JP2969618B2 - Pyridazinone derivatives and their production - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel pyridazinone derivative having a therapeutic effect on nephritis and / or an endotoxin shock protective effect, and a method for producing the same.

[0002]

2. Description of the Related Art Japanese Patent Laid-Open Publication No.
-(2-benzenesulfonamidoindan-5-yl)
It is disclosed that a benzenesulfonamidoindanyl compound such as -4,5-dihydropyridazin-3 (2H) -one has an antithrombotic effect. In addition, WO92 /
No. 15558 includes 6- [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl]-
It is disclosed that benzenesulfonaminoalkylindane derivatives such as 4,5-dihydropyridazin-3 (2H) -one have thromboxane A ₂ antagonistic activity.

JP-A-53-124279 discloses 5-methyl-6- [4- [2- (pyridin-3-ylcarbonylamino) ethyl] phenyl] -4,5-dihydropyridazine-3 (2H)-. It is disclosed that pyridineaminoalkylphenyl derivatives such as on have an antiallergic action and the like. JP-A-61-212552 discloses that benzenesulfonylaminophenyl derivatives such as 6- [4- (2-phenylsulfonylaminoethyl) phenyl] pyridazin-3 (2H) -one have antithrombotic activity and the like. It is disclosed.

On the other hand, as a remedy for endotoxin shock occurring in patients with severe infections of Gram-negative bacteria,
Steroid hormones, aprotinin (a protease inhibitor), dobutamine (a cardiotonic) and the like are used.

[0005] Prednisolone (steroid drug), cyclophosphamide (immunosuppressive drug), dipyridamole, dilazep (antiplatelet drug), heparin (anticoagulant drug) and the like have been conventionally used as therapeutic drugs for nephritis. .

[0006]

DISCLOSURE OF THE INVENTION The present invention provides a novel pyridazinone derivative which has an excellent therapeutic effect on nephritis and / or a protective effect on endotoxin shock and has few side effects on the circulatory system, and a process for producing the same.

[0007]

The present invention provides a compound of the general formula [I]

[0008]

Embedded image

(Wherein X is a hydrogen atom, a lower alkyl group which may be substituted, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a lower alkylthio group, a hydroxyl group, Represents an amino group or a halogen atom, Y represents a single bond, an oxygen atom or a sulfur atom, A represents a linear or branched alkylene group which may contain a double bond, and B and R
² is a group wherein B is a carbonyl group or a thiocarbonyl group,
R ² may be substituted with an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, a phenyl-substituted lower alkenyl group, and a lower alkoxy group which may have a substituent. , A phenoxy group, a lower alkylamino group, a lower alkenylamino group, a phenylamino group, a lower alkenyloxy group, a monocyclic or dicyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom and optionally having a substituent. A cyclic heteroaromatic group or an aryl group which may have a substituent, or B is a sulfonyl group, and R ² has 1 to 1 carbon atoms which may be substituted.
An alkyl group of 10, a cycloalkyl group having 3 to 6 carbon atoms,
A lower alkenyl group, a phenyl-substituted lower alkenyl group or a monocyclic or bicyclic heteroaromatic group which may have a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, R ¹ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group;
³ represents a hydrogen atom or an optionally substituted lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵
Represents a hydrogen atom or a lower alkyl group. ) Or a pharmacologically acceptable salt thereof.

[0010]

BEST MODE FOR CARRYING OUT THE INVENTION In the object [I] of the present invention,
Examples of the optionally substituted lower alkyl group include a halogenoalkyl group, a lower alkoxyalkyl group,
Examples include an aminoalkyl group, an alkyl group substituted with a mono- or di-lower alkylamino group, an acylaminoalkyl group, and a lower alkylthioalkyl group. Examples of the optionally substituted amino group include, for example, mono-
Or a di-lower alkylamino group, an acylamino group,
An N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-carbamoylamino group,
N-lower alkyl-N-thiocarbamoylamino group (the nitrogen atom in the carbamoyl group or thiocarbamoyl group may be further substituted with one or two lower alkyl groups) and lower alkylcarbamoyl groups And a pyrrolidino group, a piperidino group, a perhydroazepin-1-yl group, a morpholino group, a thiomorpholino group, a piperazino group (the nitrogen atom at the 4-position of the piperazino group is a lower alkyl group, a lower alkenyl group, an acyl group, an aryl group And the like, two substituents on a nitrogen atom may be bonded to each other at the terminal to form a ring structure. Examples of the halogeno lower alkyl group include a trifluoromethyl group. As the phenyl-substituted lower alkenyl group, for example,
And a styryl group. Examples of the lower alkoxy group which may have a substituent include a lower alkoxy group which may be substituted with a phenyl group. As a monocyclic or bicyclic heteroaromatic group which may have a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, for example, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group Group, lower alkylthio group, hydroxyl group,
Mercapto group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, acylamino group,
Substituted with 1 to 4 groups selected from a halogen atom, a phenoxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group Pyridyl group, furyl group, thienyl group, pyrazinyl group, pyrimidinyl group, pyridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group, indolyl group, isoindolyl group, thiazolyl group, isoxazolyl group which may be , Oxazolyl group, quinazolinyl group, thienopyrimidinyl group, triazinyl group, tetrazolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, benzooxazolyl group, benzimidazolyl group, isothiazo Group, phthalazyl group, a benzofuryl group. The aryl group which may have a substituent is, for example, selected from a lower alkoxy group, a phenyl-substituted lower alkoxy group, a halogen atom, a hydroxyl group, a trifluoromethyl group, a nitro group, a lower alkyl group and a di-lower alkylamino group. And a phenyl group which may be substituted with 1 to 3 groups. Examples of the linear or branched alkylene group which may contain a double bond include a linear or branched alkylene group having 1 to 10 carbon atoms, preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms. Can be Specific examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group,
Hexamethylene group, heptamethylene group, octamethylene group, nonamethylene group, 2-methyltetramethylene group, 2
-Ethyltetramethylene group, 1-butenylene group, etc. (however, the number indicating the position of the branched chain or double bond is counted from the carbon atom bonded to the partial structure Y in the general formula [I]. The same applies to the following), preferably, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group, 2-methyltetramethylene group, 2-ethyltetramethylene group and the like.

Among the desired compounds [I] of the present invention, examples of preferred compound groups include, for example, a group consisting of compounds having one or more of the following characteristics.

(A): X is a hydrogen atom.

(B): Y is a single bond.

(C1): A linear or branched alkylene group in which A may have a double bond having 2 to 10 carbon atoms.

(C2): A is a linear or branched alkylene group having 2 to 6 carbon atoms.

(D1): B is a carbonyl group.

(D2): B is a sulfonyl group.

(E1): R ² is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a substituted amino group, a halogen atom, a phenoxy group, a carboxy group A pyridyl group optionally having one or two substituents selected from a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group A lower alkyl group; or a lower alkenyl group, more preferably (e2): pyridyl optionally having one or two substituents wherein R ² is selected from a lower alkyl group, a lower alkylamino group and an amino group; Group, lower alkyl group or lower alkenyl group.

(E3): R ² is a lower alkyl group or a lower alkenyl group, more preferably (e4): R ² is a vinyl group or a lower alkyl group.

(E5): R ² is a pyridyl group optionally having one or two substituents selected from a lower alkyl group, a lower alkylamino group and an amino group.

(F) R ³ is a hydrogen atom.

(G) R ⁴ is a hydrogen atom.

(H) R ⁵ is a hydrogen atom.

A more preferred example of the compound group is, for example, a group consisting of compounds having the following characteristics.

(D1) and (e1). (D2) and (e)
3).

As a more preferred example of the compound group, there can be mentioned, for example, a group consisting of compounds having the following characteristics.

(D1) and (e5). (D2) and (e)
4).

As a particularly preferred example of the compound group, there can be mentioned, for example, a group consisting of compounds having the following characteristics.

(B) and (c1) and (d1) and (e)
1) and (f) and (g) and (h). (B) and (c)
1) and (d2) and (e3) and (f) and (g) and (h).

A particularly preferred compound group is, for example, a group consisting of compounds having the following characteristics.

(B) and (c2) and (d1) and (e)
5) and (f) and (g) and (h). (B) and (c)
2) and (d2) and (e4) and (f) and (g) and (h).

