JPH07252236A - Anticancer agent - Google Patents

Abstract

PURPOSE:To obtain a new anticancer agent useful for prophylaxis or treatment of intractable solid tumor such as mainly a pancreatic cancer, prostatic cancer, lung cancer, breast cancer, etc., and their long range metastasis to the other organs. CONSTITUTION:This is a 3(2H)-pyridazinone derivative (salt) of formula I (R<1> is a lower alkyl, a cycloalkyl, etc.; R<2> is H, a halogen, a lower alkoxy which may have substituents, etc.; X is O or S; Y is an alkylene or an alkenylene each of which may have substituents; Q is an aryl or a heterocyclic aryl ring each of which may have substituents), e.g. 2-t-butyl-4-chloro-5-[4-(2-pyridyl) benzylthio]-3(2H)-pyridazinone. The above mentioned derivative is obtained by e.g., reacting a compound of formula II with a compound of formula, E-Y-Q (E is a leaving group such as a halogen) in the presence of an inorganic or organic base, preferably in a solvent such as methanol, preferably at -5 to 100 deg.C for 10-24hrs.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anticancer agent containing a 3 (2H) -pyridazinone derivative or a salt thereof and a novel 3 (2H) -pyridazinone derivative or a salt thereof. More specifically, the present invention mainly relates to a prophylactic or therapeutic agent for intractable solid tumors such as pancreatic cancer, prostate cancer, lung cancer and breast cancer, and distant metastasis of these to other organs.

[0002]

BACKGROUND OF THE INVENTION Pancreatic cancer, which is conventionally known as a refractory solid tumor, is often inoperable because it may have metastasized or cancerous peritonitis at the time of discovery, and surgery can be compared to it. Even if there is, the prognosis is generally poor. For such advanced cancer patients and post-operative patients, 5-fluorouracil (5-FU) is administered alone or multidrug combination therapy using a chemotherapeutic agent such as 5-FU and mitomycin is performed. The effect is not always high. For prostate cancer, which is also known as refractory solid tumor, particularly hormone-independent cancer or recurrent cancer or metastatic cancer, chemotherapeutic agents such as adriamycin, cisplatin, 5-FU, etc. are administered alone or multiple agents using them are used. Although combination therapy is used, the therapeutic effect is not always high.

On the other hand, pyridazinone derivatives have an insecticidal or acaricidal action (see, for example, JP-A-59-39874 and JP-A-6-39874).
0-4173, JP-A-60-54370, JP-A-61-
17570, JP-A-63-215674 and Journal of Japan Pesticide Society, Volume 17, S231 (1992), etc., analgesic and anti-inflammatory action (for example, Pharmaceutical Journal, Volume 107, page 910 (1987) and Pharmasutika Acta Helvetia). (Pharm. Acta Hel
v.], 38, 510 (1963), etc.), antibacterial or antifungal action (for example, Pharmaceutical Journal, 113, 676 (1993) and 89, 1516 (1969). Year)), weeding or plant growth regulating action (Japanese Patent Publications No. 38-7998 and 40-3).
798, etc.). Further, in JP 52-91883, 3 (2H) - -SO the 5-position of the pyridazinone ring ₂ - formula having a side chain through a

[Chemical 10] [Wherein R ^a is an alkyl group or a phenyl group, R ^c is an alkyl group, a phenyl group or a benzyl group, and R ^b is an amino group, a substituted amino group, an alicyclic amino group, a heterocyclic amino group, or a hydroxyl group. Group or an alkoxy group] is reported to suppress the growth of mouse leukemia cells (L-1210), and Japanese Patent Application Laid-Open No. 5-17357 discloses a method of 3 (2H)- Formula having a side chain at the 5-position of the pyridazinone ring via -NH-

[Chemical 11] [Wherein, R ^d and R ^e are each independently a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, and Z is a chlorine atom or a bromine atom], and the aminopyridazinone derivative is a chronic myelogenous leukemia. It has been reported to be useful in the treatment of However, 5 of 3 (2H) -pyridazinone ring
Anti-cancer effect of a compound having a side chain via -O- or -S-, especially on solid tumor, particularly on intractable solid tumor such as pancreatic cancer, prostate cancer, lung cancer or breast cancer, etc. Not reported.

[0004]

Therefore, a prophylactic / therapeutic agent having an excellent anticancer activity and effective for solid tumors, particularly for intractable solid tumors such as pancreatic cancer, prostate cancer, lung cancer or breast cancer, is desired.

[0005]

Means for Solving the Problems As a result of various studies on anticancer agents, the present inventors have found that the substituent at the 5-position is -XY.
^0- Q ⁰ (X represents O or S, Y ⁰ represents a divalent aliphatic hydrocarbon residue which may have a substituent, and Q ⁰ represents a cyclic group which may have a substituent. 4,5-disubstituted-3 (2H) -pyridazinone or a salt thereof is specifically represented by the formula:

[Chemical 12] [Wherein R ¹ is a lower alkyl group, a cycloalkyl group or a phenyl group which may have a substituent, and R ² is a hydrogen atom, a halogen, a lower alkoxy group which may have a substituent, a substituent A lower alkylthio group which may have a group or an aliphatic hydrocarbon group which may have a substituent,
X is O or S, Y is an alkylene group that may have a substituent or an alkenylene group that may have a substituent, and Q is an aryl group or a substituent that may have a substituent. Represents an aromatic heterocyclic group which may have. ] The compound represented by or a salt thereof has an unexpectedly excellent anticancer activity, particularly pancreatic cancer cells of solid tumor cells,
It has an excellent growth inhibitory effect on prostate cancer cells, lung cancer cells or breast cancer cells and was found to be useful for the prevention and treatment of intractable solid tumors such as pancreatic cancer, prostate cancer, lung cancer or breast cancer. Based on this, the present invention has been completed.

That is, according to the present invention, (1) the substituent at the 5-position is --X--Y ⁰ --Q ⁰ (X is O or S, and Y ⁰ is a divalent fatty acid which may have a substituent). Group 5 hydrocarbon residue, Q ⁰ represents a cyclic group which may have a substituent) 4, 5
An anticancer composition containing -disubstituted-3 (2H) -pyridazinone or a salt thereof, (2) the anticancer composition according to (1), wherein the substituent at the 4-position is a group having 1 to 150 atoms, (3)
The anticancer composition according to (1), wherein the 2-position of 4,5-disubstituted-3 (2H) -pyridazinone may be substituted with a hydrocarbon residue which may have a substituent, (4) The anticancer composition according to (1), wherein the aliphatic hydrocarbon residue has 1 to 3 carbon atoms, (5) the anticancer composition according to (1), wherein the substituent of the aliphatic hydrocarbon residue is a hydroxyl group. An anticancer composition according to (1), wherein the cyclic group is an aromatic cyclic group, (7) an anticancer composition according to (1), wherein the cyclic group is an optionally substituted phenyl group, (8) The optionally substituted phenyl group is

[Chemical 13] (R ⁸ is halogen, lower alkyl group, lower cycloalkyl group, lower alkoxy group, halo-lower alkyl group, halo-lower alkoxy group, cyano group, trimethylsilyl group,
Nitro group,

[Chemical 14] (R ⁹ represents a halogen, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a halo-lower alkyl group, a halo-lower alkoxy group, a cyano group or a nitro group, m represents an integer of 0 to 5, and m represents In the case of an integer of 2 to 5, R ⁹ may be the same or different from each other, n is an integer of 0 to 5, and when n is an integer of 2 to 5, R ⁸ is the same or different. Is good) (7)
The described anti-cancer composition,

(9) R ⁸ is

[Chemical 15] (R ⁹ has the same meaning as above), (8) The anticancer composition according to (8), wherein R ⁹ is halogen, the anticancer composition according to (9), (11) 4,5-disubstituted- 3 (2H) -pyridazinone has the formula

[Chemical 16] [Wherein R ¹ represents a lower alkyl group, a cycloalkyl group or a phenyl group which may have a substituent, and R ² represents a hydrogen atom, a halogen, a lower alkoxy group which may have a substituent, or a substituent. A lower alkylthio group which may have a group or an aliphatic hydrocarbon residue which may have a substituent, X has the same meaning as described above, and Y is an alkylene group which may have a substituent. Alternatively, an alkenylene group which may have a substituent and Q represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. ] The anticancer composition according to (1), which is a compound represented by the above formula, (12) R ¹ is a branched lower alkyl group (1
(1) The anticancer composition according to (13), wherein R ² is halogen, a lower alkoxy group or a lower alkyl group, and the anticancer composition according to (11). (14) Y is

[Chemical 17] (R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and represent a hydrogen atom, a hydroxyl group or a lower alkyl group which may have a substituent). , (15) the 5-position substituent is

[Chemical 18] (X and Y ⁰ are as defined above, and Q ¹ is a nitrogen-containing aromatic heterocyclic group which may have a substituent)
-Disubstituted-3 (2H) -pyridazinone or a salt thereof, (1
6) 5-position substituent -X-Y ¹ -Q ⁰ (X and Q ⁰ are as defined above, Y ¹ is substituted with a hydroxyl group 2
4,5-disubstituted-3 (2H) -pyridazinone or a salt thereof, which is a valent aliphatic hydrocarbon residue),

(17) 2-tert-butyl-4-chloro-
5- [4- (1,2,4-thiadiazol-5-yl)
Benzylthio] -3 (2H) -pyridazinone, (18)
formula

[Chemical 19] [In the formula, X has the same meaning as described above. ], Represented by
-Disubstituted-3 (2H) -pyridazinone or a salt thereof, (1
9) Expression

[Chemical 20] [In the formula, X has the same meaning as described above. ], Represented by
-Disubstituted-3 (2H) -pyridazinone or salt, (20)
4,5-disubstituted-3 (2H) -pyridazinone or a salt thereof, in which the substituent at the 5-position is -X-H (X has the same meaning as defined above)

[Chemical 21] [In the formula, E represents a leaving group, and Y ⁰ and Q ¹ have the same meanings as described above. ] The manufacturing method of the compound of (15) description which reacts with the compound or its salt represented by these, (21) The substituent of 5-position is -X-H (X shows the same meaning as the above) 4, 5-
Disubstituted -3 (2H) - shown pyridazinone or a salt thereof and wherein E-Y ¹ -Q ⁰ wherein, E, Y ¹ and Q ⁰ is a cyclic group which may have a substituent. ] The manufacturing method of the compound of (16) description which reacts with the compound or its salt represented by these, (22) R ²
The anticancer composition according to (10), wherein is a halogen or a lower alkyl group,

(23) Y is

[Chemical formula 22] (10) The anticancer composition according to (10), wherein (24) Y is

[Chemical formula 23] (25) Q is a phenyl group which may have a substituent, a naphthyl group which may have a substituent, or a quinolyl group which may have a substituent. (26) The anticancer agent according to (10), wherein the substituents of the phenyl group, the naphthyl group and the quinolyl group are lower alkyl groups,
The anticancer agent according to (25), which is an aryl group which may have a substituent or a nitrogen-containing aromatic heterocyclic group, (27) formula

[Chemical formula 24] [In the formula, Q ¹ represents a nitrogen-containing heterocyclic group which may have a substituent, and other symbols have the same meanings as described above. ] The novel compound or its salt represented by these, and (28) Formula

[Chemical 25] Other symbols have the same meanings as described above. ] It is related with the compound represented by these, its salt, etc.

In the above, X represents O or S. Y
⁰ represents a divalent aliphatic hydrocarbon residue which may have a substituent. The divalent aliphatic hydrocarbon residue which may have a substituent represented by Y ⁰ is, for example, an alkylene group or an alkenylene group which may have a substituent.
As the alkylene group represented by Y ⁰ , for example, an alkylene group having 1 to 6 carbon atoms such as methylene, ethylene, propylene, butylene and the like are used, and among them, methylene, ethylene and the like are preferable. As the alkenylene group represented by Y ⁰ , for example, an alkenylene group having 1 to 6 carbon atoms such as vinylene, propenylene, butenylene and the like are used, and among them, propenylene and the like are preferable. Y ⁰
The alkylene group or alkenylene group represented by is, for example, hydroxyl group, halogen (eg, fluorine, chlorine, bromine, iodine, etc.), cyano group, nitro group, di-lower alkylamino group (eg, diC ₁ such as dimethylamino, diethylamino, etc.). _-3 alkylamino group, etc.), lower alkoxy group (eg, C _1-4 alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), lower alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, (C _1-4 alkoxy) carbonyl group such as isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, etc., a lower alkyl group which may have a substituent (for example, the same as the lower alkyl group represented by R ¹ below) And the like are used. 1 or 5 may be substituted at the substitutable position, preferably 1 or 2 at the substitutable position, and 1 or 2 may be substituted at the substitutable position. A hydroxyl group and the like are preferred. Q ⁰ represents a cyclic group which may have a substituent. The cyclic group represented by Q ⁰ is, for example, a cyclic hydrocarbon residue or an aromatic heterocyclic group.
The cyclic hydrocarbon residue represented by Q ⁰ is, for example, an aryl group or a cyclohexyl group. As the aryl group represented by Q ⁰ , for example, C _6-10 aryl group such as phenyl, 1- or 2-naphthyl and the like are used, and among them, phenyl and the like are preferable.

The aromatic heterocyclic group represented by Q ⁰ is
For example, thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl,
1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl,
1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl , Benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-isobenzothiazolyl, 1H-benzotriazolyl , Quinolyl,
Isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, alpha-carbolinyl, beta-carbolinyl, .gamma.-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathiinyl, thianthrenyl, Fenatorijiniru, Fenatororiniru, Indolidinyl, pyrrolo [1,2-b] pyridazinyl, pyrrolo [1,2-a] pyrazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] Pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a]
Pyrimidinyl, 1,2,4-triazolo [4,3-a]
In addition to carbon atoms such as pyridyl, 1,2,4-triazolo [4,3-a] pyridazinyl and the like, 1 to 4 hetero atoms selected from oxygen atom, sulfur atom, nitrogen atom and the like are included 5
A 6-membered or 6-membered aromatic heterocyclic group and a condensed heterocyclic group in which these 5-membered or 6-membered aromatic heterocyclic groups are condensed with each other or with a phenyl group are used. Among them, a 5- or 6-membered nitrogen-containing heterocyclic group such as pyridyl, benzimidazolyl, isoxazolyl, quinolyl, or a condensed heterocyclic group thereof is preferable, and quinolyl or the like is more preferable.

The aryl group, cyclohexyl group and aromatic heterocyclic group represented by Q ⁰ are, for example, hydroxyl group, amino group, cyano group, carboxyl group and lower alkoxycarbonyl group (eg methoxycarbonyl,
C such as ethoxycarbonyl and tert-butoxycarbonyl
_1-6 alkoxycarbonyl group etc.), nitro group, lower alkyl group (eg C _1-6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl etc.), lower alkenyl group (Eg, C _2-6 alkenyl group such as vinyl and 2-propenyl), lower alkynyl group (eg, C _2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl, etc.), lower alkoxy group (Eg, C _1-6 alkoxy group such as methoxy, ethoxy, propoxy, etc.), lower alkylthio group (eg, C such as methylthio, ethylthio, etc.)
_1-6 alkylthio group, etc.), halo lower alkyl group (for example, halo-C _1-6 alkyl group such as fluoromethyl, trifluoromethyl, 2,2-difluoromethyl etc.), mono- or di-C _1-6 alkyl Amino groups (eg methylamino, ethylamino, propylamino, dimethylamino,
Substituted with mono- or di-C _1-6 alkylamino groups such as diethylamino), halogens (eg fluorine, chlorine, bromine, iodine etc.), trityl groups, styryl groups, phenyl groups (eg cyano groups etc.) 1 to 5, preferably 1 to 3 at the substitutable position, preferably by a cyano group, a C _1-4 alkyl group such as tert-butyl, a phenyl group, etc. It may be replaced individually.

When Q ⁰ is a phenyl group, it may be substituted with a nitrogen-containing aromatic heterocyclic group which may have a substituent in addition to the above-mentioned substituents. Examples of such a nitrogen-containing aromatic heterocyclic group include pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl,
5- or 6-membered ring such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl An aromatic monocyclic heterocyclic group such as indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, pyrrolo [1,2-b] pyridazinyl, Pyrrolo [1,2-a] pyrazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2]
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
Aromatic condensed heterocyclic groups such as 1,2,4-triazolo [4,3-b] pyridazinyl are used, and preferably, for example, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, Quinolyl, benzimidazolyl and the like are used, and among them, pyrrolyl, imidazolyl, pyridyl, quinolyl and the like are more preferable. Such nitrogen-containing aromatic heterocyclic group is, for example, a lower alkyl group (eg, methyl,
C _1-3 alkyl groups such as ethyl, propyl and isopropyl), hydroxyl group, amino group, mono- or di-lower alkylamino group (eg methylamino, ethylamino,
Mono- or di-C such as dimethylamino, diethylamino
_1-3 alkylamino group, etc., halogen (eg fluorine,
Chlorine, bromine, iodine, etc.), trityl and the like may be substituted at 1 or 3 positions which may be the same or different and may be substituted.

As Q ⁰ , for example,

[Chemical formula 26] (R ⁸ and n are as defined above) are preferred, and R ⁸ is

[Chemical 27] (R ⁹ and m are as defined above) are preferred, and R ⁹ is preferably halogen. Examples of the halogen represented by R ⁸ and R ⁹ include fluorine, chlorine, bromine and iodine. Of these, chlorine and fluorine are preferable. Examples of the lower alkyl group represented by R ⁸ and R ⁹ include linear or branched alkyl groups having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. Used. Of these, for example, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, isobutyl, tert-butyl and the like are more preferable. As the cycloalkyl group represented by R ⁸ and R ⁹ , for example, a cycloalkyl group having 3 to 6 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used, and among them, cyclohexyl and the like are preferable. The lower alkoxy group represented by R ⁸ and R ⁹ is, for example, methoxy,
A linear or branched alkoxy group having 1 to 6 carbon atoms such as ethoxy and propoxy is used, and among them, an alkoxy group having 1 to 4 carbon atoms such as methoxy and ethoxy is preferable. Examples of the halo-lower alkyl group represented by R ⁸ and R ⁹ include linear or branched alkyl having 1 to 6 carbon atoms such as chloromethyl, fluoromethyl, trifluoromethyl and 2,2-difluoromethyl. A group in which 1 to 5 halogen atoms are substituted as described above is used as the group. Examples of the halo-lower alkoxy group represented by R ⁸ and R ⁹ include linear or branched alkoxy having 1 to 6 carbon atoms such as chloromethoxy, fluoromethoxy, trifluoromethoxy and 2,2-difluoromethoxy. A group in which 1 to 5 halogen atoms are substituted as described above is used as the group.

As the substituent at the 4-position of 4,5-disubstituted-3 (2H) -pyridazinone, a group having 1 to 150 atoms is used, preferably a group having 1 to 50 atoms, and more preferably an atom. The number 1 to 25 groups can be brought. Also 4,
The 5-disubstituted-3 (2H) -pyridazinone may have a substituent at the 2-position, and as the substituent at the 2-position, for example, an optionally substituted hydrocarbon residue or the like is used. As the optionally substituted hydrocarbon residue which is the substituent at the 2-position, for example, an optionally substituted lower alkyl group, a cycloalkyl group, an optionally substituted phenyl group or an aralkyl group is used. . Examples of the lower alkyl group as the substituent at the 2-position include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2
-Methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dibutylbutyl, 3,3-dimethylbutyl, 1,3-dibutylbutyl, 2,3-dibutylbutyl, 1-ethylbutyl, 2- Ethyl butyl, 1,
A linear or branched alkyl group having 1 to 8 carbon atoms such as 1,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, etc. is used. Of these, for example, an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl, isopropyl, isobutyl, tert-butyl and the like are more preferable. The lower alkyl group as the substituent at the 2-position is, for example, a hydroxyl group, a C _1-6 alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, etc.), C _1-3 alkoxy-C _{1- 6} alkoxy group (eg methoxymethoxy, methoxyethoxy etc.), C _1-6 alkanoyloxy group (eg acetoxy, propionyloxy, butyryloxy, pivanoyloxy etc.), di (C _1-6 alkyl)
Amino groups (eg, dimethylamino, diethylamino, etc.), di (halo-C _1-6 alkyl) amino groups (eg,
Dichloroethylamino etc.), cyclic amino group (eg 1
-Pyrrolidinyl, 1-piperidyl, etc.) may be substituted at 1 to 5 positions, preferably 1 to 3 positions. As the cycloalkyl group which is the substituent at the 2-position, for example, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used, and among them, cyclopentyl, cyclohexyl and the like are preferable.

As the phenyl group which is the substituent at the 2-position, for example, a hydroxyl group, an amino group, a carboxyl group, a nitro group and a lower alkyl group (for example, the same ones as the lower alkyl group which is the substituent at the 2-position are used. Preferably, an alkyl group having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc. is used, and a lower alkoxy group (eg, substitution at the 4-position below) The same as the lower alkoxy group as the group, etc. are used, preferably, for example, an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, etc. is used, and a halo lower alkyl group (eg, fluoromethyl, trifluoro). Methyl 2,
Halo-C _1-6 alkyl group such as 2-difluoromethyl), mono- or di-lower alkylamino group (for example, mono- or di-C _1- such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino) ₆ alkylamino group, etc.), halogen (eg fluorine, chlorine,
1 to 5, preferably 1 to 3, may be substituted at the same or different positions at which substitution with bromine, iodine, etc.) is possible. As such a substituent, for example, a halo lower alkyl group, halogen and the like are preferable, and among them, chlorine, trifluoromethyl and the like are more preferable. The aralkyl group as the substituent at the 2-position is, for example, benzyl, 1-
C _7-16 aralkyl groups such as phenylethyl, 2-phenylethyl and 1-phenylpropyl are preferable, and benzyl is more preferable. The substituent at the 2-position is preferably, for example, a hydrocarbon group having 3 or more carbon atoms and branched at the α-position, and among them, for example, tert-butyl and the like having 3 carbon atoms.
It is preferably an alkyl group or the like branched at the α-position of 6 to 6. 4,5-disubstituted-3 (2H) -pyridazinone 4
A group having 1 to 150 atoms as a substituent at the position
Examples thereof include halogen, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, and an aliphatic hydrocarbon group which may have a substituent. As the halogen that is the substituent at the 4-position of 3 (2H) -pyridazinone, for example, fluorine, chlorine, bromine, iodine and the like can be used. Among them, chlorine, bromine, etc. are preferable,
Chlorine and the like are more preferable.

Examples of the lower alkoxy group which is a substituent at the 4-position of 3 (2H) -pyridazinone include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyl. Oxy, neopentyloxy, tert-
Pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy, isohexyloxy, 1-methylpentyloxy, 2-methylpentyloxy, 3-
Methylpentyloxy, 1,1-dimethylbutyloxy, 2,2-dibutylbutoxy, 3,3-dimethylbutoxy, 1,3-dibutylbutoxy, 2,3-dibutylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy,
1,1,2-trimethylpropoxy, 1-ethyl-1-
A linear or branched alkoxy group having 1 to 8 carbon atoms such as methylpropoxy and 1-ethyl-2-methylpropoxy is used, and among them, an alkoxy group having 1 to 4 carbon atoms such as methoxy and ethoxy. Is preferred. Three
Examples of the lower alkylthio group as the substituent at the 4-position of (2H) -pyridazinone include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio. Ruthio, tert-pentylthio, 1-methylbutylthio, 2-methylbutylthio, 1,2-dimethylpropylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 1,1-dimethylbutylthio, 2,2-
Dibutylbutylthio, 3,3-dimethylbutylthio,
1,3-dibutylbutylthio, 2,3-dibutylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio,
1,1,2-trimethylpropylthio, 1-ethyl-1
-C1-C8 linear or branched alkylthio groups such as -methylpropylthio and 1-ethyl-2-methylpropylthio are used, and among them, for example, methylthio, ethylthio and other C1-C4 alkylthio groups are used. An alkylthio group and the like are preferable.

As the aliphatic hydrocarbon group which is the substituent at the 4-position of 3 (2H) -pyridazinone, for example, a lower alkyl group, a lower alkenyl group, a lower alkynyl group and the like are used, among which a lower alkyl group and the like. The case is preferred.
As such a lower alkyl group, for example, the same lower alkyl group as the above R ¹ is used, and in particular, it may be an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and isopropyl. Preferred is, for example, methyl and the like. Examples of the lower alkenyl group include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl and 3
-Butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl, 1-methyl-2-propenyl, 2-
Methyl-2-propenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 1-methyl-
1-butenyl, 2-methyl-1-butenyl, 3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-hexenyl, 2- Hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 4-methyl-3-
A straight-chain or branched alkenyl group having 2 to 8 carbon atoms such as pentenyl and 2-ethyl-1-butenyl is used, and among them, an alkenyl group having 2 to 4 carbon atoms such as vinyl and 2-propenyl is used. Etc. are preferred. Examples of the lower alkynyl group include ethynyl, 1-propynyl, 2-
Propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2
-Pentynyl, 3-pentynyl, 4-pentynyl, 1-
Methyl-3-butynyl, 2-methyl-3-butynyl, 1
-Hexynyl, 2-hexynyl, 3-hexynyl, 4-
A straight-chain or branched alkynyl group having 2 to 8 carbon atoms such as hexynyl and 5-hexenyl is used, and among them, an alkynyl group having 2 to 4 carbon atoms such as 2-propynyl is preferable. The lower alkoxy group, the lower alkylthio group and the aliphatic hydrocarbon group, which are substituents at the 4-position, are, for example, hydroxyl group, halogen (eg fluorine, chlorine, bromine, iodine etc.), amino group, mono- or di-lower alkylamino group ( 1 to 3, preferably 1 may be substituted at a substitutable position with, for example, a mono- or di-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino and the like. As such a substituent, for example, a hydroxyl group, an amino group and the like are more preferable. As the substituent at the 4-position, for example, halogen such as chlorine, alkoxy group having 1 to 4 carbon atoms such as methoxy, alkyl group having 1 to 4 carbon atoms such as methyl, etc. are preferable, and above all, chlorine, methyl and the like are more preferable. .

A preferred example of 4,5-disubstituted-3 (2H) -pyridazinone is the formula

[Chemical 28] [In the formula, R ¹¹ represents a hydrogen atom or an optionally substituted hydrocarbon residue, R ¹² represents a group having 1 to 150 atoms,
X, Y ⁰ and Q ⁰ have the same meanings as described above. ] The compound etc. which are represented by these are mentioned. The optionally substituted hydrocarbon residue represented by R ¹¹ is represented by the substituent at the 2-position of 4,5-disubstituted-3 (2H) -pyridazinone shown above,
It has the same meaning as an optionally substituted hydrocarbon residue. R
^{The group represented by 12} and having 1 to 150 atoms means 4 of the 4,5-disubstituted-3 (2H) -pyridazinone shown above.
It has the same meaning as the group having 1 to 150 atoms represented by the substituent at the position. The compound [I] is 4,5-disubstituted-3 (2
H) -pyridazinone is a more preferred example. In [I], R ¹ represents a lower alkyl group, a cycloalkyl group or an optionally substituted phenyl group. Examples of the lower alkyl group represented by R ¹ include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, 1-methylbutyl, 2-
Methylbutyl, 1,2-dimethylpropyl, 1-ethylpropyl, hexyl, isohexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 1,1
-Dimethylbutyl, 2,2-dibutylbutyl, 3,3-
Dimethylbutyl, 1,3-dibutylbutyl, 2,3-dibutylbutyl, 1-ethylbutyl, 2-ethylbutyl,
A linear or branched alkyl group having 1 to 8 carbon atoms such as 1,1,2-trimethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl and the like are used. Among them, for example, methyl, ethyl, isopropyl, isobutyl, tert-butyl and the like having 1 to 4 carbon atoms.
And the like are more preferable.

