4-methoxyphenyl)-2-(3-piperidylmethyl)-2H-- pyridazin-3-one
(203 mg, 0.5 mmol) in acetone/dimethyl sulfoxide (5/1) (6 ml), an
acetone solution of dimethyl sulfate (631 mg was dissolved with
acetone into a solution of 5 ml in total volume) (1.0 ml, 1.0 mmol)
was added, followed by stirring at 60.degree. C. for 2 hours. After
the reaction mixture was allowed to cool down, water was added to
the reaction mixture. The mixture was extracted with ethyl acetate.
The organic layer was washed successively with water and a brine
and was then dried over anhydrous sodium sulfate. The solvent was
distilled off and the residue (oil, 115 mg) was separated and
purified by silica gel preparative chromatography
[chloroform/methanol [with 10% (W/W) ammonia, (15:1)], whereby the
title compound (63.2 mg, 30.0%) was obtained as a pale yellow
oil.
[0823] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.50-2.00(6H, m), 2.27(3H,
s), 2.25-2.42(1H, m), 2.73-2.87(2H, m), 3.80(3H, s), 3.81(3H, s),
4.10(1H, dd, J=6.35, 12.69 Hz), 4.21(1H, dd, J=7.81, 12.69 Hz),
6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.55 Hz), 6.88(1H, s),
7.05(2H, d, J=8.79 Hz), 7.12(2H, d, J=9.03 Hz).
[0824] IR (film) cm.sup.-1: 1652, 1610, 1514, 1464, 1295, 1248,
1176, 1029, 833, 754.
Example 121
Preparation of
2-benzyl-5-(4-chlorophenyl)-4,5-dihydro-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one
[0825] Methyl
3-(4-chlorophenyl)-4-[4-(methylthio)phenyl]-4-oxobutanoate (525 mg,
1.505 mmol), benzyl hydrazine dihydrochloride (262.6 mg, 1.655
mmol) and sodium acetate (467.4 mg, 4.966 mmol) were dissolved in
85% ethanol (6 ml), followed by heating under reflux for 2 days.
The reaction mixture was concentrated, to which a 2 N aqueous
solution of hydrochloric acid was added. The mixture was extracted
with chloroform. The extract was washed with water and then dried
over anhydrous sodium sulfate. The solvent was distilled off and
the thus-obtained residue was separated and purified by silica gel
preparative chromatography [hexane/ethyl acetate (2/1)], whereby
the title compound (290.3 mg, 45.8%) was obtained.
[0826] Colorless prisms (ethyl acetate-hexane)
[0827] Melting point: 113.5-113.9.degree. C.
[0828] Mass (m/e): 420, 422 (M.sup.+).
[0829] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.33(3H, s), 2.68(1H, d,
J=16.47 Hz), 2.86(1H, dd, J=7.42, 16.47 Hz), 4.28(1H, d, J=7.42
Hz), 4.75(1H, d, 14.06 Hz), 5.29(1H, d, 14.06 Hz), 6.79(2H, d,
J=8.20 Hz), 7.03(2H, d, J=8.20 Hz), 7.11(2H, d, J=8.30 Hz),
7.17-7.29(3H, m), 7.31-7.38(2H, m), 7.58(2H, d, J=8.30 Hz).
[0830] IR (KBr) cm.sup.-1: 1659, 1593, 1387, 1343, 1141, 729.
Example 122
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazine-
-3-thione
[0831] Lawesson's reagent (140 mg, 0.35 mmol) was added to a
solution of
5,6-bis(4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-pyridazin-3-one
(146 mg, 0.32 mmol) in toluene (5 ml), followed by stirring at
80.degree. C. for 5 hours under a nitrogen gas atmosphere. A
saturated aqueous solution of sodium hydrogencarbonate (10 ml) was
added to the reaction mixture, followed by extraction with
chloroform. The extract was washed with a brine, and then dried
over anhydrous sodium sulfate. The solvent was distilled off, and
the thus-obtained yellow oil (321 mg) was separated and purified by
chromatography on a silica gel column (silica gel: 36 g,
chloroform), whereby the title compound (106 mg, 70.1%) was
obtained.
[0832] Orange prisms (diethyl ether-hexane)
[0833] Melting point: 173.3-176.2.degree. C.
[0834] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 3.81(3H, s),
5.52(2H, d, J=6.58 Hz), 6.57(1H, dt, J=15.86, 6.60 Hz), 6.75(1H, d,
J=15.86 Hz), 6.81(2H, d, J=9.03 Hz), 6.82(2H, d, J=8.79 Hz),
7.07(2H, d, J=8.79 Hz), 7.89(2H, d, J=8.79 Hz), 7.27(2H, d, J=8.54
Hz), 7.35(2H, d, J=8.54 Hz), 7.81(1H, s).
[0835] IR (KBr) cm.sup.-1: 1608, 1513, 1397, 1256, 1178, 1162,
1257, 1089, 836.
Example 123
Preparation of
5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazine-3-thione
[0836] Using 5,6-bis(4-methoxyphenyl)-2-benzyl-2H-pyridazin-3-one
as a starting material, the procedures of Example 122 were repeated
likewise, whereby the title compound was obtained in a yield of
83.4%.
[0837] Yellow needles (ethyl acetate-hexane).
[0838] Melting point: 134.7-148.6.degree. C.
[0839] Mass (m/e): 414 (M.sup.+).
[0840] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(6H, s), 6.00(2H, s),
6.80(2H, d, J=9.03 Hz), 6.81(2H, d, J=9.04 Hz), 7.06(2H, d, J=8.79
Hz), 7.16(2H, d, J=8.79 Hz), 7.31-7.36(2H, m).
[0841] IR (KBr) cm.sup.-: 1607, 1514, 1396, 1250, 1174, 1160, 1153,
1029, 833.
Example 124
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-fluorobenzyl)-2H-pyridazine-3-
-thione
[0842] Using
5,6-bis(4-methoxyphenyl)-2-(4-fluorobenzyl)-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 122 were repeated
likewise, whereby the title compound was obtained in a yield of
71.3%.
[0843] Yellow needles (ethyl acetate-diethyl ether).
[0844] Melting point: 137.1-137.8.degree. C.
[0845] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(6H, s), 5.95(2H, s),
6.80(4H, d, J=8.79 Hz), 7.01-7.07(2H, m), 7.06(2H, d, J=8.79 Hz),
7.15(2H, d, J=8.79 Hz), 7.31-7.36(3H, m), 7.60-7.65(2H, m),
7.79(1H, s).
[0846] IR (KBr) cm.sup.-1: 1609, 1512, 1397, 1299, 1253, 1176,
1154, 1047, 832.
Example 125
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazi-
ne-3-thione
[0847] Using
5,6-bis(4-methoxyphenyl)-2-(2,4-dichlorobenzyl)-2H-pyridazin--
3-one as a starting material, the procedures of Example 122 were
repeated likewise, whereby the title compound was obtained in a
yield of 84.4%.
[0848] Yellow needles (ethyl acetate).
[0849] Melting point: 169.6-170.2.degree. C.
[0850] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.82(3H, s),
6.01(2H, s), 6.77(2H, d, J=8.78 Hz), 6.83(2H, d, J=8.79 Hz),
7.10(2H, d, J=8.79 Hz), 7.12(2H, d, J=8.79 Hz), 7.14(2H, d, J=8.30
Hz), 7.21(1H, dd, J=1.96, 8.30 Hz), 7.45(1H, d, J=2.20 Hz),
7.83(1H, s).
[0851] IR (KBr) cm.sup.-1: 1609, 1513, 1472, 1397, 1297, 1251,
1177, 1162, 1045, 834.