In the "pyridyl group optionally having substituent (s)" for R ² , there are no particular restrictions on the substitution position of the substituent on the pyridine ring and the bonding position with the partial structure: -B-. Preferred examples include those bonded to the partial structure: -B- at the 3-position on the pyridine ring, that is, a substituted or unsubstituted pyridin-3-yl group. Preferred examples of the pyridyl group having a substituent include a 2- or 4-position monosubstituted or 2,4-disubstituted pyridin-3-yl group of a pyridine ring. Among these, more preferred examples include an unsubstituted pyridin-3-yl group and a 2-substituted pyridin-3-yl group. The position of substitution on the benzene ring of X is not particularly limited, but is preferably an ortho position relative to the substitution position of the pyridazine-3 (2H) -one moiety on the benzene ring. Can be

When the object [I] of the present invention contains an asymmetric atom, the present invention includes both stereoisomers based on the asymmetric atom and mixtures thereof.

Specific examples of the target compound of the present invention include the following
Although illustrated in Tables 21 to 21, the target compound of the present invention is not limited thereto.

[0035]

[Table 1]

[0036]

[Table 2]

[0037]

[Table 3]

[0038]

[Table 4]

[0039]

[Table 5]

[0040]

[Table 6]

[0041]

[Table 7]

[0042]

[Table 8]

[0043]

[Table 9]

[0044]

[Table 10]

[0045]

[Table 11]

[0046]

[Table 12]

[0047]

[Table 13]

[0048]

[Table 14]

[0049]

[Table 15]

[0050]

[Table 16]

[0051]

[Table 17]

[0052]

[Table 18]

[0053]

[Table 19]

[0054]

[Table 20]

[0055]

[Table 21]

The target compound [I] of the present invention can be used for a medicinal use either in a free form or in the form of a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include inorganic salts or acetates such as hydrochloride, sulfate, phosphate, hydrobromide, succinate, fumarate, oxalate, maleate, Organic acid salts such as methanesulfonate, especially hydrochloride, may be mentioned.

The object [I] of the present invention and its pharmacologically acceptable salts include all of its inner salts, adducts, complexes, solvates and hydrates.

The objective substance [I] of the present invention can be administered orally or parenterally, and can be used as a pharmaceutical preparation by mixing with an excipient suitable for oral or parenteral administration. . Pharmaceutical preparations include tablets, granules, capsules,
It may be a solid preparation such as a powder or a liquid preparation such as a solution, a suspension or an emulsion. In the case of parenteral administration, it can be used in the form of injection.

The dose varies depending on the age, weight, condition and degree of disease of the patient, but the daily dose is usually 1 to 300 mg / kg, particularly 3 to 100 mg / kg for oral administration. For parenteral administration,
0.01-50 mg / kg, especially 0.1-20 mg
/ Kg is preferred.

According to the present invention, (A) of the target compound [I], the general formula [Ia]

[0061]

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Wherein W represents an oxygen atom or a sulfur atom, and R ²¹ is an optionally substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, A substituted lower alkenyl group, a lower alkoxy group which may have a substituent, a phenoxy group, a lower alkylamino group, a lower alkenylamino group, a phenylamino group, a lower alkenyloxy group, a nitrogen atom, an oxygen atom or Represents a monocyclic or bicyclic heteroaromatic group which may have a substituent containing a sulfur atom or an aryl group which may have a substituent, and other symbols have the same meanings as described above. ) Or a pharmaceutically acceptable salt thereof is, for example, a compound represented by the general formula [II]:

[0063]

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(Wherein the symbols have the same meanings as described above) or a salt thereof is represented by the general formula [II
I]

[0065]

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(Wherein the symbols have the same meanings as described above), a reactive derivative thereof or a salt thereof, and if necessary, a pharmacologically acceptable salt to produce the compound. Can be.

(B) Of the target compound [I], a compound represented by the general formula [I-
b)

[0068]

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(In the formula, R ²² is an optionally substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, a phenyl-substituted lower alkenyl group, or nitrogen as a heteroatom atom. A monocyclic or bicyclic heteroaromatic group which contains an atom, an oxygen atom or a sulfur atom and may have a substituent, and other symbols have the same meanings as described above) or a compound thereof. Pharmaceutically acceptable salts include, for example, those of the general formula [II]

[0070]

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(Wherein the symbols have the same meanings as described above) or a salt thereof represented by the general formula [IV]

[0072]

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(Wherein R ²² has the same meaning as described above;
Represents a reactive residue. ) To react with the compound represented by
If desired, it can be produced by making it a pharmacologically acceptable salt.

(C) The target product [I] is, for example, a compound represented by the general formula [V]

[0075]

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(Wherein the symbols have the same meanings as described above). The compound can also be produced by oxidizing the compound to form a pharmaceutically acceptable salt if desired.

In the above production method (A), the compound [II
When the compound [Ia] is produced using the compound (I) or a salt thereof, the reaction can be carried out in a suitable solvent in the presence or absence of a condensing agent, and optionally in the presence of a deoxidizing agent. it can.

As the condensing agent, ordinary condensing agents such as 1,3-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide, diethylphosphoric acid cyanide and the like can be used. . As the salt of the compound [III], conventional salts such as alkali metal salts, alkaline earth metal salts and organic amine salts can be used. These salts are compounds [I
In the reaction with I), it is preferable to subject the reaction to a free compound in advance.

In the production method (A), the compound [II
When the compound [Ia] is produced using the reactive derivative of I], the reaction can be appropriately carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As the reactive derivative, for example, any of those commonly used for condensation, such as acid halides, mixed acid anhydrides, and active esters, can be used. As the salt of the reactive derivative, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid and sulfuric acid can be used.

In the production method (B), when compound [Ib] is produced using compound [IV], the reaction can be carried out in a suitable solvent in the presence of a deoxidizing agent.

The compound [Ib] is a compound [I
I] with a silylating agent such as trimethylchlorosilane, triethylchlorosilane, tert-butyldimethylchlorosilane, etc., once converted to an aminosilyl derivative in the reaction system,
It can also be produced using compound [IV].

The reactive residue of the compound [IV] includes a nucleophilically leaving group, for example, a halogen atom, an alkoxy group, a lower alkylsulfonyloxy group, a benzenesulfonyloxy group, a lower alkyl group-substituted benzenesulfonyloxy group. And a trifluoromethanesulfonyloxy group.

In the above production methods (A) and (B),
As the salt of the compound [II], for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, and a salt with an organic acid such as succinic acid, fumaric acid, and maleic acid can be used. it can.

The deoxidizing agent used in the above production methods (A) and (B) includes alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal hydrogencarbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate, and sodium hydroxide. , Potassium hydroxide and other alkali metal hydroxides, triethylamine, tributylamine, diisopropylethylamine and other lower alkylamines, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] ] Tertiary amines such as nona-5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene; and aromatic amines such as pyridine, lutidine, collidine and dimethylaniline. it can.

The solvent used in the above production methods (A) and (B) may be any inert solvent which does not adversely affect the reaction in any of the production methods (A) and (B). Halogen solvents such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as toluene and xylene; ether solvents such as tetrahydrofuran, dioxane, diethyl ether and 1,2-dimethoxyethane; ketone solvents such as acetone and methyl ethyl ketone; acetic acid Ester solvents such as ethyl, acetonitrile,
Pyridine, 2,6-lutidine, dimethylformamide,
Examples thereof include dimethyl sulfoxide, 1,3-dimethyl-2-imidazolidinone and the like, a mixed solvent of these solvents, and a combination of these solvents and water.

Further, the production methods (A) and (B)
It can be carried out under heating, for example, -30 ° C to 150
C, especially at -10C to room temperature.

The oxidation in the production method (C) can be carried out according to a conventional method. For example, the compound [V] is treated with sodium 3-nitrobenzenesulfonate in a suitable solvent under basic conditions, or under acidic conditions. The reaction can be suitably carried out by redox reaction using dimethylsulfoxide in hydrogen bromide-acetic acid, or by immediately subjecting to a dehydrohalogenation reaction after halogenation with bromine, chlorine or the like.

As the solvent, water, acetic acid, propionic acid,
Trifluoroacetic acid, methanesulfonic acid or a hydrogen bromide-acetic acid solution can be suitably used.

When a compound containing an asymmetric atom is used as the starting compound [II] or [V] in the reaction of the present invention, the corresponding target compound [I] or [I] without racemization of the asymmetric atom is used. [Ia] or [Ib] can be obtained.

The starting compound [II] of the present invention has the general formula [VI]

[0091]

Embedded image

(Wherein, R ¹¹ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group which may be substituted, and other symbols have the same meanings as described above) and hydrazine. , R ¹¹ represents a hydrogen atom,
If desired, an amino group may be further added, for example, to a corresponding aldehyde compound, sodium borohydride (NaBH ₄ ), sodium triacetoxyborohydride [NaB (OCO
[CH ₃ ) ₃ H], for example, by subjecting it to a reductive alkylation reaction in the presence of a suitable reducing agent such as alkylation, followed by oxidation.