As the cycloalkyl group represented by R ¹ , for example, a cycloalkyl group having 3 to 8 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are used, and among them, cyclopentyl, cyclohexyl and the like are preferable. The phenyl group represented by R ¹ is, for example, a hydroxyl group, an amino group, a carboxyl group, a nitro group, a lower alkyl group (for example, the same as the lower alkyl group represented by R ¹ is used, and preferably methyl, Alkyl groups having 1 to 6 carbon atoms such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, etc. are used), lower alkoxy groups (for example, lower alkoxy groups represented by R ² below) And the like, preferably an alkoxy group having 1 to 4 carbon atoms such as methoxy, ethoxy, propoxy, etc.), a halo lower alkyl group (eg fluoromethyl, trifluoromethyl,
Halo-C _1-6 alkyl group such as 2,2-difluoromethyl), mono- or di-lower alkylamino group (for example, mono- or di-C such as methylamino, ethylamino, propylamino, dimethylamino, diethylamino) _1-6 alkylamino group, etc.), halogen (eg fluorine, chlorine,
1 to 5, preferably 1 to 3, may be substituted at the same or different positions at which substitution with bromine, iodine, etc.) is possible. As such a substituent, for example, a halo lower alkyl group, halogen and the like are preferable, and among them, chlorine, trifluoromethyl and the like are more preferable. R ¹
The preferred examples include a hydrocarbon group having 3 or more carbon atoms and branching at the α-position, and among them, an alkyl group having 3 to 6 carbon atoms such as tert-butyl and the like. preferable.

R ² is a hydrogen atom, halogen, a lower alkoxy group which may have a substituent, a lower alkylthio group which may have a substituent, or an aliphatic hydrocarbon which may have a substituent. Indicates a group. Examples of the halogen represented by R ² include fluorine, chlorine, bromine, iodine and the like. Of these, for example, chlorine, bromine and the like are preferable, and chlorine and the like are more preferable. Examples of the lower alkoxy group represented by R ² include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, te.
rt-butoxy, pentyloxy, isopentyloxy,
Neopentyloxy, tert-pentyloxy, 1-methylbutoxy, 2-methylbutoxy, 1,2-dimethylpropoxy, 1-ethylpropoxy, hexyloxy,
Isohexyloxy, 1-methylpentyloxy, 2-
Methylpentyloxy, 3-methylpentyloxy,
1,1-dimethylbutyloxy, 2,2-dibutylbutoxy, 3,3-dimethylbutoxy, 1,3-dibutylbutoxy, 2,3-dibutylbutoxy, 1-ethylbutoxy, 2-ethylbutoxy, 1,1, A linear or branched alkoxy group having 1 to 8 carbon atoms such as 2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxy and the like are used, and among them, for example, methoxy, An alkoxy group having 1 to 4 carbon atoms such as ethoxy is preferred.

Examples of the lower alkylthio group represented by R ² include methylthio, ethylthio, propylthio, isopropylthio, butylthio, isobutylthio, sec-butylthio, tert-butylthio, pentylthio, isopentylthio, neopentylthio, tert-pentylthio. 1
-Methylbutylthio, 2-methylbutylthio, 1,2-
Dimethylpropylthio, 1-ethylpropylthio, hexylthio, isohexylthio, 1-methylpentylthio, 2-methylpentylthio, 3-methylpentylthio, 1,1-dimethylbutylthio, 2,2-dibutylbutylthio, 3,3-dimethylbutylthio, 1,3-dibutylbutylthio, 2,3-dibutylbutylthio, 1-ethylbutylthio, 2-ethylbutylthio, 1,1,2-
A linear or branched alkylthio group having 1 to 8 carbon atoms such as trimethylpropylthio, 1-ethyl-1-methylpropylthio, 1-ethyl-2-methylpropylthio and the like are used, and among them, for example, methylthio, An alkylthio group having 1 to 4 carbon atoms such as ethylthio is preferred.
As the aliphatic hydrocarbon group represented by R ² , for example, a lower alkyl group, a lower alkenyl group, a lower alkynyl group and the like are used, and among them, a lower alkyl group and the like are preferable. As such a lower alkyl group, for example, the same lower alkyl group as the above R ¹ is used, and in particular, it may be an alkyl group having 1 to 4 carbon atoms such as methyl, ethyl and isopropyl. Preferred is, for example, methyl and the like. Examples of the lower alkenyl group include vinyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-methyl-1-propenyl, 2-
Methyl-1-propenyl, 1-methyl-2-propenyl, 2-methyl-2-propenyl, 1-pentenyl, 2
-Pentenyl, 3-pentenyl, 4-pentenyl, 1-
Methyl-1-butenyl, 2-methyl-1-butenyl, 3
-Methyl-1-butenyl, 1-methyl-2-butenyl,
2-methyl-2-butenyl, 3-methyl-2-butenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 1-methyl-1
-Pentenyl, 2-methyl-1-pentenyl, 4-methyl-3-pentenyl, 2-ethyl-1-butenyl and the like, which is a straight-chain or branched alkenyl group having 2 to 8 carbon atoms, etc. are used. However, for example, an alkenyl group having 2 to 4 carbon atoms such as vinyl or 2-propenyl is preferable. Examples of the lower alkynyl group include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,
3-butynyl, 1-methyl-2-propynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-hexynyl, 2- A straight-chain or branched alkynyl group having 2 to 8 carbon atoms such as hexynyl, 3-hexynyl, 4-hexynyl, and 5-hexenyl is used, and among them, for example, 2-propynyl having 2 to 4 carbon atoms is used. An alkynyl group and the like are preferable. The lower alkoxy group, lower alkylthio group and aliphatic hydrocarbon group represented by R ² are, for example, hydroxyl group, halogen (eg fluorine,
Chlorine, bromine, iodine, etc.), amino group, mono- or di-lower alkylamino group (for example, mono- or di-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, etc.) It may be substituted by 1 to 3, preferably 1 position, and as such a substituent, for example, a hydroxyl group, an amino group and the like are more preferable. As R ² , for example, halogen such as chlorine, an alkoxy group having 1 to 4 carbon atoms such as methoxy, an alkyl group having 1 to 4 carbon atoms such as methyl, and the like are preferable, and among them, chlorine, methyl and the like are more preferable.

X represents O or S. O is preferable as X. Y represents an alkylene group which may have a substituent or an alkenylene group which may have a substituent.
Examples of the alkylene group represented by Y include methylene and
1 to 6 carbon atoms such as ethylene, propylene and butylene
The alkylene group and the like are used, and among them, methylene, ethylene and the like are preferable. As the alkenylene group represented by Y, for example, an alkenylene group having 1 to 6 carbon atoms such as vinylene, propenylene, butenylene and the like are used, and among them, propenylene and the like are preferable. The alkylene group or alkenylene group represented by Y is, for example, a hydroxyl group, a halogen (for example, fluorine, chlorine, bromine,
Iodine, etc.), cyano group, nitro group, di-lower alkylamino group (eg, di-C _1-3 alkylamino group such as dimethylamino, diethylamino, etc.), lower alkoxy group (eg, methoxy, ethoxy, propoxy, isopropoxy,
C _1-4 alkoxy group such as butoxy and tert-butoxy), lower alkoxycarbonyl group (eg (C _1-4 alkoxy) carbonyl group such as methoxycarbonyl, ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl and tert-butoxycarbonyl) Etc.), a lower alkyl group which may have a substituent (for example, the same lower alkyl group as the above R ¹ is used, and 1 or 2 is present at a position substitutable by a hydroxyl group or the like).
1 to 5, preferably 1 to 2, may be substituted at the substitutable position by (eg, optionally substituted) or the like, and such a substituent is, for example, preferably a hydroxyl group. As Y, for example,

[Chemical 29] (R ³ , R ⁴ , R ⁵ and R ⁶ are as defined above) and the like are often used.

R ³ , R ⁴ , R ⁵ and R ⁶ are the same or different and each represents a hydrogen atom, a hydroxyl group or a lower alkyl group which may have a substituent. The lower alkyl group represented by R ³ , R ⁴ , R ⁵ and R ⁶ is, for example, the same as the lower alkyl group represented by R ¹ and the like, and is preferably a C ¹ to C ¹ group such as methyl or ethyl. 4 alkyl groups and the like are used. Such a lower alkyl group has a 1-position at a position substitutable with, for example, a hydroxyl group.
Alternatively, two may be substituted. As Y, for example,

[Chemical 30] And the like, for example,

[Chemical 31] Is more preferable, for example,

[Chemical 32] And the like are more preferable.

Q represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. As the aryl group represented by Q, for example, a C _6-10 aryl group such as phenyl and 1- or 2-naphthyl is used, and among them, phenyl is preferable. Examples of the aromatic heterocyclic group represented by Q include thienyl, furyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3 , 4-oxadiazolyl, flazanil, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3
-Triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, benzofuranyl, isobenzofuranyl, benzo [b] thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl 1,2-benzisoxazolyl, benzothiazolyl, 1,2-isobenzothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolyl, quinoxalyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathii. Nyl, thianthrenyl, phenatridinyl, phenatorolinyl, indolizinyl, pyrrolo [1,2-b] pyridazinyl, pyrrolo [1,2-a] pyrazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, Imidazo [1,5-a] pyridyl, imidazo [1,2-ba] pyridazyl, imidazo [1,2-a] pyrimidinyl, 1,
2,4-triazolo [4,3-a] pyridyl, 1,2,
5- or 6-membered aromatic heterocyclic group containing 1 to 4 heteroatoms selected from oxygen atom, sulfur atom, nitrogen atom and the like in addition to carbon atom such as 4-triazolo [4,3-a] pyridazinyl Further, a fused heterocyclic group in which these 5-membered or 6-membered aromatic heterocyclic groups are condensed with each other or with a phenyl group is used. Among them, a 5- or 6-membered nitrogen-containing heterocyclic group such as pyridyl, benzimidazolyl, isoxazolyl, quinolyl, or a condensed heterocyclic group thereof is preferable, and quinolyl or the like is more preferable.

The aryl group and aromatic heterocyclic group represented by Q are, for example, hydroxyl group, amino group,
Cyano group, carboxyl group, lower alkoxycarbonyl group (for example, methoxycarbonyl, ethoxycarbonyl,
C _1-6 alkoxycarbonyl groups such as tert-butoxycarbonyl, etc.), nitro groups, lower alkyl groups (eg methyl,
C _1-6 alkyl groups such as ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl and hexyl), lower alkenyl groups (eg C _2-6 alkenyl groups such as vinyl and 2-propenyl), lower Alkynyl group (eg C _2-6 alkynyl group such as ethynyl, 1-propynyl, 2-propynyl, 2-butynyl etc.), lower alkoxy group (eg C _1-6 alkoxy group such as methoxy, ethoxy, propoxy etc.), lower An alkylthio group (for example, a C _1-6 alkylthio group such as methylthio or ethylthio), a halo-lower alkyl group (for example, a halo-C _1-6 alkyl group such as fluoromethyl, trifluoromethyl, 2,2-difluoromethyl or the like), mono - or di -C _1-6 alkylamino group (e.g. methylamino, ethylamino, propylamino, dimethylamino, di- Mono- such Chiruamino - or di -C _1-6 alkylamino group, etc.), halogen (e.g. fluorine, chlorine, bromine, iodine), trityl group, to 1 styryl phenyl group (e.g. cyano group is two substituents 1 to 5, preferably 1 to 3 at the substitutable position, preferably by a cyano group, a C _1-4 alkyl group such as tert-butyl, a phenyl group, etc. It may be replaced individually.

When Q is a phenyl group, it may be substituted with a nitrogen-containing aromatic heterocyclic group which may have a substituent in addition to the above-mentioned substituents. Examples of such a nitrogen-containing aromatic heterocyclic group include pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
Imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, flazanyl, 1,2,3-thiadiazolyl,
5- or 6-membered ring such as 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl An aromatic monocyclic heterocyclic group such as indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H
-Benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, carbazolyl, α-carbolinyl, β-carbolinyl, γ-carbolinyl, acridinyl, pyrrolo [1,2-b] pyridazinyl, Pyrrolo [1,2-a] pyrazinyl, pyrazolo [1,5-a] pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2]
-B] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,4-triazolo [4,3-a] pyridyl,
Aromatic condensed heterocyclic groups such as 1,2,4-triazolo [4,3-b] pyridazinyl are used, and preferably, for example, pyrrolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, Quinolyl, benzimidazolyl and the like are used, and among them, pyrrolyl, imidazolyl, pyridyl, quinolyl and the like are more preferable. Such nitrogen-containing aromatic heterocyclic group is, for example, a lower alkyl group (eg, methyl,
C _1-3 alkyl groups such as ethyl, propyl and isopropyl), hydroxyl group, amino group, mono- or di-lower alkylamino group (eg methylamino, ethylamino,
Mono- or di-C such as dimethylamino, diethylamino
_1-3 alkylamino group, etc., halogen (eg fluorine,
Chlorine, bromine, iodine, etc.), trityl and the like may be substituted at 1 or 3 positions which may be the same or different and may be substituted. Examples of Q include phenyl,
(4-tert-butyl) phenyl, biphenyl, (2-pyridyl) phenyl, naphthyl, quinolyl, (4-trifluoromethyl) phenyl, (4-tert-butylcarbonyl) phenyl and the like are preferable.

Q ¹ represents a nitrogen-containing aromatic heterocyclic group which may have a substituent. Examples of the nitrogen-containing aromatic heterocyclic group represented by Q ¹ include pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,
4-oxadiazolyl, 1,3,4-oxadiazolyl,
Flazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-
5- or 6-membered aromatic monocyclic heterocyclic groups such as triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, for example, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzo Oxazolyl, 1,2-benzisoxazolyl, benzothiazolyl, 1,2-benzisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthyridinyl, purinyl, pteridinyl, Carbazolyl, α-
Carborinyl, β-carbolinyl, γ-carbolinyl,
Acridinyl, pyrrolo [1,2-b] pyridazinyl, pyrrolo [1,2-a] pyrazinyl, pyrazolo [1,5-a]
Pyridyl, imidazo [1,2-a] pyridyl, imidazo [1,5-a] pyridyl, imidazo [1,2-b] pyridazinyl, imidazo [1,2-a] pyrimidinyl, 1,2,
A nitrogen-containing aromatic condensed heterocyclic group such as 4-triazolo [4,3-a] pyridyl, 1,2,4-triazolo [4,3-b] pyridazinyl and the like are used, and preferably, for example, pyrrolyl, imidazolyl, Oxazolyl, isoxazolyl,
Thiazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, quinolyl, benzimidazolyl and the like are used, and among them, pyrrolyl, imidazolyl, pyridyl, quinolyl and the like are more preferable. Such a nitrogen-containing aromatic heterocyclic group is, for example, a lower alkyl group (for example, a C _1-3 alkyl group such as methyl, ethyl, propyl, isopropyl, etc.), a hydroxyl group, an amino group, a mono- or di-lower alkylamino group ( Mono- or di-C _1-3 alkylamino groups such as methylamino, ethylamino, dimethylamino, diethylamino etc.), halogen (eg fluorine, chlorine, bromine, iodine etc.), trityl etc. and the same or different position at the substitutable position. 1 to 3 may be substituted.

Y ¹ is

[Chemical 33] R ⁷ represents a lower alkyl group substituted with a hydroxyl group. Examples of the lower alkyl group represented by R ⁷ include methyl, ethyl, propyl, isopropyl, butyl,
1 to 6 carbon atoms such as isobutyl, pentyl and hexyl
The straight chain or branched alkyl and the like are used, and of these, methyl and ethyl are preferable. For R ⁷ ,
For example, a hydroxy-C _1-4 alkyl group such as hydroxymethyl is preferable. As a preferred example of the combination of R ² , Y and Q, for example, 1 to 8 and the like shown in [Table 1] are used, and in such a combination, R ¹ is a lower alkyl group, X is O or S and the like. Is used.

[Table 1]

The compound [I], [II] or [III] is
For example, a carboxyl group, an acidic group such as a tetrazolyl group, or, for example, an amino group, a mono- or di-alkylamino group, when containing a basic group such as a pyridyl group in the molecule, the compound [I], [II] or [III] may form a salt in these acidic groups or basic groups, and examples of such a salt include a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, and an organic acid. And a pharmaceutically acceptable salt such as a salt with a basic or acidic amino acid. As the salt with an inorganic base, for example, an alkali metal salt (eg sodium salt, potassium salt etc.), an alkaline earth metal salt (eg calcium salt, magnesium salt etc.), an aluminum salt, an ammonium salt etc. are used. As the salt with an organic base, for example, a salt with trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, N, N′-dibenzylethylenediamine or the like is used. As the salt with an inorganic acid, for example, a salt with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid or the like is used. Examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid. And the like are used. As the salt with a basic amino acid, for example, a salt with arginine, lysine, ornithine, etc. is used. As the salt with a basic or acidic amino acid, for example, a salt with aspartic acid, glutamic acid or the like is used. As such salts, for example, sodium salts, potassium salts, ammonium salts, hydrochlorides, acetates, oxalates, citrates and the like are preferable, and sodium salts, potassium salts, hydrochlorides and the like are more preferable. When the target product is in a free state, it may be converted into a salt according to a conventional method, and when the target product is a salt, it may be converted into a free form or another salt according to a conventional method. It can also be used.

Preferred examples of the compound [I] include 2-
t-butyl-4-chloro-5- [4- (2-pyridyl)
Benzylthio] -3 (2H) -pyridazinone, 2-t-
Butyl-4-chloro-5- [4- (2-pyridyl) benzyloxy] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- (2-hydroxy-1-phenyl) ethylthio- 3 (2H) -pyridazinone, 2-t-
Butyl-4-chloro-5- (4-t-butyl) benzylthio-3 (2H) -pyridazinone, 2-t-butyl-4
-Chloro-5- (4-phenyl) benzylthio-3 (2
H) -Pyridazinone, 2-t-butyl-4-chloro-5
-(2-naphthyl) methylthio-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- (2-quinolyl) methylthio-3 (2H) -pyridazinone, 2-t-
Butyl-4-chloro-5- {4- (2-cyanophenyl)} benzylthio-3 (2H) -pyridazinone, 2-
t-Butyl-4-chloro-5- (4-trifluoromethyl) benzylthio-3 (2H) -pyridazinone, 2-t
-Butyl-4-chloro-5- (4-phenyl) benzyloxy-3 (2H) -pyridazinone,

2-t-butyl-5- (4-t-butyl)
Benzylthio-4-methyl-3 (2H) -pyridazinone, 2-t-butyl-5- (4-t-butyl) benzyloxy-4-methyl-3 (2H) -pyridazinone, 2-
t-butyl-4-chloro-5-benzylthio-3 (2
H) -Pyridazinone, 2-t-butyl-4-chloro-5
-{(3-phenyl) -2-propenylthio} -3 (2
H) -Pyridazinone, 2-t-butyl-4-chloro-5
-(4-styryl) benzylthio-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- (4-cyano) benzylthio-3 (2H) -pyridazinone, 2-t
-Butyl-4-chloro-5- (4-t-butyl) benzyloxy-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- (2-naphthyl) methyloxy-3
(2H) -Pyridazinone, 2-t-butyl-5- (4-
t-butyl) benzylthio-4-methoxy-3 (2H)
-Pyridazinone,

2-t-butyl-4-chloro-5- [4-
(1,2,4-Thiadiazol-5-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4
-Chloro-5- [4- (4-fluorobenzoyl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (4-fluorobenzoyl) benzyloxy] -3 (2H) -pyridazinone, 2
-T-butyl-4-chloro-5- [3- (4-chlorobenzoyl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [3- (4-chlorobenzoyl) ) Benzyloxy] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4-
(1,2,4-thiadiazol-5-yl) benzyloxy] -3 (2H) -pyridazinone, 2-t-butyl-
4-chloro-5- [4- (1,2,3-thiadiazol-4-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (1,
2,3-thiadiazol-4-yl) benzyloxy]
-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (1H-pyrazol-3-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl- 4-chloro-5- [4- (1H-pyrazol-3-
Il) benzyloxy] -3 (2H) -pyridazinone,
2-t-butyl-4-chloro-5- [4- (1,2-oxazol-5-yl) benzylthio] -3 (2H)-
Pyridazinone, 2-t-butyl-4-chloro-5- [4
-(1,2-Oxazol-5-yl) benzyloxy] -3 (2H) -pyridazinone, 2-t-butyl-4
-Chloro-5- [4- (1,3-oxazol-5-yl) benzylthio] -3 (2H) -pyridazinone, 2-
t-Butyl-4-chloro-5- [4- (1,3-oxazol-5-yl) benzyloxy] -3 (2H) -pyridazinone, 5- [4- [4- (2-amino) Pyridyl] benzylthio] -2-t-butyl-4-chloro-3
(2H) -Pyridazinone, 5- [4- [4- (2-amino) pyridyl] benzyloxy] -2-t-butyl-4
-Chloro-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (2-pyrimidyl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-
4-chloro-5- [4- (2-pyrimidyl) benzyloxy] -3 (2H) -pyridazinone, 5- [4- [4-
(2-Amino) thiazolyl] benzylthio] -2-t-
Butyl-4-chloro-3 (2H) -pyridazinone, 5-
[4- [4- (2-Amino) thiazolyl] benzyloxy] -2-t-butyl-4-chloro-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4-
(2-Pyridyl) benzylthio] -3 (2H) -pyridazinone hydrochloride, 2-t-butyl-4-chloro-5-
[4- (2-Pyridyl) benzyloxy] -3 (2H)
-Pyridazinone, hydrochloride, etc.

Preferred examples of the compound [II] include 2-
t-butyl-4-chloro-5- {4- (2-pyridyl)
Benzylthio} -3 (2H) -pyridazinone, 2-t-
Butyl-4-chloro-5- {4- (2-pyridyl) benzyloxy} -2-t-butyl-4-chloro-5- [4
-(1,2,4-thiadiazol-5-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-
4-chloro-5- [4- (1,2,4-thiadiazol-5-yl) benzyloxy] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (1 ，
2,3-Thiadiazol-4-yl) benzylthio]-
3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (1,2,3-thiadiazol-4-yl) benzyloxy] -3 (2H) -pyridazinone, 2
-T-Butyl-4-chloro-5- [4- (1H-pyrazol-3-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (1
H-pyrazol-3-yl) benzyloxy] -3 (2
H) -Pyridazinone, 2-t-butyl-4-chloro-5
-[4- (1,2-Oxazol-5-yl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-
4-chloro-5- [4- (1,2-oxazol-5-
Il) benzyloxy] -3 (2H) -pyridazinone,
2-t-butyl-4-chloro-5- [4- (1,3-oxazol-5-yl) benzylthio] -3 (2H)-
Pyridazinone, 2-t-butyl-4-chloro-5- [4
-(1,3-Oxazol-5-yl) benzyloxy] -3 (2H) -pyridazinone, 5- [4- [4-
(2-Amino) pyridyl] benzylthio] -2-t-butyl-4-chloro-3 (2H) -pyridazinone, 5-
[4- [4- (2-Amino) pyridyl] benzyloxy] -2-t-butyl-4-chloro-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4-
(2-Pyrimidyl) benzylthio] -3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4-
(2-Pyrimidyl) benzyloxy] -3 (2H) -pyridazinone, 5- [4- [4- (2-amino) thiazolyl] benzylthio] -2-t-butyl-4-chloro-3
(2H) -Pyridazinone, 5- [4- [4- (2-amino) thiazolyl] benzyloxy] -2-t-butyl-
4-chloro-3 (2H) -pyridazinone, 2-t-butyl-4-chloro-5- [4- (2-pyridyl) benzylthio] -3 (2H) -pyridazinone hydrochloride, 2-t-
Butyl-4-chloro-5- [4- (2-pyridyl) benzyloxy] -3 (2H) -pyridazinone / hydrochloride and the like.

Preferred examples of the compound [III] include 2
-T-butyl-4-chloro-5- (2-hydroxy-2
-Phenyl) ethoxy-3 (2H) -pyridazinone, 2
-T-butyl-4-chloro-5- (2-hydroxy-1
-Phenyl) ethoxy-3 (2H) -pyridazinone, 2
-T-butyl-4-chloro-5- (2-hydroxy-1
-Phenyl) ethylthio-3 (2H) -pyridazinone and the like. Compounds [I], [II], and [III] may be any of (+) or (−) isomers of optical isomers, if they have an asymmetric carbon in the structure. It may be a mixture of those isomers in any ratio. 5
Position the substituent ^{-X-Y 0 -Q 0 (X} , Y 0, Q 0 are as defined above shows a) 4,5-disubstituted with a -3 (2H) - pyridazinone or known of its salt The compound can be produced, for example, by the method described in JP-A-59-39874 or JP-A-60-4173, or a method analogous thereto. Furthermore, 5-position substituent ^{-X-Y 0 -Q 0 (X} , Y 0, Q 0 is as defined above) with a 4,5-disubstituted -3 (2H) -
Pyridazinone or a salt thereof has a substituent group -X-H at the 5-position.
(X represents the same meaning as described above) and the compound E-Y ⁰ -Q ⁰ (E
Is a leaving group and Y ⁰ and Q ⁰ have the same meanings as described above) or a salt thereof to produce a compound [I] by a method similar to or similar to the method for producing compound [I] described below. can do.

In a similar manner, the substituent at the 5-position is

[Chemical 34] (X, Y ⁰ and Q ¹ have the same meanings as described above)
A di-substituted-3 (2H) -pyridazinone or a salt thereof is a 4,5-di-substituted-3 (2H) -pyridazinone in which the substituent at the 5-position is -X-H (X is as defined above) or With that salt

[Chemical 35] (E, Y ⁰ and Q ¹ have the same meanings as defined above.), Or a salt thereof.

[Chemical 36] (X, Y ¹ and Q ⁰ are as defined above)
The di-substituted-3 (2H) -pyridazinone or a salt thereof also has 4,5-di-substituted-3 (2H) -pyridazinone in which the substituent at the 5-position is -X-H (X has the same meaning as above) or The salt and EY ¹ -Q ⁰ (E, Y ¹ and Q ⁰ have the same meanings as described above)
It can be produced by reacting with a compound or a salt thereof. The compound [I] containing the novel compounds [II] and [III] or a salt thereof can be produced, for example, by the method represented by the following reaction formula (1) or (2). Reaction formula (1)

[Chemical 37] Reaction formula (2)

[Chemical 38] R ¹ in the compounds [IV] to [VII] of the above reaction formula,
R ² , X, Y and Q have the same meanings as described above, E is a leaving group and Hal is halogen.

The leaving group represented by E includes (i) halogen atoms such as chlorine, bromine, iodine and fluorine;
(Ii) 1 to 3 carbon atoms, such as chlorine, bromine and fluorine, which may be substituted with 1 to 3 carbon atoms such as methanesulfonyloxy, ethanesulfonyloxy, butanesulfonyloxy and trifluoromethanesulfonyloxy. An alkylsulfonyloxy group of (ii
i) 1 to 3 may be substituted with a halogen atom such as chlorine, bromine or fluorine, or an alkyl group having 1 to 3 carbon atoms such as methyl or ethyl, for example, benzenesulfonyloxy, p-toluenesulfonyloxy. And arylsulfonyloxy groups having 6 to 10 carbon atoms such as p-bromobenzenesulfonyloxy and mesitylenesulfonyloxy. Examples of the halogen represented by Hal include fluorine, chlorine, bromine, iodine and the like. The reaction will be described in more detail. In the reaction (1) or (2), the compound [I
The target compound [I] can be obtained by reacting V] and [V] or [VI] and [VII] in the presence of a base. The relative amounts of the starting compounds [IV] to [VII] used in these reactions vary depending on the type of starting compound, reaction conditions, etc.
0.5 to 10 mol, preferably 0.75 to 1.5 mol of [V] is reacted with 1 mol, and 0.5 to 10 mol of [VII] is preferably reacted with 1 mol of [VI]. React 0.75 to 1.5 moles.