Example 126
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorobenzyl)-2H-pyridazi-
ne-3-thione
[0852] Using
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorobenzyl)-2H-pyridazin--
3-one as a starting material, the title compound was obtained in a
yield of 57.6% in a similar manner as in Example 122.
[0853] Yellow needles (ethyl acetate-diethyl ether).
[0854] Melting point: 175.4-175.7.degree. C.
[0855] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
5.98(2H, s), 6.78(2H, d, J=8.79 Hz), 6.82(2H, d, J=8.79 Hz),
6.83-6.89(2H, m), 7.08(2H, d, J=8.79 Hz), 7.13(2H, d, J=8.54 Hz),
7.47-7.56(1H, m), 7.80(1H, s).
[0856] IR (KBr) cm.sup.-1: 1609, 1514, 1504, 1397, 1300, 1252,
1174, 1156, 1046, 833.
Example 127
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyri-
dazine-3-thione
[0857] Using
5,6-bis(4-methoxyphenyl)-2-(3,4,5-trimethoxybenzyl)-2H-pyrida-
zin-3-one as a starting material, the procedures of Example 122
were repeated likewise, whereby the title compound was obtained in
a yield of 35.1%.
[0858] Yellow prisms (ethyl acetate-diethyl ether).
[0859] Melting point: 142.4-146.4.degree. C.
[0860] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(6H, s), 3.84(3H, s),
3.87(6H, s), 5.92(2H, s), 6.80(2H, d, J=9.03 Hz), 6.81(2H, d,
J=9.03 Hz), 6.97(2H, s), 7.06(2H, d, J=8.79 Hz), 7.15(2H, d, J=8.79
Hz), 7.80(1H, s).
[0861] IR (KBr) cm.sup.-1: 1606, 1511, 1459, 1423, 1250, 1127,
1033, 842.
Example 128
Preparation of
5,6-bis(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazine--
3-thione
[0862] Using
5,6-bis(4-methoxyphenyl)-2-(3-pyridylmethyl)-2H-pyridazin-3-o- ne
as a starting material, the procedures of Example 122 were repeated
likewise, whereby the title compound was obtained in a yield of
86.7%.
[0863] Yellow brown prisms.
[0864] Melting point: 162.7-163.7.degree. C.
[0865] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(6H, s), 6.00(2H, s),
6.80(2H, d, J=8.79 Hz), 6.81(2H, d, J=9.04 Hz), 7.06(2H, d, J=9.03
Hz), 7.15(2H, d, J=9.03 Hz), 7.29(1H, dd, J=4.88, 7.81 Hz),
7.79(1H, s), 8.02(1H, d, J=8.06 Hz), 8.57(1H, dd, J=1.46, 4.76 Hz),
8.86(1H, d, J=1.46).
[0866] IR (KBr) cm.sup.-1: 1608, 1514, 1397, 1249, 1181, 1152,
1020, 837.
Example 129
Preparation of
5,6-bis(4-methoxyphenyl)-2-(4-pyridylmethyl)-2H-pyridazine--
3-thione
[0867] Using
5,6-bis(4-methoxyphenyl)-2-(4-pyridylmethyl)-2H-pyridazin-3-o- ne
as a starting material, the procedures of Example 122 were repeated
likewise, whereby the title compound was obtained in a yield of
84.5%.
[0868] Yellow brown prisms (methanol-ethyl acetate).
[0869] Melting point: 159.6-159.9.degree. C.
[0870] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(3H, s), 3.82(3H, s),
5.98(2H, s), 6.81(2H, d, J=9.03 Hz), 6.82(2H, d, J=9.03 Hz),
7.09(2H, d, J=9.04 Hz), 7.15(2H, d, J=8.79 Hz), 7.40(2H, d, J=6.10
Hz), 7.81(1H, s), 8.60(2H, d, J=5.86 Hz).
[0871] In a manner known per se in the art, the methanesulfonate of
the title compound was obtained in a yield of 56.7%.
[0872] Yellow prisms (methanol-ethyl acetate).
[0873] Melting point: 198.5-199.8.degree. C.
[0874] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.89(3H, s), 3.82(3H, s),
3.82(3H, s), 6.14(2H, s), 6.82(2H, d, J=9.03 Hz), 6.84(2H, d,
J=9.04 Hz), 7.10(2H, d, J=9.04 Hz), 7.16(2H, d, J=9.04 Hz),
7.79(1H, s), 7.95(2H, d, J=6.83 Hz), 8.86(2H, d, J=6.59 Hz).
[0875] IR (KBr) cm.sup.-1: 1640, 1606, 1511, 1396, 1247, 1175,
1152, 1027, 838, 800, 769.
Example 130
Preparation of
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyrida-
zine-3-thione
[0876] Using
5,6-bis(4-methoxyphenyl)-2-(2,4-difluorocinnamyl)-2H-pyridazi-
n-3-one as a starting material, the procedures of Example 122 were
repeated likewise, whereby the title compound was obtained in a
yield of 40.6%.
[0877] Yellow needles (ethyl acetate-diethyl ether).
[0878] Melting point: 140.7-141.4.degree. C.
[0879] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 3.81(3H, s),
5.54(2H, d, J=6.59 Hz), 6.54(1H, dt, J=16.11, 6.59 Hz),
6.75-6.82(2H, m), 6.81(2H, d, J=9.03 Hz), 6.82(2H, d, J=9.04 Hz),
6.89(1H, d, J=16.12 Hz), 7.08(2H, d, J=8.79 Hz), 7.19(2H, d, J=9.03
Hz), 7.43-7.51(1H, m), 7.81(1H, s).
[0880] IR (KBr) cm.sup.-1: 1608, 1502, 1398, 1255, 1237, 1180,
1154, 1035, 963, 835.
Example 131
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-cyclopropylme-
thyl-2H-pyridazine-3-thione
[0881] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-cyclopropylmeth-
yl-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 64.5%.
[0882] Yellow prisms (ethyl acetate-hexane).
[0883] Melting point: 135.3-135.4.degree. C.
[0884] Mass (m/e): 398, 400 (M.sup.+).
[0885] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.54-0.62(4H, m),
1.68-1.75(1H, m), 4.63(2H, d, J=7.42 Hz), 7.10(2H, d, J=8.20 Hz),
7.14(4H, s), 7.30(2H, d, J=8.20 Hz), 7.81(1H, s).
[0886] IR (KBr) cm.sup.-1: 1600, 1490, 1477, 1129, 1101, 828.
Example 132
Preparation of
2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyr-
idazine-3-thione
[0887] Using
2-benzyl-5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2H-pyrid-
azin-3-one as a starting material, the procedures of Example 122
were repeated likewise, whereby the title compound was obtained in
a yield of 77.6%.
[0888] Yellow needles (ethyl acetate-hexane).
[0889] Melting point: 103.2-103.3.degree. C.
[0890] Mass (m/e): 434, 436 (M.sup.+).
[0891] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48(3H, s), 5.99(2H, s),
7.07-7.14(8H, m), 7.26-7.39(3H, m), 7.60(2H, d, J=6.64 Hz),
7.79(1H, s).
[0892] IR (KBr) cm.sup.-1: 1597, 1491, 1413, 1345, 1145, 1100,
825.
Example 133
Preparation of
5-(4-chlorophenyl)-2-(2,4-difluorobenzyl)-6-[4-(methylthio)-
phenyl]-2H-pyridazine-3-thione
[0893] Using
5-(4-chlorophenyl)-2-(2,4-difluorobenzyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 65.6%.
[0894] Yellow needles (ethyl acetate-hexane).