In the above reaction, the reaction of compound [VI] with hydrazine can be carried out as appropriate in a suitable solvent or in the absence of a solvent.

The solvent may be any inert solvent which does not adversely affect the reaction, for example, lower alcohols such as methanol and ethanol, lower fatty acids such as acetic acid and propionic acid, aromatic hydrocarbons such as toluene and xylene, and tetrahydrofuran. And ethers such as dioxane, water and a mixed solvent of the above solvent and water. This reaction can be carried out widely from room temperature to the boiling point of the reaction mixture, and can be suitably carried out, for example, at 10 ° C to 200 ° C, particularly preferably at 20 ° C to 150 ° C.

The oxidation reaction can be carried out in the same manner as in the above-mentioned production method (C).

The starting compound [VI] is, for example, optionally a compound of the general formula [VII]

[0097]

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(Wherein the symbols have the same meanings as described above), after protecting the amino group of the compound represented by the general formula [VIII]

[0099]

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(Wherein R ⁶ represents an ester residue and Z represents a reactive residue) or a compound of the general formula [IX]

[0101]

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(Where R ⁴¹ represents a lower alkyl group;
⁵¹ represents a lower alkyl group. ), And then removing the ester residue and / or protecting group, or by the method described in Examples below.

The starting compound [VI] is, for example, a compound represented by the general formula [VII]:

[0104]

Embedded image

(Wherein the symbols have the same meanings as described above), after protecting the amino group of the compound represented by the general formula [X]

[0106]

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(Where V is a halogen atom, and other symbols have the same meanings as described above).

[0108]

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(Where R ⁷ represents a protecting group for an amino group,
Other symbols have the same meaning as described above. The compound represented by the general formula [XII]

[0110]

Embedded image

(Wherein the symbols have the same meanings as described above), and the compound represented by the general formula [XIII]

[0112]

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(Wherein the symbols have the same meanings as described above) can be produced by a method of hydrolyzing and / or removing a protecting group, or a method described in Examples described later.

Further, the starting compound [VI] is, for example, a compound represented by the general formula [VII]:

[0115]

Embedded image

(Wherein the symbols have the same meanings as described above), after protecting the amino group of the compound represented by the general formula [XIV]

[0117]

Embedded image

(Wherein the symbols have the same meanings as described above), and the compound represented by the general formula [XV]

[0119]

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(Wherein the symbols have the same meanings as described above), for example, by reacting acetocyanohydrin or the like with the compound represented by the general formula [XVI]

[0121]

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(Wherein the symbols have the same meanings as described above) can be produced by a method of hydrolyzing and / or removing a protecting group, or a method described in Examples described later.

Examples of the amino-protecting group include common protecting groups which can be amino-protecting groups, and include, for example, acyl groups such as acetyl and phthaloyl.

Examples of the ester residue include a lower alkyl group.

In the present specification, examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group,
t-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like having 1 to 6, preferably 1 to 4, especially 1 to 3 carbon atoms, and as the lower alkoxy group, For example, a methoxy group, an ethoxy group,
A C 1-6 carbon atom such as a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, an isopentyloxy group,
Particularly, the lower alkenyl group includes, for example, vinyl group, 1-propenyl group, allyl group, 1-methylallyl group, 1 or 2 or 3-butenyl group, 1 or 2 or 3 or 4- Those having 2 to 7 carbon atoms, particularly 2 to 5 carbon atoms, such as a pentenyl group, 1 or 2 or 3 or 4 or a 5-hexenyl group are exemplified.

In the present specification, the substituted amino group means a mono- or di-lower alkylamino group, an acylamino group, an N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-carbamoylamino group. , N-lower alkyl-N-thiocarbamoylamino group (the nitrogen atom in the carbamoyl group or thiocarbamoyl group may be further substituted with one or two lower alkyl groups) and a lower alkylcarbamoyl group. And further includes a pyrrolidino group, a piperidino group, a perhydroazepin-1-yl group, a morpholino group, a thiomorpholino group, and a piperazino group (the 4-position nitrogen atom of the piperazino group is a lower alkyl group, a lower alkenyl group, an acyl group, and an aryl group. Two of which may be substituted with a group or the like) Substituent also include those forms a ring structure to each other at an end.

Examples of the acyl group include a formyl group; an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group and a hexanoyl group;
Preferably a lower alkylcarbonyl group having 2 to 4 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, and a hexyloxycarbonyl group; Preferably 2
And 4 lower alkoxycarbonyl groups.

The lower alkyl group, lower alkoxy group and lower alkenyl group include straight-chain and branched-chain ones.

Examples of the halogen atom include chlorine, bromine, fluorine and iodine.

[0130]

[Action]

Experimental Example 1 Antinephritis Action Rabbit glomerular basement membrane fraction obtained from WKY rats was immunized with rabbits several times with adjuvant, and then whole blood was collected to obtain nephrotoxin serum (NTS). This NTS was diluted 50-fold with physiological saline, and 2.5 ml / kg body weight was intravenously injected once into 8-week-old male WKY rats to induce nephritis. The normal group received the same amount of physiological saline intravenously.

In the experiment, one group consisted of 6 animals, and the test compound was suspended in purified water using a small amount of Tween 80 (manufactured by Nacalai Tesque), and a dose of 30 mg / kg / 10 ml was administered twice a day for 8 consecutive days. Oral administration. The same amount of purified water was orally administered to the normal group and the control group. On the 7th day, the rats were placed in metabolic cages, urine was collected for 24 hours, and the protein concentration in urine was measured by the sulfosalicylic acid method.
D) and the protein excretion inhibition rate was calculated by the following equation.

[0132]

(Equation 1)

The results are as shown in Table 22.

[0134]

[Table 22]

As is clear from Table 22, the protein excretion in the group to which the object of the present invention was administered was suppressed at a rate as high as about 65 to 90%.

Experimental Example 2 Adverse Effects on the Cardiovascular System In the experiment, one group consisted of 4 animals, and a small amount of the test compound was used in Tween.
Suspended in purified water using 80 (manufactured by Nacalai Tesque),
A dose of 30 mg / kg / 10 ml was orally administered to normal awake rats, and the systolic blood pressure and heart rate before and 2 hours after administration were examined. Systolic blood pressure and heart rate were determined by tail-cuff method (KN-
210, manufactured by Natsume Seisakusho). Each change rate was calculated by the following equation.

[0137]

(Equation 2)

The results are as shown in Table 23.

[0139]

[Table 23]

As is clear from Table 23, the target compound of the present invention has little effect on heart rate and blood pressure, and has few side effects on the circulatory system.

Experimental Example 3 Adverse effects on the circulatory system Anesthesia was induced by intravenous administration of 30 mg / kg of sodium pentobarbital using 12 male and female mongrel dogs (6 per sample), and thereafter 5 mg / kg / hr was injected. The depth of anesthesia was maintained by continuous infusion, and tracheal intubation was performed to perform artificial respiration. An anesthetic injection cannula and a sample administration cannula were inserted from the left and right femoral veins. A blood pressure measurement cannula was inserted from the right femoral artery and the distal end was placed in the abdominal aorta. A left ventricular pressure measuring catheter was inserted through the left common carotid artery and the distal end was placed in the left ventricle. The sample was 25% hydroxy-
It was dissolved in a β-cyclodextrin solution and administered intravenously. The administration liquid volume was 0.15 ml / kg. The test compound was administered at a dose of 300 μg / kg, and blood pressure, heart rate, and left ventricular pressure rise rate LVdp / dt before and 1 hour after the administration were examined. L as an index of left ventricular contractility
Vdp / dtmax was used. The blood pressure is measured from the arterial cannula by a strain pressure amplifier (AP-621G, manufactured by Nihon Kohden) via a pressure transducer (TP-400T, manufactured by Nihon Kohden), and a capacitance resistance circuit (time constant 3 sec,
AD-601G (manufactured by Nihon Kohden Corporation) was used to determine the average blood pressure.
The left ventricular pressure rise rate is determined by using a left ventricular pressure as a categorical tip pressure transducer (SPC-350, Millarii).
As with the blood pressure, the strain was measured with a strain pressure amplifier through the same instrument and the differential amplifier (EQ-601G, manufactured by Nihon Kohden) was used to determine LVdp / dtmax (the maximum rise rate of LVP). The heart rate was measured with a heart rate meter (AC-601G, manufactured by Nihon Kohden) using the left ventricular pressure pulse wave as a trigger.