As the base, an inorganic base or an organic base is used. Examples of the inorganic base include alkyl metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkyl metal carbonates (eg sodium carbonate, potassium carbonate,
Cesium carbonate, etc.), alkyl hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydride (eg, sodium hydride etc.), alkali metal (eg, sodium metal etc.) and the like are used. Examples of the organic base include alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), trialkylamines (eg, triethylamine, tributylamine, diethylisopropylamine, etc.), aromatic amines (eg, pyridine, lutidine, DBU ( 1-8-diazabicyclo [5,4,0] -7-undecene) etc.) and the like are used. The amount of base is usually compound [IV] or [VI
It is used in an equimolar amount to about 10 times the molar amount with respect to I], and preferably in an equimolar amount or a small excess amount (for example, 1.
05 to 1.5 times the molar amount). When the reaction system is a two-layer system such as solid-liquid or liquid-liquid,
Reaction (1), (2) by adding a phase transfer catalyst such as a quaternary ammonium salt (eg, triethylbenzylammonium chloride, trioctylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium bromide) to the reaction system. Can be promoted. In addition, such a reaction (1),
(2) can be advantageously carried out in a solvent, and examples of the solvent include lower alcohols (eg, methanol, ethanol, propanol, isopropanol, etc.), hydrocarbons (eg, pentane, hexane, cyclohexane, benzene, etc.). ), Ethers (eg diethyl ether, tetrahydrofuran, dioxane etc.), amides (eg N, N-dimethylformamide, hexamethylphosphoric triamide etc.), halogenated hydrocarbons (eg dichloromethane, chloroform etc.), sulfoxides (For example, dimethylformamide and the like), ureas (for example, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidine and the like) and the like are used. These solvents may be used alone or, if necessary, may be used by mixing two or more kinds of them in an appropriate ratio or as a mixed solvent with water. The amount of the solvent used in the reaction (1) is the compound [I
0 for V] 1 _g. 1 to 100 ml, preferably 5
In the reaction (2), 0.1 to 100 ml, preferably 5 to 20 ml of solvent is used per 1 g of compound [VI]. The reaction temperature is usually −
20 ° C to 120 ° C is used, preferably -5 ° C
To 100 ° C. While the reaction time varies depending on the amounts, types, reaction temperatures and the like of the raw material compounds, the base and the solvent, it is generally 10 minutes to 72 hours, preferably 10 minutes to 24 hours.

Of the starting compounds in the above reactions (1) and (2), as the compounds [IV] and [VI], commercially available compounds are used, or JP-A Nos. 61-17570, 61-243078 and Raymond N are used. Castle [Raymondo N Castle], "Pyridazins [Pyridaz
ines], John Willey & Sons Inc. (1973
Year) issue, manufactured by the method described in Chapter 2 and Chapter 3 or the like. Compounds [V] and [VI
I] uses commercially available compounds or Stanley
Earl Sandler and Wolf Caro [Stanley
R Sandler and Wolf Karo], Organic Functional Group Preparations I 2nd Edition [Organic Functonal Group Preparations I 2nd. E
d.], Academic Press (Academic Press) (1983
Year) issue, manufactured by the method described in Chapter 4, Chapter 6, Chapter 18 and Chapter 21 or the like. The compound [I] in which R ² is a lower alkoxy group or a lower alkylthio group can be prepared by using the compound [VIII] in which R ² is a halogen in the compound [I] as a starting material. In addition to the method according to the method described in -159372, it can be produced, for example, by the method represented by the following reaction formula (3).

Reaction formula (3)

[Chemical Formula 39] In the compounds [VIII] to [X] of the above reaction formula, R ¹ ,
X, Y, Q and Hal have the same meanings as described above, and X ′ is O
Alternatively, S and R represent an optionally substituted lower alkyl group. Examples of the lower alkyl group represented by R include linear or branched alkyl having 1 to 6 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl and hexyl. Such a lower alkyl group is, for example, a hydroxyl group, a halogen (eg, fluorine, chlorine, bromine, iodine etc.), an amino group,
1 to 3 substituents, preferably 1 substituent at a substitutable position by a mono- or di-lower alkylamino group (for example, a mono- or di-C _1-6 alkylamino group such as methylamino, ethylamino, propylamino, dimethylamino, etc.) As such a substituent, a hydroxyl group, an amino group and the like are more preferable. The reaction (3) will be described in detail. Compounds [VIII] and [IX]
The target compound [X] can be obtained by reacting the compound in the presence of a base. In addition, the compound [IX] may be converted into an alcoholate or thiolate form by treating with a base in advance. The relative amounts of the raw material compounds [VIII] and [IX] used in these reactions vary depending on the type of the raw material compound, the reaction conditions and the like, but the amount of [IX] is 0.5 to 0.5 per 1 mol of [VIII]. 1
The reaction amount is 0 mol, preferably 0.75 to 1.5 mol.

An inorganic base or an organic base is used as the base. Examples of the inorganic base include alkyl metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkyl metal carbonates (eg sodium carbonate, potassium carbonate, etc.).
Cesium carbonate, etc.), alkyl hydrogen carbonate (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydride (eg, sodium hydride etc.), alkali metal (eg, sodium metal etc.) and the like are used. Examples of the organic base include alkali metal alkoxides (eg, sodium methoxide, sodium ethoxide, etc.), trialkylamines (eg, triethylamine, tributylamine, diethylisopropylamine, etc.), aromatic amines (eg, pyridine, lutidine, DBU ( 1-8-diazabicyclo [5,4,0] -7-undecene) etc.) and the like are used. The amount of base is usually the compound [VIII],
It is used in an equimolar amount to about 10 times the molar amount, and preferably,
An equimolar amount or a small excess amount (for example, 1.05 to 1.
5 times the molar amount) is used. In addition, the reaction system is solid-liquid, liquid-
In the case of a two-layer system such as a liquid, the addition of a phase transfer catalyst such as a quaternary ammonium salt (eg, triethylbenzylammonium chloride, trioctylmethylammonium chloride, trimethyldecylammonium chloride, tetramethylammonium bromide, etc.) Can accelerate the reaction. Further, such a reaction can be advantageously carried out in a solvent, and examples of the solvent include lower alcohols (eg, methanol, ethanol, propanol, isopropanol, etc.), hydrocarbons (eg, pentane, hexane, etc.). Cyclohexane, benzene etc.), ethers (eg diethyl ether, tetrahydrofuran, dioxane etc.), amides (eg N, N-dimethylformamide, hexamethylphosphoric triamide etc.), halogenated hydrocarbons (eg dichloromethane, chloroform etc.) ), Sulfoxides (eg, dimethylformamide, etc.), ureas (eg, 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidine, etc.) and the like are used. These solvents can be used alone, or if necessary, two or more kinds can be mixed in an appropriate ratio or can be used as a mixed solvent with water. The amount of the solvent used is usually 0.1 to 100 ml, preferably 5 to 20 per 1 g of compound [VIII].
ml. The reaction temperature is usually from -20 ° C to 120 ° C, preferably from -5 ° C to 100 ° C. The reaction time will differ depending on the amounts and types of starting compounds, bases and solvents, reaction temperature, etc., but is usually 10 minutes to 7 minutes.
It is 2 hours, preferably 10 minutes to 24 hours.

Among the starting compounds in the reaction (3), the compound [VIII] is produced, for example, by the method represented by the above reaction formulas (1) or (2), and the compound [IX] is a commercially available compound. Or Stanley Earl
Sandler and Wolf Caro [Stanley R. Sandle
r and Wolf Karo], "Organic Functional Group Preparations I 2nd Edition [Or
ganic Functonal Group Preparations I, 2nd.e
d.] ", Academic Press (198
Issued for 3 years, manufactured by the method described in Chapter 4 and Chapter 18 or the like. In addition, the compound [XII] in which R ² is an optionally substituted aliphatic hydrocarbon group in the compound [I] is prepared by using, for example, the reaction formula (4 It can also be produced by the method represented by (). Reaction formula (4)

[Chemical 40] In the compounds [VIII], [XI] and [XII] of the above reaction formula, R ¹ , X, Y and Hal have the same meanings as described above,
R'represents an aliphatic hydrocarbon group which may have a substituent, and M represents, for example, magnesium halide, lithium, copper or the like. As the aliphatic hydrocarbon group which may have a substituent represented by R ′, the same aliphatic hydrocarbon group which may have a substituent represented by R ² and the like are used. The reaction formula (4) will be described in detail. The target compound [XII] can be obtained by reacting the compound [VIII] with the organometallic compound [XI] in a solvent. Examples of the solvent include hydrocarbons (for example, pentane, hexane, cyclohexane, benzene, etc.), ethers (for example, diethyl ether, tetrahydrofuran,
Dioxane), amides (eg N, N-dimethylformamide, hexamethylphosphoric triamide etc.), sulfoxides (eg dimethylformamide etc.), ureas (eg 1,3-dimethyl-3,4,5,6-). Tetrahydro-2 (1H) -pyrimidine and the like are used.
These solvents may be used alone, or if necessary, two or more kinds may be mixed and used in an appropriate ratio. The amount of the solvent to be used is generally 0.1-100 ml, preferably 5-20 ml, relative to 1 g of compound [VIII].

As the organometallic compound [XI], for example, a Grignard reagent, an organolithium reagent, an organocopper reagent, or the like is used.
VI ", Maruzen Co., Ltd., (1992) or the like, or a method analogous thereto, and is usually an equimolar amount to 10-fold molar amount, preferably an equimolar amount to 2 with respect to 1 mol of the compound [VIII]. A double molar amount is used. In addition, a metal salt (for example, zinc chloride, cerium chloride, tin chloride,
The reaction may be advantageously carried out by adding copper bromide, copper iodide, nickel chloride phosphorus complex, dilithium tetrachlorocuprate, etc.). The amount to be added is usually 0.1 to 10 times mol, preferably 0.1 to 2 times mol, relative to 1 mol of [XI]. The reaction temperature is usually from −78 ° C. to the boiling point of the solvent used in the reaction, etc., preferably −5 ° C.
To 30 ° C. While the reaction time varies depending on the amounts, types, reaction temperatures and the like of the raw material compounds, the base and the solvent, it is generally 10 minutes to 72 hours, preferably 10 minutes to 24 hours. In the compound [I], R ² is a hydrogen atom, the compound [VIII] is used as a starting material,
For example, Masahiro Takatani et al., Pharmaceutical Journal, Vol. 98, p. 1472, (197
It can also be produced by carrying out a reduction reaction by a method similar to the method described in (8 years). Further, the above compound [IV],
[V], [VI], [VII], [VIII], [IX], [X],
[XII] can also be used as a salt when these compounds include an acidic group or a basic group as a substituent.

When the target compound is produced by the method represented by the above reaction formulas (1) to (4), R ¹ , Y or Q in the compounds [IV] to [XII] is a hydroxyl group, an amino group or a mono group. When it contains a functional group such as —C _1-6 alkylamino group, carboxyl group or tetrazolyl group, these functional groups may be protected.・ Green and PGM
d PGM Muts], “Protective Groups in Organic Chemistry 2nd Edition [Protective G
roups in Organic Synthnthesis, 2nd.ed.] ”, John Wiley & Sons, Inc. (1991), etc., or a method similar thereto. Further, the raw materials and intermediates can be isolated and purified from the synthetic reaction mixture by a known method, but may be supplied as the raw material of the next step as the reaction mixture. The compound [I] or a salt thereof thus obtained can be obtained by a method known per se (eg, phase transfer,
It can be isolated and purified by concentration, solvent extraction, fractional distillation, crystallization, recrystallization, chromatography, etc.).

The anticancer agent of the present invention can be obtained by incorporating the compound [I] or a salt thereof to produce an anticancer agent. Although the content of the compound [I] or a salt thereof in the preparation of the present invention varies depending on the form of the preparation, it is generally 0.1 to 100% by weight, preferably 1 to 5% by weight based on the whole preparation.
It is 0% by weight, more preferably 5 to 20% by weight.
To the preparation of the present invention, additives generally used in preparations can be added, and commonly used preparation carriers such as excipients (eg calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, starches, crystalline cellulose). , Talc, granulated sugar, porous substances, etc.), binders (eg dextrin, gums, pregelatinized starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, pullulan etc.), disintegrants (eg carboxymethylcellulose calcium, croscarmellose) Sodium, crospovidone, low-substituted hydroxypropylcellulose, partially pregelatinized starch, etc., lubricants (eg magnesium stearate, calcium stearate, talc, starch, sodium benzoate etc.), colorants (eg tar dye, caramel) , Iron sesquioxide, titanium oxide, riboflavins, etc.), corrigents (eg sweeteners, flavors etc.), stabilizers (eg sodium sulfite etc.) and / or preservatives (eg parabens, sorbic acid etc.) etc. It can be added at the time of preparation according to the method. For example, as an oral pharmaceutical carrier, starch, mannitol, crystalline cellulose, sodium carboxymethyl cellulose, etc. are used, and as an injectable carrier, distilled water, physiological saline, glucose solution, infusion solution, etc. are used. The amount of these pharmaceutical carriers to be used varies depending on, for example, the active ingredient and the amount thereof to be used, but is usually 0.01 to 100% by weight, preferably 0.1% to 1% by weight of the compound [I] or a salt thereof.
It is 5 to 50 weight, more preferably 0.1 to 10 weight. Examples of the form of the preparation include tablets (including sugar-coated tablets, film-coated tablets, etc.), pills, capsules, granules, fine granules, powders, syrups, emulsions, suspensions, injections, etc. . Preferred formulations include, for example, injections and tablets.

The anticancer agent of the present invention is produced, for example, according to a known method for producing a pharmaceutical preparation (for example, the method described in the Japanese Pharmacopoeia, etc.). For example, tablet compound [I] or its salt as it is, or an excipient, a binder, a disintegrating agent or other appropriate additives are uniformly mixed and granulated by an appropriate method, and then lubricated. Add agents etc. and press-mold or
The compound [I] or a salt thereof, as it is, or an even mixture of an excipient, a binder, a disintegrant or other appropriate additives, is directly compression molded or preliminarily prepared. It is also possible to manufacture the granules as they are, or after adding an appropriate additive and mixing them evenly, followed by compression molding. Moreover, a coloring agent, a flavoring agent, etc. can be added if necessary. Furthermore, a coating can be applied with a suitable coating agent. Further, for example, injectable solutions are prepared by dissolving and suspending a certain amount of compound [I] or a salt thereof in the case of an aqueous solvent, such as water for injection, physiological saline, Ringer's solution, etc., and in the case of a non-aqueous solvent, usually vegetable oil, etc. Alternatively, it can be produced by emulsifying to a fixed amount, or by aliquoting a fixed amount of the compound [I] or a salt thereof and sealing it in a container for injection.

[0047]

The thus-obtained anti-cancer agent of the present invention has an excellent anti-cancer effect, particularly an excellent selective growth inhibitory effect on pancreatic cancer, prostate cancer lung cancer and breast cancer cells. Side effects and toxicity are extremely low, and no death was observed even when the compound [I] was intraperitoneally administered to mice at 20 mg / kg. Therefore, the anticancer agent of the present invention is useful for treating malignant tumors of mammals (eg, humans, mice, rats, hamsters, rabbits, dogs, cats, cows, pigs, horses, sheep, monkeys, etc.), particularly solid tumors such as pancreatic cancer or prostate cancer. It can be used safely for the treatment of refractory solid tumors such as (hormone-independent cancer or recurrent cancer) and metastatic lesions in which they metastasize to organs such as lungs and liver, or for the prevention of those metastases. . The administration route may be oral or parenteral. The dose of the anticancer agent of the present invention may be, for example, age,
Although it varies depending on the body weight, symptoms, administration route, number of administrations, etc., for example, for the treatment of prostate cancer, the compound [I] or a salt thereof is usually administered to an adult in an amount of 0.1 to 20 per day.
mg / kg, preferably 1 to 10 mg / kg,
It is advisable to administer orally in 1 to 3 divided doses daily.

[0048]

EXAMPLES The present invention will be further explained in detail by the following reference examples, examples and test examples, but these examples are merely implementations and do not limit the present invention, and deviate from the scope of the present invention. You may change it in the range which does not. Elution in the column chromatography of the reference example was carried out by TLC (Thin Layer
Chromatography, thin layer chromatography). In the TLC observation, the 60F ₂₅₄ Merck (Merck) manufactured as a TLC plate, the solvent used as an elution solvent in column chromatography as a developing solvent, employing a UV detector as a detection method. As the column silica gel, Kieselgel 60 (70 to 230 mesh) also manufactured by Merck & Co. was used. NM
R spectra were measured with a Gemini 200 type spectrometer using tetramethylsilane as an internal or external standard, and all δ values are shown in ppm. In the mixed solvent, the value shown in parentheses is the volume mixing ratio of each solvent. Further,% in the solution represents the number of g in 100 ml of the solution. In addition, “room temperature” in Reference Examples and Examples indicates 0 to 25 ° C., and each symbol has the following meaning. s: singlet d: doublet t: triplet q: quartet ABq: AB type quartet dd: double doublet m: multiplet bs : Broad singlet J: Coupling constant Hz: Herz DMSO: Dimethyl sulfoxide
e)

Reference Example 1 Preparation of 4- (2-pyridyl) benzyl bromide

[Chemical 41] P-Tolylpyridine (846 in carbon tetrachloride (80 ml)
mg), N-bromosuccinimide (979 mg) and benzoyl peroxide (40 mg) were heated under reflux for 8.5 hours, cooled to room temperature and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure, the residue was purified by silica gel column chromatography (carrier 40 g; developing solvent: hexane-ethyl acetate = 9: 1), and 4- (2-pyridyl) benzyl bromide (1.06 g). : Yield 85%) was obtained. NMR (CDCl ₃ ) δ: 4.55 (2H, s), 7.20-7.29 (1H, m), 7.50 (2
H, d, J = 8.2Hz), 7.65-7.79 (2H, m), 7.98 (2H, dm, J = 8.2Hz),
8.65-8.72 (1H, m). IR (KBr): 3050,3000,1580,1540,1460,1430,1400c
m ^-1 .. Reference Example 2 Production of 5- (4-methylphenyl) tetrazole

[Chemical 42] Dibutyltin oxide (249 mg) was added to a toluene (20 ml) solution of p-tolunitrile (1.17 g) and trimethylsilyl azide (2.30 g) to give 90
Stir at 70 ° C. for 70 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, and then concentrated again under reduced pressure. Ethyl acetate and 10% aqueous sodium hydrogen carbonate solution were added to the residue, and the organic layer was separated and further extracted with 10% aqueous sodium hydrogen carbonate solution. The extract of the aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and then extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and 5- (4-methylphenyl) tetrazole (1.
60 g: yield 100%) was obtained. NMR (DMSO-d ₆ ) δ: 2.39 (3H, s), 7.41 (2H, d, J = 8.0Hz),
7.93 (2H, d, J = 8.0Hz) .MS (m / z): 160 (M ⁺ )

Reference Example 3 Production of N- (triphenylmethyl) -5- (4-methylphenyl) tetrazole

[Chemical 43] 5- (4-methylphenyl) tetrazole (1.60
After adding triethylamine (1.53 g) and triphenylmethyl chloride (3.07 g) to a DMF (20 ml) solution of g), the mixture was stirred at room temperature for 3 hours. Water was added and the precipitated solid was collected by filtration and washed successively with water, a small amount of methanol and ether, and then under reduced pressure on phosphorus pentoxide at 60 ° C.
After drying with N- (triphenylmethyl) -5- (4-methylphenyl) tetrazole (3,19 g, yield 79)
%) Was obtained. NMR (DMSO-d ₆ ) δ: 2.37 (3H, s), 7.07-7.12 (6H, m), 7.33
-7.44 (11H, m), 7.91 (2H, d, J = 8.2Hz). IR (KBr): 3050,3040,1680,1615,1590,1540cm ^-1 . Reference Example 4 Production of N- (triphenylmethyl) -5- (4-bromomethylphenyl) tetrazole

[Chemical 44] In the same manner as in Reference Example 1, N- (triphenylmethyl)-
5- (4-methylphenyl) tetrazole (3.00
g) to N- (triphenylmethyl) -5- (4-bromomethylphenyl) tetrazole (2.62 g: yield 7)
3%) was obtained. NMR (DMSO-d ₆ ) δ: 4.77 (2H, s), 7.07-7.13 (6H, m), 7.39
-7.48 (9H, m), 7.62 (2H, d, J = 8.2Hz), 8.02 (2H, d, J = 8.2Hz) .IR (KBr): 3050,3020,1590,1540,1490,1460,1440 , 1420
cm ^-1 .

Reference Example 5 Preparation of 2- (t-butyldimethylsilyloxy) -1-phenylethanol

[Chemical formula 45] A solution of 1-phenylethanediol (1.00 g) in dichloromethane (10 ml) was cooled in ice with triethylamine (1.11 ml), t-butyldimethylchlorosilane (1.20 g) and dimethylaminopyridine (35.
4 mg) was added, and the mixture was stirred overnight at room temperature. Water was added to the reaction solution, and the product was extracted with dichloromethane. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (carrier 40 g; developing solvent: ether-hexane = 1: 4) to give 2- (t-butyldimethylsilyloxy) -1-phenylethanol (1.82 g: yield 93). %) As a colorless oil. NMR (CDCl ₃ ) δ: 0.06 (3H, s), 0.07 (3H, s), 0.91 (9H, s)
2.96 (1H, d, J = 2.0Hz), 3.54 (1H, dd, J = 8.5Hz, 11.0Hz), 3.77
(1H, dd, J = 3.5Hz, 8.5Hz), 4.70-4.80 (1H, m), 7.25 (5H, m). Reference Example 6 2-t-butyl-4-chloro-5- (4-t- Butyl)
Preparation of benzylthio-3 (2H) pyridazinone (Compound 1)

[Chemical formula 46] The method described in JP-A-61-17570 or a method similar thereto was used. A solution of 2-t-butyl-4-chloro-5-mercapto-3 (2H) pyridazinone (500 mg) in N, N-dimethylformamide (DMF: 5 ml) was added to anhydrous sodium carbonate (242 mg) and 4-t-butylbenzyl chloride. (418 mg) was added, and the mixture was stirred at 80 ° C. for 2 hours. After cooling to room temperature, water was added, and the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to obtain Compound 1 (667 mg: yield 80%) as colorless scaly crystals. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 1.63 (9H, s), 4.25 (2H, s),
7.30-7.45 (4H, m), 7.64 (1H, s).

Reference Example 7 2-t-butyl-4-chloro-5-benzylthio-3
Production of (2H) pyridazinone (Compound 2)

[Chemical 47] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (300m
g), anhydrous sodium carbonate (218 mg) and benzyl bromide (235 mg) to compound 2 (339 mg:
Yield 80%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.27 (2H, s), 7.25-7.45 (5
H, m), 7.62 (1H, s). Reference Example 8 Preparation of 2-t-butyl-4-chloro-5- (4-phenyl) benzylthio-3 (2H) pyridazinone (Compound 3)

[Chemical 48] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (300m
g), anhydrous sodium carbonate (145 mg) and 4-
Compound 3 (404 mg: yield 76%) was obtained as colorless needle crystals from (chloromethyl) biphenyl (306 mg). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.32 (2H, s), 7.30-7.65 (5
H, m), 7.65 (1H, s).

Reference Example 9 Preparation of 2-t-butyl-4-chloro-5- (2-naphthyl) methylthio-3 (2H) pyridazinone (Compound 4)

[Chemical 49] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (500m
g), anhydrous sodium carbonate (242 mg) and 2-bromomethylnaphthalene (531 mg) to compound 4 (7).
(75 mg: 94% yield) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.61 (9H, s), 4.43 (2H, s), 7.45-7.55 (3
H, m), 7.64 (1H, s), 7.80-7.90 (4H, m). Reference Example 10 2-t-butyl-4-chloro-5- (2-phenyl) ethylthio-3 (2H) pyridazinone (compound 5) Manufacturing

[Chemical 50] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (500m
g), anhydrous sodium carbonate (242 mg) and 2-phenylbromoethane (444 mg) were reacted and purified by silica gel column chromatography (carrier 25 g; developing solvent: ether-hexane = 1: 4) to give compound 5 (737 mg). : Yield 99%) was obtained as a colorless oil. NMR (CDCl ₃ ) δ: 1.64 (9H, s), 4.32 (2H, s), 7.30-7.65 (5
H, m), 7.65 (1H, s).

Reference Example 11 2-t-butyl-4-chloro-5-{(3-phenyl)
Preparation of 2-propenylthio} -3 (2H) pyridazinone (Compound 6)

[Chemical 51] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (500m
Compound 6 (622 mg: yield 81%) was obtained as colorless needles from g), anhydrous sodium carbonate (242 mg) and 3-chloro-1-phenylpropene (349 mg). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 3.87 (1H, dd, J = 1.5Hz, 7.0
Hz), 6.25 (1H, dt, J = 7.0Hz, 16Hz), 6.64 (1H, dt, J = 1.5Hz, 16
Hz), 7.25-7.40 (5H, m), 7.68 (1H, s). Reference Example 12 2-t-butyl-4-chloro-5- (1-naphthyl) methylthio-3 (2H) pyridazinone (Compound 7) Manufacturing of

[Chemical 52] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (150m
g), anhydrous sodium carbonate (72 mg) and 1-chloromethylnaphthalene (121 mg) to give compound 7 (16
9 mg: 69% yield) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.65 (9H, s), 4.73 (2H, s), 7.40-7.55 (4
H, m), 7.71 (1H, s), 7.80-7.95 (2H, m), 8.07 (1H, m).

Reference Example 13 Preparation of 2-t-butyl-4-chloro-5- (2-pyridyl) methylthio-3 (2H) pyridazinone (Compound 8)

[Chemical 53] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (100m
g), anhydrous sodium carbonate (97 mg) and 2-chloromethylpyridine hydrochloride (108 mg) are reacted,
Purification by silica gel column chromatography (carrier 25 g; developing solvent: ether-hexane = 1: 1) gave compound 8 (138 mg: yield 97%) as a colorless oil. NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.39 (2H, s), 7.24 (1H, dd
d, J = 1.0Hz, 5.0Hz, 7.5Hz), 7.46 (1H, br.d, J = 7.0Hz), 7.72
(1H, dt, J = 2.0Hz, 7.5Hz), 7.85 (1H, s), 8.59 (1H, m). Reference Example 14 2-t-butyl-4-chloro-5- (3-pyridyl) methylthio- Production of 3 (2H) pyridazinone (Compound 9)

[Chemical 54] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (100m
g), anhydrous sodium carbonate (97 mg) and 3-chloromethylpyridine hydrochloride (108 mg) are reacted,
Purification by silica gel column chromatography (carrier 25 g; developing solvent: ethyl acetate-hexane = 2: 1) gave compound 9 (122 mg: yield 86%) as a white powder. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.28 (2H, s), 7.33 (1H, m),
7.60 (1H, s), 7.77 (1H, m), 7.58 (1H, m), 7.66 (1H, m).

Reference Example 15 Preparation of 2-t-butyl-4-chloro-5- (4-pyridyl) methylthio-3 (2H) pyridazinone (Compound 10)

[Chemical 55] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (100m
g), anhydrous sodium carbonate (97 mg) and 4-chloromethylpyridine hydrochloride (75 mg) were reacted and purified by silica gel column chromatography (carrier 25 g; developing solvent: ethyl acetate-hexane = 3: 2). Compound 10 (64 mg: yield 45%) was obtained as a white powder. NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.24 (2H, s), 7.37 (2H, br.
d, J = 6.0Hz), 7.49 (1H, s), 8.63 (1H, br.d, J = 6.0Hz). Reference Example 16 2-t-butyl-4-chloro-5- (benzimidazole-2- Preparation of (yl) methylthio-3 (2H) pyridazinone (Compound 11)

[Chemical 56] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (100m
Compound 11 (61 mg: yield 38%) was obtained as colorless needles from g), anhydrous sodium carbonate (97 mg) and 2-chloromethylbenzimidazole (114 mg). NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 4.78 (2H, s), 7.10-7.25
(2H, m), 7.45-7.65 (2H, m), 8.30 (1H, s).

Reference Example 17 Preparation of 2-t-butyl-4-chloro-5- (2-quinolyl) methylthio-3 (2H) pyridazinone (Compound 12)

[Chemical 57] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (200m
Compound 12 (262 mg: 80% yield) was obtained as pale yellow needles from g), anhydrous sodium carbonate (193 mg) and 2-chloromethylquinoline.hydrochloride (294 mg). NMR (CDCl ₃ ) δ: 1.60 (9H, s), 4.55 (2H, s), 7.50-7.65 (2
H, m), 7.70-7.85 (2H, m), 8.01 (1H, s), 8.08 (1H.br.d, J = 7.5
Hz), 8.19 (1H, br.d, J = 8.5Hz). Reference Example 18 2-t-butyl-4-chloro-5- {4- (2-cyanophenyl)} benzylthio-3 (2H) pyridazinone ( Production of compound 13)

[Chemical 58] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (500m
g), anhydrous sodium carbonate (242 mg) and 2-
(4-Bromomethylphenyl) benzonitrile (622
Compound 13 (710 mg: yield 63%) was obtained as colorless needles from (mg). NMR (CDCl ₃ ) δ: 1.64 (9H, s), 4.34 (2H, s), 7.45-7.85 (8
H, m), 7.66 (1H, s).