[0895] Melting point: 176.5-176.6.degree. C.
[0896] Mass (m/e): 470, 472 (M.sup.+).
[0897] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 5.97(2H, s),
6.86(2H, t, J=8.30 Hz), 7.05-7.12(6H, m), 7.30(2H, d, J=8.59 Hz),
7.53(1H, dd, J=14.64, 8.20 Hz), 7.80(1H, s).
[0898] IR (KBr) cm.sup.-1: 1604, 1506, 1410, 1336, 1154, 1101,
1089, 829.
Example 134
Preparation of
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)-
phenyl]-2H-pyridazine-3-thione
[0899] Using
5-(4-chlorophenyl)-2-(2,4-dichlorobenzyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 77.2%.
[0900] Yellow needles (ethyl acetate-hexane).
[0901] Melting point: 183.2-183.4.degree. C.
[0902] Mass (m/e): 502 (M.sup.+).
[0903] .sup.1H-NMR (CDCl.sub.3) .delta.5: 2.46(3H, s), 6.00(2H, s),
7.04-7.32(10H, m), 7.46(1H, d, J=2.15 Hz), 7.82(1H, s).
[0904] IR (KBr) cm.sup.-1: 1594, 1477, 1409, 1138, 1099, 824.
Example 135
Preparation of
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmet-
hyl)-2H-pyridazine-3-thione
[0905] Using
5-(4-chlorophenyl)-6-[4-(methylthio)phenyl]-2-(3-pyridylmethy-
l)-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 99%.
[0906] Yellow needles (ethyl acetate-hexane).
[0907] Melting point: 130.3-131.0.degree. C.
[0908] Mass (m/e): 435, 437 (M.sup.+).
[0909] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.48(3H, s), 5.99(2H, s),
7.06-7.15(6H, m), 7.29-7.31(3H, m), 7.78(1H, s), 8.05(1H, d, J=8.20
Hz), 8.58(1H, d, J=3.32 Hz), 8.86(1H, s).
[0910] IR (KBr) cm.sup.-1: 1596, 1413, 1147, 1101, 826.
Example 136
Preparation of
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazine-3-
-thione
[0911] Using
5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyridazin-3-on- e as
a starting material, the procedures of Example 122 were repeated
likewise, whereby the title compound was obtained in a yield of
84.3%.
[0912] Yellow prisms (ethyl acetate-hexane).
[0913] Melting point: 218.7-218.9.degree. C.
[0914] Mass (m/e): 328 (M.sup.+).
[0915] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 7.03(2H, t,
J=8.59 Hz), 7.09-7.16(6H, m).
[0916] IR (KBr) cm.sup.-1: 3133, 1605, 1597, 1509, 1388, 1318,
1109, 842, 827.
Example 137
Preparation of
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)phe-
nyl]-2H-pyridazine-3-thione
[0917] Using
2-cyclopropylmethyl-5-(4-fluorophenyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 95.6%.
[0918] Yellow prisms (ethyl acetate-hexane).
[0919] Melting point: 135.7-135.8.degree. C.
[0920] Mass (m/e): 382 (M.sup.+).
[0921] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.54-0.64(4H, m),
1.67-1.77(1H, m), 2.47(3H, s), 4.64(2H, d, J=7.32 Hz), 7.02(2H, t,
J=8.66 Hz), 7.09-7.17(6H, m), 7.81(1H, s).
[0922] IR (KBr) cm.sup.-1: 1605, 1509, 1476, 1412, 1230, 1158,
1101, 843.
Example 138
Preparation of
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyr-
idazine-3-thione
[0923] Using
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylthio)phenyl]-2H-pyrid-
azin-3-one as a starting material, the procedures of Example 122
were repeated likewise, whereby the title compound was obtained in
a yield of 95.6%.
[0924] Yellow prisms (diethyl ether-hexane).
[0925] Melting point: 108.1-108.2.degree. C.
[0926] Mass (m/e): 418 (M.sup.+).
[0927] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.46(3H, s), 5.99(2H, s),
6.97-7.14(7H, m), 7.32-7.37(3H, m), 7.60(2H, d, J=6.10 Hz),
7.79(1H, s).
[0928] IR (KBr) cm.sup.-1: 1605, 1509, 1417, 1162, 1101, 836.
Example 139
Preparation of
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-
-pyridazine-3-thione
[0929] Using
2-benzyl-5-(4-fluorophenyl)-6-[4-(methylsulfonyl)phenyl]-2H-p-
yridazin-3-one as a starting material, the procedures of Example
122 were repeated likewise, whereby the title compound was obtained
in a yield of 100%.
[0930] Yellow prisms (ethyl acetate-hexane).
[0931] Melting point: 181.8-182.0.degree. C.
[0932] Mass (m/e): 450 (M.sup.+).
[0933] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.06(3H, s), 5.99(2H, s),
7.00-7.11(4H, m), 7.30-7.42(5H, m), 7.58(2H, dd, J=8.01, 1.56 Hz),
7.84(1H, s), 7.87(2H, d, J=10.35 Hz).
[0934] IR (KBr) cm.sup.-1: 1604, 1511, 1308, 1163, 1152, 1083, 848,
571.
Example 140
Preparation of
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)phe-
nyl]-2H-pyridazine-3-thione
[0935] Using
5-(4-fluorophenyl)-2-(4-methoxybenzyl)-6-[4-(methylthio)pheny-
l]-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 92.2%.
[0936] Yellow powder (ethyl acetate-hexane).
[0937] Melting point: 112.7-112.9.degree. C.
[0938] Mass (m/e): 448 (M.sup.+).
[0939] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.47(3H, s), 3.79(3H, s),
5.92(2H, s), 6.89(2H, d, J=8.54 Hz), 6.99(2H, d, J=8.54 Hz),
7.09-7.14(6H, m), 7.60(2H, d, J=8.54 Hz), 7.78(1H, s).
[0940] IR (KBr) cm.sup.-1: 1607, 1511, 1248, 1162, 1101.
Example 141
Preparation of
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)-
phenyl]-2H-pyridazine-3-thione
[0941] Using
2-(2,4-dichlorobenzyl)-5-(4-fluorophenyl)-6-[4-(methylthio)ph-
enyl]-2H-pyridazin-3-one as a starting material, the procedures of
Example 122 were repeated likewise, whereby the title compound was
obtained in a yield of 79.8%.
[0942] Yellow needles (ethyl acetate-hexane).
[0943] Melting point: 154.0-154.2.degree. C.
[0944] Mass (m/e): 487 (M.sup.+).
[0945] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.45(3H, s), 6.00(2H, s),
7.00-7.10(6H, m), 7.13-7.22(4H, m), 7.45(1H, d, J=1.95 Hz),
7.82(1H, s).
[0946] IR (KBr) cm.sup.-1: 1597, 1509, 1414, 1099, 839, 824.
Example 142
Preparation of
2-(4-chlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyr-
idazine-3-thione
[0947] Using
2-(4-chlorobenzyl)-6-(4-methoxyphenyl)-5-(4-pyridyl)-2H-pyrid-
azin-3-one as a starting material, the procedures of Example 122
were repeated likewise, whereby the title compound was obtained in
a yield of 45.3%.
[0948] Yellow prisms (chloroform-hexane).
[0949] Melting point: 144.4-145.1.degree. C.
[0950] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 5.92(2H, s),
6.81(2H, d, J=8.90 Hz), 7.05(2H, dd, J=1.65, 4.45 Hz), 7.11(2H, d,
J=8.90 Hz), 7.31(2H, d, J=8.42 Hz), 7.55(2H, d, J=8.42 Hz),
7.77(1H, s), 8.57(2H, dd, J=1.65, 4.45 Hz).