The blood pressure, heart rate and LVdp / d are calculated by the following equations.
The rate of change of tmax was calculated.

[0143]

(Equation 3)

Table 24 shows the values obtained when the respective rates of change became maximum up to one hour after the administration of the sample.

[0145]

[Table 24]

As is clear from Table 24, the target compound of the present invention has little effect on the heart rate, blood pressure, and the rise rate LVdp / dtmax (ie, left ventricular contractile force) of the left ventricular pressure, and has a small effect on the circulatory system. It turns out that there are few side effects.

[0147]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. In addition, Embodiments 1 to 29, 65, and 6
6. The starting compounds were described in Examples 77 to 86 and 88, and the target compounds were described in Examples 30 to 64, 67 to 76, 87 and 89 to 103. .

Example 1 45.9 g of oxalyl chloride and 5 drops of dimethylformamide were added to a dichloroethane solution (500 ml) of 45.5 g of methyl hydrogen succinate, and the mixture was stirred at room temperature for 3 hours. [4- (acetylamino) butyl] under ice-cooling
A solution of 31.3 g of benzene in dichloroethane (60 m
l), 91.9 g of anhydrous aluminum chloride are added and stirred for 1 hour. The reaction solution is poured into ice water, and the organic layer is separated. The organic layer was washed with water, dried, and then the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate to give 4- [4- (acetylamino) butyl] -1- (3-methoxycarbonylpropionyl) 42.3 g of benzene are obtained.

M. p. : 94-95 ° C Example 2-5 The corresponding starting compound was treated in the same manner as in Example 1 to obtain the compound described in Table 25.

[0150]

[Table 25]

Example 6 43.0 g of 4- [4- (acetylamino) butyl] -1- (3-methoxycarbonylpropionyl) benzene was suspended in 480 ml of 10N hydrochloric acid, and the mixture was heated under reflux overnight. 1
0N hydrochloric acid was distilled off, and 350 ml of acetic acid and 20.7 g of hydrazine monohydrate were added to the obtained crude crystals (36.5 g).
Heat to reflux for 3 hours. The acetic acid is concentrated to a half volume, 400 ml of ethyl ether is added, and the precipitated crystals are collected by filtration. This is dissolved in 200 ml of water and neutralized with aqueous ammonia. The precipitated crystals are collected by filtration, dried and then recrystallized from methanol to give 6- [4- (4-aminobutyl).
Phenyl] -4,5-dihydropyridazine-3 (2H)
30.1 g of -on are obtained.

M. p. 167-168 ° C Example 7-10 The corresponding starting compound was treated in the same manner as in Example 6 to obtain the compound described in Table 26.

[0153]

[Table 26]

Example 11 [2-Methyl-4-phthalimidobutyl] benzene 1
To a suspension of 2.83 g and 9.29 g of succinic anhydride in 250 ml of dichloroethane was added 24.86 g of anhydrous aluminum chloride under ice-cooling, followed by stirring at room temperature for 2 hours. The reaction solution is poured into ice water, and the organic layer is separated. The organic layer was washed with water, dried and then the solvent was distilled off. The obtained crude crystals were recrystallized from ethyl acetate-hexane to give 4- (2-methyl-
16.11 g of 4-phthalimidobutyl) -1- (3-hydroxycarbonylpropionyl) benzene are obtained.

M. p. : 142-143 ° C Examples 12-14 The corresponding starting compounds were treated in the same manner as in Example 11 to give the compounds described in Table 27.

[0156]

[Table 27]

Example 15 4- (2-methyl-4-phthalimidobutyl) -1-
(3-hydroxycarbonylpropionyl) benzene 1
9.61 g of hydrazine monohydrate is added to 5.06 g of an ethanol solution (500 ml), and the mixture is heated under reflux for 2.5 hours. After cooling, the precipitated crystals were collected by filtration and recrystallized from ethyl acetate to give 6- [4- (4-amino-2-methylbutyl) -phenyl] -4,5-dihydropyridazine-.
8.14 g of 3 (2H) -one are obtained.

M. p. : 112-114 ° C Examples 16-18 By treating the corresponding starting compounds in the same manner as in Example 15, the compounds shown in Table 28 are obtained.

[0159]

[Table 28]

Example 19 6- [4- (4-Aminobutyl) phenyl] -4,5-
15.00 g of dihydropyridazin-3 (2H) -one was suspended in 200 ml of acetic acid, and a 25% hydrogen bromide-acetic acid solution 1 was added.
Add 00 ml and then 5.35 g of dimethyl sulfoxide and stir at room temperature for 4.5 hours. 400 ml of isopropyl ether was added to the reaction solution, and the crystals were collected by filtration and recrystallized from methanol to give 6- [4- (4-aminobutyl) phenyl] pyridazin-3 (2H) -one.hydrobromide. 18.94 g are obtained.

M. p. : 271 to 273 ° C (decomposition) Examples 20 to 29 The corresponding starting compounds are treated in the same manner as in Example 19, to give the compounds described in Tables 29 to 30.

[0162]

[Table 29]

[0163]

[Table 30]

Example 30 Dimethylformamide of 1.65 g of 6- [4- (4-aminobutyl) phenyl] pyridazin-3 (2H) -one hydrobromide, 0.78 g of nicotinic acid and 1.55 g of triethylamine To the suspension (30 ml) was added dropwise a solution of 1.06 g of diethyl phosphate cyanide in dimethylformamide (10 ml) under ice cooling, and the mixture was stirred for 1 hour. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration. The obtained crystals are washed with water, dried, and recrystallized from methanol to give 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-3 (2H)-.
1.11 g are obtained.

M. p. : 190-191 [deg.] C Examples 31-47 The corresponding starting compounds were treated in the same manner as in Example 30 to give the compounds described in Tables 31-33.

[0166]

[Table 31]

[0167]

[Table 32]

[0168]

[Table 33]

Example 48 A suspension of 2.01 g of 6- [4- (4-aminobutyl) phenyl] pyridazin-3 (2H) -one hydrobromide in 40 ml of ethyl acetate and 10 ml of tetrahydrofuran An aqueous solution containing 4.30 g of anhydrous potassium carbonate (2
5ml), and under ice cooling, 2.23 g of nicotinic acid chloride / hydrochloride was added thereto, followed by stirring for 3 hours. The precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from methanol to give 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-3.
1.30 g of (2H) -one are obtained.

M. p. : Consistent with Example 30.

Examples 49-51 The corresponding starting compounds were treated in the same manner as in Example 48, to give the compounds shown in Table 34.

[0172]

[Table 34]

Example 52 (1) 6- [4- (3-Aminopropyl) phenyl]-
4,5-dihydropyridazin-3 (2H) -one 7.5
7.50 g of triethylamine is added to 1 g of 1,3-dimethyl-2-imidazolidinone suspension (75 ml), and the mixture is stirred at room temperature for 10 minutes. Then, a solution of 5.85 g of chloroethylsulfonyl chloride in tetrahydrofuran (40 m
l) and stir at room temperature for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from acetonitrile to give 6- [4- (3-vinylsulfonylaminopropyl) phenyl] -4,5-dihydropyridazine-3 (2H). 5.39 g of -on are obtained.

M. p. 133-135 ° C (2) 6- [4- (3-vinylsulfonylaminopropyl) phenyl] -4,5-dihydropyridazine-3 (2
H) -one 5.30 g of a 25% hydrogen bromide-acetic acid suspension (50 ml) was added with dimethyl sulfoxide 1.7 g,
Stir at room temperature for 4.5 hours. Hydrogen bromide-acetic acid is distilled off,
A 15% aqueous methyl mercaptan solution (1
00 ml) and stirred at 60 ° C. for 1.5 hours. After cooling, the mixture was neutralized with hydrochloric acid, the crystals were collected by filtration, washed with water, dried, and recrystallized from acetonitrile to give 6- [4- (3-
(2-methylthioethyl) sulfonylaminopropyl)
3.90 g of [phenyl] pyridazin-3 (2H) -one are obtained.

M. p. 173-174 ° C (3) 6- [4- [3- (2-methylthioethyl) sulfonylaminopropyl] phenyl] pyridazine-3 (2
H) -one An aqueous solution (25 ml) of 3.20 g of sodium metaperiodate was added dropwise to a suspension of 5.36 g of acetic acid (100 ml) and stirred at room temperature for 1.5 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and dried to give 6-
[4- [3- (2-methylsulfinylethyl) sulfonylaminopropyl] phenyl] pyridazine-3 (2
5.00 g of H) -one are obtained.