Reference Example 19 Preparation of 2-t-butyl-4-chloro-5- (4-styryl) benzylthio-3 (2H) pyridazinone (Compound 14)

[Chemical 59] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (200m
g), anhydrous sodium carbonate (97 mg) and 4-chloromethylstilbene (209 mg) to compound 14 (2
32 mg: yield 62%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.28 (2H, s), 7.08 (1H, d, J
= 16Hz), 7.14 (1H, d, J = 16Hz), 7.20-7.55 (9H, m), 7.62 (1H,
s). Reference Example 20 2-t-butyl-4-chloro-5- (3,5-dimethylisoxazol-4-yl) methylthio-3 (2H).
Production of pyridazinone (Compound 15)

[Chemical 60] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (200m
g), anhydrous sodium carbonate (97 mg) and 4-chloromethyl-3,5-dimethylisoxazole (133
Compound 15 (280 mg: yield 93%) was obtained as colorless needles from (mg). NMR (CDCl ₃ ) δ: 1.65 (9H, s), 2.32 (3H, s), 2.41 (3H, s),
4.01 (2H, s), 7.65 (1H, s).

Reference Example 21 Preparation of 2-t-butyl-4-chloro-5- (4-cyano) benzylthio-3 (2H) pyridazinone (Compound 16)

[Chemical formula 61] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (1.50
g), anhydrous sodium carbonate (0.73 g) and 4-bromomethylbenzonitrile (1.34 g) to give compound 1
6 (2.14 g: 94% yield) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.30 (2H, s), 7.51 (1H, s),
7.50-7.60 (2H, m), 7.65-7.75 (2H, m). Reference Example 22 2-t-butyl-4-chloro-5- (4-trifluoromethyl) benzylthio-3 (2H) pyridazinone (Compound 17 )Manufacturing of

[Chemical formula 62] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) pyridazinone (500m
Compound 17 (547 g: yield 64%) was obtained as pale yellow prism crystals from g), anhydrous potassium carbonate (682 mg) and 4-trifluoromethylbenzyl bromide (656 mg). NMR (DMSO-d ₆ ) δ: 1.57 (9H, s), 4.66 (2H, s), 7.71 (1H,
s), 7.65-7.75 (2H, m), 7.75-7.85 (2H, m), 8.05 (1H, s).

Reference Example 23 2-t-butyl-4-chloro-5- (4-phenyl) benzyloxy-3 (2H) pyridazinone (Compound 18)
Manufacturing of

[Chemical formula 63] The method described in JP-A-59-98064 or a method similar thereto was used. A solution of 2-t-butyl-4-chloro-5-hydroxy-3 (2H) pyridazinone (2.03 g) in N, N-dimethylformamide (DMF: 20 ml) was added anhydrous potassium carbonate (2.10 g) and 4- (. Chloromethyl) biphenyl (2.03g) was added to 100 ° C.
It was stirred for 1.5 hours. After cooling to room temperature, water was added, and the precipitated solid was collected by filtration, washed with water, dried and recrystallized from ethanol to obtain compound 18 (2.32 g: yield 63%) as colorless needle crystals. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.51 (2H, s), 7.35-7.60
(5H, m), 7.65-7.80 (4H.m), 8.30 (1H, s). Reference Example 24 2-t-butyl-4-chloro-5- (4-t-butyl)
Benzyloxy-3 (2H) pyridazinone (Compound 1
9) Manufacturing

[Chemical 64] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) pyridazinone (2.22)
g), anhydrous sodium carbonate (1.74 g) and 4-t
-Butylbenzyl bromide (2.0 g) to compound 19
(2.94 g, yield 77%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.64
(9H, s), 5.28 (2H, s) 7.30-7.4
0 (2H, m), 7.40-7.50 (2H, m),
7.74 (1H, s).

Reference Example 25 Preparation of 2-t-butyl-4-chloro-5- (2-naphthyl) methyloxy-3 (2H) pyridazinone (Compound 20)

[Chemical 65] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) pyridazinone (1.00
g), anhydrous potassium carbonate (1.36 g) and 2-bromomethylnaphthalene (1.31 g) to compound 20
(1.08 g: yield 64%) was obtained as colorless needle crystals. NMR (DMSO-d ₆ ) δ: 1.57 (9H, s), 5.63 (2H, s),
7.51-7.61 (3H, m), 7.88-8.04 (4H, m), 8.31 (1H, s). Reference Example 26 2-t-butyl-4-chloro-5- (1-naphthyl) methyloxy-3 ( 2H) Preparation of pyridazinone (compound 21)

[Chemical formula 66] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) pyridazinone (500 m
g), anhydrous potassium carbonate (682 mg) and 1-chloromethylnaphthalene (523 mg) to compound 21 (4
(93 mg, yield 58%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.59 (9H, s), 5.92
(2H, s), 7.50-7.67 (3H, m), 7.
73 (1H, d, J = 7.0 Hz), 7.95-8.0
4 (2H, m), 8.47 (2H, s), 8.47 (1
H, s).

Reference Example 27 2-t-butyl-4-chloro-5-benzyloxy-3
(2H) Pyridazinone (Production of Compound 22

[Chemical formula 67] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) pyridazinone (500 m
g), anhydrous potassium carbonate (682 mg) and benzyl bromide (422 mg) to compound 22 (367 mg:
Yield 51%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.32 (2H, s), 7.35
-7.45 (3H, m), 7.73 (1H, s). Reference Example 28 2-t-butyl-4-chloro-5- (4-trifluoromethyl) benzyloxy-3 (2H) pyridazinone (Compound 23) Manufacturing

[Chemical 68] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-mercapto-3 (2H) pyridazinone (800 m
Compound 23 (726 mg: yield 52%) was obtained as colorless prism crystals from g), anhydrous potassium carbonate (1.09 g) and 4-trifluoromethylbenzyl bromide (1.11 g). NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.30
(2H, s), 7.51 (1H, s), 7.50-7.
60 (2H, m), 7.65-7.75 (2H, m).

Reference Example 29 Preparation of 2-t-butyl-5- (4-t-butyl) benzylthio-3 (2H) pyridazinone (Compound 24)

[Chemical 69] 2-t-butyl-4-chloro-5- (4-t-butyl)
Benzylthio-3 (2H) pyridazinone (Compound 1: 5
To a solution of 00 mg) in methanol (10 ml) was added 10% palladium-carbon (500 mg), and the mixture was stirred overnight under a hydrogen atmosphere. After the catalyst was filtered off, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: 50 g; developing solvent: ether-hexane = 1: 4) to obtain compound 24 (5.1 mg: yield 1%) as a white powder. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.62 (9H, s), 4.10 (2H, s),
6.52 (1H, d, J = 2.5Hz), 7.25-7.40 (4H, m), 7.49 (1H, s). Reference Example 30 2-t-butyl-5- (4-t-butyl) benzylthio-4- Mercapto-3 (2H) pyridazinone (Compound 2
5) Manufacturing

[Chemical 70] 2-t-butyl-4-chloro-5- (4-t-butyl)
Benzylthio-3 (2H) pyridazinone (Compound 1:
3.8 g of ethanol (70 ml) in water (2 m
1) and 70% sodium hydrosulfide hydrate (2.8 g)
Was added and the mixture was heated and stirred for 1.5 hours. After cooling to room temperature, the mixture was concentrated under reduced pressure and ethyl acetate and 1N hydrochloric acid were added.
The organic layer was separated, and the aqueous layer was further extracted with ethyl acetate.
The organic layer and the extract were combined, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting residue was recrystallized from ethanol to give compound 25
(3.31 g, yield 88%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.63 (9H, s), 4.22 (2H, s),
7.25-7.40 (4H, m), 7.56 (1H, s).

Reference Example 31 2-t-butyl-5- (4-t-butyl) benzylthio-4-methylthio-3 (2H) pyridazinone (Compound 2
6) Manufacturing

[Chemical 71] 2-t-butyl-5- (4-t-butyl) benzylthio-4-mercapto-3 (2H) pyridazinone (Compound 2
5: 300 mg) in DMF (3 ml) was added with sodium hydride (60% oiliness: 36 mg) under ice cooling to give 3
Stir for 0 minutes. Furthermore, methyl iodide (0.1 ml)
After adding and stirring for 1 hour, water was added to stop the reaction, and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: 30 g; developing solvent: ethyl acetate-hexane = 5: 95) and recrystallized from ethanol to give compound 26 (267 mg: yield 86%) as colorless. Obtained as needle crystals. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.63 (9H, s), 2.56 (3H, s),
4.20 (2H, s), 7.30-7.45 (4H, m), 7.62 (1H, s). Reference Example 32 2-t-butyl-5- (4-t-butyl) benzylthio-4-methyl-3 (2H ) Pyridazinone (Compound 27)
Manufacturing of

[Chemical 72] 2-t-butyl-5-mercapto-4-methyl-3 (2
H) Pyridazinone (JP-A-61-243078: 108)
Anhydrous sodium carbonate (434 mg) and 4-t-butylbenzyl chloride (748 mg) were added to a solution of (mg) in DMF (5 ml), and the mixture was stirred for 30 minutes. Water was added to the reaction solution to stop the reaction, and the product was extracted with ether.
The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (carrier: 20 g; developing solvent: acetone-hexane = 1: 20) and recrystallized from hexane to give compound 27 (70 mg: yield 37%) as colorless needles. Obtained as crystals. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.63 (9H, s), 2.12 (3H, s),
4.18 (2H, s), 7.25-7.40 (4H, m), 7.65 (1H, s).

Reference Example 33 2-t-butyl-5- (4-t-butyl) benzylthio-4-ethyl-3 (2H) pyridazinone (Compound 28)
Manufacturing of

[Chemical formula 73] 2-t-butyl-4-chloro-5- (4-t-butyl)
Benzylthio-3 (2H) pyridazinone (Compound 1: 5
(00 mg) in a tetrahydrofuran (THF: 5 ml) solution under ice-cooling, ethylmagnesium chloride (2M).
THF solution: 0.69 ml) was added dropwise. After stirring for 30 minutes, water was added to the reaction solution to stop the reaction, and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: 5
0 g; Purification with a developing solvent: ether-hexane = 1: 9) to obtain Compound 28 (84 mg: yield 17%) as a white powder. NMR (CDCl ₃ ) δ: 1.07 (3H, t, J = 7.5Hz), 1.31 (9H, s), 1.6
3 (9H, s), 2.66 (2H, d, J = 7.5Hz), 4.17 (2H, s), 7.20-7.40 (4
H, m), 7.65 (1H, s). Reference Example 34 2-t-butyl-5- (4-t-butyl) benzylthio-4-vinyl-3 (2H) pyridazinone (Compound 29)
Manufacturing of

[Chemical 74] In the same manner as in Reference Example 33, 2-t-butyl-4-chloro-5- (4-t-butyl) benzylthio-3 (2H) pyridazinone (Compound 1: 500 mg) and vinylmagnesium bromide (1M THF solution: 2) Compound 29 (132 mg: yield 27%) was obtained as a white powder from 0.0 ml). NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.64 (9H, s), 4.20 (2H, s),
5.74 (1H, dd, J = 2.0Hz, 11.5Hz), 6.47 (1H, dd, J = 2.0Hz, 17.5
Hz), 6.81 (1H, dd, J = 11.5Hz, 17.5Hz), 7.25-7.40 (4H, m), 7.
71 (1H, s).

Reference Example 35 Preparation of 2-t-butyl-5- (4-t-butyl) benzylthio-4- (2-propenyl) -3 (2H) pyridazinone (Compound 30)

[Chemical 75] In the same manner as in Reference Example 33, 2-t-butyl-4-chloro-5- (4-t-butyl) benzylthio-3 (2H) pyridazinone (Compound 1: 500 mg) and allylmagnesium bromide (1M ether solution: 3). 0.0 ml)
Compound 30 (297 mg: yield 59%) was obtained as a white powder from. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.62 (9H, s), 3.41 (2H, dt,
J = 1.5Hz, 6.5Hz), 4.18 (2H, s), 4.95-5.15 (2H, m), 5.70-5.9
5 (1H, m), 7.25-7.40 (4H, m), 7.67 (1H, s). Reference Example 36 2-t-butyl-5- (4-t-butyl) benzyloxy-4-methyl-3 ( 2H) Pyridazinone (Compound 3
1) production

[Chemical 76] Sodium hydride (60% oiliness: 163 mg) in DMF
It was suspended in (5 ml), 4-t-butylbenzyl alcohol (0.58 ml) was added, and the mixture was stirred for 30 minutes. Then 2-t-butyl-5-chloro-4-methyl-3 (2H)
Pyridazinone (JP-A-61-243078: 150 m
A DMF (5 ml) solution of g) was added, and the mixture was further stirred for 2 hours. Water was added to the reaction solution to stop the reaction, and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier:
20 g; developing solvent: acetone-hexane = 1: 15) and further recrystallized from isopropyl ether to obtain Compound 31 (88 mg: yield 36%) as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.64 (9H, s), 2.06 (3H, s),
5.16 (2H, s), 7.25-7.45 (4H, m), 7.73 (1H, s).

Reference Example 37 2-t-butyl-5- (4-t-butyl) benzyloxy-4-vinyl-3 (2H) pyridazinone (Compound 3
Production of 2) (1) 2-t-butyl-5-chloro-4-vinyl-3
Production of (2H) pyridazinone

[Chemical 77] 2-t-Butyl-4,5-dichloro-3 (2H) pyridazinone (1.00 g) in tetrahydrofuran (THF:
Vinylmagnesium bromide (1M THF solution: 13.5 ml) was added dropwise to the 5 ml solution under ice cooling. 1
After stirring for an hour, water was added to the reaction solution to stop the reaction, and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The obtained residue was subjected to silica gel column chromatography (carrier: 50 g; developing solvent: ether-hexane = 1:
9-) and purified by 2-t-butyl-5-chloro-4-vinyl-3 (2H) pyridazinone (334 mg: yield 35).
%) As a white powder. NMR (CDCl ₃ ) δ: 1.65 (9H, s), 5.83 (H, dd, J = 6.0Hz, 8.0H
z), 6.83 (1H, d, J = 8.0Hz), 6.84 (1H, d, J = 6.0Hz), 7.70 (1H,
s). (2) Preparation of 2-t-butyl-5- (4-t-butyl) benzyloxy-4-vinyl-3 (2H) pyridazinone (Compound 32)

[Chemical 78] In the same manner as in Reference Example 35, sodium hydride (60% oiliness: 85 mg), 4-t-butylbenzyl alcohol (0.30 ml) and 2-t-butyl-5-chloro-.
Compound 32 (91 mg: yield 19%) was obtained as a white powder from 4-vinyl-3 (2H) pyridazinone (300 mg). NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.64 (9H, s), 5.22 (2H, s),
5.62 (1H, dd, J = 3.0Hz, 12.0Hz), 6.57 (1H, dd, J = 3.0Hz, 18.0
Hz), 6.94 (1H, dd, J = 12.0Hz, 18.0Hz), 7.30-7.50 (4H, m), 7.
78 (1H, s). Reference Example 38 Preparation of 2-t-butyl-4-chloro-5- {4- (t-butoxycarbonyl) benzylthio} -3 (2H) -pyridazinone (Compound 33)

[Chemical 79] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (1.39
g), anhydrous potassium carbonate (1.90 g) and butyl 4-bromomethylbenzoate (1.90 g) to give compound 33.
(1.54 g: 59% yield) was obtained as pale yellow prism crystals. NMR (DMSO-d ₆ ) δ: 1.54 (9H, s), 1.56 (9H, s), 4.62 (2H,
s), 7.59 (2H, d, J = 8.4Hz), 7.89 (2H, d, J = 8.4Hz), 8.01 (1H,
s). IR (KBr): 2960,2940,1700,1650,1605,1560,1500 cm ^-1 . Melting point: 101-102 ° C. Elemental _{analysis: C 20 H 25 ClN 2 O} 3 S Calculated: C: 58.74%; H: 6.16%; N: 6.85% Found: C:. 58.83%; H : 6.27%; N: 6.88%.

Reference Example 39 Preparation of 2-t-butyl-4-chloro-5- {4- (t-butoxycarbonyl) benzyloxy} -3 (2H) -pyridazinone (Compound 34)

[Chemical 80] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (1.2
4 g), anhydrous potassium carbonate (1.69 g) and butyl 4-bromomethylbenzoate (1.82 g) to give compound 3
4 (1.27 g, yield 53%) was obtained as colorless needle crystals. NMR (DMSO-d ₆ ) δ: 1.55 (9H, s), 1.57 (9H, s), 5.55 (2H,
s), 7.57 (2H, d, J = 8.0Hz), 7.96 (2H, d, J = 8.0Hz), 8.23 (1H,
s) .IR (KBr): 2970,2930,1705,1650,1640,1605,1500,147
5,1445,1400 cm ^-1 . Melting point: 178-179 ° C. Elemental _{analysis: C 20 H 25 ClN 2 O} 4 Calculated: C: 61,14%; H: 6.41%; N: 7.13% Found: C:. 61,18%; H : 6.39%; N: 7.13 %.

Reference Example 40 Preparation of 2-t-butyl-4-chloro-5- {4- (carboxyl) benzylthio} -3 (2H) -pyridazinone (Compound 35)

[Chemical 81] 2-t-butyl-4-chloro-5- {4- (t-butoxycarbonyl) benzylthio} -3 (2H) -pyridazinone (500 mg) was dissolved in 4N hydrochloric acid in ethyl acetate (8 m
After dissolving in 1), the mixture was stirred at room temperature for 3.5 hours. After evaporating the solvent under reduced pressure, ether was added to the residue and the mixture was subjected to an ultrasonic cleaner. The obtained powder was collected by filtration, washed with ether and dried under reduced pressure to obtain Compound 35 (415 mg: yield 96%) as a pale green powder. NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.63 (2H, s), 7.59 (2H,
d, J = 8.0Hz), 7.94 (2H, d, J = 8.0Hz), 8.03 (1H, s). IR (KBr): 2960,2900,1710,1600,1560,1500cm ^-1 . Melting point: 215-217 ° C. Elemental analysis: Calculated as C ₁₆ H ₁₇ ClN ₂ O ₃ S: C: 54.47%; H: 4.86%; N: 7.94%. Found: C: 54.26%; H: 4.93%; N: 7.82%.

Reference Example 41 Preparation of 2-t-butyl-4-chloro-5- {4- (carboxyl) benzyloxy} -3 (2H) -pyridazinone (Compound 36)

[Chemical formula 82] In the same manner as in Reference Example 40, from 2-t-butyl-4-chloro-5- {4- (t-butoxycarbonyl) benzyloxy} -3 (2H) -pyridazinone (500 mg) to compound 36 (399 mg: yield) 93%) as a white powder. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.55 (2H, s), 7.57 (2H,
d, J = 8.4Hz), 8.00 (2H, d, J = 8.4Hz), 8.24 (1H, s) .IR (KBr): 3080,2960,2930,1690,1660,1605,1570,1500
cm ⁻¹ .Melting point: 208-209 ° C. Elemental _{analysis: C 16 H 17 ClN 2 O} 4 Calculated: C: 57.06%; H: 5.09%; N: 8.32% Found: C:. 56.94%; H : 4.99%; N: 8.65%. Reference Example 42 2-t-butyl-5- (4-t-butyl) benzylthio-4-methoxy-3 (2H) pyridazinone (Compound 3
7) Manufacturing

[Chemical 83] Sodium hydride (274m) in methanol (2ml)
g) was added slowly. After the shots subsided, 2-t-butyl-4-chloro-5- (4-t-butyl) benzylthio-3 (2H) pyridazinone (Compound 1: 500 mg)
In methanol (2 ml) was added and the mixture was stirred for 3 days.
Water was added to the reaction solution to stop the reaction, and the product was extracted with ether. The extract was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (carrier: 50
g; Purified with a developing solvent: ether-hexane = 1: 4) to obtain Compound 37 (67 mg: yield 14%) as a white powder. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 1.63 (9H, s), 4.10
(3H, s), 4.15 (2H, s), 7.25-7.40 (4H, m), 7.59 (1H, s).

Reference Example 43 5- (4-t-butyl) benzylthio-4-chloro-2
-Phenyl-3 (2H) pyridazinone (Compound 38)

[Chemical 84] In the same manner as in Reference Example 4, 4-chloro-5-mercapto-
2-Phenyl-3 (2H) pyridazinone (300m
g), anhydrous sodium carbonate (133 mg) and 4-t
-Butylbenzyl chloride (230 mg) to compound 3
8 (276 mg: 57% yield) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 4.32 (2H, s), 7.30-7.60 (9
H, m), 7.82 (1H, s). Reference Example 44 2-t-butyl-4-chloro-5- [6- (4-fluorobenzyloxy) -3-pyridyl] methoxy-3 (2
H) -Pyridazinone (Compound 49)

[Chemical 85] 2-t-Butyl-4,5-dichloro-3 (2H) -pyridazinone (663 mg) was dissolved in DMF (10 ml), 6- (4-fluorobenzyloxy) -3-pyridinemethanol (840 mg), anhydrous carbonic acid. Cesium (97
7 mg) was added and the mixture was stirred at 80 ° C. for 17 hours. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was subjected to silica gel column chromatography (developing solvent:
It was purified by hexane-ethyl acetate = 2: 1) and recrystallized from ether to obtain Compound 49 (552 mg) as a white powder. NMR (CDCl ₃ ) δ: 1.64 (9H, s), 5.
23 (2H, s), 5.36 (2H, s), 6.85
(1H, d, J = 8Hz), 7.06 (2H, dd, J
= 9 Hz, 9 Hz), 7.43 (2H, dd, J = 5H
z, 9 Hz), 7.68 (1 H, dd, J = 3 Hz, 8
Hz), 7.76 (1H, s), 8.21 (1H, d,
J = 3 Hz).

Reference Example 45 2-t-butyl-4-chloro-5- [6- (4-fluorobenzyloxy) -3-pyridyl] methylthio-3
Production of (2H) -pyridazinone (Compound 50)

[Chemical 86] 2-t-butyl-4-chloro-5-mercapto-3 (2
H) -pyridazinone (875 mg) in DMF (10 m
l) and dissolved in 6- (4-fluorobenzyloxy)-
3-Chloromethylpyridine (977 mg) and potassium carbonate (829 mg) were added, and the mixture was stirred at room temperature for 17 hours. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed successively with water and a saturated sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 4: 1), and recrystallized from hexane-ether to give compound 50 (60).
0 mg) was obtained as colorless crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.
21 (2H, s), 5.34 (2H, s), 6.81
(1H, d, J = 8Hz), 7.06 (2H, dd, J
= 9 Hz, 9 Hz), 7.43 (2H, dd, J = 5H
z, 9 Hz), 7.63 (1H, s), 7.65 (1
H, dd, J = 3 Hz, 8 Hz), 8.17 (1 H,
d, J = 3 Hz). Elemental analysis: Calculated as C ₂₁ H ₂₁ N ₃ O ₂ SClF: C: 58.13%, H: 4.88%, N: 9.68%, Found: C: 57.84%, H: 4.80%, N: 9.72%.

Reference Example 46 Preparation of 2-t-butyl-5- (4-t-butylcyclohexyl) methoxy-4-chloro-3 (2H) -pyridazinone (Compound 51)

[Chemical 87] 2-t-butyl-4-chloro-5-hydroxy-3 (2
H) -pyridazinone (203 mg) in DMF (5 ml)
Was dissolved in water, 4-t-butyl-1-bromomethylcyclohexane (280 mg) and potassium carbonate (207 mg) were added, and the mixture was stirred at 80 ° C. for 17 hours. Add water to the reaction mixture,
After extraction with ether, the organic layer was washed successively with water and saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 4: 1) to give compound 51 (312m).
g) was obtained as a white powder. NMR (CDCl ₃ ) δ: 0.86 (9H, s), 1.
20-0.90 (5H, m), 1.65 (9H, s),
1.70-2.00 (5H, m), 4.00 (2H,
d, J = 6 Hz), 7.72 (1H, s). Elemental analysis: Calculated as C ₁₉ H ₃₁ N ₂ O ₂ Cl: C: 64.30%, H: 8.80%, N: 7.89%, Found: C: 64.31%, H: 8.69%, N: 8.03%.

Reference Example 47 Preparation of 2-t-butyl-5- (4-t-butylcyclohexyl) methylthio-4-chloro-3 (2H) -pyridazinone (Compound 52)

[Chemical 88] 2-t-butyl-4-chloro-5-mercapto-3 (2
H) -pyridazinone (131 mg) in DMF (5 ml)
The mixture was dissolved in water, 4-t-butyl-1-bromomethylcyclohexane (168 mg) and potassium carbonate (124 mg) were added, and the mixture was stirred at room temperature for 17 hours. After water was added to the reaction solution and the mixture was extracted with ether, the organic layer was washed successively with water and a saturated sodium chloride aqueous solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 4: 1), and recrystallized from hexane to give compound 52 (98 mg) as colorless crystals. Obtained. NMR (CDCl ₃ ) δ: 0.85 (9H, s), 0.
90-2.10 (10H, m), 1.65 (9H,
s), 2.88 (2H, d, J = 7Hz), 7.59
(1H, s). Elemental analysis: Calculated as C ₁₉ H ₃₁ N ₂ OSCl: C: 61.51%, H: 8.42%, N: 7.55%, Found: C: 61.40%, H: 8.28%, N: 7.27%.

Reference Example 48 2-t-butyl-5- (4-t-butyl-1-hydroxycyclohexyl) methylthio-4-chloro-3 (2
H) -Pyridazinone (Compound 53)

[Chemical 89] Sodium hydride (60% oiliness: 84 mg) was dissolved in methanol (10 ml), and after the foaming stopped, 2-t-
Butyl-4-chloro-5-mercapto-3 (2H) -pyridazinone (459 mg) was added, and the mixture was stirred at room temperature for 20 minutes. Then 4-t-butylmethylenecyclohexane
Oxide (353 mg) was added, and the mixture was stirred at room temperature for 17 hours. After water was added to the reaction solution and the mixture was extracted with ethyl acetate-THF, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 4: 1) and recrystallized from hexane to give compound 53 (600
mg) was obtained as a white powder. NMR (CDCl ₃ ) δ: 0.87 (9H, s), 0.
90-2.00 (9H, m), 1.64 (9H, s),
3.12 (2H, s), 7.78 (1H, s). Elemental analysis: Calculated as C ₁₉ H ₃₁ N ₂ O ₂ SCl: C: 58.97%, H: 8.07%, N: 7.24%, Found: C: 58.98%, H: 8.05%, N: 7.10%.

Reference Example 49 2-t-butyl-5- (1-chloroacetylcarbamoyloxy-4-t-butylcyclohexyl) methylthio-4-chloro-3 (2H) -pyridazinone (Compound 5
4) Manufacturing

[Chemical 90] Compound 53 (271 mg) in dichloromethane (5 ml)
Dissolved in chloroacetyl isocyanate (100 m
g) was added under ice cooling, and the mixture was stirred at room temperature for 17 hours. After water was added to the reaction solution and the mixture was extracted with dichloromethane, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 4: 1) to give compound 54.
(322 mg) was obtained as a white powder. NMR (CDCl ₃ ) δ: 0.87 (9H, s), 0.
90-1.80 (7H, m), 1.64 (9H, s),
2.40-2.60 (2H, m), 3.63 (2H,
s), 4.42 (2H, s), 7.67 (1H, s),
7.87 (1H, brs). Elemental _{analysis: C 22 H 33 N 3 O} 4 SCl 2 Calculated: C: 52.17%, H: 6.57%, N: 8.30%, Found: C: 52.12%, H: 6.31%, N: 8.17%.

Reference Example 50 2-t-butyl-5- (4-t-butyl-1-carbamoyloxycyclohexyl) methylthio-4-chloro-
Production of 3 (2H) -pyridazinone (Compound 55)

[Chemical Formula 91] Compound 54 (101 mg) was added to methanol-THF (1:
1) The mixture was dissolved in a mixed solvent (5 ml), 1N sodium hydroxide solution (0.4 ml) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. After water was added to the reaction solution and the mixture was extracted with ethyl acetate, the organic layer was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The residue obtained by concentrating this under reduced pressure was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 2: 1) to obtain Compound 55 (61 mg) as a white powder. NMR (CDCl ₃ ) δ: 0.87 (9H, s), 0.
90-1.90 (7H, m), 1.64 (9H, s),
2.45-2.60 (2H, m), 3.65 (2H,
s), 4.56 (2H, brs), 7.73 (1H,
s). Elemental analysis: Calculated as C ₂₀ H ₃₂ N ₃ O ₃ SCl: C: 55.86%, H: 7.50%, N: 9.77%, Found: C: 55.82%, H: 7.49%, N: 9.74%.