[0951] IR (KBr) cm.sup.1: 1609, 1516, 1491, 1477, 1416, 1399, 1343,
1252, 1163, 1146.
Example 143
Preparation of
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridaz-
ine-3-thione
[0952] To a solution of sodium periodate (1.66 g) in water (10 ml),
sulfuric acid (0.163 ml) was added under ice cooling, followed by
the addition of a solution of tartaric acid (1.16 g) in water (3
ml). The resulting solution was stirred at room temperature for 30
minutes. Added to the solution were
3'-fluoro-4'-methoxy-2-(4-methoxyphenyl)acetophenone (2.12 g, 7.73
mmol), a solution of sodium hydroxide (0.92 g) in water (15 ml) and
ethanol (20 ml), followed by stirring overnight at room
temperature. After the mixture was heated at 70.degree. C. for 40
minutes, the ethanol was distilled off, and water was then added.
The mixture was washed with ethyl acetate. The water layer was
acidified with hydrochloric acid, followed by extraction with ethyl
acetate. The extract was washed successively with water and a
brine, and was then dried over anhydrous sodium sulfate. The
solvent was distilled off under reduced pressure. The crude oil
(1.29 g) was dissolved in ethanol (50 ml) and subsequent to
addition of hydrazine hydrate (356 mg), the resultant mixture was
heated overnight under reflux. A 2 N aqueous solution of sodium
hydroxide (40 ml) was added to the reaction mixture, followed by
heating under reflux for 2 hours. After the reaction mixture was
neutralized with hydrochloric acid, the thus-obtained mixture was
extracted with ethyl acetate. The organic layer was washed with a
brine and was then dried over anhydrous sodium sulfate. The solvent
was distilled off. The residue was separated and purified by
chromatography on a silica gel column and was then crystallized
from ethanol, whereby the title compound (764 mg, 30.3%) was
obtained as yellow prisms.
[0953] Melting point: 221.8-223.0.degree. C.
[0954] Mass (m/Z): 326 (M.sup.+).
[0955] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.82(3H, s), 3.88(3H, s),
6.80-6.87(3H, m), 6.91(1H, ddd, J=8.5, 2.2, 1.0 Hz), 6.94(1H, s),
6.98(1H, dd, J=12.0, 2.2 Hz), 7.06(2H, d, J=9.0 Hz), 11.90(1H,
brs).
[0956] IR (KBr) cm.sup.-1: 1652, 1610, 1515, 1311, 1298, 1271,
1261, 1249, 1025.
Example 144
Preparation of
2-benzyl-6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2-
H-pyridazin-3-one
[0957] Using
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-
-3-one and benzyl bromide as starting materials, the procedures of
Example 12 were repeated likewise, whereby the title compound was
obtained in a yield of 95.8%.
[0958] Pale yellow prisms (ethyl acetate-hexane).
[0959] Melting point: 136.6-137.8.degree. C.
[0960] Mass (m/Z): 416 (M.sup.+).
[0961] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(3H, s), 3.87(3H, s),
5.41(2H, s), 6.76-6.83(3H, m), 6.85(1H, dd, J=8.5, 2.0 Hz),
6.88(1H, s), 6.97(1H, dd, J=12.0, 2.0 Hz), 7.02(2H, d, J=8.5 Hz),
7.27-7.41(3H, m), 7.53(2H, d, J=7.1 Hz).
[0962] IR (KBr) cm.sup.-1: 1671, 1610, 1519, 1511, 1432, 1304,
1292, 1275, 1249, 1177, 822.
Example 145
Preparation of
2-(4-chlorocinnamyl)-6-(3-fluoro-4-methoxyphenyl)-5-(4-meth-
oxyphenyl)-2H-pyridazin-3-one
[0963] Using
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-
-3-one and 4-chlorocinnamyl chloride as starting materials, the
procedures of Example 12 were repeated likewise, whereby the title
compound was obtained in a yield of 72.5%.
[0964] Colorless crystalline powder (ethyl acetate-hexane).
[0965] Melting point: 144.0-145.4.degree. C.
[0966] Mass (m/Z): 476 (M.sup.+).
[0967] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.81(3H, s), 3.87(3H, s),
4.99(2H, d, J=6.6 Hz), 6.44(1H, dt, J=15.9, 6.6 Hz), 6.69(1H, d,
J=15.9 Hz), 6.79-6.90(4H, m), 6.91(1H, s), 7.01(1H, dd, J=12.2, 2.0
Hz), 7.04(2H, d, J=8.5 Hz), 7.27(2H, d, J=8.5 Hz), 7.32(2H, d,
J=8.5 Hz).
[0968] IR (KBr) cm.sup.-1: 1666, 1610, 1520, 1512, 1279, 1247.
Example 146
Preparation of
2-ethyl-6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-
-pyridazin-3-one
[0969] To a solution of
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2-
H-pyridazin-3-one (150 mg, 0.46 mmol) in N,N-dimethylformamide (1.5
ml), potassium carbonate (317.6 mg) and ethyl iodide (179.2 mg)
were added, followed by stirring at 70.degree. C. for 3 hours. The
reaction mixture was concentrated, followed by the addition of
water. The mixture was extracted with ethyl acetate, and the
extract was dried over anhydrous sodium sulfate. The solvent was
distilled off under reduced pressure. The residue was separated and
purified by preparative silica gel chromatography and then
crystallized from ethyl acetate-hexane, whereby the title compound
(156 mg, 95.8%) was obtained as pale yellow needles.
[0970] Melting point: 122.6-123.5.degree. C.
[0971] Mass (m/Z): 354 (M.sup.+).
[0972] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46(3H, t, J=7.2 Hz),
3.81(3H, s), 3.87(3H, s), 4.30(2H, q, J=7.2 Hz), 6.79-6.86(3H, m),
6.87-6.92(2H, m), 7.01(1H, dd, J=12.2, 2.0 Hz), 7.04(2H, d, J=8.8
Hz).
[0973] IR (KBr) cm.sup.-1: 1659, 1609, 1520, 1512, 1305, 1297,
1277, 1244, 1181, 1131, 1022, 837.
Example 147
Preparation of
6-(3-fluoro-4-methoxyphenyl)-2-isobutyl-5-(4-methoxyphenyl)-
-2H-pyridazin-3-one
[0974] Using
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-
-3-one and isobutyl bromide as starting materials, the procedures
of Example 146 were repeated likewise, whereby the title compound
was obtained in a yield of 91.3%.
[0975] Colorless needles (diethyl ether-hexane).
[0976] Melting point: 86.8-87.4.degree. C.
[0977] Mass (m/Z): 382 (M.sup.+).
[0978] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01(6H, d, J=6.8 Hz),
2.37(1H, tsep, J=7.3, 6.8 Hz), 3.81(3H, s), 3.87(3H, s), 4.08(2H,
d, J=7.3 Hz), 6.79-6.86(3H, m), 6.87(1H, dd, J=2.1, 0.6 Hz),
6.89(1H, s), 7.00(1H, dd, J=12.1, 2.1 Hz), 7.05(2H, d, J=9.0
Hz).
[0979] IR (KBr) cm.sup.-1: 1660, 1610, 1521, 1512, 1305, 1297,
1277, 1245, 1177.
Example 148
Preparation of
2-cyclopropylmethyl-6-(3-fluoro-4-methoxyphenyl)-5-(4-metho-
xyphenyl)-2H-pyridazin-3-one
[0980] Using
6-(3-fluoro-4-methoxyphenyl)-5-(4-methoxyphenyl)-2H-pyridazin-
-3-one and (chloromethyl)cyclopropane as starting materials, the
procedures of Example 146 were repeated likewise, whereby the title
compound was obtained in a yield of 93.0%.
[0981] Colorless prisms (ethyl acetate-hexane).
[0982] Melting point: 132.2-132.6.degree. C.
[0983] Mass (m/Z): 380 (M.sup.+).
[0984] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.46-0.62(4H, m), 1.45(1H,
ttt, J=7.8, 7.3, 4.9 Hz), 3.82(3H, s), 3.87(3H, s), 4.11(2H, d,
J=7.3 Hz), 6.80-6.91(5H, m), 7.01(1H, dd, J=12.2, 2.0 Hz), 7.06(2H,
d, J=9.0 Hz).
[0985] IR (KBr) cm.sup.-1: 1660, 1612, 1521, 1511, 1306, 1295,
1278, 1244, 1176, 1019, 828.
Example 149
Preparation of
4,5-dihydro-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl-
)-2H-pyridazin-3-one
[0986] Using ethyl
3-(3-fluoro-4-methoxyphenyl)-4-(4-methoxyphenyl)-4-oxob- utanoate
as a starting material, the procedures of Example 1 were repeated
likewise, whereby the title compound was obtained in a yield of
55.3%.
[0987] Pale yellow scales (ethyl acetate-hexane).
[0988] Melting point: 171.2-173.4.degree. C.
[0989] Mass (m/Z): 328 (M.sup.+).
[0990] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.75(1H, dd, J=16.8, 1.2
Hz), 2.97(1H, dd, J=16.8, 7.7 Hz), 3.82(3H, s), 3.85(3H, s),
4.40(1H, dd, J=7.6, 1.2 Hz), 6.85-6.98(5H, m), 7.64(2H, d, J=8.8
Hz), 8.54(1H, brs).
[0991] IR (KBr) cm.sup.-1: 1675, 1660, 1616, 1516, 1351, 1278,
1255, 1174.
Example 150
Preparation of
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridaz-
in-3-one
[0992] Using
4,5-dihydro-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)--
2H-pyridazin-3-one as a starting material, the procedures of
Example 7 were repeated likewise, whereby the title compound was
obtained in a yield of 90.2%.
[0993] Colorless needles (ethyl acetate-hexane).
[0994] Melting point: 212.8-213.4.degree. C.
[0995] Mass (m/Z): 326 (M.sup.+).
[0996] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.80(3H, s), 3.89(3H, s),
6.79(2H, d, J=8.8 Hz), 6.85(1, d, J=11.7 Hz), 6.87-6.93(2H, m),
6.96(1H, s), 7.13(2H, d, J=8.8 Hz), 12.75(1H, brs).
[0997] IR (KBr) cm.sup.-1: 1667, 1614, 1520, 1308, 1278, 1254,
1132, 1022, 835.
Example 151
Preparation of
2-benzyl-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2-
H-pyridazin-3-one
[0998] Using
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-
-3-one and benzyl bromide as starting materials, the procedures of
Example 12 were repeated likewise, whereby the title compound was
obtained in a yield of 95.6%.
[0999] Colorless needles (ethyl acetate-hexane).
[1000] Melting point: 109.6-111.6.degree. C.
[1001] Mass (m/Z): 416 (M.sup.+).
[1002] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.87(3H, s),
5.41(2H, s), 6.76-6.89(6H, m), 7.10(2H, d, J=8.8 Hz), 7.27-7.38(3H,
m), 7.50-7.55(2H, m).
[1003] IR (KBr) cm.sup.-1: 1667, 1608, 1516, 1462, 1295, 1276,
1248, 1181, 1131, 1021, 873.
Example 152
Preparation of
2-(4-chlorocinnamyl)-5-(3-fluoro-4-methoxyphenyl)-6-(4-meth-
oxyphenyl)-2H-pyridazin-3-one
[1004] Using
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-
-3-one and 4-chlorocinnamyl chloride as starting materials, the
procedures of Example 12 were repeated likewise, whereby the title
compound was obtained in a yield of 58.7%.
[1005] Colorless crystalline powder (ethyl acetate-hexane).
[1006] Melting point: 109.2-111.0.degree. C.
[1007] Mass (m/Z): 476 (M.sup.+).
[1008] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.88(3H, s),
4.99(2H, d, J=6.6 Hz), 6.44(1H, dt, J=15.9, 6.6 Hz), 6.68(1H, d,
J=15.9 Hz), 6.80(2H, d, J=9.0 Hz), 6.82-6.90(3H, m), 6.91(1H, s),
7.13(2H, d, J=9.0 Hz), 7.26(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5
Hz).
[1009] IR (KBr) cm.sup.-1: 1655, 1611, 1515, 1491, 1306, 1275,
1250, 1177, 1129.
Example 153
Preparation of
2-ethyl-5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-
-pyridazin-3-one
[1010] Using
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-
-3-one and ethyl iodide as starting materials, the procedures of
Example 146 were repeated likewise, whereby the title compound was
obtained in a yield of 97.8%.
[1011] Colorless needles (ethyl acetate-hexane).
[1012] Melting point: 161.7-162.2.degree. C.
[1013] Mass (m/Z): 354 (M.sup.+).
[1014] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46(3H, t, J=7.1 Hz),
3.80(3H, s), 3.89(3H, s), 4.31(2H, q, J=7.1 Hz), 6.78-6.92(6H, m),
7.13(1H, d, J=8.8 Hz).
[1015] IR (KBr) cm.sup.-1: 1655, 1612, 1519, 1515, 1305, 1297,
1278, 1252, 1175, 1130, 1022, 833.
Example 154
Preparation of
5-(3-fluoro-4-methoxyphenyl)-2-isobutyl-6-(4-methoxyphenyl)-
-2H-pyridazin-3-one
[1016] Using
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-
-3-one and isobutyl iodide as starting materials, the procedures of
Example 146 were repeated likewise, whereby the title compound was
obtained in a yield of 75.1%.
[1017] Colorless prisms (ethyl acetate-hexane).
[1018] Melting point: 124.6-125.0.degree. C.
[1019] Mass (m/Z): 382 (M.sup.+).
[1020] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01(6H, d, J=6.8 Hz),
2.37(1H, tsep, J=7.6, 6.8 Hz), 3.80(3H, s), 3.89(3H, s), 4.08(2H,
d, J=7.6 Hz), 6.80(2H, d, J=9.0 Hz), 6.84(1H, dd, J=11.3, 1.3 Hz),
6.87-6.91(3H, m), 7.12(2H, d, J=9.0 Hz).
[1021] IR (KBr) cm.sup.-1: 1660, 1612, 1517, 1463, 1443, 1308,
1299, 1281, 1251, 1238, 1178, 1133, 1023.
Example 155
Preparation of
2-cyclopropylmethyl-5-(3-fluoro-4-methoxyphenyl)-6-(4-metho-
xyphenyl)-2H-pyridazin-3-one
[1022] Using
5-(3-fluoro-4-methoxyphenyl)-6-(4-methoxyphenyl)-2H-pyridazin-
-3-one and (chloromethyl)cyclopropane as starting materials, the
procedures of Example 146 were repeated likewise, whereby the title
compound was obtained in a yield of 93.8%.
[1023] Colorless prisms (ethyl acetate-hexane).
[1024] Melting point: 135.2-135.7.degree. C.
[1025] Mass (m/Z): 380 (M.sup.+).
[1026] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.46-0.62(4H, m), 1.42(1H,
ttt, J=7.8, 7.3, 4.9 Hz), 3.80(3H, s), 3.89(3H, s), 4.11(2H, d,
J=7.3 Hz), 6.80(2H, d, J=8.8 Hz), 6.82-6.93(4H, m), 7.13(2H, d,
J=8.8 Hz).
[1027] IR (KBr) cm.sup.-1: 1661, 1611, 1586, 1519, 1309, 1295,
1282, 1249, 1181, 1130, 1021, 823.
Example 156
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-4,5-dihydro-2H-pyridazin--
3-one
[1028] Using ethyl 3,4-bis(3-fluoro-4-methoxyphenyl)-4-oxobutanoate
as a starting material, the procedures of Example 1 were repeated
likewise, whereby the title compound was obtained in a yield of
22.9%.
[1029] Colorless needles (ethyl acetate-hexane).
[1030] Melting point: 195.7-197.7.degree. C.
[1031] Mass (m/Z): 346 (M.sup.+).
[1032] .sup.1H-NMR (CDCl.sub.3) .delta.: 2.76(1H, d, J=17.1 Hz),
2.97(1H, dd, J=17.1, 7.6 Hz), 3.85(3H, s), 3.89(3H, s), 4.35(1H, d,
J=7.6 Hz), 6.84-6.95(4H, m), 7.35(1H, d, J=8.8 Hz), 7.51(1H, dd,
J=12.6, 1.6 Hz), 8.71(1H, brs).
[1033] IR (KBr) cm.sup.-1: 1661, 1622, 1519, 1351, 1279.
Example 157
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
[1034] Using
5,6-bis(3-fluoro-4-methoxyphenyl)-4,5-dihydro-2H-pyridazin-3-- one
as a starting material, the procedures of Example 7 were repeated
likewise, whereby the title compound was obtained in a yield of
94.9%.
[1035] Yellow prisms (chloroform-methanol-hexane).
[1036] Melting point: 204.8-205.7.degree. C.
[1037] Mass (m/Z): 344 (M.sup.+).
[1038] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.89(3H, s), 3.91(3H, s),
6.81-6.95(6H, m), 6.97(1H, dd, J=12.0, 2.2 Hz), 12.04(1H, brs).
[1039] IR (KBr) cm.sup.-1: 1652, 1618, 1589, 1519, 1439, 1308,
1278, 1139, 1128, 1023, 815.
Example 158
Preparation of
2-benzyl-5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-o- ne
[1040] Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
and benzyl bromide as starting materials, the procedures of Example
12 were repeated likewise, whereby the title compound was obtained
in a yield of 99.9%.
[1041] Colorless prisms (ethyl acetate-hexane).
[1042] Melting point: 114.1-115.2.degree. C.
[1043] Mass (m/Z): 434 (M.sup.+).
[1044] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.88(3H, s), 3.89(3H, s),
5.40(2H, s), 6.78-7.01(7H, m), 7.28-7.39(3H, m), 7.52(2H, dd,
J=8.2, 1.3 Hz).
[1045] IR (KBr) cm.sup.-1: 1671, 1517, 1430, 1424, 1308, 1276,
1130.
Example 159
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-2-(4-chlorocinnamyl)-2H-p-
yridazin-3-one
[1046] Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
and 4-chlorocinnamyl chloride as starting materials, the procedures
of Example 12 were repeated likewise, whereby the title compound
was obtained in a yield of 42.9%.
[1047] Yellow crystalline powder (diethyl ether-hexane).
[1048] Melting point: 72.5-74.9.degree. C.
[1049] Mass (m/Z): 494 (M.sup.+).
[1050] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.88(3H, s), 3.90(3H, s),
4.99(2H, d, J=6.6 Hz), 6.43(1H, dt, J=15.9, 6.6 Hz), 6.69(1H, d,
J=15.9 Hz), 6.80-6.95(6H, m), 6.99(1H, dd, J=12.1, 1.8 Hz),
7.27(2H, d, J=8.5 Hz), 7.32(2H, d, J=8.5 Hz).
[1051] IR (KBr) cm.sup.-1: 1664, 1619, 1589, 1520, 1491, 1440,
1307, 1278, 1133, 1025.
Example 160
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-on- e
[1052] Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
and ethyl iodide as starting materials, the procedures of Example
146 were repeated likewise, whereby the title compound was obtained
in a yield of 97.2%.
[1053] Colorless needles (ethyl acetate-hexane).
[1054] Melting point: 177.8-178.5.degree. C.
[1055] Mass (m/Z): 372 (M.sup.+).
[1056] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46(3H, t, J=7.1 Hz),
3.89(3H, s), 3.91(3H, s), 4.30(2H, q, J=7.1 Hz), 6.79-6.95(6H, m),
7.00(1H, dd, J=11.1, 1.8 Hz).
[1057] IR (KBr) cm.sup.-1: 1655, 1519, 1306, 1286, 1275, 1133,
1127, 1023.
Example 161
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-2-isobutyl-2H-pyridazin-3-
-one
[1058] Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
and isobutyl iodide as starting materials, the procedures of
Example 146 were repeated likewise, whereby the title compound was
obtained quantitatively.
[1059] Colorless prisms (ethyl acetate-hexane).
[1060] Melting point: 154.0-154.5.degree. C.
[1061] Mass (m/Z): 400 (M.sup.+).
[1062] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.01(6H, d, J=6.8 Hz),
2.36(1H, tsep, J=7.3, 6.8 Hz), 3.89(3H, s), 3.91(3H, s), 4.08(2H,
d, J=7.3 Hz), 6.81-6.94(6H, m), 6.99(1H, dd, J=12.3, 1.8 Hz).
[1063] IR (KBr) cm.sup.-1: 1660, 1521, 1438, 1308, 1289, 1274,
1134, 1021.
Example 162
Preparation of
5,6-bis(3-fluoro-4-methoxyphenyl)-2-cyclopropylmethyl-2H-py-
ridazin-3-one
[1064] Using 5,6-bis(3-fluoro-4-methoxyphenyl)-2H-pyridazin-3-one
and (chloromethyl)cyclopropane as starting materials, the
procedures of Example 146 were repeated likewise, whereby the title
compound was obtained quantitatively.
[1065] Colorless prisms (ethyl acetate-hexane).
[1066] Melting point: 142.3-142.7.degree. C.
[1067] Mass (m/Z): 398 (M.sup.+).
[1068] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.45-0.52(2H, m),
0.54-0.62(2H, m), 1.44(1H, ttt, J=7.6, 7.3, 4.9 Hz), 3.89(3H, s),
3.91(3H, s), 4.11(2H, d, J=7.3 Hz), 6.81-6.94(6H, m), 7.00(1H, dd,
J=12.1, 1.8 Hz).
[1069] IR (KBr) cm.sup.-1: 1660, 1590, 1522, 1515, 1447, 1427,
1308, 1278, 1145, 1129, 1018, 862, 761.
Example 163
Preparation of
5,6-bis(4-methoxyphenyl)-2-ethyl-2H-pyridazin-3-one
[1070] Ethyl iodide (280 mg, 1.8 mmol) was added to a suspension of
5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one (463 mg, 1.5 mmol) and
potassium carbonate (311 mg, 2.25 mmol) in N,N-dimethylformamide (5
ml), followed by heating at 70.degree. C. under stirring for 9.5
hours. Water was added to the reaction mixture, and the
thus-obtained mixture was extracted with ethyl acetate. The extract
was washed successively with water and a brine, and was then dried
over anhydrous sodium sulfate. The solvent was distilled off, and
the residue so obtained was separated and purified by
chromatography on a silica gel column (silica gel: 11 g), whereby
yellow crystals (466 mg) were obtained. The crystals were
recrystallized from ethyl acetate-n-hexane, whereby the title
compound (360 mg, 78.3%) was obtained as pale yellow prisms.
[1071] Melting point: 142.8-143.4.degree. C.
[1072] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.46(3H, t, J=7.08 Hz),
3.80(3H, s), 3.81(3H, s), 4.31(2H, q, J=7.08 Hz), 6.79(2H, d,
J=9.03 Hz), 6.81(2H, d, J=8.79 Hz), 6.89(1H, s), 7.04(2H, d, J=8.79
Hz), 7.14(2H, d, J=9.03 Hz).
[1073] IR (KBr) cm.sup.-1: 3447, 1656, 1608, 1513, 1294, 1249,
1183, 1023, 840.
Example 164
Preparation of
5,6-bis(4-methoxyphenyl)-2-methyl-2H-pyridazin-3-one
[1074] Similarly to Example 163, the title compound was obtained in
a yield of 100%.
[1075] Colorless oil.
[1076] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.80(3H, s),
3.88(3H, s), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz),
6.91(1H, s), 7.04(2H, d, J=8.78 Hz), 7.14(2H, d, J=9.03 Hz).
[1077] IR (film) cm.sup.-1: 3479, 2972, 2937, 2839, 1660, 1609,
1514, 1296, 1247, 1180, 1032, 997, 834.
Example 165
Preparation of
5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one
[1078] Similarly to Example 163, the title compound was obtained in
a yield of 100%.
[1079] Pale yellow amorphous.
[1080] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.44(6H, d, J=6.54 Hz),
3.80(3H, s), 3.81(3H, s), 5.39(1H, seplet, J=6.60 Hz), 6.79(2H, d,
J=8.79 Hz), 6.83(2H, d, J=8.79 Hz), 6.87(1H, s), 7.06(2H, d, J=8.79
Hz), 7.50(2H, d, J=9.04 Hz).
[1081] IR (KBr) cm.sup.-1: 1656, 1609, 1513, 1295, 1248, 1176,
1026, 833.
Example 166
Preparation of
5,6-bis(4-methoxyphenyl)-2-isopropyl-2H-pyridazin-3-one
[1082] Similarly to Example 163, the title compound was obtained in
a yield of 68.1%.
[1083] Colorless prisms (ethyl acetate-diethyl ether).
[1084] Melting point: 128.3-129.1.degree. C.
[1085] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00(3H, s), 1.02(3H, s),
2.35-2.40(1H, m), 3.79(3H, s), 3.81(3H, s), 4.08(2H, d, J=7.57 Hz),
6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.79 Hz), 6.89(1H, s),
7.05(2H, d, J=8.79 Hz), 7.12(2H, d, J=9.04 Hz).
[1086] IR (KBr) cm.sup.-1: 2958, 1660, 1606, 1515, 1248, 1177,
1027, 837.
Example 167
Preparation of
2-allyl-5,6-bis(4-methoxyphenyl)-2H-pyridazin-3-one
[1087] Similarly to Example 163, the title compound was obtained in
a yield of 40.2%.
[1088] Pale yellow needles (ethyl acetate-n-hexane).
[1089] Melting point: 114.0-115.0.degree. C.
[1090] .sup.1H-NMR (CDCl.sub.3) .delta.: 3.79(3H, s), 3.81(3H, s),
4.86(2H, d, J=5.86 Hz), 5.28(1H, d, J=10.25 Hz), 5.33(1H, d,
J=17.09 Hz), 6.10(1H, tdd, J=5.86, 10.25, 17.09 Hz), 6.78(2H, d,
J=8.79 Hz), 6.81(2H, d, J=8.79 Hz), 6.90(1H, s), 7.04(2H, d, J=9.03
Hz), 7.12(2H, d, J=8.79 Hz).
[1091] IR (KBr) cm.sup.-1: 1662, 1608, 1511, 1296, 1250, 1022,
836.
Example 168
Preparation of
5,6-bis(4-methoxyphenyl)-2-cyclopropyl-2H-pyridazin-3-one
[1092] Similarly to Example 163, the title compound was obtained in
a yield of 2.3%.
[1093] Pale yellow oil.
[1094] Mass (m/e): 348 (M.sup.+).
[1095] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.00-1.18(2H, m),
1.20-2.25(2H, m), 3.79(3H, s), 3.81(3H, s), 4.20-4.30(1H, m),
6.77(2H, d, J=9.28 Hz), 6.81(2H, d, J=8.79 Hz), 6.89(1H, s),
7.05(2H, d, J=9.03 Hz), 7.14(2H, d, J=9.03 Hz).
[1096] IR (KBr) cm.sup.-1: 1733, 1661, 1652, 1609, 1515, 1296,
1250, 1179, 1111, 1026, 834.
Example 169
Preparation of
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-
-one
[1097] Similarly to Example 163, the title compound was obtained in
a yield of 89.6%.
[1098] Pale yellow crystalline powder (chloroform-diethyl
ether-n-hexane).
[1099] Melting point: 128.8-129.3.degree. C.
[1100] .sup.1H-NMR (CDCl.sub.3) .delta.: 0.46-0.62(4H, m),
1.38-1.54(1H, m), 3.80(3H, s), 3.81(3H, s), 4.12(2H, d, J=7.08 Hz),
6.79(2H, d, J=9.04 Hz), 6.81(2H, d, J=8.79 Hz), 6.90(1H, s),
7.06(2H, d, J=8.79 Hz), 7.10(2H, d, J=8.79 Hz).
[1101] IR (KBr) cm.sup.-1: 1656, 1609, 1566, 1514, 1247, 1183,
1028, 838.
Example 170
Preparation of
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazine--
3-thione
[1102] Lawesson's reagent (184 mg, 0.46 mmol) was added to a
solution of
5,6-bis(4-methoxyphenyl)-2-cyclopropylmethyl-2H-pyridazin-3-one
(165 mg, 0.46 mmol) in toluene (6 ml), followed by stirring at
70.degree. C. for 1 hour under a nitrogen gas atmosphere. The
solvent was distilled off, and the resulting residue was separated
and purified by chromatography on a silica gel column [silica gel:
18 g, n-hexane/ethyl acetate (4/1)]. Crystallization was then
effected from ethyl acetate-diethyl ether, whereby the title
compound (127 mg, 72.9%) was obtained as yellow scales.
[1103] Melting point: 147.5-148.5.degree. C. .sup.1H-NMR
(CDCl.sub.3) .delta.: 0.56-0.62(4H, m), 1.68-1.75(1H, m), 3.81(3H,
s), 3.82(3H, s), 4.64(2H, d, J=7.33 Hz), 6.81(2H, d, J=9.04 Hz),
6.82(2H, d, J=9.03 Hz), 7.09(2H, d, J=8.79 Hz), 7.19(2H, d, J=9.03
Hz), 7.82(1H, s).
[1104] IR (KBr) cm.sup.-1: 1609, 1513, 1416, 1248, 1186, 1181,
1122, 1021, 834.
Example 171
Preparation of
5,6-bis(4-methoxyphenyl)-2-cyclopentyl-2H-pyridazin-3-one
[1105] Similarly to Example 163, the title compound was obtained in
a yield of 65.4%.
[1106] Pale yellow prisms (chloroform-n-hexane).
[1107] Melting point: 141.2-142.2.degree. C.
[1108] Mass (m/e): 376 (M.sup.+).
[1109] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.60-1.80(2H, m),
1.80-2.20(6H, m), 3.80(3H, s), 3.81(3H, s), 5.25(2H, quintet,
J=6.60 Hz), 6.78(2H, d, J=8.79 Hz), 6.82(2H, d, J=8.79 Hz),
6.86(1H, s), 7.06(2H, d, J=9.03 Hz), 7.14(2H, d, J=9.03 Hz).
[1110] IR (KBr) cm.sup.-1: 1661, 1611, 1512, 1295, 1255, 1175,
1020, 833.
Example 172
Preparation of
5,6-bis(4-methoxyphenyl)-2-cyclopentylmethyl-2H-pyridazin-3-
-one
[1111] Similarly to Example 163, the title compound was obtained in
a yield of 57.1%.
[1112] Colorless scales (ethyl acetate-diethyl ether).
[1113] Melting point: 130.3-131.4.degree. C.
[1114] .sup.1H-NMR (CDCl.sub.3) .delta.: 1.37-1.79(8H, m), 2.56(1H,
quintet, J=7.57 Hz), 3.80(3H, s), 3.81(3H, s), 4.21(2H, d, J=7.82
Hz), 6.79(2H, d, J=8.79 Hz), 6.81(2H, d, J=8.54 Hz), 6.89(1H, s),
7.05(2H, d, J=9.04 Hz), 7.13(2H, d, J=9.04 Hz).
[1115] IR (KBr) cm.sup.-1: 1664, 1609, 1513, 1292, 1250, 1179,
1023, 831.
[1116] Test 1
[1117] (Inhibitory Activity Against Interleukin-1.beta.
Production)
[1118] HL-60 cells were cultured for 4 days until confluence on
RPMI 1640 medium with 10% fetal bovine serum (FBS) added thereto.
The HL-60 cells were centrifuged. The supernatant was discarded,
and the cells were then suspended at 1.times.10.sup.6 cells/ml on
RPMI 1640 medium with 3% FBS, and lipopolysaccharide was added to
give a final concentration of 10 .mu.g/ml. The culture was
inoculated at 1 ml/well to a 24-well plate. A test sample was added
at 1 .mu.l/well, followed by culturing for 3 days. Three days
later, the amount of interleukin-1.beta. in each of the cultures
was measured by ELISA. Its IC.sub.50 value was determined by a
comparison in yield with a control to which no test sample was
added. Results on some representative compounds are shown in Table
1.
1TABLE 1 Inhibitory Activity against Interleukin-1.beta.
(IL-1.beta.) Production Test compound IL-1.beta. Test compound
IL-1.beta. (Example No.) IC.sub.50(.mu.M) (Example No.)
IC.sub.50(.mu.M) 12 0.10 123 0.19 13 0.26 126 0.15 14 0.094 128
0.31 16 0.23 134 0.20 19 0.079 135 0.39 23 0.36 137 0.27 24 0.20
142 0.18 25 0.18 160 0.49 26 0.15 163 0.61 27 0.18 164 1.13 28 0.29
165 1.32 30 0.17 168 7.98 31 0.095 169 1.80 35 0.21 170 1.19 40
0.27 171 0.51 44 0.43 172 0.11 51 0.29 Comp. Comp'd 1 29 55 0.25
Comp. Comp'd 2 46 61 0.21 Comp. Comp'd 3 >100 65 0.39 Comp.
Comp'd 4 31.6 78 0.39 5 6 7 8
[1119] Test 2
[1120] (Inhibitory Activity Against TNF-.alpha. Production)
[1121] RAW 264.7 cells were cultured until confluence on DMEM
culture with 10% fetal bovine serum (FBS), and were diluted to
1.times.10.sup.6 cells/ml with the same medium and then inoculated
at 100 .mu.l/well to a 96-well plate. To the cells, a test sample
which had been diluted with the same medium and lipopolysaccharide
of 4 .mu.g/ml was added at 50 .mu.l/well, respectively. Subsequent
to culturing for 20 hours, the cultures were collected.
[1122] Making use of cytotoxicity to L-929 cell strain, a
TNF-.alpha. sensitive cell strain, the amount of TNF-.alpha. in
each of the cultures was measured as will be described next.
Described specifically, L-929 cells which had been cultured on MEM
medium with 10% FBS added thereto were diluted to 2.times.10.sup.5
cells/ml with the same medium, and were then inoculated at 100
.mu.l/well to a 96-well plate. Subsequent to overnight incubation,
standard TNF-.alpha. solutions, or 100-fold, 200-fold and 500-fold
dilute solutions of the above-described culture of RAW 264.7 cells
were added at 50 .mu.l/well, and actinomycin D (4 .mu.g/ml) was
also added at 50 .mu.l/well, followed by further culturing for 20
hours. Twenty hours later, each well was washed with PBS, viable
cells were stained with crystal violet, and the inhibitory activity
against TNF-.alpha. production was determined with reference to a
standard curve of TNF-.alpha.. The results are shown in Table
2.
[1123] (Inhibitory Activity Against IL-6 Production)
[1124] RAW 264.7 cells, which had been cultured until confluence on
DMEM culture with 10% fetal bovine serum (FBS) added thereto, were
diluted to 1.times.10.sup.6 cells/ml with the same medium, and were
then inoculated at 100 .mu.l/well to a 96-well plate. A test sample
which had been diluted with the same medium and lipopolysaccharide
of 4 .mu.g/ml in concentration was added at 50 .mu.l/well,
respectively. Subsequent to culturing for 20 hours, the cultures
were collected.
[1125] The amount of IL-6 in each of the thus-obtained cultures of
RAW 264.7 cells was measured by ELISA, and the inhibitory activity
against IL-6 production was determined with reference to a standard
curve of IL-6. The results are shown in Table 2.
2TABLE 2 Inhibitory Activity against TNF-.alpha. and IL-6
Production Test compound TNF-.alpha. IL-6 (Example No.) IC.sub.50
(.mu.M) IC.sub.50 (.mu.M) 163 1.2 0.40 Comparative Compound 1 10 65
Comparative Compound 2 26 44
[1126] As is apparent from Tests 1 and 2 described above, the
compounds according to the present invention have been found to
have extremely good IL-1.beta. inhibitory activity compared with
Comparative Compounds 1 to 4, which are compounds disclosed in EUR.
J. MED. CHEM., 14, 53-60, 1979 and are known to have
anti-inflammatory and analgesic action.
[1127] Test 3
[1128] In accordance with the disclosure of Nature 283, 666-668,
1980, therapeutic effects for arthritis were evaluated by using
collagen-induced arthritis models of mice. As a result, the
compound according to the present invention showed excellent
arthritis treatment effects as shown in Table 3.
3 TABLE 3 Percent.sup.1) Percent.sup.2) inhibition inhibition Test
comp'd Dose to arthritis to (Ex. No.) (mg/kg, P.O.) development
swelling 51 1 40 33.3 51 3 50 77.4 .sup.1)Determined depending on
the existence or non-existence of swelling. .sup.2)Determined by
quantitation of swelling.
[1129] Test 4
[1130] The compound of Example 51 was administered orally once a
day to rats and dogs for 2 weeks to determine its maximum no-effect
level (the amount which does not show toxicity). As a result, no
toxicity was observed at all at the dose levels of the compound
shown in Table 4, so that the compounds according to the present
invention have been found to have high safety.
4TABLE 4 Test compound Maximum no-effect Maximum no-effect (Example
No.) level (rat) level (dog) 51 100 mg/kg 30 mg/kg
Capability of Exploitation in Industry
[1131] The pyridazine derivatives (1) and their salts, which
pertain to the present invention, have excellent inhibitory
activity against interleukin-1.beta. production, and are useful as
medicines such as preventives and therapeutics for immune system
diseases, inflammatory diseases and ischemic diseases.
* * * * *