M. p. 176-177 ° C (4) A solution of 2.48 g of 6- [4- [3- (2-methylsulfinylethyl) sulfonylaminopropyl] phenyl] pyridazin-3 (2H) -one in ethylene glycol (25 ml) at 180 ° C. And stir for 1 hour. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration, washed with water, and dried.
By recrystallization from methanol, 6- [4- (3-
1.60 g of vinylsulfonylaminopropyl) phenyl] pyridazin-3 (2H) -one are obtained.

M. p. 166-168 ° C Example 53 6- [4- (3-Aminopropyl) phenyl] pyridazin-3 (2H) -one hydrobromide 3.10 g of 1,
3-dimethyl-2-imidazolidinone suspension (35 m
To 1), 3.54 g of triethylamine is added, and then a solution of 1.95 g of chloroethylsulfonyl chloride in 15 ml of tetrahydrofuran is added, followed by stirring at room temperature for 5 hours. The reaction solution is poured into ice water and extracted with chloroform.
After the chloroform layer is washed with water and dried, the solvent is distilled off. The residue was purified by silica gel column chromatography [eluent, chloroform-methanol (10: 1)] to give 6- [4- (3-vinylsulfonylaminopropyl) phenyl] pyridazin-3 (2H) -one. 1
9 g are obtained.

M. p. : Consistent with Example 52- (4).

Example 54 A suspension of 6- [4- (3-aminopropoxy) phenyl] pyridazin-3 (2H) -one hydrobromide (100 mg) and dimethylaniline (37 mg) in dichloromethane (4 m
l), triethylamine (276 mg) was added, and
Stir for 0 minutes. Under ice cooling, 86 mg of trimethylchlorosilane is added thereto, and the mixture is stirred at room temperature for 2 hours. Under ice cooling again, a dichloromethane solution (1 ml) of chloroethylsulfonyl chloride (65 mg) was added dropwise, and the mixture was stirred at room temperature for 30 minutes. 5 ml of 1N-hydrochloric acid is added, and the organic layer is separated. After washing with water and drying, the solvent was distilled off, and the residue was purified by silica gel column chromatography [eluent, chloroform-methanol (30: 1)] to give 6- [4-
(3-vinylsulfonylaminopropoxy) phenyl]
73 mg of pyridazine-3 (2H) -one are obtained.

M. p. 197-198 ° C Examples 55-63 The corresponding starting compounds are treated in the same manner as in Example 54, to give the compounds listed in Tables 35-36.

[0181]

[Table 35]

[0182]

[Table 36]

Example 64 (1) 6- [4- (5-Aminopentyl) phenyl]-
4,5-Dihydropyridazin-3 (2H) -one and nicotinic acid were treated in the same manner as in Example 30 to give 6- [4- [5
-(Pyridin-3-ylcarbonylamino) pentyl]
Phenyl] -4,5-dihydropyridazine-3 (2H)
-Get on.

M. p. : 133-134 ° C (2) 6- [4- [5- (pyridin-3-ylcarbonylamino) pentyl] phenyl] -4,5-dihydropyridazin-3 (2H) -one was treated in the same manner as in Example 19. After treatment, 6- [4- [5- (pyridin-3-ylcarbonylamino) pentyl] phenyl] pyridazine-3 (2
H) -On is obtained.

M. p. : Consistent with Example 37.

Example 65 10% palladium was added to a methanol solution (100 ml) of 6- [2-chloro-5- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one (2.0 ml). 1.0 g of carbon (Pd / C) and 9.0 g of ammonium formate are added. The suspension is heated at reflux for 12 hours. After cooling, the mixture is filtered and the filtrate is distilled off. The residue was subjected to silica gel column chromatography [eluent, chloroform-
Methanol-28% aqueous ammonia (50: 10: 1)]
To give 6- [5- (4-aminobutyl) phenyl] -4,5-dihydropyridazine-3 (2
1.3 g of H) -one are obtained.

M. p. Example 128: 6- [3-chloro-6- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one was treated in the same manner as in Example 65. 6- [6- (4-aminobutyl) phenyl] -4,5-dihydropyridazine-
3 (2H) -one is obtained.

M. p. : 78-80 ° C Example 67 (1) 6- [4- (4-aminobutyl) phenyl]-
4,5-dihydropyridazin-3 (2H) -one 9.0
g of N, N-dimethylacetamide suspension (270 m
To 1), at an internal temperature of 0 ° C., 50 g of anhydrous potassium carbonate and then 8.5 g of nicotinic acid chloride hydrochloride are added. After stirring the reaction solution for 30 minutes, it is poured into 200 ml of ice water. After stirring at room temperature for 2 hours, additional water (300 ml) was added.
And the precipitated crystals are collected by filtration. The obtained crystals were washed with water and then recrystallized from methanol to give 6- [4
-[4- (pyridin-3-ylcarbonylamino) butyl] phenyl] -4,5-dihydropyridazine-3 (2
10.3 g of H) -one are obtained.

M. p. 178-179 ° C (2) 10.0 g of 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] -4,5-dihydropyridazin-3 (2H) -one was treated with acetic acid (100 m
l), and 25% hydrogen bromide-acetic acid (100
ml) and stirred at room temperature for 5 minutes. At room temperature, 2.9 g of dimethyl sulfoxide is added thereto, and the mixture is stirred for 1 hour. Ethanol (150 ml) was added to the reaction solution, and 2
Stir for hours. Further diisopropyl ether (150
ml) and stirred for 2 hours. The crystals are collected by filtration, washed with diisopropyl ether, dissolved in aqueous ethanol, and neutralized with aqueous ammonia. The precipitated crystals were collected by filtration, washed with water and recrystallized from methanol to give 6- [4- [4
8.9 g of-(pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazin-3 (2H) -one are obtained.

M. p. : Consistent with Example 30.

Example 68 (1) The corresponding starting compound was treated in the same manner as in Example 67- (1), to give 6- [4- [3- (pyridine-3-
Ylcarbonylamino) propoxy] phenyl] -4,
5-Dihydropyridazin-3 (2H) -one is obtained.

M. p. 197-198 ° C. (2) 6- [4- [3- (Pyridin-3-ylcarbonylamino) propoxy] phenyl] -4,5-dihydropyridazin-3 (2H) -one was prepared according to Example 67- (2 ) To give 6- [4- [3- (pyridin-3-ylcarbonylamino) propoxy] phenyl] pyridazin-3 (2H) -one.

M. p. : Consistent with Example 36.

Example 69 8.9 g of 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazin-3 (2H) -one is dissolved in 180 ml of hot ethanol.
An 18% hydrochloric acid-ethanol solution (10 ml) is added thereto, and the mixture is left at room temperature. The precipitated crystals are collected by filtration, washed with cold ethanol, and treated with 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-3.
9.3 g of (2H) -one hydrochloride are obtained.

M. p. : 245-247 ° C (recrystallized from ethanol) hydrochloride monohydrate; m. p. : 240-243 ° C (water-
Examples 70-73 The corresponding starting compounds were treated in the same manner as in Example 69, to give compounds as shown in Table 37.

[0196]

[Table 37]

Example 74 To a solution of 2.0 g of 6- [4- (4-aminobutoxy) phenyl] pyridazin-3 (2H) -one hydrobromide in 50 ml of dimethylformamide was added 868 nicotinic acid.
mg, N-hydroxybenzotriazole 954 mg,
Triethylamine (1.23 ml) is added, and under cooling at 0 ° C., 1.35 g of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide is added and stirred. After stirring at room temperature for 6 hours, the mixture is poured into ice water, and the precipitated crystals are collected by filtration. Recrystallization from ethanol gives 1.75 g of 6- [4- [4- (pyridin-3-ylcarbonylamino) butoxy] phenyl] pyridazin-3 (2H) -one.

M. p. 155-157 ° C Example 75 The corresponding starting compound was treated in the same manner as in Example 74, to give 6- [4- [6- (pyridin-3-ylcarbonylamino) hexyl] phenyl] pyridazine-3 (2H).
-Get on.

M. p. 178-179 ° C Example 76 By reacting the corresponding starting compound with 2-aminonicotinic acid in the same manner as in Example 74, 6- [4- [3- (2-
Aminopyridin-3-ylcarbonylamino) propoxy] phenyl] pyridazin-3 (2H) -one is obtained.

M. p. : 232 to 234 ° C Example 77 (1) The corresponding starting compound was treated in the same manner as in Example 11, to give 4- (4-phthalimidobutoxy) -1.
-(3-Hydroxycarbonylpropionyl) benzene is obtained.