Reference Example 51 4,5-Dichloro-2-pivaloyloxymethyl-3
Production of (2H) -pyridazinone

[Chemical Formula 92] 4,5-Dichloro-3 (2H) -pyridazinone (2.4
Anhydrous potassium carbonate (1.10 g) and pivaloyloxymethyl chloride (3.39 g) were added to a solution of 8 g) of DMF (25 ml), and the mixture was stirred at 55 ° C for 2 hours.
The solvent was distilled off under reduced pressure to separate an ether-soluble substance from the obtained residue, and this crude product was subjected to flash column chromatography (developing solvent: hexane-ethyl acetate = 9:
The title compound (1.67 g) was obtained by purification in 1). NMR (CDCl ₃ ) δ: 1.21 (9H, s), 6.
05 (2H, s), 7.81 (1H, s). IR (KBr): 3420, 3330, 3100, 30
70, 2980, 2970, 2930, 2870, 17
20, 1675, 1580, 1480, 1460, 14
40, 1360, 1320, 1270, 1220, 11
50, 1130, 1030, 1005 cm ^{- 1} .

Reference Example 52 Preparation of 4-chloro-5-mercapto-2-pivaloyloxymethyl-3 (2H) -pyridazinone

[Chemical formula 93] 70% sodium hydrosulfide hydrate (1.60 g) was added to water (2
0 ml) and then 4,5-dichloro-2-pivaloyloxymethyl-3 (2H) -pyridazinone (2.
8 g) was added and the mixture was stirred at 60 ° C. for 3 hours. The insoluble material was filtered off and washed with water. The filtrate and washings were combined and adjusted to acidic (pH <2) with concentrated hydrochloric acid, and the precipitate was collected by filtration, washed with water and dried to give the title compound (2.39 g). NMR (CDCl ₃ ) δ: 1.21 (9H, s), 4.
17 (1H, s), 6.02 (2H, s), 7.65
(1H, s).

Reference Example 53 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2-pivaloyloxymethyl-3 (2H) -pyridazinone (Compound 56)

[Chemical 94] 4,5-Dichloro-2-pivaloyloxymethyl-3
(2H) -Pyridazinone (4.51 g) in DMF (85
(ml) solution, anhydrous cesium carbonate (3.16 g) and 4-t-butylbenzyl alcohol (3.98 g) were added, and the mixture was stirred at 80 ° C for 12 hr. The insoluble material was filtered off, and the solvent was evaporated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by flash column chromatography (developing solvent: hexane-ethyl acetate = 9: 1 to 4: 1) to obtain compound 56 (4.54 g). . NMR (CDCl ₃ ) δ: 1.19 (9H, s), 1.
33 (9H, s), 5.33 (2H, s), 6.05
(2H, s), 7.33 (2H, d, J = 8Hz),
7.44 (2H, d, J = 8Hz), 7.84 (1H,
s). IR (KBr): 3430, 2960, 2900, 28
70, 1745, 1725, 1650, 1600, 15
10, 1475, 1455, 1440, 1400, 13
95, 1380, 1375, 1365, 1310, 12
80, 1205, 1190, 1135, 1110, 10
80,1030 cm ^{- 1} .

Reference Example 54 5- (4-t-butylbenzylthio) -4-chloro-2
-Preparation of pivaloyloxymethyl-3 (2H) -pyridazinone (Compound 57)

[Chemical 95] DM of 4-chloro-5-mercapto-2-pivaloyloxymethyl-3 (2H) -pyridazinone (2.07 g)
To the F (39.5 ml) solution, anhydrous potassium carbonate (0.7
77 g) and 4-t-butylbenzyl chloride (1.
64 g) was added, and the mixture was stirred at room temperature for 15 hours. The insoluble material was filtered off, the solvent was evaporated under reduced pressure, and the obtained residue was dissolved in ethyl acetate. After washing with a saturated aqueous solution of sodium chloride, it was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash column chromatography (developing solvent: hexane-ethyl acetate = 9: 1 to 4:
Compound 57 (0.56 g) was obtained by purification in 1). NMR (CDCl ₃ ) δ: 1.19 (9H, s), 1.
31 (9H, s), 4.28 (2H, s), 6.03
(2H, s), 7.32 (2H, d, J = 9Hz),
7.39 (2H, d, J = 9Hz), 7.72 (1H,
s). IR (KBr): 3430, 3100, 2960, 28
60, 1725, 1650, 1570, 1510, 14
80, 1460, 1440, 1395, 1360, 12
80, 1230, 1210, 1190, 1150, 11
20,1030,1015 cm ^{- 1} .

Reference Example 55 5- (4-t-butylbenzyloxy) -4-chloro-
Production of 3 (2H) -pyridazinone (Compound 58)

[Chemical 96] 5- (4-t-butylbenzyloxy) -4-chloro-
2-Pivaloyloxymethyl-3 (2H) -pyridazinone (Compound 56) (2.78 g) was added to methanol-THF.
The mixture was dissolved in (2: 1) mixed solvent (120 ml), 0.5N aqueous sodium hydroxide solution (27.2 ml) was added, and the mixture was stirred at room temperature for 15 hr. 1N Hydrochloric acid (13.6 ml) was added, and the solvent was evaporated under reduced pressure. The precipitated crystals were collected by filtration, washed with water and ether, and dried to give compound 58 (1.53 g). NMR (CDCl ₃ ) δ: 1.33 (9H, s), 5.
33 (2H, s), 7.33 (2H, d, J = 8H
z), 7.44 (2H, d, J = 8 Hz), 7.85
(1H, s). IR (KBr): 3430, 3200, 3120, 30
20, 2960, 2870, 1645, 1600, 15
15, 1460, 1400, 1320, 1280, 11
40,1100,1020cm ^{- 1.} Elemental _{analysis: C 15 H 17 N 2 O} 2 Cl · 0.3H 2 O Calculated: C: 60.42%, H: 5.95%, N: 9.40%, Found: C: 60.35%, H: 5.70%, N: 9.38%.

Reference Example 56 5- (4-t-butylbenzylthio) -4-chloro-3
Production of (2H) -pyridazinone (Compound 59)

[Chemical 97] In the same manner as in Reference Example 55, 5- (4-t-butylbenzylthio) -4-chloro-2-pivaloyloxymethyl-
3 (2H) -pyridazinone (Compound 57) (1.01
g), 0.5N sodium hydroxide aqueous solution (9.52 m
l) Compound 1 from 1N hydrochloric acid (4.76 ml)
(0.518 g) was obtained. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 4.
29 (2H, s), 7.32 (2H, d, J = 9H
z), 7.40 (2H, d, J = 9 Hz), 7.74
(1H, s). IR (KBr): 3440, 3280, 3220, 31
70, 3100, 3030, 2960, 2900, 28
50, 1650, 1565, 1515, 1470, 14
60, 1440, 1410, 1360, 1300, 12
60, 1230, 1175, 1140, 1100, 10
70,1020 cm ^{- 1} . Elemental analysis Calculated as C ₁₅ H ₁₇ N ₂ OSCl · 0.5H ₂ O: C: 56.68%, H: 5.71%, N: 8.81%, Found: C: 56.89%, H: 5.23%, N: 8.73 %.

Reference Example 57 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2-piperidinomethyl-3 (2H) -pyridazinone (Compound 60)

[Chemical 98] 5- (4-t-butylbenzyloxy) -4-chloro-
3 (2H) -pyridazinone (Compound 58) (59 mg)
Was suspended in ethanol (0.4 ml), and piperidine (1
8.8 mg) and 37% formaldehyde aqueous solution (0.02 ml) were added, and it heated at 55 degreeC for 3 minutes.
The reaction mixture was ice-cooled, and the precipitated colorless needle crystals were collected by filtration.
Compound 60 (49 mg) was obtained by washing with ethanol and ether and then drying. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.
34-1.68 (6H, m), 2.66 (4H, t, J
= 5 Hz), 5.04 (2H, s), 5.30 (2H,
s), 7.34 (2H, d, J = 8Hz), 7.44
(2H, d, J = 8Hz), 7.78 (1H, s). IR (KBr): 3450, 3100, 3060, 29
40, 2860, 2810, 1650, 1630, 16
00, 1520, 1460, 1405, 1380, 13
60, 1310, 1280, 1180, 1150, 11
10,1095,1020cm ^{- 1.}

Reference Example 58 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2-dimethylaminomethyl-3 (2H) -pyridazinone (Compound 61)

[Chemical 99] In the same manner as in Reference Example 57, 5- (4-t-butylbenzyloxy) -4-chloro-3 (2H) -pyridazinone (Compound 58) (293 mg), ethanol (2 ml), 5
Compound 61 (20 mg) from 0% dimethylamine aqueous solution (99 mg) and 37% formaldehyde aqueous solution (0.1 ml).
4 mg) was obtained. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 2.
42 (6H, s), 4.99 (2H, s), 5.32
(2H, s), 7.35 (2H, d, J = 9Hz),
7.45 (2H, d, J = 9Hz), 7.80 (1H,
s). IR (KBr): 3450, 3100, 3060, 29
60, 2860, 2800, 1640, 1600, 15
20, 1470, 1460, 1440, 1400, 13
80, 1360, 1315, 1290, 1270, 11
60,1140,1095,1060,1020cm ^-
1 .

Reference Example 59 2-bis (2-chloroethyl) aminomethyl-5- (4
-T-butylbenzyloxy) -4-chloro-3 (2
H) -Pyridazinone (Compound 62)

[Chemical 100] In the same manner as in Reference Example 57, 5- (4-t-butylbenzyloxy) -4-chloro-3 (2H) -pyridazinone (Compound 58) (147 mg), ethanol (1.5 m
l), bis (2-chloroethyl) amine (106.5 m
g), 37% aqueous formaldehyde solution (0.06 ml)
From this, compound 62 (86 mg) was obtained. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 3.
18 (4H, t, J = 6.6Hz), 3.59 (4H,
t, J = 7 Hz), 5.15 (2H, s), 5.31
(2H, s), 7.34 (2H, d, J = 8Hz),
7.44 (2H, d, J = 8Hz), 7.80 (1H,
s). IR (KBr): 3430, 3100, 3060, 29
60, 2860, 1650, 1630, 1595, 15
15, 1450, 1410, 1385, 1365, 13
10, 1270, 1230, 1150, 1120, 11
10,1090,1035,1015cm ^{- 1.}

Reference Example 60 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2-hydroxymethyl-3 (2H) -pyridazinone (Compound 63)

[Chemical 101] In the same manner as in Reference Example 57, 5- (4-t-butylbenzyloxy) -4-chloro-3 (2H) -pyridazinone (Compound 58) (147 mg), ethanol (1.5 m
l), 37% formaldehyde aqueous solution (0.15 ml)
From this, compound 63 (72 mg) was obtained. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 4.
12 (1H, t, J = 7Hz), 5.34 (2H,
s), 5.54 (2H, d, J = 7Hz), 7.33
(2H, d, J = 8Hz), 7.45 (2H, d, J =
8 Hz), 7.82 (1H, s). IR (KBr): 3440, 3280, 2960, 16
25, 1595, 1510, 1460, 1420, 14
00, 1360, 1320, 1310, 1270, 12
40,1170,1095,1070cm ^{- 1.}

Reference Example 61 Preparation of 2-t-butyl-5-hydroxy-3 (2H) -pyridazinone

[Chemical 102] 2-t-butyl-4-chloro-5-hydroxy-3 (2
H) -pyridazinone (608 mg) in methanol (60
10% Pd-carbon (304 mg) was added to the solution, and the mixture was vigorously stirred under a hydrogen atmosphere for 20 hours. After removing the catalyst by filtration and washing with methanol, sodium hydrogen carbonate (252 mg) and water (20 ml) were added and the mixture was stirred. When methanol was distilled off under reduced pressure, colorless needle crystals were precipitated, which was collected by filtration, washed with water, methanol and ether, and dried to obtain the title compound (349 mg). NMR (CDCl ₃ ) δ: 1.64 (9H, s), 6.
05 (1H, d, J = 3Hz), 7.58 (1H, d,
J = 3 Hz). IR (KBr): 3440, 3060, 3020, 2
980, 2930, 1645, 1600, 1565, 1
540, 1470, 1395, 1365, 1325, 1
270, 1230, 1190, 1150, 1130, 1
020,1005cm ^{- 1.}

Reference Example 62 Preparation of 5- (4-t-butylbenzyloxy) -2-t-butyl-3 (2H) -pyridazinone (Compound 64)

[Chemical 103] To a solution of 2-t-butyl-5-hydroxy-3 (2H) -pyridazinone (169 mg) in DMF (7.5 ml),
Sodium carbonate (106 mg) and 4-t-butylbenzyl chloride (219 mg) were added, and the mixture was stirred at 70 ° C for 7 hr. The insoluble material was filtered off, the solvent was distilled off under reduced pressure, and the resulting residue was subjected to flash column chromatography (developing solvent: hexane-ethyl acetate = 19: 1 to 13: 1).
Compound 64 (287 mg) was obtained by purification with. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.
62 (9H, s), 4.95 (2H, s), 6.12
(1H, d, J = 3Hz), 7.32 (2H, d, J =
8 Hz), 7.43 (2H, d, J = 8 Hz), 7.5
4 (1H, d, J = 3 Hz). IR (KBr): 3430, 3060, 2970, 29
30, 2860, 1655, 1600, 1540, 15
15, 1450, 1405, 1390, 1360, 13
40, 1310, 1265, 1240, 1195, 11
45,1105,1085,1020,1010cm ^-
1 .

Reference Example 63 Preparation of 2-t-butyl-4,5-difluoro-3 (2H) -pyridazinone

[Chemical 104] Under an argon atmosphere, 2-t-butyl-4,5-dichloro-3 (2H) -pyridazinone (6.91 g) and spray-dried potassium fluoride (7.26 g) were suspended in anhydrous dimethyl sulfoxide (300 ml), and 25 at ℃
Stir for hours. The reaction mixture was poured into water (1.51), and the product was extracted with ether (1l). The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to flash column chromatography (developing solvent: hexane-
The title compound (1.13g) was obtained by refine | purifying with ethyl acetate = 99: 1. NMR (CDCl ₃ ) δ: 1.65 (9H, s), 7.
80 (1H, d, J = 8Hz). IR (KBr): 3430, 3000, 2980, 29
40, 2870, 1680, 1665, 1530, 15
05, 1490, 1460, 1400, 1365, 13
40, 1320, 1260, 1225, 1190, 11
40,1090 cm ^{- 1} .

Reference Example 64 Preparation of 5- (4-t-butylbenzyloxy) -2-t-butyl-4-fluoro-3 (2H) -pyridazinone (Compound 65)

[Chemical 105] In the same manner as in Reference Example 53, 2-t-butyl-4,5-difluoro-3 (2H) in DMF (7.4 ml) solvent was used.
-Pyridazinone (303 mg), anhydrous cesium carbonate (2
65 mg), 4-t-butylbenzyl alcohol (36
Compound 65 (347 mg) was obtained from 5 mg). NM
R (CDCl ₃ ) δ: 1.33 (9H, s), 1.63
(9H, s), 5.30 (2H, d, J = 2Hz),
7.33 (2H, d, J = 8Hz), 7.43 (2H,
d, J = 8 Hz), 7.61 (1H, d, J = 8H
z). IR (KBr): 3430, 2990, 2950, 29
00, 2870, 1655, 1650, 1640, 15
10, 1460, 1405, 1380, 1365, 13
40, 1315, 1280, 1270, 1230, 11
90,1150,1115,1020cm ^{- 1.} Elemental _{analysis: C 1 9 H 2 5 N} 2 O 2 F Calculated: C: 68.65%, H: 7.58%, N: 8.43%,
F: 5.72%, measured value: C: 68.51%, H: 7.34%, N: 8.46%,
F: 5.55%.

Reference Example 65 5- (4-t-butylbenzylthio) -2-t-butyl-4-fluoro-3 (2H) -pyridazinone (Compound 6
6) Manufacturing

[Chemical formula 106] In the same manner as in Reference Example 53, in DMF (10 ml) solvent,
2-t-butyl-4,5-difluoro-3 (2H) -pyridazinone (377 mg), anhydrous cesium carbonate (652
mg), 4-t-butylbenzylthiol (577m
Compound 66 (207 mg) was obtained from g). NMR
(CDCl ₃ ) δ: 1.31 (9H, s), 1.62
(9H, s), 4.23 (2H, s), 7.27 (2
H, d, J = 8Hz), 7.36 (2H, d, J = 8H)
z), 7.56 (1H, d, J = 8Hz). IR (KBr): 3450, 2970, 2940, 2
870, 1645, 1600, 1560, 1540, 1
520, 1510, 1480, 1460, 1420, 1
395, 1365, 1325, 1270, 1225, 1
180, 1140, 1105, 1020 cm ^{- 1} . Elemental _{analysis: C 1 9 H 2 5 N} 2 OSF Calculated: C: 65.49%, H: 7.23%, N: 8.04%,
F: 5.45%, measured value: C: 65.17%, H: 7.04%, N: 7.99%,
F: 5.42%.

Reference Example 66 4-Bromo-2-t-butyl-5- (4-t-butyl)
Benzyloxy-3 (2H) pyridazinone (Compound 6
7) Manufacturing

[Chemical formula 107] To a solution of 4,5-dibromo-2-t-butyl-3 (2H) pyridazinone (500 mg) in DMF (5 ml) was added anhydrous cesium carbonate (613 mg) and 4-t-butylbenzyl alcohol (0.33 ml) to obtain 100. 3 at ℃
Stir for hours. After cooling to room temperature, water was added and the product was extracted with ether. The extract was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: ether-hexane =
It was purified by 1: 4) and recrystallized from ether-hexane to obtain Compound 67 (188 mg: yield 25%) as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.
64 (9H, s), 5.29 (2H, s), 7.30-
7.50 (4H, m), 7.66 (1H, s).

Reference Example 67 2-benzyl-5- (4-t-butyl) benzylthio-
Preparation of 4-chloro-3 (2H) pyridazinone (Compound 68)

[Chemical 108] 2-Benzyl-4-chloro-5 in the same manner as in Reference Example 6.
-Mercapto-3 (2H) pyridazinone (505m
g), anhydrous sodium carbonate (212 mg) and 4-t
Compound 68 (518 mg: yield 65%) was obtained as colorless needles from -butylbenzyl chloride (0.39 ml). NMR (CDCl ₃ ) δ: 1.30 (9H, s), 4.
23 (2H, s), 5.30 (2H, s), 7.25-
7.45 (9H, m), 7.67 (1H, s).

Reference Example 68 2-Benzyl-5- (4-t-butyl) benzyloxy-4-chloro-3 (2H) pyridazinone (Compound 69)
Manufacturing of

[Chemical 109] In the same manner as in Reference Example 66, 2-benzyl-4,5-dichloro-3 (2H) pyridazinone (510 mg), anhydrous cesium carbonate (651 mg) and 4-t-butylbenzyl alcohol (0.53 ml) were used to give compound 69 ( 518
mg: yield 65%) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 5.
27 (2H, s), 5.32 (2H, s), 7.25-
7.45 (9H, m), 7.79 (1H, s).

Reference Example 69 4-chloro-2-cyclohexyl-5- (4-phenyl) benzylthio-3 (2H) pyridazinone (Compound 7
0) Manufacturing

[Chemical 110] In the same manner as in Reference Example 6, 4-chloro-2-cyclohexyl-5-mercapto-3 (2H) pyridazinone (20 m
g), anhydrous sodium carbonate (17 mg) and 4- (chloromethyl) biphenyl (17 mg) to compound 70.
(18 mg: 54% yield) was obtained as colorless needle crystals. NMR (CDCl ₃ ) δ: 1.10-1.19 (10
H, m), 4.32 (2H, s), 4.80-4.95.
(1H, m), 7.30-7.65 (9H, m), 7.
72 (1H, s).

Reference Example 70 Preparation of 2-t-butyl-4-chloro-5- (3,4-methylenedioxyphenyl) methoxy-3 (2H) -pyridazinone (Compound 71)

[Chemical 111] To a solution of 2-t-butyl-4,5-dichloro-3 (2H) pyridazinone (220 mg) in DMF (5 ml) was added anhydrous cesium carbonate (485 mg) and piperonyl alcohol (152 mg), and the mixture was stirred at room temperature for 2 days. did. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1:
Compound 71 (225 mg: yield 67)
%) As colorless crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.
21 (2H, s), 5.90 (2H, s), 6.80-
6.90 (3H, m), 7.22 (1H, s). Reference Example 71 Preparation of 1- (4-biphenyl) -1,2-ethanediol

[Chemical 112] 4-Methylmorpholine-N-oxide (1.29 g) was added to water (25 ml) -acetone (20 ml) -THF (20
ml) in a mixed solvent of osmium oxide (1% t
-Butanol solution: 7 ml) and then 4-vinylbiphenyl (1.8 g) were added, and the mixture was stirred at room temperature for 8 hours. The reaction solution was treated with NaSO ₃ , the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed with saturated aqueous sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1: 3) to obtain the title compound (1.89 g: yield 88%). It was NMR (CDCl ₃ -CD ₃ OD) δ: 3.65 (1
H, dd, J = 11Hz, 8Hz), 3.79 (1H,
dd, J = 11 Hz, 3 Hz), 4.83 (1H, d
d, J = 8 Hz, 3 Hz), 7.29-7.64 (9
H, m).

Reference Example 72 Preparation of 1- (4-biphenyl) -2- (t-butyldimethylsilyloxy) -ethanol

[Chemical 113] 1- (4-biphenyl) -1,2-ethanediol was dissolved in a mixed solution of dichloromethane (30 ml) -THF (30 ml), and triethylamine (520 m was prepared under ice cooling.
g), t-butyldimethylchlorosilane (775 mg)
And dimethylaminopyridine (23 mg) were added, the temperature was raised to room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1: 9).
The title compound (1.25 g, yield 96%) was obtained. NMR (CDCl ₃ ) δ: 0.01 (6H, s), 0.
82 (9H, s), 2.90 (1H, d, J = 2H
z), 3.48 (1H, dd, J = 10Hz, 9H)
z), 3.71 (1H, dd, J = 10Hz, 4H
z), 4.70 (1H, ddd, J = 9Hz, 4Hz,
2 Hz), 7.25-7.60 (9H, m). Reference Example 73 Preparation of 3-t-butoxycarbonylamino-6- (4-methylphenyl) pyridine

[Chemical 114] 3-amino-6- (4-methylphenyl) pyridine (3
50 mg) and dimethylaminopyridine (278 m
g) was dissolved in dichloromethane (10 ml), and di-t-butyl dicarbonate (497 mg) was added under ice cooling. The temperature was raised to room temperature and the mixture was stirred for 5 hours. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 1: 8) to give the title compound (186 mg: yield). Rate of 34%). NMR (CDCl ₃ ) δ: 1.47 (9H, s), 2.
41 (3H, s), 7.28 (1H, d, J = 9H
z), 7.64-7.78 (2H, m), 7.90 (2
H, d, J = 9 Hz), 8.63 (1H, m).

Reference Example 74 Preparation of 3-t-butoxycarbonylamino-6- (4-bromomethylphenyl) pyridine

[Chemical 115] In the same manner as in Reference Example 1, 3-t-butoxycarbonylamino-6- (4-methylphenyl) pyridine (175 m
The title compound was obtained from g), N-bromosuccinimide (121 mg) and benzoyl peroxide (15 mg). NMR (CDCl ₃ ) δ: 1.47 (9H, s), 4.
55 (2H, s), 7.51 (2H, d, J = 8H
z), 7.66-7.78 (2H, m), 8.00 (2
H, d, J = 8 Hz), 8.66 (1 H, m).

Reference Example 75 Preparation of 2-t-butoxycarbonylamino-4- (4-methylphenyl) pyridine

[Chemical formula 116] 2-Amino-4- (4-methylphenyl) pyridine (1.87 g) was dissolved in anhydrous THF (70 ml), di-t-butyl dicarbonate (2.32 g) was added, and the mixture was heated under reflux for 3 hours. After cooling to room temperature, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (carrier 50 g; developing solvent: dichloromethane) to obtain the title compound (1.01 g). NMR (CDCl ₃ ) δ: 1.55 (9H, s), 2.
40 (3H, s), 7.18 (1H, dd, J = 5H
z, 2 Hz), 7.26 (2H, d, J = 8 Hz) 7.
59 (2H, d, J = 8Hz), 7.84 (1H, br
s), 8.21 (1H, s), 8.26 (1H, d, J
= 5 Hz). Reference Example 76 Preparation of 2-t-butoxycarbonylamino-4- (4-bromomethylphenyl) pyridine

[Chemical 117] In the same manner as in Reference Example 1, 2-t-butoxycarbonylamino-4- (4-bromomethylphenyl) pyridine (9
71 mg), N-bromosuccinimide (704 mg)
And benzoyl peroxide (26 mg) gave the title compound (1.23 g). NMR (CDCl ₃ ) δ: 1.55 (9H, s), 4.
54 (2H, s), 7.18 (1H, dd, J = 5H
z, 2 Hz), 7.47-7.69 (4H, m), 8.
22 (1H, s), 8.28 (1H, d, J = 5H
z).

Reference Example 77 Preparation of 2- (4-bromomethylphenyl) pyrimidine

[Chemical 118] In the same manner as in Reference Example 1, the title compound (454 mg) was obtained from 2- (4-methylphenyl) pyrimidine (300 mg), N-bromosuccinimide (345 mg) and benzoyl peroxide (12 mg). NMR (CDCl ₃ ) δ: 4.56 (3H, s), 7.
20 (1H, t, J = 5Hz), 7.52 (2H, d,
J = 8 Hz), 8.43 (2H, d, J = 8 Hz),
8.81 (2H, d, J = 5Hz). Reference Example 78 Preparation of 2- (4-bromomethylphenyl) -4,6-dichloropyrimidine

[Chemical formula 119] In the same manner as in Reference Example 1, 4,6-dichloro-2- (4-
From methylphenyl) pyrimidine (500 mg), N-bromosuccinimide (409 mg) and benzoyl peroxide (15 mg), the title compound (515 mg: yield 7
7%). NMR (CDCl ₃ ) δ: 4.54 (3H, s), 7.
29 (1H, s), 7.52 (2H, d, J = 8H
z), 8.42 (2H, d, J = 8Hz). Reference Example 79 Preparation of 2- (4-bromomethylphenyl) -4,6-dimethoxypyrimidine

[Chemical 120] In the same manner as in Reference Example 1, 4,6-dimethoxy-2- (4
The title compound (425 mg: yield 63%) was obtained from -methylphenyl) pyrimidine (500 mg), N-bromosuccinimide (425 mg) and benzoyl peroxide (16 mg). NMR (CDCl ₃ ) δ: 4.05 (6H, s), 4.
55 (3H, s), 5.98 (1H, s), 7.48
(2H, d, J = 8Hz), 8.43 (2H, d, J =
8 Hz).

Reference Example 80 Preparation of 2-bromo-4'-bromomethylacetophenone

[Chemical 121] In the same manner as in Reference Example 1, the title compound (291 mg: yield 85%) was obtained from 2-bromo-4′-methylacetophenone (200 mg), N-bromosuccinimide (184 mg) and benzoyl peroxide (7 mg). Obtained. NMR (CDCl ₃ ) δ: 4.44 (3H, s), 4.
51 (3H, s), 7.52 (2H, d, J = 9H
z), 7.97 (2H, d, J = 9 Hz). Reference Example 81 Preparation of 2-amino-4- (4-bromomethylphenyl) thiazole / hydrobromide

[Chemical formula 122] 2-Bromo-4′-bromomethylacetophenone (20
0 mg) and thiourea (52 mg) to ethanol (4 mg
ml) and heated under reflux for 30 minutes. After cooling to room temperature, the solvent was distilled off under reduced pressure to obtain a crude product of the title compound. This crude product was used in the next reaction without further purification. NMR (CDCl ₃ ) δ: 4.52 (2H, s), 7.1
9 (1H, s), 7.50 (2H, d, J = 8Hz),
7.76 (2H, d, J = 8Hz), 8.95-9.25
(3H, m).

Reference Example 82 Production of N- (triphenylmethyl) -5- (4-methylphenyl) -1,2,4-triazole

[Chemical 123] After adding triethylamine (1.54 g) and triphenylmethyl chloride (3.08 g) to a DMF (20 ml) solution of 5- (4-methylphenyl) -1,2,4-triazole (1.60 g), at room temperature. Stir for 4 hours.
Water was added and the precipitated solid was collected by filtration, washed successively with water, a small amount of methanol and ether, and then under reduced pressure over phosphorus pentoxide (6).
The title compound was dried at 0 ° C. (3.28 g: yield 81%).
Got NMR (DMSO-d ₆ ) δ: 2.34 (3H, s),
7.10-7.16 (6H, m), 7.25 (2H, d,
J = 8 Hz), 7.36-7.44 (9H, m), 7.8
5 (2H, d, J = 8Hz), 8.15 (1H, s). IR (KBr): 3050, 3010, 1590, 148
0.1440 cm ^-1 . Reference Example 83 Production of N- (triphenylmethyl) -5- (4-bromomethylphenyl) -1,2,4-triazole

[Chemical formula 124] N- (triphenylmethyl) -5- (4-methylphenyl) -1,2,4-triazole (3.20 g), N-bromosuccinimide (1.56 g) and carbon tetrachloride (100 ml). Benzoyl peroxide (135mg)
The mixture was heated to reflux for 4.5 hours, cooled to room temperature, and the insoluble material was filtered off. The filtrate was evaporated under reduced pressure to give the title compound (3.83 g: yield 100%). NMR (DMSO-d ₆ ) δ: 4.74 (2H, s),
7.10-7.17 (6H, m), 7.35-7.46 (9
H, m), 7.52 (2H, d, J = 8Hz), 7.95
(2H, d, J = 8Hz), 8.20 (1H, s).

Reference Example 84 Preparation of N- (triphenylmethyl) -3- (4-methylphenyl) -pyrazole

[Chemical 125] In the same manner as in Reference Example 82, 3- (4-methylphenyl)
From the pyrazole (3.16 g) the title compound (6.9
9 g: yield 87%) was obtained. NMR (DMSO-d ₆ ) δ: 2.30 (3H, s), 6.73
(1H, d, J = 3Hz), 7.09-7.23 (6H,
m), 7.14 (2H, d, J = 8Hz), 7.33-
7.39 (10H, m), 7.63 (2H, d, J = 8H
z). Reference Example 85 Production of N- (triphenylmethyl) -3- (4-bromomethylphenyl) pyrazole

[Chemical formula 126] N- (triphenylmethyl) in the same manner as in Reference Example 83.
-3- (4-methylphenyl) -pyrazole (6.81
From g), the title compound (8.15 g: yield 100%) was obtained. NMR (DMSO-d ₆ ) δ: 4.71 (2H, s),
6.80 (1H, d, J = 3Hz), 7.09-7.15
(8H, m), 7.33-7.48 (10H, m), 7.
74 (2H, d, J = 8Hz).

Reference Example 86 Preparation of 5- (4-bromomethylphenyl) -1,2-oxazole

[Chemical 127] In the same manner as in Reference Example 83, 5- (4-methylphenyl)
The title compound (2.61 g: yield 100%) was obtained from -1,2-oxazole (1.59 g). NMR (CDCl ₃ ) δ: 4.52 (2H, s), 6.
55 (1H, d, J = 2Hz), 7.51 (2H, d,
J = 8 Hz), 7.79 (2H, d, J = 8 Hz),
8.31 (1H, d, J = 2Hz). Reference Example 87 Preparation of 5- (4-bromomethylphenyl) -1,2,4-thiadiazole

[Chemical 128] In the same manner as in Reference Example 83, 5- (4-methylphenyl)
The title compound (1.59 g, yield 42%) was obtained from -1,2,4-thiadiazole (2.64 g). NMR (CDCl ₃ ) δ: 4.53 (2H, s), 7.54 (2
H, d, J = 8Hz), 7.94 (2H, d, J = 8H
z), 8.72 (1H, s).

Reference Example 88 Preparation of 5- (4-bromomethylphenyl) -1,3-oxazole

[Chemical formula 129] In the same manner as in Reference Example 83, 5- (4-methylphenyl)
The title compound (1.42 g, yield 59%) was obtained from -1,3-oxazole (1.59 g). NMR (CDCl ₃ ) δ: 4.52 (2H, s), 7.39
(1H, s), 7.47 (2H, d, J = 8Hz), 7.
65 (2H, d, J = 8Hz), 7.94 (1H,
s). Reference Example 89 Preparation of 2-t-butyl-4-chloro-5- [4- (4-chlorobenzoyl) benzylthio] -3 (2H) -pyridazinone (Compound 72)

[Chemical 130] 2-t-butyl-4-chloro-5 in the same manner as in Reference Example 6.
-Mercapto-3 (2H) -pyridazinone (547m
g) and 4- (4-chlorobenzoyl) benzyl bromide (851 mg) were reacted and recrystallized from chloroform-ether to give compound 72 (729 mg: yield 65%).
Was obtained as pale yellow crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.34
(2H, s), 7.45 (2H, d, J = 8Hz), 7.
55 (2H, d, J = 8Hz), 7.59 (1H,
s), 7.75 (2H, d, J = 8Hz), 7.79 (2
H, d, J = 8 Hz). IR (KBr): 3100, 2980, 2930, 164
0, 1600, 1580, 1560, 1495, 146
0. Elemental analysis: Calculated as C ₂₂ H ₂₀ Cl ₂ N ₂ O ₂ S: C: 59.06%; H: 4.51%; N: 6.26%, Found: C: 58.77%; H: 4.51%; N: 6.21% ．

Reference Example 90 Preparation of 2-t-butyl-4-chloro-5- [4- (4-chlorobenzoyl) benzyloxy] -3 (2H) -pyridazinone (Compound 73)

[Chemical 131] In the same manner as in Reference Example 23, 2-t-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (608
mg) and 4- (4-chlorobenzoyl) benzyl bromide (1.02 g) were reacted and recrystallized from chloroform-ether to give compound 73 (791 mg: yield 61).
%) As colorless crystals. NMR (CDCl ₃ ) δ: 1.65 (9H, s), 5.40
(2H, s), 7.48 (2H, d, J = 8Hz), 7.
56 (2H, d, J = 8Hz), 7.74 (1H,
s), 7.77 (2H, d, J = 8Hz), 7.84 (2
H, d, J = 8 Hz). IR (KBr): 3050, 2960, 2940, 166
0, 1640, 1600, 1580, 1560, 149
5,1460 cm ^{- 1} . Elemental _{analysis: C 22 H 20 Cl 2 N} 2 O 3 Calculated: C: 61.26%, H: 4.67%, N: 6.49%, Found: C: 60.87%, H: 4.56%, N: 6.61%. Reference Example 91 Preparation of 5- (4-benzyloxybenzylthio) -2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 74)

[Chemical 132] In the same manner as in Reference Example 2, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (547m
g) and 4-benzyloxybenzyl chloride (6
40 mg) was reacted and pulverized with hexane to give compound 7
4 (968 mg: 93% yield) was obtained as a white powder. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.
23 (2H, s), 5.07 (2H, s), 6.97
(2H, d, J = 9 Hz), 7.32 (2H, d, J =
9 Hz), 7.34-7.45 (5 H, m), 7.62
(1H, s). IR (KBr): 2970, 2925, 2850, 16
50, 1645, 1600, 1580, 1560, 15
05cm ^{- 1} . Elemental analysis: Calculated as C _{2 2} H _{2 3} ClN ₂ O ₂ S: C: 63.68%, H: 5.59%, N:
6.75%, measured value: C: 63.69%, H: 5.74%, N:
6.86%.

Reference Example 92 5- (4-benzyloxybenzyloxy) -2-t-
Production of butyl-4-chloro-3 (2H) -pyridazinone (Compound 75)

[Chemical 133] 2-t-butyl-4-chloro-as in Reference Example 23
5-Hydroxy-3 (2H) -pyridazinone (608m
g) and 4-benzyloxybenzyl chloride (7
68 mg) was reacted and recrystallized from chloroform-ether to obtain Compound 75 (473 mg: yield 40%) as colorless crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.
08 (2H, s), 5.25 (2H, s), 7.01
(2H, d, J = 9 Hz), 7.34 (2H, d, J =
9Hz), 7.30-7.48 (5H, m), 7.74
(1H, s). IR (KBr): 3040, 2960, 2940, 16
45,1600,1585,1510cm ^{- 1.} Elemental analysis: Calculated as C _{2 2} H _{2 3} ClN ₂ O ₃ C: 66.24%, H: 5.81%, N:
7.02%, measured value: C: 65.84%, H: 5.84%, N:
7.30%. Reference Example 93 5- (4-t-butylbenzylthio) -4-chloro-2
-Methyl-3 (2H) -pyridazinone (Compound 76)

[Chemical 134] In the same manner as in Reference Example 6, 4-chloro-2-methyl-5-mercapto-3 (2H) -pyridazinone (361 mg) and 4-t-butylbenzyl dil chloride (502 m
g) was reacted and purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 5: 1) to obtain Compound 76 (498 mg: yield 62%) as a colorless powder. NMR (CDCl ₃ ) δ: 1.31 (9H, s), 3.
78 (3H, s), 4.26 (2H, s), 7.33
(2H, d, J = 8 Hz), 7.39 (2H, d, J =
8 Hz), 7.65 (1 H, s). IR (KBr): 3050, 2955, 2900, 28
60, 1640, 1560, 1505 cm ^{- 1} . Elemental _{analysis: C 1 6 H 1 9 ClN} 2 OS Calculated: C: 59.52%, H: 5.93%, N:
8.63%, measured value: C: 59.40%, H: 5.70%, N:
8.69%.

Reference Example 94 5- (4-t-butylbenzyloxy) -4-chloro-
2-Methyl-3 (2H) -pyridazinone (Compound 77)
Manufacturing of

[Chemical 135] To a solution of 4,5-dichloro-2-methyl-3 (2H) -pyridazinone (1.00 g) in DMF (10 ml) was added anhydrous cesium carbonate (1.09 g) and 4-t-butylbenzyl alcohol (1.10 g). In addition, the mixture was stirred at 80 ° C for 24 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. After washing the extract with saturated aqueous sodium chloride solution,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 9: 1 to 4: 1) to give compound 77 (580 mg: yield 34%) as a colorless powder. Obtained. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 3.
79 (3H, s), 5.30 (2H, s), 7.33
(2H, d, J = 8Hz), 7.43 (2H, d, J =
8 Hz), 7.76 (1 H, s). IR (KBr): 2960, 2950, 2900, 28
60,1650,1640,1600,1520cm ^-
1 . Mp: 119-120 ° C. Elemental _{analysis: C 16 H 19 ClN 2 O} 2 Calculated: C: 62.64%, H: 6.24%, N:
9.13%, measured value: C: 62.66%, H: 6.14%, N:
9.32%.

Reference Example 95 5- (4-t-butylbenzylthio) -4-chloro-2
Preparation of-(2-propyl) -3 (2H) -pyridazinone (Compound 78)

[Chemical 136] 4,5-Dichloro-2- (2-propyl) -3 (2H)
To a solution of -pyridazinone (621 mg) in DMF (5 ml) was added anhydrous cesium carbonate (977 mg) and 4-t-butylbenzylthiol (541 mg), and the mixture was stirred at 60 ° C for 1 hour. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 19: 1) to obtain compound 78 (582 mg: yield 55%) as a colorless powder. NMR (CDCl ₃ ) δ: 1.32 (9H, s), 1.
33 (6H, d, J = 6.6Hz), 4.26 (2H,
s), 5.27 (1H, quintet, J = 7H
z), 7.32 (2H, d, J = 8 Hz), 7.39
(2H, d, J = 8 Hz), 7.73 (1H, s). IR (KBr): 3050, 2950, 2940, 28
60, 1645, 1560, 1505 cm ^{- 1} . Elemental _{analysis: C 1 8 H 2 3 ClN} 2 OS Calculated: C: 61.61%, H: 6.61%, N:
7.98%, actual value: C: 61.71%, H: 6.48%, N:
8.17%.

Reference Example 96 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2- (2-propyl) -3 (2H) -pyridazinone (Compound 79)

[Chemical 137] In the same manner as in Reference Example 94, 4,5-dichloro-2- (2-
Propyl) -3 (2H) -pyridazinone (725 mg)
And 4-t-butylbenzyl alcohol (690 m
Compound 79 (588 mg: yield 50%) was obtained as a colorless powder from g). NMR (CDCl ₃ ) δ: 1.33 (9H, s), 1.
33 (6H, d, J = 7Hz), 5.29 (2H,
s), 5.31 (1H, quintet, J = 7H
z), 7.34 (2H, d, J = 8 Hz), 7.44
(2H, d, J = 8 Hz), 7.84 (1H, s). IR (KBr): 3050, 2960, 2900, 28
60,1630,1590,1510cm ^{- 1.} Elemental _{analysis: C 1 8 H 2 3 ClN} 2 O 2 Calculated: C: 64.57%, H: 6.92%, N:
8.37%, measured value: C: 64.28%, H: 6.81%, N:
8.45%. Reference Example 97 4,5-Dichloro-2-methoxymethyl-3 (2H)-
Production of pyridazinone

[Chemical 138] Sodium hydride (60% oiliness: 880 mg) was washed with hexane and dried. DMF (10 ml) was added thereto, and after cooling to 0 ° C., a solution of 4,5-dichloro-3-hydroxypyridazine (3.30 g) in DMF (25 ml) was added dropwise. After stirring at 0 ° C. for 15 minutes, a solution of chloromethyl methyl ether (1.77 g) in DMF (5 ml) was added. After stirring at room temperature for 2.5 hours, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 5: 1) to give the title compound (3.06 g: yield 73%) as a colorless powder. . NMR (CDCl ₃ ) δ: 3.49 (3H, s), 5.
47 (2H, s), 7.82 (1H, s). IR (KBr): 3090, 3050, 3000, 29
50,2820,1655,1580,1505cm ^-
1 .

Reference Example 98 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2-methoxymethyl-3 (2H) -pyridazinone (Compound 80)

[Chemical 139] In the same manner as in Reference Example 94, 4,5-dichloro-2-methoxymethyl-3 (2H) -pyridazinone (700 mg)
And 4-t-butylbenzyl alcohol (660 m
Compound 80 (619 mg: 55% yield) was obtained as a colorless powder from g). NMR (CDCl ₃ ) δ: 1.33 (9H, s), 3.
45 (3H, s), 5.33 (2H, s), 5.45
(2H, s), 7.33 (2H, d, J = 9Hz),
7.44 (2H, d, J = 9Hz), 7.84 (1H,
s). IR (KBr): 2960, 2940, 1660, 16
00 cm ^{- 1} . Elemental _{analysis: C 1 7 H 2 1 ClN} 2 O 3 Calculated: C: 60.62%, H: 6.28%, N:
8.32%, actual value: C: 60.52%, H: 6.25%, N:
8.15%. Reference Example 99 Production of 4,5-dichloro-2- (2-methoxyethoxymethyl) -3 (2H) -pyridazinone

[Chemical 140] A colorless powder of the title compound (3.57 g, yield 71%) was obtained from 4,5-dichloro-3-hydroxypyridazine (3.30 g) and β-methoxyethoxymethyl chloride (2.74 g) in the same manner as in Reference Example 97. Got as. NMR (CDCl ₃ ) δ: 3.36 (3H, s), 3.51-
3.56 (2H, m), 3.81-3.86 (2H,
m), 5.57 (2H, s), 7.81 (1H, s). IR (KBr): 3100, 3050, 2940, 28
80, 1670, 1580 cm ^{- 1} .

Reference Example 100 5- (4-t-butylbenzyloxy) -4-chloro-
Preparation of 2- (2-methoxyethoxymethyl) -3 (2H) -pyridazinone (Compound 81)

[Chemical 141] In the same manner as in Reference Example 94, 4,5-dichloro-2- (2-
Compound 81 (1.06 g: yield 5) was obtained from methoxyethoxymethyl) -3 (2H) -pyridazinone (1.27 g) and 4-t-butylbenzyl alcohol (986 mg).
6%) was obtained as a colorless powder. NMR (CDCl ₃ ) δ: 1.33 (9H, s), 3.
34 (3H, s), 3.49-3.54 (2H, m),
3.79-3.84 (2H, m), 5.33 (2H,
s), 5.55 (2H, s), 7.33 (2H, d, J
= 8 Hz), 7.44 (2H, d, J = 8 Hz), 7.
83 (1H, s). IR (KBr): 2955, 2860, 2805, 16
50,1600,1515cm ^{- 1.} Elemental _{analysis: C 1 9 H 2 5 ClN} 2 O 4 Calculated: C: 59.52%, H: 6.62%, N:
7.36%, measured value: C: 59.76%, H: 6.59%, N:
7.32%. Reference Example 101 2-tert-butyl-4-chloro-5- [4- (2,
4-Dichlorobenzoyl) benzylthio] -3 (2H)
-Production of pyridazinone

[Chemical 142] 2-tert-butyl-4-chloro-5-mercapto-
3 (2H) -pyridazinone (547 mg) in DMF (1
5 ml) solution was added anhydrous potassium carbonate (380 mg) and 4- (2,4-dichlorobenzoyl) benzyl bromide (946 mg), and the mixture was stirred at 80 ° C for 3 hours.
After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from methanol to give the title compound as pale yellow scaly crystals (676 m
g: 56% yield). NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.33
(2H, s), 7.34 (1H, d, J = 8.2Hz),
7.39 (1H, dd, J = 1.6, 8.6Hz), 7.5
1 (1H, d, J = 1.6Hz), 7.53 (2H, d,
J = 8.4 Hz), 7.56 (1H, s), 7.80 (2
H, d, J = 8.4 Hz). IR (KBr): 3090, 2980, 2920, 168
0,1640,1580,1560 cm ^{- 1} .

Reference Example 102 2-tert-butyl-4-chloro-5- [4- (2,
4-dichlorobenzoyl) benzyloxy] -3 (2
H) -Production of pyridazinone

[Chemical 143] 2-tert-butyl-4-chloro-5-hydroxy-
3 (2H) -pyridazinone (608 mg) in DMF (2
Anhydrous potassium carbonate (456 mg) and 4- (2,4-dichlorobenzoyl) benzyl bromide (1.14 g) were added to the solution (0 ml), and the mixture was stirred at 80 ° C for 3 hours.
After cooling to room temperature, water was added to generate a precipitate. This product was collected by filtration and washed with water. The obtained solid was recrystallized from methanol to give the title compound as colorless needle crystals (925 mg:
Yield 66%). NMR (CDCl ₃ ) δ: 1.64 (9H, s), 5.39
(2H, s), 7.35 (1H, d, J = 8.0Hz),
7.40 (1H, dd, J = 1.8, 8.0Hz), 7.5
1 (1H, d, J = 1.8Hz), 7.55 (2H, d,
J = 8.4Hz), 7.72 (1H, s), 7.86 (2
H, d, J = 8.4 Hz). IR (KBr): 2980, 2940, 1640, 160
5,1580,1550cm ^{- 1.}

Example 1 Preparation of 2-t-butyl-4-chloro-5- {4- (2-pyridyl) benzylthio} -3 (2H) -pyridazinone (Compound 39)

[Chemical 144] 2-t-butyl-4-chloro-5-mercapto-3 (2
H) -pyridazinone (400 mg) in DMF (5 ml)
Anhydrous potassium carbonate (379 mg) and 4- (2
-Pyridyl) benzyl bromide (500 mg) was added, and the mixture was stirred at 100 ° C for 3.5 hr. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (carrier 40 g; developing solvent: ethyl acetate-hexane =).
It was purified by 1: 5) and recrystallized from methanol to obtain Compound 39 (492 mg: yield 70%) as pale yellow prism crystals. NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.61 (2H, s), 7.32-7.38
(1H, m), 7.59 (2H, d, J = 8.4Hz), 7.84-7.99 (2H, m), 8.07 (1H,
. s), 8.09 (2H, d, J = 8.4Hz), 8.65-8.68 (1H, m) IR (KBr): 2980,2940,1640,1590,1530cm -1 mp:. 143-144 ° C.. Elemental analysis: C ₂₀ H ₂₀ ClN ₃ OS Calculated: C: 60.35%; H: 5.79%; N: 10.05%. Found: C: 60.46%; H: 5.50%; N: 10.29%.

Example 2 Preparation of 2-t-butyl-4-chloro-5- [4- {N- (triphenylmethyl) tetrazol-5-yl} benzylthio] -3 (2H) -pyridazinone (Compound 40)

[Chemical 145] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (620m
g), anhydrous potassium carbonate (587 mg) and N- (triphenylmethyl) -5- (4-bromomethylphenyl) tetrazole (1.50 g) to compound 40 (80).
8 mg: 47% yield) was obtained as a white powder. NMR (DMSO-d ₆ ) δ: 1.55 (9H, s), 4.63 (2H, s), 7.05-7.
13 (6H, m), 7.38-7.46 (9H, m), 7.65 (2H, d, J = 8.0Hz), 8.0
3 (2H, d, J = 8.0Hz), 8.04 (1H, s). IR (KBr): 3050, 2980, 2930, 1735, 1640, 1590, 156
0, 1490, 1465, 1440, 1420 cm ⁻¹ . Melting point: 188-189 ° C.

Example 3 Preparation of 2-t-butyl-4-chloro-5- {4- (1H-tetrazol-5-yl) benzylthio} -3 (2H) -pyridazinone (Compound 41)

[Chemical 146] 2-t-butyl-4-chloro-5- {4- [N- (triphenylmethyl) tetrazol-5-yl} benzylthio] -3 (2H) -pyridazinone (450 mg) was added to 10 parts.
% Hydrochloric acid (5 ml) and tetrahydrofuran (10 m
It was dissolved in 1) and stirred at room temperature for 5.5 hours. 1 in the reaction solution
After adding 0% aqueous sodium hydroxide solution (5 ml),
The solvent was distilled off under reduced pressure. Water was added to the residue, insoluble materials were filtered off, and the filtrate was adjusted to pH 3 with hydrochloric acid. The precipitated solid was collected by filtration, washed successively with a small amount of water, methanol and ether, and dried over phosphorus pentoxide at 50 ° C. under reduced pressure to give compound 41 (79 mg: yield 28%) as a white powder. NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.65 (2H, s), 7.71 (2
H, d, J = 8.0Hz), 8.04 (2H, d, J = 8.0Hz), 8.06 (1H, s). Melting point: 258-259 ° C.

Example 4 Preparation of 2-t-butyl-4-chloro-5- {4- (2-pyridyl) benzyloxy} -3 (2H) -pyridazinone (Compound 42)

[Chemical 147] 2-t-butyl-4-chloro-5-hydroxy-3 (2
H) -pyridazinone (411 mg) in DMF (5 ml)
Anhydrous potassium carbonate (420 mg) and 4- (2
-Pyridyl) benzyl bromide (554 mg) was added, and the mixture was stirred at 120 ° C for 3 hr. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (carrier 40 g; developing solvent: ethyl acetate-hexane = 1: 1).
After purification in 5) and recrystallization from methanol, compound 42 (261 mg: yield 35%) was obtained as colorless needle crystals. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.53 (2H, s), 7.37 (1
H, ddd, J = 1.4, 4.8, 7.5Hz), 7.58 (2H, d, J = 8.2Hz), 7.89
(1H, dt, J = 1.8,7.5Hz), 7.99 (1H, dm, J = 7.5Hz), 8.15 (2H,
d, J = 8.2Hz), 8.29 (1H, s), 8.68 (1H, dm, J = 4.8Hz). IR (KBr): 3100, 3060, 2995, 2940, 1630, 1600, 158
0,1560,1500 cm ^-1 . Melting point: 164-165 ° C. Elemental _{analysis: C 20 H 20 ClN 3 O} 2 Calculated: C: 64.95%; H: 5.45%; N: 11.36%. Found: C: 65.07%; H: 5.51%; N: 11.33%.

Example 5 2-t-Butyl-4-chloro-5- [4- {N- (triphenylmethyl) tetrazol-5-yl} benzyloxy] -3 (2H) -pyridazinone (Compound 43) Manufacturing

[Chemical 148] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-Hydroxy-3 (2H) -pyridazinone (574m
g), anhydrous potassium carbonate (1.27 g) and N- (triphenylmethyl) -5- (4-bromomethylphenyl) tetrazole (1.50 g) to compound 43 (13).
1 mg: yield 8%) was obtained as a pale yellow powder. NMR (DMSO-d ₆ ) δ: 1.57 (9H, s), 5.55 (2H, s), 7.07-7.
15 (6H, m), 7.38-7.46 (9H, m), 7.64 (2H, d, J = 8.2Hz), 8.1
0 (2H, d, J = 8.2Hz), 8.26 (1H, s). IR (KBr): 3050, 2970, 1740, 1635, 1600, 1490,
1470, 1455, 1440, 1405 cm ^-1 . Melting point: 200-201 ° C.

Example 6 2-t-butyl-4-chloro-5- {4- (1H-tetrazol-5-yl) benzyloxy} -3 (2H)-
Production of pyridazinone (compound 44)

[Chemical 149] In the same manner as in Example 3, 2-t-butyl-4-chloro-
Compound 45 (28 mg: yield 46%) was obtained as a white powder from 5- [4- {N- (triphenylmethyl) tetrazol-5-yl} benzyloxy] -3 (2H) -pyridazinone (100 mg). . NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.60 (2H, s), 7.68
(2H, d, J = 8.0Hz), 8.11 (2H, d, J = 8.0Hz), 8.28 (1H, s). Melting point: 247-249 ° C.

Example 7 2-t-butyl-4-chloro-5- (2-hydroxy-
2-Phenyl) ethoxy-3 (2H) -pyridazinone (Compound 46) and 2-t-butyl-4-chloro-5.
-(2-Hydroxy-1-phenyl) ethoxy-3 (2
H) -Pyridazinone (Compound 47)

[Chemical 150] 2-tert-Butyl-4,5-dichloro-3 (2H) -pyridazinone (440 mg) and 2-hydroxy-2-phenylethanol (1.38 g) in DMF (100 m).
l) Anhydrous cesium carbonate (1.95 mg) was added to the solution and stirred overnight. The reaction solution was diluted with ether, washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (carrier 40 g), and hexane-ethyl acetate =
Elution with 4: 1 gave compound 46 (210 mg),
Further, it was eluted with hexane-ethyl acetate = 3: 1 to obtain Compound 47 (125 mg) as a colorless oily substance. Compound 46 NMR (CDCl ₃ ) δ: 1.64 (9H, s), 2.72 (1H, br.d, J = 3.0H
z), 4.26 (1H, dd, J = 8.0Hz, 10.0Hz), 4.34 (1H, dd, J = 3.5H
z, 10.0Hz), 5.10-5.25 (1H, m), 7.35-7.50 (5H, m), 7.73
(1H, s). Compound 47 NMR (CDCl ₃ ) δ: 1.59 (9H, s), 2.34 (1H, m), 3.80-4.05
(2H, m), 5.43 (1H, dd, J = 3.5Hz, 8.0Hz), 7.30-7.50 (5H,
m), 7.54 (1H, s).

Example 8 2-t-butyl-4-chloro-5- (2-hydroxy-
Preparation of 1-phenyl) ethylthio-3 (2H) -pyridazinone (Compound 48)

[Chemical 151] Methanesulfonyl chloride (0.42 ml) was added dropwise to a DMF (5 ml) solution of 2- (t-butyldimethylsilyloxy) -1-phenylethanol (1.27 g) and triethylamine (0.96 ml) under ice cooling. . After stirring for 30 minutes, the precipitate was filtered off and the 2- (t
A solution of -butyldimethylsilyloxy) -1-methanesulfonyloxy-1-phenylethane in DMF was obtained. Two
-T-butyl-4-chloro-5-mercapto-3 (2
H) -pyridazinone (1.00 g) in DMF (5 ml)
Sodium hydride (60% oiliness: 27
4 mg) was gradually added and stirred for 10 minutes. In the reaction solution, the above-mentioned 2- (t-butyldimethylsilyloxy)-
D of 1-methanesulfonyloxy-1-phenylethane
The MF solution was added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the product was extracted with ether. The extract was washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-t-butyl-4-chloro-5- [2
A crude product of-(t-butyldimethylsilyloxy) -1-phenyl] ethylthio-3 (2H) -pyridazinone was obtained. This was dissolved in THF (10 ml), tetrabutylammonium fluoride (1M THF solution: 8.5 ml) was added under ice cooling, and the mixture was stirred for 15 minutes. Water was added to the reaction solution, and the product was extracted with ether. The extract is
After washing with water, it was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (carrier: 50 g; developing solvent: ethyl acetate-hexane = 1: 2), and recrystallized from ethyl acetate-hexane to give compound 48 (268 mg) as colorless needle crystals. It was NMR (CDCl ₃ ) δ: 1.60 (9H, s), 1.89 (1H, br.t, J = 6.5H
z), 3.90-4.15 (2H, m), 4.64 (1H, t, J = 6.5Hz), 7.25-7.50
(5H, m), 7.60 (1H, s).