M. p. : 133-134 ° C (2) 4- (4-phthalimidobutoxy) -1- (3-
Hydroxycarbonylpropionyl) benzene is treated in the same manner as in Example 15 to give 6- [4- (4-aminobutoxy) phenyl] -4,5-dihydropyridazin-3 (2H) -one.

M. p. 191-192 ° C (3) 6- [4- (4-aminobutoxy) phenyl]-
4,5-Dihydropyridazin-3 (2H) -one was treated in the same manner as in Example 19 to give 6- [4- (4-aminobutoxy) phenyl] pyridazin-3 (2H) -one.hydrobromic acid Get the salt.

M. p. : 247-250 ° C Example 78 (1) The corresponding starting compound was treated in the same manner as in Example 1 to give 4- [6- (acetylamino) hexyl].
-1- (3-Methoxycarbonylpropionyl) benzene is obtained.

M. p. : 87-89 ° C (2) 4- [6- (acetylamino) hexyl] -1-
6- [4- (6-Aminohexyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one is obtained by treating (3-methoxycarbonylpropionyl) benzene in the same manner as in Example 6.

M. p. 153-154 ° C (3) 6- [4- (6-aminohexyl) phenyl]-
4,5-Dihydropyridazin-3 (2H) -one was treated in the same manner as in Example 19 to give 6- [4- (6-aminohexyl) phenyl] pyridazin-3 (2H) -one.hydrobromic acid. Get the salt.

M. p. : 251 to 253 ° C Example 79 (1) [4- (acetylamino) butyl] benzene 1
0.0 g and 9.96 g of 2-chloropropionic chloride
20.9 g of anhydrous aluminum chloride was added to 200 ml of a dichloroethane solution of the above under ice-cooling, followed by stirring at 5 ° C. for 1 hour.
The reaction solution is poured into ice water, and the organic layer is separated. After the organic layer is washed with water and dried, the solvent is distilled off to obtain 13.71 g of 4- [4- (acetylamino) butyl] -1- (2-chloropropionyl) benzene.

M. p. : 66-67 ° C (2) Malonic acid (tert-butyl) ester 27.90 g was dropped into 300 ml of a dimethylformamide suspension of 5.17 g of 60% sodium hydride, and the mixture was stirred at room temperature overnight. 4- [4- (acetylamino)
Butyl] -1- (2-chloropropionyl) benzene 2
4.2 g of dimethylformamide solution (100 ml) are added dropwise, and the mixture is stirred at room temperature for 1 hour and further at 50 ° C. for 1 hour. The reaction solution is poured into ice water and extracted with chloroform. After the chloroform layer was washed with water and dried, the solvent was distilled off and 4- [4
35.21 g (oil) of-(acetylamino) butyl] -1-[[3,3-di (tert-butoxycarbonyl) -2-methyl] propionyl] benzene are obtained.

(3) 4- [4- (acetylamino) butyl] -1-[[3,3- (di-tert-butoxycarbonyl) -2-methyl] propionyl] benzene 35.
70 ml of trifluoroacetic acid was added to 600 ml of a dichloromethane solution of 21 g, and the mixture was stirred at room temperature for 1.5 hours.
Heat to reflux for hours. The solvent was distilled off under reduced pressure, and the residue was treated with acetic acid 4
Dissolve in 00 ml and heat to reflux for 3 hours. The acetic acid was distilled off, and 4- [4- (acetylamino) butyl] -1-
19.60 g of [(3-hydroxycarbonyl-2-methyl) propionyl] benzene are obtained.

IR (neat) cm ^-1 : 1720, 16
80,1610 MS (ESI) m / z : 323 (M + NH 4) (4) 4- [4- (acetylamino) butyl] -1-
[(3-Hydroxycarbonyl-2-methyl) propionyl] benzene (760 mg) is suspended in 10 N hydrochloric acid (24 ml) and heated under reflux overnight. The hydrochloric acid is distilled off, and the residue is treated with acetic acid 15
Then, 880 mg of hydrazine monohydrate was added, and the mixture was refluxed for 18 hours. The acetic acid is distilled off, and the residue is dissolved in water. After washing the chloroform layer with water and drying, the solvent was distilled off.
The obtained crude crystals were recrystallized from ethyl acetate to give 6- [4-
(4-aminobutyl) phenyl] -4,5-dihydro-
421 mg of 5-methylpyridazin-3 (2H) -one are obtained.

M. p. 135-137 ° C Example 80 (1) [3- (phthalimido) propoxy] benzene and 2-chloropropionic acid chloride were prepared in Example 79- (1).
To give 4- [3- (phthalimido) propoxy] -1- (2-chloropropionyl) benzene.

M. p. 137-138 ° C (2) 4- [3- (phthalimido) propoxy] -1-
(2-chloropropionyl) benzene and malonic acid (te
rt-butyl) ester was treated in the same manner as in Example 79- (2) to give 4- [3- (phthalimido) propoxy] -1-[[3,3-di (tert-butoxycarbonyl) -2-methyl. ] Propionyl] benzene.

M. p. : 103-105 ° C (3) 4- [3- (phthalimido) propoxy] -1-
[[3,3-di (tert-butoxycarbonyl) -2
-Methyl] propionyl] benzene in Example 79-
By treating in the same manner as in (3), 4- [3- (phthalimido) propoxy] -1-[(3-hydroxycarbonyl-2-methyl) propionyl] benzene is obtained.

M. p. : 122-123 ° C (4) 4- [3- (phthalimido) propoxy] -1-
[(3-Hydroxycarbonyl-2-methyl) propionyl] 200 g of ethanol suspension of 10.0 g of benzene
6.50 g of hydrazine monohydrate is added to 1 and heated under reflux for 5 hours. Ethanol is distilled off, and the residue is dissolved in chloroform. After the chloroform layer was washed with water and dried, the solvent was distilled off to give 6- [4- (3-aminopropoxy) phenyl]-.
4,5-dihydro-5-methylpyridazine-3 (2H)
6.61 g of on are obtained.

M. p. 136-138 ° C Example 81 (1) [4- (acetylamino) butyl] benzene 59
1.64 g of anhydrous aluminum chloride was added to 18 ml of a dichloroethane solution of 0 mg and 790 mg of 2,3-dimethylsuccinic anhydride under ice cooling, followed by stirring for 1 hour. The reaction solution is poured into ice water and extracted with chloroform. After the chloroform layer is washed with water and dried, the solvent is distilled off. The residue was purified by silica gel chromatography (elution solvent, chloroform: methanol = 4: 1) to give 4- [4- (acetylamino)
Butyl] -1-[(3-hydroxycarbonyl-2,3
Dimethyl) propionyl] benzene (960 mg).

IR (neat) cm ^-1 : 1710, 16
80,1610 MS (ESI) m / z : 337 (M + NH 4) (2) 4- [4- (acetylamino) butyl] -1-
80 ml of hydrazine monohydrate is added to 4.02 g of [(3-hydroxycarbonyl-2,3-dimethyl) propionyl] benzene, and the mixture is heated under reflux for 4 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. After the ethyl acetate layer is washed with water and dried, the solvent is distilled off. The residue was subjected to silica gel chromatography (elution solvent, chloroform: methanol:
28% ammonia water = 10: 1: 0.1)
2.09 g of-[4- (4-aminobutyl) phenyl] -4,5-dihydro-4,5-dimethylpyridazin-3 (2H) -one are obtained.

IR (neat) cm ^-1 : 1680 MS (ESI) m / z: 278 (MH) ⁺ (3) 6- [4- (4-aminobutyl) phenyl]-
4,5-dihydro-4,5-dimethylpyridazine-3
(2H) -one 2.20 g of acetic acid solution (44 ml) was added to 2
44 ml of a 5% hydrogen bromide-acetic acid solution is added, and the mixture is stirred at room temperature for 5 minutes. Then, 0.75 ml of dimethyl sulfoxide is added, and the mixture is stirred for 6 hours. The solvent was distilled off, and the residue was treated with 150 m of water.
1), made alkaline with ammonia, and extracted with chloroform. After the chloroform layer is washed with water and dried, the solvent is distilled off. The residue was subjected to silica gel chromatography (elution solvent, chloroform: methanol: 28% ammonia water =
10: 1: 0.1), and purified by 6- [4- (4-aminobutyl) phenyl] -4,5-dimethylpyridazine-3.
1.52 g of (2H) -one are obtained.

M. p. 162-163 ° C Example 82 (1) [4- (Acetylamino) butyl] By treating benzene and crotonic chloride in the same manner as in Example 79- (1), 4- [4- (acetylamino) butyl ]-
1- (2-butenoyl) benzene is obtained.