Example 9 2-t-butyl-4-chloro-5- [2-hydroxy-
2- (4-biphenyl)] ethoxy-3 (2H) -pyridazinone (Compound 82) and 2-t-butyl-4-chloro-5- [2-hydroxy-1- (4-biphenyl)] ethoxy-3 ( 2H) -pyridazinone (compound 8
3) Manufacturing

[Chemical 152] In the same manner as in Example 7, 2-t-butyl-4,5-dichloro-3 (2H) -pyridazinone (220 mg), 1-
(4-biphenyl) -1,2-ethanediol (214
mg) and anhydrous cesium carbonate (975 mg) to give compound 82 (68 mg: yield 40%) and compound 83 (4
1 mg: yield 24%) was obtained. Compound 82 NMR (CDCl ₃ ) δ: 1.64 (9H, s), 2.8
8 (1H, d, J = 3Hz), 4.29 (1H, dd,
J = 10Hz, 8Hz), 4.37 (1H, dd, J =
10Hz, 4Hz), 5.21 (1H, dd, J = 8H
z, 4 Hz), 7.30-7.65 (9H, m), 7.4
4 (1H, s). Compound 83 NMR (CDCl ₃ ) δ: 1.60 (9H, s), 2.50
(1H, brs), 3.87 (1H, dd, J = 12H
z, 3 Hz), 4.06 (1H, dd, J = 12 Hz,
8Hz), 5.48 (1H, dd, J = 8Hz, 3H
z), 7.32-7.64 (9H, m), 7.65 (1
H, s).

Example 10 2-t-butyl-4-chloro-5- [2- (t-butyldimethylsilyloxy) -1- (p-biphenyl)] ethylthio-3 (2H) -pyridazinone (Compound 84) Manufacturing of

[Chemical 153] A solution of 1- (4-biphenyl) -2- (t-butyldimethylsilyloxy) -ethanol (918 mg) and carbon tetrabromide (1.02 g) in THF (15 ml) under ice-cooling tributylphosphine (1.36 g). ) Was added dropwise, the temperature was raised to room temperature, and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 2: 98) to give 1
-(4-Biphenyl) -1-bromo-2- (t-butyldimethyloxy) ethane (810 mg) was obtained. Of this, 293 mg was dissolved in DMF (5 ml), and 2-t-butyl-4-chloro-5-mercapto-3 (2H) -pyridazinone (109 mg) and sodium carbonate (105
mg) was added and the mixture was stirred overnight. The reaction mixture was diluted with ethyl acetate and washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (developing solvent: ethyl acetate-hexane = 5: 95) to give compound 84 (171 mg: yield). 65%) was obtained. _{NMR (CDCl 3) δ: -0.06} (6H, s), 0.79
(9H, s), 1.55 (9H, s), 3.92 (1H,
dd, J = 11 Hz, 7 Hz), 4.03 (1H, d
d, J = 11 Hz, 6 Hz), 4.62 (1H, dd,
J = 7Hz, 6Hz), 7.30-7.60 (9H,
m), 7.62 (1H, s).

Example 11 2-t-butyl-4-chloro-5- [2-hydroxy-
Preparation of 1- (p-biphenyl)] ethylthio-3 (2H) -pyridazinone (Compound 85)

[Chemical 154] A solution of compound 84 (212 mg) in THF (4 ml) was cooled with ice to obtain tetrabutylammonium fluoride (1N T
HF solution: 0.44 ml) was added dropwise and stirred for 1 hour.
The reaction liquid and water were added, and the product was extracted with ether. The extract was washed with 1N hydrochloric acid and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (developing solvent: ether-hexane = 1: 1).
Compound 85 (45 mg) was obtained after purification. NMR (CDCl ₃ ) δ: 1.60 (9H, s), 2.04
(1H, t, J = 6Hz), 4.00 (1H, dd, J
= 12 Hz, 7 Hz), 4.08 (1H, dd, J = 1
2Hz, 6Hz), 4.69 (1H, dd, J = 7H)
z, 6 Hz), 7.30-7.65 (10H, m).

Example 12 2-t-butyl-4-chloro-5- [4- [2- (5-
Preparation of t-butoxycarbonylamino) pyridyl] benzylthio] -3 (2H) -pyridazinone (Compound 86)

[Chemical 155] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (33m
g), 3-t-butoxycarbonylamino-6- (4-
Compound 86 (28) was obtained from bromomethylphenyl) pyridine (50 mg) and anhydrous sodium carbonate (22 mg).
mg) was obtained. NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.62
(9H, s), 4.33 (2H, s), 7.53 (2H,
d, J = 8 Hz), 7.61 (1H, s), 7.70-
7.80 (2H, m), 8.00 (2H, d, J = 8H
z), 8.65 (1H, m).

Example 13 2-t-butyl-4-chloro-5- [4- [2- (5-
Preparation of t-butoxycarbonylamino) pyridyl] benzyloxy] -3 (2H) -pyridazinone (Compound 87)

[Chemical 156] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-hydroxy-3 (2H) -pyridazinone (31m
g), 3-t-butoxycarbonylamino-6- (4-
Compound 87 (37) was obtained from bromomethylphenyl) pyridine (50 mg) and anhydrous sodium carbonate (22 mg).
mg) was obtained. NMR (CDCl ₃ ) δ: 1.47 (9H, s), 1.63
(9H, s), 5.39 (2H, s), 7.53 (2H,
d, J = 8 Hz), 7.73 (1H, s), 7.74-
7.85 (2H, m), 8.06 (2H, d, J = 8H
z), 8.66 (1H, m).

Example 14 Preparation of 5- [4- [2- (5-amino) pyridyl] benzylthio] -2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 88)

[Chemical 157] Compound 86 (27 mg) in dichloromethane (0.5 m
l) in solution, under ice cooling, trifluoroacetic acid (0.1 m
1) was added, and the mixture was stirred at room temperature for 2 hours. After evaporating the solvent under reduced pressure, the residue was dissolved in ethyl acetate, the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol = 98: 2) to obtain compound 88 (16 mg). NMR (CDCl ₃ -CD ₃ OD) δ: 1.63 (9H, s), 4.
36 (2H, s), 7.54 (2H, d, J = 8H
z), 7.71 (1H, s), 7.73 (1H, d, J =
9Hz), 7.91 (2H, d, J = 8Hz), 8.30
(1H, dd, J = 9Hz, 3Hz), 8.47 (1
H, d, J = 3 Hz).

Example 15 Preparation of 5- [4- [2- (5-amino) pyridyl] benzyloxy] -2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 89)

[Chemical 158] Compound 87 (33 mg) was treated with trifluoroacetic acid (0.1 ml) in the same manner as in Example 32 to give compound 89.
(16 mg) was obtained. NMR (CDCl ₃ -CD ₃ OD) δ: 1.63 (9H, s), 5.
41 (2H, s), 7.53 (2H, d, J = 8H
z), 7.74 (1H, d, J = 9Hz), 7.82 (1
H, s), 7.96 (2H, d, J = 8Hz), 8.32
(1H, dd, J = 9Hz, 2Hz), 8.47 (1
H, d, J = 2 Hz). Example 16 2-t-butyl-4-chloro-5- [4- [4- (2-
Preparation of t-butoxycarbonylamino) pyridyl] benzylthio] -3 (2H) -pyridazinone (Compound 90)

[Chemical 159] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (274m
g), 4-t-butoxycarbonylamino-4- (4-
Compound 90 from bromomethylphenyl) pyridine (429 mg) and anhydrous sodium carbonate (136 mg).
(364 mg) was obtained. NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.63
(9H, s), 4.31 (2H, s), 7.17 (1H,
dd, J = 4 Hz, 2 Hz), 7.46-7.56 (m,
3H), 7.60 (1H, s), 7.68 (2H, d, J
= 8 Hz), 8.20 (1H, s), 8.28 (1H,
d, J = 5 Hz).

Example 17 2-t-butyl-4-chloro-5- [4- [4- (2-
Preparation of t-butoxycarbonylamino) pyridyl] benzyloxy] -3 (2H) -pyridazinone (Compound 91)

[Chemical 160] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-hydroxy-3 (2H) -pyridazinone (465m
g), 2-t-butoxycarbonylamino-4- (4-
Compound 91 from bromomethylphenyl) pyridine (797 mg) and anhydrous sodium carbonate (246 mg).
(629 mg) was obtained. NMR (CDCl ₃ ) δ: 1.54 (9H, s), 1.64
(9H, s), 5.37 (2H, s), 7.18 (1H,
dd, J = 5Hz, 2Hz), 7.41 (1H, br
s), 7.50 (2H, d, J = 8Hz), 7.72 (1
H, s), 7.73 (2H, d, J = 8Hz), 8.21
(1H, s), 8.28 (1H, d, J = 5Hz).

Example 18 Preparation of 5- [4- [4- (2-amino) pyridyl] benzylthio] -2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 92)

[Chemical 161] Compound 90 (289 mg) was treated with trifluoroacetic acid (0.5 ml) in the same manner as in Example 14 to give compound 92.
(143 mg) was obtained. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.31
(2H, s), 4.52 (2H, brs), 6.68 (1
H, s), 6.86 (1H, dd, J = 5Hz, 1H
z), 7.44-7.64 (5H, m), 8.12 (1
H, d, J = 5 Hz). Example 19 Preparation of 5- [4- [4- (2-amino) pyridyl] benzyloxy] -2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 93)

[Chemical 162] Compound 91 (511 mg) was treated with trifluoroacetic acid (1 ml) in the same manner as in Example 14 to give compound 93 (3).
60 mg) was obtained. NMR (CDCl ₃ ) δ: 1.64 (9H, s), 4.52
(2H, brs), 5.36 (2H, s), 6.69 (1
H, m), 6.88 (1H, dd, J = 5Hz, 2H
z), 7.50 (2H, d, J = 8Hz), 7.64 (2
H, d, J = 8 Hz), 7.74 (1H, s), 8.13
(1H, d, J = 5Hz).

Example 20 Preparation of 4-chloro-2-cyclohexyl-5- [4- (2-pyridyl)] benzylthio-3 (2H) -pyridazinone (Compound 94)

[Chemical formula 163] In the same manner as in Example 1, 4-chloro-2-cyclohexyl-5-mercapto-3 (2H) -pyridazinone (25
mg), 4- (2-pyridyl) benzyl bromide (51
Compound 94 (16 mg: yield 38%) was obtained as colorless crystals from (mg) and anhydrous sodium carbonate (11 mg) (recrystallization solvent: hexane-benzene). NMR (CDCl ₃ ) δ: 1.05-1.95 (10H,
m), 4.33 (2H, s), 4.75-4.95 (1
H, m), 7.25 (1H, m), 7.52 (2H, d,
J = 8 Hz), 7.65-7.80 (3H, m), 8.0
0 (2H, d, J = 8Hz), 8.67 (1H, m). Elemental _{analysis: C 22 H 22 N 3 OSCl} · 0.3H 2 O Calculated: C: 63.31%, H: 5.46%, N: 1
0.07%, measured value: C: 63.37%, H: 5.29%, N: 1
0.14%. Melting point: 192-193 [deg.] C. Example 21 Preparation of 4-chloro-2-cyclopropyl-5- [4- (2-pyridyl)] benzylthio-3 (2H) -pyridazinone (Compound 95)

[Chemical 164] In the same manner as in Example 1, 4-chloro-2-cyclopropyl-5-mercapto-3 (2H) -pyridazinone (26
mg), 4- (2-pyridyl) benzyl bromide (63
Compound 95 (12 mg: yield 44%) was obtained as colorless crystals from (mg) and anhydrous sodium carbonate (11 mg) (recrystallization solvent: hexane-benzene). NMR (CDCl ₃ ) δ: 0.95-1.15 (4H, m),
4.00-4.15 (1H, m), 4.33 (2H,
s), 7.27 (1H, m), 7.52 (2H, d, J =
8Hz), 7.60 (1H, m), 7.70-7.85
(2H, m), 8.01 (2H, d, J = 8Hz), 8.
70 (1H, m). Elemental analysis: Calculated as C ₁₉ H ₁₆ N ₃ OSCl: C: 61.70%, H: 4.36%, N: 1
1.36%, measured value: C: 61.56%, H: 4.37%, N: 1
1.44%. Melting point: 169-170 ° C.

Example 22 Preparation of 2-t-butyl-4-chloro-5- [4- (2-pyrimidyl)] benzylthio-3 (2H) -pyridazinone (Compound 96)

[Chemical 165] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (132m
g), 4- (2-pyrimidyl) benzyl bromide (15
0 mg) and anhydrous sodium carbonate (64 mg),
Compound 96 (194 mg: yield 83%) was obtained as colorless crystals (recrystallization solvent: ethanol). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.34
(2H, s), 7.21 (1H, t, J = 5Hz), 7.
50 (2H, d, J = 9Hz), 7.60 (1H,
s), 8.44 (2H, d, J = 9Hz), 8.81 (2
H, d, J = 5 Hz). Elemental analysis: Calculated as C ₁₉ H ₁₉ N ₄ OSCl: C: 58.98%, H: 4.95%, N: 1
4.48%, measured value: C: 59.14%, H: 4.98%, N: 1
4.44%. Melting point: 169-170 ° C.

Example 23 Preparation of 2-t-butyl-4-chloro-5- [4- (2-pyrimidyl)] benzyloxy-3 (2H) -pyridazinone (Compound 97)

[Chemical 166] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-hydroxy-3 (2H) -pyridazinone (203m
g), 4- (2-pyrimidyl) benzyl bromide (25
Compound 97 (124 mg: yield 33%) was obtained as colorless crystals from 0 mg) and anhydrous sodium carbonate (106 mg) (recrystallization solvent: ethanol). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.40
(2H, s), 7.22 (1H, t, J = 5Hz), 7.
54 (2H, d, J = 8Hz), 7.72 (1H,
s), 8.49 (2H, d, J = 8Hz), 8.82 (2
H, d, J = 5 Hz). Elemental analysis: Calculated as C ₁₉ H ₁₉ N ₄ O ₂ Cl: C: 61.54%, H: 5.16%, N: 1
5.18%, actual value: C: 61.26%, H: 5.13%, N: 1
5.10%. Melting point: 193-194 [deg.] C. Example 24 2-t-butyl-4-chloro-5- [4- [2- (4
6-Dimethoxy) pyrimidyl]] benzylthio-3 (2
H) -Pyridazinone (Compound 98)

[Chemical 167] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (109m
g), 4- [2- (4,6-dimethoxy) pyrimidyl]
Compound 98 (107 mg: yield 48%) was obtained as colorless crystals from benzyl bromide (155 mg) and anhydrous sodium carbonate (53 mg) (recrystallization solvent: ethyl acetate). NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.04
(6H, s), 4.33 (2H, s), 5.98 (1H,
s), 7.51 (2H, d, J = 8Hz), 7.60 (1
H, s), 8.45 (2H, d, J = 8Hz). Elemental analysis: Calculated as C ₂₁ H ₂₃ N ₄ O ₃ SCl: C: 56.43%, H: 5.19%, N: 1
2.54%, measured value: C: 56.68%, H: 5.13%, N: 1
2.36%.

Example 25 2-t-butyl-4-chloro-5- [4- [2- (4
6-dimethoxy) pyrimidyl]] benzyloxy-3
Production of (2H) -pyridazinone (Compound 99)

[Chemical 168] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-Hydroxy-3 (2H) -pyridazinone (164m
g), 4- [2- (4,6-dimethoxy) pyrimidyl]
Compound 99 (227 mg: yield 65%) was obtained as colorless crystals from benzyl bromide (250 mg) and anhydrous sodium carbonate (86 mg) (recrystallization solvent: ethyl acetate). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.05
(6H, s), 5.40 (2H, s), 5.99 (1H,
s), 7.50 (2H, d, J = 8Hz), 7.71 (1
H, s), 8.50 (2H, d, J = 8Hz). Elemental analysis: Calculated as C ₂₁ H ₂₃ N ₄ O ₄ Cl: C: 58.54%, H: 5.38%, N: 1
3.00%, measured value: C: 58.56%, H: 5.38%, N: 1
2.99%.

Example 26 2-t-butyl-4-chloro-5- [4- [2- (4,
6-Dichloro) pyrimidyl]] benzylthio-3 (2
Preparation of (H) -pyridazinone (Compound 100)

[Chemical 169] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (103m
g), 4- [2- (4,6-dichloro) pyrimidyl] benzyl bromide (150 mg) and anhydrous sodium carbonate (50 mg) to give compound 100 (75 mg: yield 3).
5%) was obtained as colorless crystals (recrystallization solvent: ethanol). NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.33
(2H, s), 7.29 (1H, s), 7.54 (2H,
d, J = 9 Hz), 7.57 (1H, s), 8.43 (2
H, d, J = 9 Hz). Elemental analysis: Calculated as C ₁₉ H ₁₇ N ₄ OSCl ₃ : C: 50.07%, H: 3.76%, N: 1
2.29%, measured value: C: 49.77%, H: 3.73%, N: 1
2.46%.

Example 27 2-t-butyl-4-chloro-5- [4- [2- (4
6-Dichloro) pyrimidyl]] benzyloxy-3 (2
H) -Pyridazinone (Compound 101)

[Chemical 170] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-hydroxy-3 (2H) -pyridazinone (203m
Compound 101 (242 mg: yield 55%) was obtained as colorless crystals from g), 4- [2- (4,6-dichloro) pyrimidyl] benzyl bromide (318 mg) and anhydrous sodium carbonate (106 mg) (recrystallization). Solvent: ethanol). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.40
(2H, s), 7.30 (1H, s), 7.54 (2H,
d, J = 9 Hz), 7.70 (1H, s), 8.48 (2
H, d, J = 9 Hz). Elemental analysis: Calculated as C ₁₉ H ₁₇ N ₄ O ₂ Cl ₃ : C: 51.90%, H: 3.90%, N: 1
2.74%, measured value: C: 51.67%, H: 3.88%, N: 1
2.60%.

Example 28 Preparation of 5- [4- [4- (2-aminothiazolyl]] benzylthio-2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 102)

[Chemical 171] In the same manner as in Example 1, 2-t-butyl-4-chloro-
5-Mercapto-3 (2H) -pyridazinone (109m
g), 2-amino-4- (4-bromomethylphenyl)
From thiazole hydrobromide (240 mg) and anhydrous sodium carbonate (80 mg) to compound 102 (40 m
g: yield 20%) was obtained as colorless crystals (recrystallization solvent:
ethanol). NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.54
(2H, brs), 7.02 (1H, s), 7.06 (2
H, brs), 7.45 (2H, d, J = 8Hz), 7.7
9 (2H, d, J = 8Hz), 8.05 (1H, s). Elemental analysis: Calculated as C ₁₈ H ₁₉ N ₄ OS ₂ Cl: C: 53.13%, H: 4.71%, N: 1
3.77%, measured value: C: 52.97%, H: 4.53%, N: 1
3.86%.

Example 29 Preparation of 5- [4- [4- (2-aminothiazolyl]] benzyloxy-2-t-butyl-4-chloro-3 (2H) -pyridazinone (Compound 103)

[Chemical 172] In the same manner as in Example 4, 2-t-butyl-4-chloro-
5-hydroxy-3 (2H) -pyridazinone (1.01
g), 2-amino-4- (4-bromomethylphenyl)
From thiazole hydrobromide (3.85 g) and anhydrous sodium carbonate (1.06 g) to compound 103 (83
mg: yield 4%) was obtained as colorless crystals (recrystallization solvent:
ethanol). NMR (DMSO-d ₆ ) δ: 1.57 (9H, s), 5.45
(2H, brs), 7.04 (1H, s), 7.06 (1
H, brs), 7.44 (2H, d, J = 9Hz), 7.8
3 (2H, d, J = 9Hz), 8.26 (1H, s). Elemental analysis: Calculated as C ₁₈ H ₁₉ N ₄ O ₂ SCl.H ₂ O: C: 52.87%, H: 5.18%, N: 1
3.70%, measured value: C: 52.79%, H: 4.85%, N: 1
3.42%.

Example 30 Preparation of 2-t-butyl-4-methyl-5- [4- (2-pyridyl)] benzyloxy-3 (2H) -pyridazinone (Compound 104)

[Chemical 173] In the same manner as in Example 1, 2-t-butyl-4-methyl-
5-hydroxy-3 (2H) -pyridazinone (1.61
g), 4- (2-pyridyl) benzyl bromide (3.2
0 g) and anhydrous sodium carbonate (936 mg),
Compound 104 (140 mg: yield 5%) was obtained as colorless crystals (recrystallization solvent: isopropyl ether). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 2.09
(3H, s), 5.27 (2H, s), 7.27 (1H,
m), 7.50 (2H, d, J = 9Hz), 7.72 (1
H, s), 7.68-7.80 (2H, m), 8.03
(2H, d, J = 9 Hz), 8.70 (1H, m). Elemental analysis: Calculated as C ₂₁ H ₂₃ N ₃ O ₂ .H ₂ O: C: 71.45%, H: 6.68%, N: 1
1.90%, measured value: C: 71.43%, H: 6.59%, N: 1
1.93%.

Example 31 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) -1H-1,2,4-triazole-
Preparation of 5-yl] benzylthio] -3 (2H) -pyridazinone (Compound 105)

[Chemical 174] 2-t-butyl-4-chloro-5-mercapto-3 (2
H) -pyridazinone (792 mg) in DMF (30 m
l) solution with anhydrous potassium carbonate (751 mg) and N
-(Triphenylmethyl) -5- (4-bromomethylphenyl) -1,2,4-triazole (1.85 g) was added, and the mixture was stirred at 100 ° C for 3.5 hr. After cooling to room temperature, water (300 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give compound 105 (1.30 g:
Yield 58%) was obtained as pale green prism crystals. NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.58
(2H, s), 7.10-7.17 (6H, m), 7.3
5-7.43 (9H, m), 7.55 (2H, d, J = 8
Hz), 7.96 (2H, d, J = 8Hz), 8.03
(1H, s), 8.19 (1H, s). Melting point: 212-213 [deg.] C. Elemental analysis: Calculated as C ₃₆ H ₃₂ ClN ₅ OS: C: 69.94%, H: 5.22%, N: 1
1.33%, measured value: C: 69.76%, H: 5.14%, N: 1
1.25%.

Example 32 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) -1H-1,2,4-triazole-
Preparation of 5-yl] benzyloxy] -3 (2H) -pyridazinone (Compound 106)

[Chemical 175] 2-t-butyl-4-chloro-5-hydroxy-3 (2
H) -pyridazinone (792 mg) in DMF (30 m
l) solution with anhydrous potassium carbonate (751 mg) and N
-(Triphenylmethyl) -5- (4-bromomethylphenyl) -1,2,4-triazole (1.85 g) was added, and the mixture was stirred at 100 ° C for 2.5 hr. After cooling to room temperature, water (300 ml) was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from ethyl acetate to give compound 106 (1.03 g:
Yield 47%) was obtained as colorless crystals. NMR (DMSO-d ₆ ) δ: 1.57 (9H, s),
5.50 (2H, s), 7.09-7.18 (6H,
m), 7.29-7.45 (9H, m), 7.54 (2
H, d, J = 8 Hz, 8.01 (2H, d, J = 8H)
z), 8.21 (1H, s), 8.25 (1H, s). Melting point: 168-169 ° C. Elemental analysis: Calculated as C ₃₆ H ₃₂ ClN ₅ O ₂ : C: 71.81%, H: 5.36%, N: 1
1.63%, measured value: C: 71.57%, H: 5.37%, N: 1
1.26%.

Example 33 2-t-butyl-4-chloro-5- [4- (1H-1,
2,4-triazol-5-yl) benzylthio] -3
Production of (2H) -pyridazinone (Compound 107)

[Chemical 176] 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) -1H-1,2,4-triazole-
5-yl] benzylthio] -3 (2H) -pyridazinone (618 mg) was dissolved in 10% hydrochloric acid (2 ml) and tetrahydrofuran (4 ml), and the mixture was stirred at 75 ° C for 3 hr. The solvent was evaporated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (developing solvent: chloroform-methanol = 95: 5) to give compound 107 (199m).
g: 53% yield) was obtained as a white powder. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.32
(2H, s), 7.51 (2H, d, J = 8Hz), 7.
62 (2H, d, J = 8Hz), 8.09 (1H,
s), 8.26 (1H, s). IR (KBr): 3210, 3100, 2990, 294
0,1620,1555,1495 cm ^-1 . Melting point: 199-200 ° C.

Example 34 2-t-butyl-4-chloro-5- [4- (1H-1,
2,4-triazol-5-yl) benzyloxy]-
Preparation of 3 (2H) -pyridazinone (Compound 108)

[Chemical 177] In the same manner as in Example 33, 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) -1H-
From 1,2,4-triazol-5-yl] benzyloxo] -3 (2H) -pyridazinone (602 mg),
Compound 108 (114 mg: yield 32%) was obtained as a white powder. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.51
(2H, s), 7.57 (2H, d, J = 8Hz), 8.
07 (2H, d, J = 8Hz), 8.27 (1H,
s), 8.46 (1H, s). IR (KBr): 3155, 3100, 3000, 284
0,1625,1595,1555,1500 cm ^-1 . Melting point: 220-221 ° C. Elemental _{analysis: C 17 H 18 ClN 5 O} 2 Calculated: C: 56.75%, H, 5: 04%, N: 1
9.46%, Example: C: 56.54%, H: 4.95%, N: 1
9.49%.

Example 35 2-t-Butyl-4-chloro-5- [4- [1- (triphenylmethyl) pyrazolo-3-yl] benzylthio]
Preparation of -3 (2H) -pyridazinone (Compound 109)

[Chemical 178] 2-t-butyl-4-chloro-as in Example 31
5-mercapto-3 (2H) -pyridazinone (1.69
Compound 109 (3.41 g, yield 72%) was obtained as colorless crystals from g) and N- (triphenylmethyl) -3- (4-bromomethylphenyl) pyrazole (4.08 g). NMR (DMSO-d ₆ ) δ: 1.56 (9H, s), 4.56
(2H, s), 6.80 (1H, d, J = 2Hz), 7.
08-7.16 (6H, m), 7.34-7.46 (10
H, m), 7.49 (2H, d, J = 8Hz), 7.76
(2H, d, J = 8Hz), 8.05 (1H, s). Melting point: 187-188 [deg.] C.

Example 36 2-t-Butyl-4-chloro-5- [4- [1- (triphenylmethyl) pyrazolo-3-yl] benzyloxy] -3 (2H) -pyridazinone (Compound 110) Manufacturing

[Chemical 179] 2-t-butyl-4-chloro-as in Example 32
5-hydroxy-3 (2H) -pyridazinone (1.44
Compound 110 (2.24 g, yield 52%) was obtained as colorless crystals from g) and N- (triphenylmethyl) -3- (4-bromomethylphenyl) pyrazole (4.08 g). NMR (DMSO-d ₆ ) δ: 1.57 (9H, s), 5.47
(2H, s), 6.82 (1H, d, J = 2.6Hz),
7.08-7.17 (6H, m), 7.33-7.45 (1
0H, m), 7.48 (2H, d, J = 8Hz), 7.8
1 (2H, d, J = 8Hz), 8.26 (1H, s). Melting point: 89-91 ° C.

Example 37 Preparation of 2-t-butyl-4-chloro-5- [4- (1H-pyrazol-3-yl) benzylthio] -3 (2H) -pyridazinone (Compound 111)

[Chemical 180] In the same manner as in Example 33, 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) pyrazolo-
Compound 111 (139 mg: 60% yield) was obtained as a white powder from 3-yl] benzylthio] -3 (2H) -pyridazinone (379 mg). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.31
(2H, s), 6.65 (1H, d, J = 2Hz), 7.
47 (2H, d, J = 8Hz), 7.63 (1H,
s), 7.64 (1H, d, J = 2Hz). 7.79 (2
H, d, J = 8 Hz). IR (KBr): 3250, 3000, 2970, 294
0,2890,1630,1560,1520 cm ^-1 . Melting point: 161-163 ° C. Elemental analysis: Calculated as C ₁₈ H ₁₉ ClN ₄ OS: C: 57.67%, H: 5.11%, N: 1
4.94%, actual value: C: 57.66%, H: 4.90%, N: 1
5.01%.

Example 38 Preparation of 2-t-butyl-4-chloro-5- [4- (1H-pyrazol-3-yl) benzyloxy] -3 (2H) -pyridazinone (Compound 112)

[Chemical 181] In the same manner as in Example 33, 2-t-butyl-4-chloro-5- [4- [1- (triphenylmethyl) pyrazolo-
Compound 112 (311 mg: yield 87%) was obtained as a white powder from 3-yl] benzyloxy] -3 (2H) -pyridazinone (601 mg). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 5.35
(2H, s), 6.66 (1H, d, J = 2Hz), 7.
47 (2H, d, J = 8Hz), 7.64 (1H, d,
J = 2 Hz), 7.74 (1H, s). 7.85 (2H,
d, J = 8 Hz). IR (KBr): 3000, 2960, 2940, 286
0,1620,1600,1515 cm ^-1 . Melting point: 198-200 ° C. Elemental _{analysis: C 18 H 19 ClN 4 O} 2 Calculated: C: 60.25%, H: 5.34%, N: 1
5.61%, measured value: C: 59.91%, H: 5.24%, N: 1
5.78%.

Example 39 2-t-butyl-4-chloro-5- [4- (1,2-oxazol-5-yl) benzylthio] -3 (2H)-
Production of pyridazinone (Compound 113)

[Chemical 182] In the same manner as in Example 31, 2-t-butyl-4-chloro-5-mercapto-3 (2H) -pyridazinone (350
mg) and 5- (4-bromomethylphenyl) -1,
2-oxazole (419 mg) to compound 113 (2
7 mg: yield 4%) was obtained as a white powder. NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.31
(2H, s), 6.54 (1H, d, J = 2Hz), 7.
53 (2H, d, J = 8Hz), 7.59 (1H,
s), 7.81 (2H, d, J = 8Hz), 8.30 (1
H, d, J = 2 Hz). IR (KBr): 3080, 2950, 2920, 16
40, 1605, 1590, 1560, 1500c
m ^-1 . Melting point: 147-149 ° C. Elemental _{analysis: C 18 H 18 ClN 3 O} 2 S Calculated: C: 57.52%, H: 4.83%, N: 1
1.18%, calculated value: C: 57.48%, H: 4.89%, N: 1
1.04%.

Example 40 2-t-Butyl-4-chloro-5- [4- (1,2-oxazol-5-yl) benzyloxy] -3 (2H)
-Production of pyridazinone (Compound 114)

[Chemical 183] In a manner similar to Example 32, 2-tert-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (608
mg) and 5- (4-bromomethylphenyl) -1,
2-oxazole (786 mg) to compound 114 (4
7 mg: yield 4%) was obtained as a pale yellow powder. NMR (CDCl ₃ ) δ: 1.64 (9H, s), 5.37
(2H, s), 6.57 (1H, d, J = 2Hz), 7.
54 (2H, d, J = 8Hz), 7.73 (1H,
s), 7.87 (2H, d, J = 8Hz), 8.32 (1
H, d, J = 2 Hz). IR (KBr): 3110, 2990, 2930, 164
0,1600,1555,1500 cm ^-1 . Melting point: 194-195 ° C. Elemental _{analysis: C 18 H 18 ClN 3 O} 3 Calculated: C: 60.09%, H: 5.04%, N: 1
1.68%, measured value: C: 59.70%, H: 5.00%, N: 1
1.42%.

Example 41 2-t-butyl-4-chloro-5- [4- (1,2,3)
-Thiadiazol-4-yl) benzylthio] -3 (2
H) -Pyridazinone (Compound 115)

[Chemical 184] In a similar manner to Example 31, 2-t-butyl-4-chloro-5-mercapto-3 (2H) -pyridazinone (437
mg) and 4- (4-bromomethylphenyl) -1,
2,3-thiadiazole (561 mg) was reacted and recrystallized from chloroform / ether to give compound 115 (47
0 mg: 60% yield) was obtained as pale yellow crystals. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.34
(2H, s), 7.55 (1H, s), 7.61 (2H,
d, J = 8 Hz), 8.07 (2H, d, J = 8H
z), 8.68 (1H, s). IR (KBr): 3050, 2980, 2955, 164
0,1560 cm ^-1 . Melting point: 175-177 ° C.

Example 42 2-t-butyl-4-chloro-5- [4- (1,2,3)
-Thiadiazol-4-yl) benzyloxy] -3
Production of (2H) -pyridazinone (Compound 116)

[Chemical 185] In a manner similar to Example 32, 2-tert-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (608
mg) and 4- (4-bromomethylphenyl) -1,
Compound 116 (40) was reacted with 2,3-thiadiazole (842 mg) and purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 3: 1).
mg: yield 4%) was obtained as a yellow powder. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.54
(2H, s), 7.64 (2H, d, J = 8Hz), 8.
21 (2H, d, J = 8Hz), 8.29 (1H,
s), 9.66 (1H, s). IR (KBr): 3050, 2990, 2940, 163
5,1600 cm ^-1 . Melting point: 240-242 ° C.

Example 43 2-t-butyl-4-chloro-5- [4- (1,2,4)
-Thiadiazol-5-yl) benzylthio] -3 (2
H) -Pyridazinone (Compound 117)

[Chemical 186] Similarly to Example 49, 2-tert-butyl-4-chloro-5-mercapto-3 (2H) -pyridazinone (437
mg) and 5- (4-bromomethylphenyl) -1,
2,4-thiadiazole (561 mg) was reacted and purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 8: 1 to 6: 1) to give compound 11
7 (330 mg: 42% yield) was obtained as a colorless powder. NMR (CDCl ₃ ) δ: 1.62 (9H, s), 4.33
(2H, s), 7.57 (2H, d, J = 8Hz), 7.
58 (1H, s), 8.00 (2H, d, J = 8H
z), 8.72 (1H, s). IR (KBr): 2990, 2960, 2940, 164
0,1560 cm ^-1 . Melting point: 93-95 ° C.

Example 44 2-t-butyl-4-chloro-5- [4- (1,2,4)
-Thiadiazol-5-yl) benzyloxy] -3
Production of (2H) -pyridazinone (Compound 118)

[Chemical 187] 2-t-Butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (709
mg) and 5- (4-bromomethylphenyl) -1,
2,4-thiadiazole (982 mg) was reacted and recrystallized from methanol to obtain compound 118 (887 mg: yield 67%) as colorless crystals. NMR (DMSO-d ₆ ) δ: 1.58 (9H, s), 5.58
(2H, s), 7.68 (2H, d, J = 8Hz), 8.
14 (2H, d, J = 8Hz), 8.28 (1H,
s), 9.00 (1H, s). IR (KBr): 3050, 3000, 2960, 292
5,1635,1600,1500 cm ^-1 . Melting point: 197-200 ° C. Elemental analysis: Calculated as C ₁₇ H ₁₇ ClN ₄ O ₂ S: C: 54, 18%, H: 4.55%, N: 1
4.87%, measured value: C: 53.92%, H: 4.44%, N: 1
4.93%.

Example 45 2-t-butyl-4-chloro-5- [4- (1,3-oxazol-5-yl) benzylthio] -3 (2H)-
Production of pyridazinone (Compound 119)

[Chemical 188] 2-t-butyl-4-chloro-as in Example 31
5-Mercapto-3 (2H) -pyridazinone (437m
g) and 5- (4-bromomethylphenyl) -1,3
-Oxazole (524 mg) was reacted and purified by silica gel column chromatography (developing solvent: hexane-ethyl acetate = 1: 1) to give compound 119 (658 mg:
Yield 88%) was obtained as a colorless powder. NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.30
(2H, s), 7.39 (1H, s), 7.49 (2H,
d, J = 8 Hz), 7.60 (1H, s), 7.68 (2
H, d, J = 8 Hz), 7.94 (1H, s). IR (KBr): 3140, 3120, 2995, 295
5,1640,1560,1505,1485 cm ^-1 . Melting point: 98-99 ° C. Elemental _{analysis: C 18 H 18 ClN 3 O} 2 S Calculated: C: 57.52%, H: 4.83%, N: 1
1.18%, measured value: C: 57.80%, H: 4.88%, N: 1
1.14%.

Example 46 2-t-butyl-4-chloro-5- [4- (1,3-oxazol-5-yl) benzyloxy] -3 (2H)
-Production of pyridazinone (Compound 120)

[Chemical 189] In a manner similar to Example 32, 2-tert-butyl-4-chloro-5-hydroxy-3 (2H) -pyridazinone (608
mg) and 5- (4-bromomethylphenyl) -1,
3-Oxazole (786 mg) was reacted and recrystallized from methanol to give compound 120 (733 mg: yield 68).
%) As pale yellow crystals. NMR (CDCl ₃ ) δ: 1.64 (9H, s), 5.34
(2H, s), 7.40 (1H, s), 7.49 (2H,
d, J = 8Hz), 7.72 (2H, d, J = 8H
z), 7.73 (1H, s), 7.94 (1H, s). IR (KBr): 3050,3000,2950,29
30, 1630, 1600, 1515, 1490c
m ^-1 . Melting point: 182-183 [deg.] C. Elemental _{analysis: C 18 H 18 ClN 3 O} 3 Calculated: C: 60.09%, H: 5.04%, N: 1
1.68%, measured value: C: 59.81%, H: 5.06%, N: 1
1.86%.

Example 47 (1) Compound 1 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Compound 1 (10.0 mg ), Lactose (60.0 mg) and corn starch (35.0 mg) using 10% aqueous gelatin solution (0.03 ml: 3.0 mg as gelatin), granulated through a 1 mm mesh sieve and dried at 40 ° C. Then it was sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 48 (1) Compound 1 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 1 (10. 0 mg) and lactose (70.0 mg) were granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and then magnesium stearate (3.0 mg) and corn starch (50.0).
mg). The mixture was compressed to give tablets.

Example 49 (1) Compound 1 20.0 mg (2) Lactose 70.0 mg (3) Magnesium stearate 3.0 mg The above ingredients and amounts were thoroughly mixed and filled into No. 3 capsule to give a capsule preparation. It was Example 50 (1) Compound 2 20.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl cellulose 3.0 mg (5) Magnesium stearate 2.0 mg Compound 2 (20.0 mg) A lactose (60.0 mg) and corn starch (35.0 mg) mixture was granulated using a 10% aqueous solution of hydroxypropyl cellulose (0.03 ml: 3.0 mg as hydroxypropyl cellulose) through a 1 mm mesh sieve, then 40 It was dried at ℃ and sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets. Example 51 (1) Compound 19 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 19 (10.0 mg) Lactose (70.0 mg) was granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and magnesium stearate (3.0 mg) and corn starch (50.
0 mg). The mixture was compressed to give tablets.

Example 52 (1) Compound 3 20.0 mg (2) Lactose 70.0 mg (3) Magnesium stearate 3.0 mg The above ingredients and amounts were thoroughly mixed and filled into No. 3 capsule to obtain a capsule. It was Example 53 (1) Compound 4 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl cellulose 3.0 mg (5) Magnesium stearate 2.0 mg Compound 4 (10.0 mg) A lactose (60.0 mg) and corn starch (35.0 mg) mixture was granulated using a 10% aqueous solution of hydroxypropyl cellulose (0.03 ml: 3.0 mg as hydroxypropyl cellulose) through a 1 mm mesh sieve, then 40 It was dried at ℃ and sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 54 (1) Compound 6 20.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 6 (20. 0 mg) and lactose (70.0 mg) were granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and then magnesium stearate (3.0 mg) and corn starch (50.0).
mg). The mixture was compressed to give tablets. Example 55 (1) Compound 12 10.0 mg (2) Lactose 70.0 mg (3) Magnesium stearate 3.0 mg The above ingredients and amounts were sufficiently mixed and filled into a No. 3 capsule to obtain a capsule. Example 56 (1) Compound 12 7.2 mg (2) 1N hydrochloric acid 0.02 ml (3) Mannit 90.0 mg (4) Distilled water Total amount 3 ml Compound 12 (7.2 mg), 1N hydrochloric acid (0) 0.02 ml) and mannitol (90.0 mg) were dissolved in distilled water to a total volume of 3.0 ml. Filter the solution with a Millipore filter,
Fill 3 ml ampoules under aseptic conditions. The ampoule was sterilized and then sealed to obtain an injection solution.

Example 57 (1) Compound 17 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Gelatin 3.0 mg (5) Magnesium stearate 2.0 mg Compound 17 (10.0 mg) ), Lactose (60.0 mg) and corn starch (35.0 mg) using 10% aqueous gelatin solution (0.03 ml: 3.0 mg as gelatin), granulated through a 1 mm mesh sieve and dried at 40 ° C. Then it was sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets. Example 58 (1) Compound 39 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 39 (10.0 mg) Lactose (70.0 mg) was granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and magnesium stearate (3.0 mg) and corn starch (50.
0 mg). The mixture was compressed to give tablets.

Example 59 (1) Compound 18 20.0 mg (2) Lactose 70.0 mg (3) Magnesium stearate 3.0 mg The above ingredients and amounts were thoroughly mixed and filled into No. 3 capsule to give a capsule preparation. It was Example 60 (1) Compound 20 20.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl cellulose 3.0 mg (5) Magnesium stearate 2.0 mg Compound 20 (20.0 mg) A lactose (60.0 mg) and corn starch (35.0 mg) mixture was granulated using a 10% aqueous solution of hydroxypropyl cellulose (0.03 ml: 3.0 mg as hydroxypropyl cellulose) through a 1 mm mesh sieve, then 40 It was dried at ℃ and sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 61 (1) Compound 42 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 42 (10. 0 mg) and lactose (70.0 mg) were granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and then magnesium stearate (3.0 mg) and corn starch (50.
0 mg). The mixture was compressed to give tablets. Example 62 (1) Compound 27 10.0 mg (2) Lactose 70.0 mg (3) Magnesium stearate 3.0 mg The above ingredients and amounts were sufficiently mixed and filled into No. 3 capsule to obtain a capsule. Example 63 (1) Compound 31 10.0 mg (2) Lactose 60.0 mg (3) Corn starch 35.0 mg (4) Hydroxypropyl cellulose 3.0 mg (5) Magnesium stearate 2.0 mg Compound 31 (10.0 mg) A lactose (60.0 mg) and corn starch (35.0 mg) mixture was granulated using a 10% aqueous solution of hydroxypropyl cellulose (0.03 ml: 3.0 mg as hydroxypropyl cellulose) through a 1 mm mesh sieve, then 40 It was dried at ℃ and sieved again. The granules thus obtained were mixed with magnesium stearate (2.0 mg) and compressed. The obtained central tablets were sugar-coated with an aqueous solution of sucrose, titanium dioxide, talc and gum arabic. The coated tablets were polished with beeswax to obtain coated tablets.

Example 64 (1) Compound 48 10.0 mg (2) Lactose 70.0 mg (3) Corn starch 50.0 mg (4) Soluble starch 7.0 mg (5) Magnesium stearate 3.0 mg Compound 48 (10. 0 mg) and lactose (70.0 mg) were granulated with an aqueous solution of soluble starch (0.07 ml: 7.0 mg as soluble starch), dried and magnesium stearate (3.0 mg) and corn starch (50.
0 mg). The mixture was compressed to give tablets. Example 65 2-tert-butyl-4-chloro-5- [4- (4-
Fluorobenzoyl) benzylthio] -3 (2H) -pyridazinone

[Chemical 190] 2-tert-butyl-4-chloro-5-mercapto-
3 (2H) -pyridazinone (547 mg) in DMF (1
5 ml) solution to anhydrous potassium carbonate (380 mg) and 4- (4-fluorobenzoyl) benzyl bromide (8
(06 mg) was added and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was chloroform / n-
Recrystallization from hexane gave the title compound as pale yellow scaly crystals (827 mg: 77% yield). ¹ H-NMR (CDCl ₃ ) δ: 1.63 (9H, s),
4.35 (2H, s), 7.18 (2H, t, J = 8.6
Hz), 7.55 (2H, d, J = 8.4Hz), 7.6
0 (1H, s), 7.79 (2H, d, J = 8.4H
z), 7.85 (2H, t, J = 5.4, 8.6Hz). IR (KBr): 3100, 2980, 2950, 164
0,1595,1560,1500 cm ^-1 .

Example 66 2-tert-butyl-4-chloro-5- [3- (4-
Preparation of chlorobenzoyl) benzylthio] -3 (2H) -pyridazinone

[Chemical 191] 2-tert-butyl-4-chloro-5-mercapto-
3 (2H) -pyridazinone (547 mg) in DMF (1
5 ml) solution to anhydrous potassium carbonate (380 mg) and 3- (4-chlorobenzoyl) benzyl bromide (85
1 mg) was added and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was triturated in n-hexane to give the title compound as a white powder (982 mg: yield 88%). NMR (CDCl ₃ ) δ: 1.63 (9H, s), 4.33
(2H, s), 7.48 (2H, d, J = 8.6Hz),
7.51 (2H, d, J = 8.6Hz), 7.61 (1
H, s), 7.68 (1H, dt, J = 8.6, 1.4H
z), 7.75 (1H, dt, J = 8.6, 1.4H
z), 7.83 (1H, t, J = 1.4Hz). IR (KBr): 2970, 2940, 1640, 160
0,1580,1560 cm ^-1 .

Example 67 2-tert-butyl-4-chloro-5- [4- (4-
Fluorobenzoyl) benzyloxy] -3 (2H)-
Production of pyridazinone

[Chemical 192] 2-tert-butyl-4-chloro-5-hydroxy-
3 (2H) -pyridazinone (608 mg) in DMF (2
0 ml) solution into anhydrous potassium carbonate (456 mg) and 4- (4-fluorobenzoyl) benzyl bromide (9
67 mg) was added and the mixture was stirred at 80 ° C. for 3 hours. After cooling to room temperature and adding water, a precipitate was generated. This product was collected by filtration and washed successively with water, methanol and n-hexane.
The obtained solid was recrystallized from methanol to give the title compound as colorless scale-like crystals (1.01 g: yield 81%). ¹ H-NMR (CDCl ₃ ) δ: 1.65 (9H, s), 5.4
1 (2H, s), 7.19 (2H, t, J = 8.8H
z), 7.56 (2H, d, J = 8.4Hz), 7.75
(1H, s), 7.84 (2H, d, J = 8.4H
z), 7.86 (2H, dd, J = 5.4, 8.8H
z). IR (KBr): 3070, 2970, 2940, 164
5,1595,1500 cm ^-1 .

Example 68 2-tert-butyl-4-chloro-5- [3- (4-
[Chlorobenzoyl) benzyloxy] -3 (2H) -pyridazinone

[Chemical formula 193] 2-tert-butyl-4-chloro-5-hydroxy-
3 (2H) -pyridazinone (608 mg) in DMF (1
5 ml) solution to anhydrous potassium carbonate (456 mg) and 3- (4-chlorobenzoyl) benzyl bromide (1.
02 g) was added and the mixture was stirred at 80 ° C. for 2.5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, the residue was triturated in methanol / n-hexane to give the title compound as a pale green powder (615 m
g: yield 48%). NMR (CDCl ₃ ) δ: 1.65 (9H, s), 5.37
(2H, s), 7.46-7.85 (4H, m), 7.4
9 (2H, d, J = 8.6Hz), 7.76 (1H,
s), 7.77 (2H, d, J = 8.6Hz). IR (KBr): 3050, 2970, 2940, 165
0,1600,1560 cm ^-1 .

Test Example 1 In Vitro Cell Growth Inhibitory Effect of Pancreatic Cancer and Prostate Cancer (Test Method) Pancreatic cancer cell line AsPC-1 inactivated 10% fetal bovine serum, 1 mM sodium pyruvate and 2
R containing 5 mM HEPES [2- {4- (2-hydroxyethyl) -1-piperazinyl} ethanesulfonic acid]
PMI1640 medium (Flow Laboratories [Flow Lab
oratories]) suspended cell suspension (2000
0 cells / ml) on a 96-well microplate (50μ)
1 / well) 37 ° C in 5% carbon dioxide incubator
It was cultured in. Next day, dissolve in dimethylformamide for 3
Each compound solution (50 μl / well) that had been serially diluted by a factor of 2 was added, and the cells were cultured for 3 days. After removing the culture medium containing the compound and washing the cells, the number of surviving cells was quantified by adding an MTT dye solution (Tada et al., Journal of Immunological Methods, Vol. 93,
Pp. 157, (1986)). Taking the cell amount of the control group to which the compound solution was not added as 100%, the ratio of the cell amount of each compound added group was calculated, and the compound concentration necessary to suppress the viable cell amount by 50% of the control group (IC ₅₀ value ) Was calculated. For the prostate cancer cell line PC-3, 1
F-12K medium containing 0% inactivated fetal bovine serum (manufactured by Flow Laboratories [Flow Laboratories]) was used, and the number of culture days after addition of the compound was 4 days.
The test was conducted in the same manner as in the case of sPC-1, and the IC ₅₀ value (nm) was calculated. (Test Results) The results are shown in [Table 2] and [Table 3]. Each of the test compounds showed a remarkable growth inhibitory effect on pancreatic cancer cells and prostate cancer cells. From this, it is clear that the anticancer agent of the present invention exhibits an excellent tumor cell growth inhibitory action.

[0170]

[Table 2]

[0171]

[Table 3]

Test Example 2 In Vivo Inhibition of Pancreatic Cancer (Test Method) 3 million human pancreatic cancer cells AsPC-1
Alb / c nude mice (7 weeks old) transplanted subcutaneously on the flank,
On the 35th day after transplantation, 5 cells per group were used for the experiment, in which the tumor cell size was measured and the tumor size was made uniform. A corn oil solution of the compounds 1, 2, and 19 of the present invention is applied once every two days to 1
It was administered intraperitoneally for 4 days. The tumor diameter was measured on the day after the administration, and the tumor volume was calculated by the formula: tumor volume = major axis × minor axis × minor axis × (1/2), and the ratio with the control group administered with corn oil was determined as the growth rate. . (Test results) The results are shown in [Table 4]. All the test compounds suppressed the growth of human pancreatic cancer AsPC-1 cell line transplanted into nude mice. From this, it is clear that the anticancer agent of the present invention exhibits an excellent tumor cell growth inhibitory action.

[Table 4]

[0173]

INDUSTRIAL APPLICABILITY Since the anticancer agent of the present invention has a tumor cell growth inhibitory action, it is useful for the treatment of refractory solid tumors such as pancreatic cancer and prostate cancer.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Office reference number FI technical display location // (C07D 401/12 213: 28 237: 16) (C07D 401/12 213: 28 237: 14) ) (C07D 403/12 237: 16 257: 04) (C07D 403/12 237: 14 257: 04)

Claims (21)

[Claims] 1. A substituent at the 5-position is -X-Y ⁰ -Q ⁰ (X is O or S, Y ⁰ is a divalent aliphatic hydrocarbon residue which may have a substituent, Q ⁰ represents a cyclic group which may have a substituent), and an anticancer composition containing 4,5-disubstituted-3 (2H) -pyridazinone or a salt thereof. 2. The anticancer composition according to claim 1, wherein the substituent at the 4-position is a group having 1 to 150 atoms. 3. The anticancer composition according to claim 1, wherein the 2-position of 4,5-disubstituted-3 (2H) -pyridazinone may be substituted with a hydrocarbon residue which may have a substituent. object. 4. An aliphatic hydrocarbon residue having 1 to 3 carbon atoms.
The anticancer composition according to claim 1, which is 5. The anticancer composition according to claim 1, wherein the substituent of the aliphatic hydrocarbon residue is a hydroxyl group. 6. The anticancer composition according to claim 1, wherein the cyclic group is an aromatic cyclic group. 7. The anticancer composition according to claim 1, wherein the cyclic group is an optionally substituted phenyl group. 8. An optionally substituted phenyl group is represented by: (R ⁸ is halogen, lower alkyl group, lower cycloalkyl group, lower alkoxy group, halo-lower alkyl group, halo-lower alkoxy group, cyano group, trimethylsilyl group,
Nitro group, (R ⁹ represents a halogen, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a halo-lower alkyl group, a halo-lower alkoxy group, a cyano group or a nitro group, m represents an integer of 0 to 5, and m represents In the case of an integer of 2 to 5, R ⁹ may be the same or different from each other, n is an integer of 0 to 5, and when n is an integer of 2 to 5, R ⁸ is the same or different. The anticancer composition according to claim 7. 9. R ⁸ is (R ⁹ represents a halogen, a lower alkyl group, a lower cycloalkyl group, a lower alkoxy group, a halo-lower alkyl group, a halo-lower alkoxy group, a cyano group or a nitro group, m represents an integer of 0 to 5, and m represents R ⁹ if 2 to 5
May be the same or different from each other). 10. The anticancer composition according to claim 9, wherein R ⁹ is halogen. 11. A 4,5-disubstituted-3 (2H) -pyridazinone is represented by the formula: [Wherein R ¹ represents a lower alkyl group, a cycloalkyl group or a phenyl group which may have a substituent, and R ² represents a hydrogen atom, a halogen, a lower alkoxy group which may have a substituent, or a substituent. A lower alkylthio group which may have a group or an aliphatic hydrocarbon residue which may have a substituent, X is O or S, Y is an alkylene group which may have a substituent, or An alkenylene group which may have a substituent and Q represents an aryl group which may have a substituent or an aromatic heterocyclic group which may have a substituent. ] The anticancer composition of Claim 1 which is a compound represented by these. 12. The anticancer composition according to claim 11, wherein R ¹ is a branched lower alkyl group. 13. The anticancer composition according to claim 11, wherein R ² is halogen, a lower alkoxy group or a lower alkyl group. 14. Y is ^{(R 3, R 4, R} 5 and R ⁶ are the same or different, a hydrogen atom, a hydroxyl group or have a substituent indicates a lower alkyl group) 11. anticancer composition according . 15. The substituent at the 5-position is represented by: (X is O or S, Y ⁰ is a divalent aliphatic hydrocarbon residue which may have a substituent, and Q ¹ is a nitrogen-containing aromatic heterocyclic group which may have a substituent. Is shown)
Disubstituted-3 (2H) -pyridazinone or a salt thereof. 16. The substituent at the 5-position is --X--Y ¹ --Q ⁰ (X is O
Or S, Y ¹ is substituted with a hydroxyl group 2
A divalent aliphatic hydrocarbon residue, Q ⁰ represents a cyclic group which may have a substituent), 4,5-disubstituted-3 (2H)
-Pyridazinone or a salt thereof. 17. 2-tert-butyl-4-chloro-5-
[4- (1,2,4-thiadiazol-5-yl) benzylthio] -3 (2H) -pyridazinone. 18. The formula: [In formula, X shows O or S. ], Represented by]
Disubstituted-3 (2H) -pyridazinone or a salt thereof. 19. The formula: [In formula, X shows O or S. ], Represented by]
Disubstituted-3 (2H) -pyridazinone or salt. 20. A 4,5-disubstituted-3 (2H) -pyridazinone or a salt thereof having a substituent at the 5-position of which is -X-H (X represents O or S) and a compound of the formula: [Wherein E is a leaving group, Y ⁰ is a divalent aliphatic hydrocarbon residue which may have a substituent, and Q ¹ is a nitrogen-containing aromatic group which may have a substituent] Indicates a heterocyclic group. ] The manufacturing method of the compound of Claim 15 which makes it react with the compound represented by this, or its salt. 21. 5-position substituent -X-H (X is O or indicating S) 4,5-di-substituted -3 (2H) - pyridazinone or a salt thereof and wherein E-Y ¹ -Q ⁰ wherein, E is a leaving group, Y ¹ is a divalent aliphatic hydrocarbon residue which is substituted with a hydroxyl group, Q ⁰ is a cyclic group which may have a substituent. ] The manufacturing method of the compound of Claim 16 which makes it react with the compound represented by this, or its salt.