M. p. : 64-66 ° C (2) 4- [4- (acetylamino) butyl] -1-
(2-Butenoyl) 10% in 510 mg of benzene and 1.69 g of acetocyanhydrin in 15 ml of methanol solution
1.1 ml of aqueous sodium carbonate solution is added, and the mixture is heated under reflux for 2 hours. The solvent is distilled off, and the residue is subjected to silica gel chromatography (elution solvent, chloroform: methanol = 40: 1).
To give 4- [4- (acetylamino) butyl] -1
450 mg of-(3-cyanobutanoyl) benzene are obtained.

M. p. : 89-90 ° C (3) 4- [4- (acetylamino) butyl] -1-
7.50 g of (3-cyanobutanoyl) benzene in 10N
Suspend in 180 ml of hydrochloric acid and heat to reflux overnight. The reaction solution is concentrated to half the volume, and the precipitated crystals are collected by filtration. The crystals were dissolved in 110 ml of acetic acid, and 5.29 g of hydrazine monohydrate was obtained.
And heat to reflux for 4 hours. The acetic acid is distilled off and the residue is dissolved in water, made alkaline with ammonia and left overnight. The precipitated crystals are collected by filtration, washed with water, dried, and then washed with ethyl acetate.
Recrystallization from methanol gives 4.23 g of 6- [4- (4-aminobutyl) phenyl] -4,5-dihydro-4-methylpyridazin-3 (2H) -one.

M. p. Example 118 (1) [3- (4-phthalimidobutyl) -4-methyl] chlorobenzene and succinic anhydride were treated in the same manner as in Example 11 to obtain [5- (4-phthalimidobutyl). -2- (3-hydroxycarbonylpropionyl)
-4-methyl] chlorobenzene is obtained.

M. p. : 116-118 ° C (2) [5- (4-phthalimidobutyl) -2- (3-
Hydroxycarbonylpropionyl) -4-methyl] chlorobenzene and hydrazine monohydrate were treated in the same manner as in Example 15 to give 6- [2-chloro-5-methyl-4- (4-aminobutyl) phenyl]- 4,5-Dihydropyridazin-3 (2H) -one is obtained.

M. p. 181-182 ° C (3) 6- [2-chloro-5-methyl-4- (4-aminobutyl) phenyl] -4,5-dihydropyridazine-
6- [3-Methyl-4- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one is obtained by treating 3 (2H) -one in the same manner as in Example 65. .

M. p. 145-147 ° C Examples 84-86 The corresponding starting compounds are treated in the same manner as in Example 67- (1) to give the compounds described in Table 38.

[0224]

[Table 38]

Example 87 6- [4- (4-Aminobutyl) phenyl] -4,5-
To a solution of 1.39 g of dimethylpyridazin-3 (2H) -one in 80 ml of dimethylformamide, 690 ml of nicotinic acid was added.
mg and N-hydroxybenzotriazole (760 mg), 1-ethyl-3- (3'-dimethylaminopropyl) carbodiimide (1.08 g) was added thereto under ice cooling, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from 2-propanol.
There are obtained 1.41 g of 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] -4,5-dimethylpyridazin-3 (2H) -one.

M. p. Example 211: Treatment of 6- [3-methyl-4- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one and nicotinic acid in the same manner as in Example 87. To give 6- [4- [3-methyl-4- (pyridin-3-ylcarbonylamino) butyl] phenyl] -4,5-dihydropyridazin-3 (2H) -one.

M. p. : 160-161 ° C. Example 89 6- [4- (4-Aminobutyl) phenyl] pyridazin-3 (2H) -one and pyridazine-4-carboxylic acid were treated in the same manner as in Example 87 to give 6- [ 4- [4-
(Pyridazin-4-ylcarbonylamino) butyl] phenyl] pyridazin-3 (2H) -one is obtained.

M. p. 183-185 ° C Examples 90-95 The corresponding starting compounds are treated in the same manner as in Example 67- (2), to give the compounds listed in Table 39.

[0229]

[Table 39]

Examples 96-102 The corresponding starting compounds were treated in the same manner as in Example 69, to give compounds as shown in Table 40.

[0231]

[Table 40]

Example 103 6- [4- (4-Aminobutyl) phenyl] pyridazin-3 (2H) -one and 3-methyl-5-carboxyisoxazole were treated in the same manner as in Example 87 to give 6-. [4- [4- [3-methylisoxazole-5-
Ylcarbonylamino) butyl] phenyl] pyridazin-3 (2H) -one is obtained.

M. p. : 236-238 ° C

[0234]

The object of the present invention, the pyridazinone derivative [I] and a pharmaceutically acceptable salt thereof, have an excellent antinephritis action and / or an endotoxin shock protection action. Therefore, the object of the present invention is nephritis [eg, glomerulonephritis (immunoglobulin A nephropathy, nephrotic syndrome,
Lupus nephritis, etc.) and / or renal failure. In addition, prevention of endotoxin shock that occurs in patients with severe infections of Gram-negative bacteria
It is also useful as a therapeutic.

The objective compound [I] of the present invention has low toxicity.
3-ylcarbonylamino) butyl) phenyl] pyridazin-3 (2H) -one hydrochloride at 1000 mg / k
g orally and observed for 3 days,
No mortality was observed even after intraperitoneal administration at a dose of mg / kg and observation for 3 days.

The objective product [I] of the present invention has excellent drug efficacy as described above, but has very few side effects on the circulatory system and is highly safe as a pharmaceutical.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 403/12 237 C07D 403/12 237 // A61K 31/00 609 A61K 31/00 609 613 613G 31/50 601 31/50 601 31/505 601 31/505 601 (72) Inventor Fumikazu Okumura 675-1-C403, Kokuki, Shiraoka-cho, Minami-Saitama-gun, Saitama (56) Reference JP-A-7-233152 (JP, A) JP-A-6-205 73020 (JP, A) JP-A-5-221992 (JP, A) JP-A-1-68360 (JP, A) JP-A-60-89421 (JP, A) JP-A-53-124279 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) C07D 237/14 A61K 31/50 A61K 31/505 C07D 401/12 C07D 403/12 CA (STN) REGISTRY (STN)

Claims (26)

(57) [Claims] 1. A compound of the general formula [I] (Wherein X is a hydrogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a lower alkylthio group, a hydroxyl group, an optionally substituted amino Y represents a single bond, an oxygen atom or a sulfur atom, A represents a linear or branched alkylene group which may contain a double bond, and B and R ² represent Or a thiocarbonyl group, wherein R ² is an optionally substituted alkyl group having 1 to 10 carbon atoms, 3 to 6 carbon atoms
A cycloalkyl group, a lower alkenyl group, a phenyl-substituted lower alkenyl group, a lower alkoxy group which may have a substituent, a phenoxy group, a lower alkylamino group, a lower alkenylamino group, a phenylamino group, a lower alkenyloxy group, A nitrogen atom, an oxygen atom or a sulfur atom, as a hetero atom, a monocyclic or bicyclic heteroaromatic group which may have a substituent or an aryl group which may have a substituent, Alternatively, B is a sulfonyl group, and R ²
Is an optionally substituted alkyl group having 1 to 10 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group,
A phenyl-substituted lower alkenyl group or a monocyclic or bicyclic heteroaromatic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom and optionally having a substituent, wherein R ¹ is hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group, R ³ represents a hydrogen atom or an optionally substituted lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, R ⁵ Represents a hydrogen atom or a lower alkyl group. Or a pharmacologically acceptable salt thereof. 2. X represents a hydrogen atom, a lower alkoxy group or a halogen atom, Y represents a single bond, an oxygen atom or a sulfur atom, and A represents a linear or branched alkylene group which may contain a double bond. Wherein B and R ² are such that B is a carbonyl group or a thiocarbonyl group, and R ² is an optionally substituted alkyl group having 1 to 10 carbon atoms, and 3 to 6 carbon atoms.
A cycloalkyl group, a lower alkenyl group, a phenyl-substituted lower alkenyl group, a lower alkoxy group which may have a substituent, a phenoxy group, a lower alkylamino group, a lower alkenylamino group, a phenylamino group, a lower alkenyloxy group, A nitrogen atom, an oxygen atom or a sulfur atom, as a hetero atom, a monocyclic or bicyclic heteroaromatic group which may have a substituent or an aryl group which may have a substituent, Alternatively, B is a sulfonyl group, and R ²
Is an optionally substituted alkyl group having 1 to 10 carbon atoms,
A cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group,
A phenyl-substituted lower alkenyl group or a monocyclic or bicyclic heteroaromatic group which may have a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, and R ¹ is hydrogen An atom, an optionally substituted lower alkyl group or a lower alkenyl group, R ³ represents a hydrogen atom or an optionally substituted lower alkyl group, R ⁴ represents a hydrogen atom, and R ⁵ represents a hydrogen atom A compound according to claim 1. 3. B is a carbonyl group or a thiocarbonyl group, and R ² is a lower alkyl group optionally substituted by a halogen atom; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; a phenyl-substituted lower alkenyl. A lower alkoxy group optionally substituted with a phenyl group; a phenoxy group; a lower alkylamino group; a lower alkenylamino group; a phenylamino group; a lower alkenyloxy group; a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group; Lower alkylthio group, hydroxyl group, mercapto group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, Lower alkylcarbonyl group, carbamo Group, may be substituted with 1-4 group selected from mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, a pyridyl group,
Furyl, thienyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, imidazolyl, pyrazolyl, quinolyl, isoquinolyl, isoxazolyl, oxazolyl, indolyl or isoindolyl; or lower alkoxy, phenyl substituted lower An alkoxy group, a halogen atom, a hydroxyl group, a trifluoromethyl group, a nitro group, a lower alkyl group and a phenyl group which may be substituted with 1 to 3 groups selected from di-lower alkylamino groups, or B is A lower alkyl group wherein R ² may be substituted with a halogen atom; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; a phenyl-substituted lower alkenyl group; or a lower alkyl group or a halogeno lower alkyl group. , Lower alkoxy group, lower alkylthio , Hydroxyl group, mercapto group, cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl A group, a carbamoyl group, a mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, which may be substituted with 1 to 4 groups selected from a pyridyl group,
3. The compound according to claim 1, which is a furyl group, a thienyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolyl group, an imidazolyl group, a pyrazolyl group, a quinolyl group, an isoquinolyl group, an indolyl group or an isoindolyl group. 4. R ² is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a substituted amino group, a halogen atom, a phenoxy group, a carboxy group, or a lower group. A pyridyl group optionally having one or two substituents selected from an alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group, a mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group; lower 3. The compound according to claim 1, which is an alkyl group or a lower alkenyl group. 5. A pyridyl group, lower alkyl group, lower alkenyl group or halogenophenyl group, wherein R ² may have one or two substituents selected from a lower alkyl group, a lower alkylamino group and an amino group. The compound according to claim 1, which is: 6. The compound according to claim 1, wherein R ² is a pyridyl group or a vinyl group optionally having one or two substituents selected from a methyl group and an amino group. 7. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom. 8. The compound according to claim 1, wherein R ¹ is a lower alkyl group. 9. The compound according to claim 1, wherein R ³ is a hydrogen atom. 10. The compound according to claim 1, wherein B is a carbonyl group. 11. The compound according to claim 1, wherein B is a sulfonyl group. 12. The compound according to claim 1, wherein Y is a single bond. 13. The compound according to claim 1, wherein X is a hydrogen atom. 14. R ² is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group,
Hydroxyl group, mercapto group, cyano group, amino group, substituted amino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group,
A pyridyl group optionally having one or two substituents selected from a mono-lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group; a lower alkyl group; a lower alkenyl group; or a halogenophenyl group, and B is a carbonyl group. The compound according to claim 1. 15. The compound according to claim 1, wherein R ² is a lower alkyl group or a lower alkenyl group, and B is a sulfonyl group. 16. The compound according to claim 1, wherein A is a linear or branched alkylene group having 2 to 6 carbon atoms. 17. R ² is a lower alkyl group, lower alkylamino group and 1 to 2 amino pyridyl group which may have a substituent group selected from an amino group, R ³ is a hydrogen atom, B
Is a carbonyl group; and Y is a single bond. 18. The compound according to claim 1, wherein R ² is a lower alkyl group or a lower alkenyl group, B is a sulfonyl group, and Y is a single bond. 19. R ¹ is a hydrogen atom, and R ² is a lower alkyl group, a lower alkylamino group or an amino group.
A pyridyl group optionally having two or more substituents, R
^3. The compound according to claim 1, wherein ³ is a hydrogen atom, B is a carbonyl group, and Y is a single bond. 20. The compound according to claim ¹ , wherein R ¹ is a hydrogen atom, R ² is a lower alkyl group or a lower alkenyl group, B is a sulfonyl group, and Y is a single bond. 21. R ¹ is a hydrogen atom, R ² is a pyridyl group optionally having one or two substituents selected from a methyl group and an amino group, R ³ is a hydrogen atom, B is a carbonyl group, 20. The compound according to claim 1, 2 or 19, wherein Y is a single bond. 22. The method according to claim ¹ , wherein R ¹ is a hydrogen atom, R ² is a vinyl group, B is a sulfonyl group, and Y is a single bond.
The compound according to 0. 23. 6- [4- [4- (Pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-
3 (2H) -one or a pharmaceutically acceptable salt thereof. 24. A compound of the general formula [II] (Wherein X is a hydrogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a lower alkylthio group, a hydroxyl group, an optionally substituted amino Represents a group or a halogen atom, Y represents a single bond, an oxygen atom or a sulfur atom, A represents a linear or branched alkylene group which may contain a double bond, R ¹ represents a hydrogen atom, Represents an optionally substituted lower alkyl group or a lower alkenyl group, R ³ represents a hydrogen atom or an optionally substituted lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a hydrogen atom or a lower alkyl group. A pyridazinone compound represented by the general formula [II
I] Wherein W represents an oxygen atom or a sulfur atom, and R ²¹ is an optionally substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, and a phenyl-substituted lower alkenyl. Group, a lower alkoxy group which may have a substituent, a phenoxy group, a lower alkylamino group, a lower alkenylamino group, a phenylamino group, a lower alkenyloxy group, a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A monocyclic or bicyclic heteroaromatic group which may have a substituent or an aryl group which may have a substituent.), A reactive derivative thereof, or a salt thereof. To give a pharmacologically acceptable salt, if desired, characterized by the general formula [Ia]: (Wherein the symbols have the same meanings as described above.) Or a pharmacologically acceptable salt thereof. 25. A compound of the general formula [II] (Wherein X is a hydrogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a lower alkylthio group, a hydroxyl group, an optionally substituted amino Represents a group or a halogen atom, Y represents a single bond, an oxygen atom or a sulfur atom, A represents a linear or branched alkylene group which may contain a double bond, R ¹ represents a hydrogen atom, Represents an optionally substituted lower alkyl group or a lower alkenyl group, R ³ represents a hydrogen atom or an optionally substituted lower alkyl group, R ⁴ represents a hydrogen atom or a lower alkyl group, and R ⁵ represents a hydrogen atom or a lower alkyl group. A pyridazinone compound or a salt thereof represented by the general formula [IV]: (Wherein, R ²² represents an optionally substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, a phenyl-substituted lower alkenyl group, Represents a monocyclic or bicyclic heteroaromatic group which contains an atom or a sulfur atom and may have a substituent, and Z represents a reactive residue.) General formula [Ib], characterized in that the salt is a chemically acceptable salt. (Wherein the symbols have the same meanings as described above.) Or a pharmacologically acceptable salt thereof. 26. The general formula [V] (Wherein X is a hydrogen atom, an optionally substituted lower alkyl group, a lower alkoxy group, a carboxy group, a lower alkoxycarbonyl group, a nitro group, a cyano group, a lower alkylthio group, a hydroxyl group, an optionally substituted amino Y represents a single bond, an oxygen atom or a sulfur atom, A represents a linear or branched alkylene group which may contain a double bond, and B and R ² represent A group or a thiocarbonyl group, wherein R ² may have a substituted alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, a phenyl-substituted lower alkenyl group, Lower alkoxy group, phenoxy group, lower alkylamino group, lower alkenylamino group, phenylamino group, lower alkenyloxy group, heteroatom which may be A monocyclic or bicyclic heteroaromatic group containing a nitrogen atom, an oxygen atom or a sulfur atom and optionally having a substituent, or an aryl group optionally having a substituent, or B Is a sulfonyl group, and R ² may be substituted; an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group, a phenyl-substituted lower alkenyl group or a nitrogen atom as a heteroatom atom; Represents a monocyclic or bicyclic heteroaromatic group which may have a substituent containing an oxygen atom or a sulfur atom,
R ¹ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group, R ³ represents a hydrogen atom or an optionally substituted lower alkyl group, and R ⁴ represents a hydrogen atom or a lower alkyl group. And R ⁵ represents a hydrogen atom or a lower alkyl group. The compound of formula (I) is oxidized to a pharmaceutically acceptable salt if desired. Wherein the symbols have the same meanings as described above, or a method for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof.