JP3060454B2 - Pharmaceutical composition - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pharmaceutical composition useful as a prophylactic / therapeutic agent for nephritis and / or an endotoxin shock protective agent.

[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.

[0004] On the other hand, endotoxin causes platelet aggregation,
In addition to activating leukocytes, bronchoconstriction, damage to the gastrointestinal mucosa,
It is known that it suppresses cardiac function, lowers renal function, and causes damage to important organs such as kidney, lung, and liver. Conventionally, steroid hormones, aprotinin (a protease inhibitor), dobutamine (a cardiotonic), and the like have been used as therapeutic agents for endotoxin shock occurring in patients with severe infections of Gram-negative bacteria.

[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 pharmaceutical composition comprising a novel pyridazinone derivative as an active ingredient, which has an excellent therapeutic effect on nephritis and / or an endotoxin shock protective effect and has few side effects on the circulatory system. Is what you do.

[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 as an active ingredient.

The pyridazinone derivative [I] or a pharmacologically acceptable salt thereof, which is an active ingredient of the present invention, has an excellent therapeutic effect on nephritis and / or a protective effect on endotoxin shock, and is an agent for preventing or treating nephritis. Alternatively, it is useful as an endotoxin shock protective agent, especially as a preventive / therapeutic agent for nephritis.

[0011]

BEST MODE FOR CARRYING OUT THE INVENTION In the pyridazinone derivative [I] which is the active ingredient of the present invention, examples of the substituent of the optionally substituted lower alkyl group for X include a halogen atom, a lower alkoxy group, an amino group, A lower alkylamino group, a di-lower alkylamino group, an acylamino group or a lower alkylthio group; examples of the substituent of the optionally substituted lower alkyl group in R ¹ and R ³ include a phenyl group, a halogenophenyl group and a thienyl group; Group, pyridyl group, morpholino group, lower alkylamino group, di-lower alkylamino group, piperazinyl group which may be substituted with a lower alkyl group, imidazolyl group, lower alkoxycarbonyl group, cyano group, di-lower alkylcarbamoyl group or hydroxy A carbonyl group.

The amino group which may be substituted includes:
For example, lower alkylamino group, di-lower alkylamino group, acylamino group, N-lower alkyl-N-lower alkoxycarbonylamino group, N-lower alkyl-N-carbamoylamino group, N-lower alkyl-N-thiocarbamoylamino Group (the nitrogen atom in the carbamoyl group or the thiocarbamoyl group may be further substituted with one or two lower alkyl groups), a lower alkylcarbamoyl group, and a pyrrolidino group, a piperidino group, a perhydro group. Azepin-1-yl group, morpholino group, thiomorpholino group, piperazino group (the 4-position nitrogen atom of the piperazino group may be further substituted with a lower alkyl group, a lower alkenyl group, an acyl group, an aryl group, etc.) A ring structure in which two substituents on a nitrogen atom are bonded to each other at the terminal Those that are formed, and the like.

The phenyl-substituted lower alkenyl group includes
An example is a styryl group.

The lower alkoxy group which may have a substituent includes, for example, a lower alkoxy group which may be substituted by a phenyl group.

The monocyclic or bicyclic heteroaromatic group which contains a nitrogen atom, oxygen atom or sulfur atom as a hetero atom and may have a substituent includes, for example, 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 lower alkylamino group, a di-lower alkylamino group,
1-4 groups selected from acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group, lower alkylcarbamoyl group and di-lower alkylcarbamoyl group May be substituted with a pyridyl group, a furyl group, a 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, oxazolyl group, quinazolinyl group, thienopyrimidinyl group, triazinyl group, tetrazolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, benzooxazolyl group, benzimidazolyl group, Examples include an isothiazolyl group, a phthalazyl group, and a benzofuryl group.

Examples of the halogeno lower alkyl group include a trifluoromethyl group.

The aryl group which may have a substituent includes, for example, 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 selected from the groups.

The linear or branched alkylene group which may contain a double bond includes a linear or branched alkylene group having 1 to 10 carbon atoms, preferably 2 to 10 carbon atoms which may contain a double bond. And more preferably a linear or branched alkylene group having 2 to 6 carbon atoms. Specific examples include methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene, nonamethylene, 2-methyltetramethylene, and 2-ethyltetramethylene. , A 1-butenylene group and the like (provided that 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 pyridazinone derivative [I]; the same applies hereinafter); Preferable examples include a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, a hexamethylene group, a 2-methyltetramethylene group, and a 2-ethyltetramethylene group.

Among the pyridazinone derivatives [I] which are the active ingredients of the present invention, specific compounds include: 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, Is a linear or branched alkylene group which may contain a double bond, B and R ² are
B is a carbonyl group or a thiocarbonyl group, and R ² is a lower alkyl group which may be substituted with a halogen atom, a phenyl group, a halogenophenyl group, a pyridyl group, a thienyl group or a lower alkylthio group; Cycloalkyl group; lower alkenyl group; phenyl-substituted lower alkenyl group; lower alkoxy group optionally substituted with phenyl group; phenoxy group; lower alkylamino group; lower alkenylamino group; phenylamino group; lower alkenyloxy group; Alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkylthio group, hydroxyl group,
Mercapto group, cyano group, amino group, lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group A pyridyl group, a furyl group, a thienyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyridazinyl group, a pyrrolyl group, and an imidazolyl group which may be substituted with 1 to 4 groups selected from a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. Group, pyrazolyl group, quinolyl group, isoquinolyl group, indolyl group, isoindolyl group, thiazolyl group, isoxazolyl group, oxazolyl group, quinazolinyl group, thienopyrimidinyl group, triazinyl group, tetrazolyl group, quinoxalinyl group, Nzochieniru group, benzothiazolyl group, benzoxazolyl group, benzoimidazolyl group, isothiazolyl group, phthalazyl group or benzofuryl group; or a lower alkoxy group, a phenyl-substituted lower alkoxy group, a halogen atom, a hydroxyl group, a trifluoromethyl group,
R is a phenyl group which may be substituted with 1 to 3 groups selected from a nitro group, a lower alkyl group and a di-lower alkylamino group, or B is a sulfonyl group;
² is a halogen atom, a phenyl group, a halogenophenyl group,
A lower alkyl group which may be substituted with a pyridyl group, a thienyl group or a lower alkylthio group; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; a phenyl-substituted lower alkenyl group; or a lower alkyl group, a halogeno lower alkyl group, Lower alkoxy group, lower alkylthio group, hydroxyl group, mercapto group, cyano group, amino group, lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyl An oxy group, a lower alkylcarbonyl group, a carbamoyl group, optionally substituted with 1 to 4 groups selected from a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group, a pyridyl group, a furyl group, a thienyl group, a pyrazinyl group, Pyrimidinyl group, Ridazinyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, quinolyl group, isoquinolyl group, indolyl group, isoindolyl group, thiazolyl group, isoxazolyl group, oxazolyl group, quinazolinyl group, thienopyrimidinyl group, triazinyl group, tetrazolyl group, quinoxalinyl group, benzo A thienyl group, a benzothiazolyl group, a benzoxazolyl group, a benzimidazolyl group, an isothiazolyl group, a phthalazyl group or a benzofuryl group, R ¹ is a hydrogen atom or a lower alkyl group, R ³
Is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group, and R ⁵ is a hydrogen atom or a lower alkyl group.

Among these, preferred compounds are those wherein X is a hydrogen atom, a lower alkoxy group or a halogen atom, Y is a single bond or an oxygen atom, A is a linear or branched alkylene group having 2 to 6 carbon atoms, B and R ^2, B is carbonyl group or thiocarbonyl group, R ² is a lower alkyl group; a lower alkenyl group; or 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 , Amino group, lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group, lower alkylcarbamoyl group And 1 selected from di-lower alkylcarbamoyl groups A pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group or an indolyl group which may be substituted with up to 4 groups, or B
Is a sulfonyl group, and R ² is a lower alkyl group; a lower alkenyl group; or 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, and a lower alkylamino group , A di-lower alkylamino group, an 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 lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group. May be, pyridyl group, pyrazinyl group, pyrrolyl group, isoxazolyl group or indolyl group, R ¹ is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group,
Compounds in which R ⁴ is a hydrogen atom or a lower alkyl group, and R ⁵ is a hydrogen atom or a lower alkyl group.

Of these, more preferred compounds include
X is a hydrogen atom, a lower alkoxy group or a halogen atom, Y
Is a single bond or an oxygen atom, A is a linear or branched alkylene group having 2 to 6 carbon atoms, B and R ² are B is a carbonyl group or a thiocarbonyl group, and R ² is a lower alkyl group; a lower alkenyl group Or may be substituted with 1 to 4 groups selected from a lower alkyl group and an amino group;
A pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group or an indolyl group, or B is a sulfonyl group, and R ² is a lower alkyl group; a lower alkenyl group; or a 1-4 selected from a lower alkyl group and an amino group. A pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group or an indolyl group, R ¹ may be a hydrogen atom or a lower alkyl group, R ³
Is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group, and R ⁵ is a hydrogen atom or a lower alkyl group.

Among the specific examples of the pyridazinone derivative [I], which is an active ingredient of the present invention, compounds that are preferable in terms of medicinal effect include X being a hydrogen atom, a lower alkoxy group or a halogen atom, Y being a single bond or an oxygen atom, Is a linear or branched alkylene group having 2 to 6 carbon atoms, B and R ² are B is a carbonyl group, and R ² is a lower alkyl group; a lower alkenyl group; or a 1 selected from a lower alkyl group and an amino group.
A pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group, or an indolyl group, or B is a sulfonyl group, and R ² is a lower alkyl group or a lower alkenyl group, which may be substituted with Compounds in which R ¹ is a hydrogen atom or a lower alkyl group, R ³ is a hydrogen atom or a lower alkyl group, R ⁴ is a hydrogen atom or a lower alkyl group, and R ⁵ is a hydrogen atom or a lower alkyl group.

Among these compounds, X is preferably a hydrogen atom, Y is a single bond, and A is a compound having 2 to 6 carbon atoms.
A linear or branched alkylene group, B and R ² , wherein B is a carbonyl group, and R ² is a pyridyl group optionally substituted with one or two groups selected from a lower alkyl group and an amino group. Or, a compound in which B is a sulfonyl group, R ² is a lower alkenyl group, R ¹ is a hydrogen atom, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom.

Among these compounds, X is preferably a hydrogen atom, Y is a single bond, and A is a compound having 2 to 2 carbon atoms.
6, a linear or branched alkylene group, B is a carbonyl group, R ² is a pyridyl group optionally substituted with one or two groups selected from a lower alkyl group and an amino group, R ¹ is a hydrogen atom, R ³ is a hydrogen atom, R ⁴ is a hydrogen atom,
Compounds in which R ⁵ is a hydrogen atom are mentioned, and particularly preferred compounds are 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-
3 (2H) -one.

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 pyridazinone derivative [I], which is the active ingredient 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 pyridazinone derivative which is an active ingredient of the present invention are shown in Tables 1 to 21 below, but the target compound of the present invention is not limited thereto.

[0028]

[Table 1]

[0029]

[Table 2]

[0030]

[Table 3]

[0031]

[Table 4]

[0032]

[Table 5]

[0033]

[Table 6]

[0034]

[Table 7]

[0035]

[Table 8]

[0036]

[Table 9]

[0037]

[Table 10]

[0038]

[Table 11]

[0039]

[Table 12]

[0040]

[Table 13]

[0041]

[Table 14]

[0042]

[Table 15]

[0043]

[Table 16]

[0044]

[Table 17]

[0045]

[Table 18]

[0046]

[Table 19]

[0047]

[Table 20]

[0048]

[Table 21]

The pyridazinone derivative [I], which is an active ingredient of the present invention, can be used for a pharmaceutical use in a free form or a pharmaceutically acceptable salt form 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 pyridazinone derivative [I] and the pharmaceutically acceptable salt thereof, which are the active ingredients of the present invention, include their internal salts, adducts, complexes, solvates and hydrates thereof. Including both.

The pyridazinone derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, is administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously, etc.). And used as a pharmaceutical preparation together with a pharmaceutical carrier suitable for oral or parenteral administration. The pharmaceutical preparation may be a solid preparation such as a tablet, a granule, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbite, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants Any of conventional materials such as (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrant (potato starch, etc.) or wetting agent (sodium lauryl sulfate, etc.) can be used. 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.

The active ingredient of the present invention, the pyridazinone derivative [I] and a pharmaceutically acceptable salt thereof have an excellent anti-nephritis effect and / or an endotoxin shock protective effect. Therefore, the pharmaceutical composition of the present invention, nephritis [for example,
It is useful as a prophylactic / therapeutic agent for glomerulonephritis (immunoglobulin A nephropathy, nephrotic syndrome, lupus nephritis, etc.) and / or a prophylactic agent for renal failure. It is also useful as a prophylactic / therapeutic agent for endotoxin shock occurring in patients with severe infections of Gram-negative bacteria.

The pyridazinone derivative [I], which is the active ingredient of the present invention, has low toxicity.
[4- (4- (pyridin-3-ylcarbonylamino)
Butyl) phenyl] pyridazin-3 (2H) -one hydrochloride was orally administered at a dose of 1000 mg / kg and observed for 3 days, and also administered intraperitoneally at a dose of 300 mg / kg and observed for 3 days. No deaths were found.

Further, the pyridazinone derivative [I], which is an active ingredient of the present invention, has excellent medicinal effects as described in the experimental examples described below, but also has side effects on the circulatory system, such as little influence on heart rate and blood pressure. Extremely low and highly safe as pharmaceuticals.

(A) Among the pyridazinone derivatives [I] which are the active ingredients of the present invention, those represented by the general formula [Ia]

[0057]

Embedded image

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]:

[0059]

Embedded image

(Wherein the symbols have the same meanings as described above) or a salt thereof (for example, a salt with an inorganic acid such as hydrochloride, a salt with an organic acid such as succinate, etc.) ,
General formula [III]

[0061]

Embedded image

(Wherein the symbols have the same meanings as described above) or a salt thereof (eg, an alkali metal salt, an organic amine salt, etc.) with a conventional binder (eg,
In the presence of 1,3-dicyclohexylcarbodiimide), the reaction is carried out in a suitable solvent (eg, dimethylformamide, etc.), or a reactive derivative of compound [III] (eg, acid halide, mixed acid anhydride, etc.) It can be produced by reacting in a solvent (for example, chloroform or the like) in the presence or absence of a deoxidizing agent (for example, alkali metal carbonate or the like) to form a pharmaceutically acceptable salt if desired.

(B) Among the pyridazinone derivatives [I] which are the active ingredients of the present invention, the compounds represented by the general formula [Ib]

[0064]

Embedded image

(Wherein 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, 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]

[0066]

Embedded image

(Wherein the symbols have the same meanings as described above) or a salt thereof (for example, a salt with an inorganic acid such as hydrochloride, a salt with an organic acid such as succinate, etc.)
General formula [IV]

[0068]

Embedded image

(Wherein R ²² has the same meaning as described above;
Represents a reactive residue (for example, a nucleophilically leaving group such as a halogen atom or an alkoxy group). ) In a suitable solvent (eg, ethyl acetate, etc.) in a deoxidizing agent (eg, alkali metal carbonate, alkali metal hydroxide, etc.)
The reaction can be carried out in the presence or absence of a compound, if desired, to give a pharmacologically acceptable salt, if desired.

(C) The pyridazinone derivative [I], which is the active ingredient of the present invention, has, for example, the general formula [V]

[0071]

Embedded image

(Wherein the symbols have the same meanings as described above) by oxidation of the compound represented by the general formula (for example, oxidation with dimethyl sulfoxide in hydrogen bromide-acetic acid under acidic conditions). However, if desired, a pharmacologically acceptable salt can be used for the production.

In the above reaction, the starting compound [I
When a compound containing an asymmetric atom is used as [I] or [V], the corresponding target compound [I], [Ia] or [Ib] is obtained without racemization of the asymmetric atom. Can be.

The starting compound [II] has the general formula [VI]

[0075]

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. When the reaction is carried out in the presence or absence of a suitable solvent (for example, methanol or the like), and R ¹¹ represents a hydrogen atom, an amino group may be added, if desired, to, for example, a corresponding aldehyde compound and sodium borohydride (NaB
H ₄ ), sodium triacetoxyborohydride [Na
B (OCOCH ₃ ) ₃ H], by subjecting it to a reductive alkylation reaction in the presence of a suitable reducing agent, or the like, followed by alkylation and further oxidation.

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

The starting compound [VI] may be, for example, a compound of the general formula [VII] if necessary.

[0079]

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 [VIII]

[0081]

Embedded image

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

[0083]

Embedded image

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

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

[0086]

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]

[0088]

Embedded image

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

[0090]

Embedded image

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

[0092]

Embedded image

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

[0094]

Embedded image

(Where 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 the following Production Examples.

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

[0097]

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]

[0099]

Embedded image

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

[0101]

Embedded image

(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]

[0103]

Embedded image

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

Examples of the amino-protecting group include conventional protecting groups that can serve as amino-protecting groups, and include, for example, acyl groups such as acetyl and phthaloyl.

The ester residue includes, for example, 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 and a tertiary alkyl 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- Examples thereof include 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.

In the present specification, the substituted amino group means a lower alkylamino group; a di-lower alkylamino group, an acylamino group, an N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-carbamoylamino group. A N-lower alkyl-N-thiocarbamoylamino group (the nitrogen atom in the carbamoyl group or the thiocarbamoyl group may be further substituted with one or two lower alkyl groups) or a lower alkylcarbamoyl group. And a pyrrolidino group, a piperidino group, a perhydroazepin-1-yl group, a morpholino group,
Thiomorpholino group, piperazino group (the 4-position nitrogen atom of the piperazino group may be further substituted with a lower alkyl group, a lower alkenyl group, an acyl group, an aryl group, etc.)
And those in which two substituents on a nitrogen atom are bonded to each other at the terminal to form a ring structure.

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.

The halogen atom includes chlorine, bromine, fluorine and iodine.

[0112]

[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 a test compound (compound obtained in the following Production Example) was suspended in purified water using a small amount of Tween 80 (manufactured by Nacalai Tesque, Inc.) to give 30 mg / k.
A dose of g / 10 ml was orally administered twice a day for 8 consecutive days. 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, the urinary protein concentration was measured by the sulfosalicylic acid method, and the protein excretion (mg / day) was determined. Calculated.

[0114]

(Equation 1)

The results are as shown in Table 22.

[0116]

[Table 22]

As is evident from Table 22, the protein excretion in the group administered with the compound as the active ingredient of the present invention was suppressed by about 65 to 65%.
It was suppressed at a rate as high as 90%.

Experimental Example 2 Adverse effects on the circulatory system In the experiment, one group consisted of 4 animals, and a small amount of the test compound was added to 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.

[0119]

(Equation 2)

The results are as shown in Table 23.

[0121]

[Table 23]

As is clear from Table 23, it is found that the compound which is the active ingredient 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 Cardiovascular System Anesthesia was induced by intravenous administration of 30 mg / kg of sodium pentobarbital in 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 test compound was dissolved in a 25% hydroxy-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. LVdp / dtmax was used as an index of left ventricular contractility. 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)
c, AD-601G, manufactured by Nihon Kohden Corporation) to determine the average blood pressure. The left ventricular pressure rise rate is determined by measuring the left ventricular pressure with a cat tip pressure transducer (SPC-350, Millar
instruments), measured by a strain pressure amplifier as in the case of blood pressure, and a differential amplifier (EQ-601G,
LVdp / dtmax (maximum rising speed of LVP) was determined by Nihon Kohden. The heart rate is measured by a heart rate monitor (AC-601G,
(Manufactured by Nihon Kohden Corporation).

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

[0125]

(Equation 3)

In the period up to one hour after administration of the test compound,
Table 24 shows the values when the respective rates of change are maximum.

[0127]

[Table 24]

As is clear from Table 24, the compound which is the active ingredient of the present invention has little effect on heart rate, blood pressure, and the rising speed LVdp / dtmax of left ventricular pressure (ie, left ventricular contractile force). It can be seen that there are few side effects on the organ system.

[0129]

[Production example]

Production Example 1 To a dichloroethane solution (500 ml) of 45.5 g of methyl hydrogen succinate, 45.9 g of oxalyl chloride and 5 drops of dimethylformamide are added, and the mixture is 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 Preparation Example 2-5 The corresponding starting compound was treated in the same manner as in Preparation Example 1 to give the compounds described in Table 25.

[0131]

[Table 25]

Production 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 refluxed 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 Production Example 7-10 The corresponding starting compound was treated in the same manner as in Production Example 6 to give the compounds described in Table 26.

[0134]

[Table 26]

Production 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 Preparation Example 12-14 The corresponding starting compound was treated in the same manner as in Preparation Example 11 to give the compound described in Table 27.

[0137]

[Table 27]

Production 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 Production Examples 16-18 By treating the corresponding starting compounds in the same manner as in Production Example 15, the compounds shown in Table 28 are obtained.

[0140]

[Table 28]

Production 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) Production Examples 20 to 29 The corresponding starting compounds are treated in the same manner as in Production Example 19 to give compounds shown in Tables 29 to 30.

[0143]

[Table 29]

[0144]

[Table 30]

Production 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 of on are obtained.

M. p. : 190-191 ° C Production Examples 31-47 By treating the corresponding starting compounds in the same manner as in Production Example 30, the compounds described in Tables 31 to 33 are obtained.

[0147]

[Table 31]

[0148]

[Table 32]

[0149]

[Table 33]

Production Example 48 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 Production Example 30.

Examples 49 to 51 By treating the corresponding starting compounds in the same manner as in Example 48, the compounds shown in Table 34 are obtained.

[0153]

[Table 34]

Production 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 the mixture was 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 Production 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 Production Example 52- (4).

Production Example 54 A suspension of 6- [4- (3-aminopropoxy) phenyl] pyridazin-3 (2H) -one hydrobromide in 100 mg and dimethylaniline in 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 Production Example 55-63 The corresponding starting compound is treated in the same manner as in Production Example 54, to give compounds as shown in Tables 35 to 36.

[0162]

[Table 35]

[0163]

[Table 36]

Production 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 Production 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 prepared in the same manner as in Production Example 19. After treatment, 6- [4- [5- (pyridin-3-ylcarbonylamino) pentyl] phenyl] pyridazine-3 (2
H) -On is obtained.

M. p. : Consistent with Production Example 37.

Preparation 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 g). 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. : 128-130 ° C Preparation Example 66 6- [3-Chloro-6- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one was treated in the same manner as in Preparation Example 65. 6- [6- (4-aminobutyl) phenyl] -4,5-dihydropyridazine-
3 (2H) -one is obtained.

M. p. : 78-80 ° C Production 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 Production Example 30.

Production Example 68 (1) The corresponding starting compound was treated in the same manner as in Production 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) Preparation of 6- [4- [3- (pyridin-3-ylcarbonylamino) propoxy] phenyl] -4,5-dihydropyridazin-3 (2H) -one ) To give 6- [4- [3- (pyridin-3-ylcarbonylamino) propoxy] phenyl] pyridazin-3 (2H) -one.

M. p. : Consistent with Production Example 36.

Production 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-
(Recrystallization from ethanol) Production Examples 70-73 The corresponding starting compounds were treated in the same manner as in Production Example 69, to give compounds as shown in Table 37.

[0177]

[Table 37]

Production Example 74 Nicotic acid 868 was added to a dimethylformamide solution (50 ml) of 6- [4- (4-aminobutoxy) phenyl] pyridazin-3 (2H) -one hydrobromide.
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 Production Example 75 By treating the corresponding starting compound in the same manner as in Production Example 74, 6- [4- [6- (pyridin-3-ylcarbonylamino) hexyl] phenyl] pyridazine-3 (2H)
-Get on.

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

M. p. : 232 to 234 ° C Production Example 77 (1) The corresponding raw material compound was treated in the same manner as in Production 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 Production Example 15 to obtain 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 Production Example 19 to give 6- [4- (4-aminobutoxy) phenyl] pyridazin-3 (2H) -one.hydrobromic acid. Get the salt.

M. p. : 247-250 ° C Production Example 78 (1) By treating the corresponding starting compound in the same manner as in Production Example 1, 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 Production 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 Production Example 19 to give 6- [4- (6-aminohexyl) phenyl] pyridazin-3 (2H) -one.hydrobromic acid. Get the salt.

M. p. : 251-253 ° C Production 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 Production Example 80 (1) Production of [3- (phthalimido) propoxy] benzene and 2-chloropropionic acid chloride Production 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 Production 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 was prepared in Production 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 Production 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. Production Example 82 (1) [4- (acetylamino) butyl] benzene and crotonic acid chloride were treated in the same manner as in Production Example 79- (1) to give 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. : 118-120 ° C Production Example 83 (1) [3- (4-phthalimidobutyl) -4-methyl] chlorobenzene and succinic anhydride were treated in the same manner as in Production Example 11 to give [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 Production 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 Production Example 65. .

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

[0205]

[Table 38]

Production 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. : 211-212 ° C Preparation Example 88 6- [3-Methyl-4- (4-aminobutyl) phenyl] -4,5-dihydropyridazin-3 (2H) -one and nicotinic acid were treated in the same manner as in Preparation 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 Production Example 89 6- [4- (4-Aminobutyl) phenyl] pyridazin-3 (2H) -one and pyridazine-4-carboxylic acid were treated in the same manner as in Production Example 87 to give 6- [ 4- [4-
(Pyridazin-4-ylcarbonylamino) butyl] phenyl] pyridazin-3 (2H) -one is obtained.

M. p. 183-185 ° C Preparation Example 90-95 The corresponding starting compound is treated in the same manner as in Preparation Example 67- (2) to give the compounds described in Table 39.

[0210]

[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.

[0212]

[Table 40]

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

M. p. : 236-238 ° C

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI C07D 403/12 C07D 403/12 409/12 409/12 417/12 417/12 (72) Inventor Fumikazu Okumura Minamisaitama-gun, Saitama 675-1-Kokuki, Shiraoka-cho C403 (56) References JP-A-7-233152 (JP, A) JP-A-3-236378 (JP, A) JP-A-9-228761 (JP, A) European patent application Publication 194548 (EP, A2) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/501 A61K 31/506 A61P 13/12 C07D 237/14 C07D 401/12 C07D 403/12 C07D 409 / 12 C07D 417/12 CA (STN) MEDLINE (STN) REGISTRY (STN)

Claims (13)

(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 as an active ingredient. 2. X is a hydrogen atom; a halogen atom, a lower alkoxy group, an amino group, a lower alkylamino group, a di-lower alkylamino group, a lower alkyl group which may be substituted with an acylamino group or a lower alkylthio group; A lower alkoxycarbonyl group; a nitro group; a cyano group; a lower alkylthio group; a hydroxyl group; a lower alkylamino group; a di-lower alkylamino group;
Acyl-amino group; N-lower alkyl-N-lower alkoxycarbonylamino group; N-lower alkyl-N-carbamoylamino group; N-lower alkyl-N-thiocarbamoylamino group (nitrogen atom in the carbamoyl group or thiocarbamoyl group) May be further substituted with one or two lower alkyl groups); a lower alkylcarbamoyl group; a pyrrolidino group; a piperidino group; a perhydroazepin-1-yl group; a morpholino group; a thiomorpholino group; The 4-position nitrogen atom of the piperazino group may further be a lower alkyl group, a lower alkenyl group, an acyl group,
Or a halogen atom, B and R ² , wherein B is a carbonyl group or a thiocarbonyl group, and R ² is a halogen atom, a phenyl group, a halogenophenyl group, a pyridyl group, a thienyl group Or a lower alkyl group optionally substituted with a lower alkylthio group;
A cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group;
A phenyl-substituted lower alkenyl group; 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; Lower alkoxy group, lower alkylthio group, hydroxyl group, mercapto group, cyano group, amino group, lower alkylamino group, di-lower alkylamino group,
1-4 groups selected from acylamino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group, lower alkylcarbamoyl group and di-lower alkylcarbamoyl group May be substituted with a pyridyl group, a furyl group, a 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, oxazolyl group, quinazolinyl group, thienopyrimidinyl group, triazinyl group, tetrazolyl group, quinoxalinyl group, benzothienyl group, benzothiazolyl group, benzooxazolyl group, benzimidazolyl group, An isothiazolyl group, a phthalazyl group or a benzofuryl group; or one to three lower alkoxy groups, phenyl-substituted lower alkoxy groups, halogen atoms, hydroxyl groups, trifluoromethyl groups, nitro groups, lower alkyl groups and di-lower alkylamino groups A phenyl group which may be substituted with a group, or B is a sulfonyl group, and R ² is a halogen atom, a phenyl group,
A lower alkyl group which may be substituted with a halogenophenyl group, a pyridyl group, a thienyl group or a lower alkylthio group; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; a phenyl-substituted lower alkenyl group; Lower alkyl group, lower alkoxy group, lower alkylthio group, hydroxyl group, mercapto group, cyano group,
Amino group, lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom, phenoxy group,
Carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group,
A pyridyl group, a furyl group, a thienyl group, a pyrazinyl group, a pyrimidinyl group, a pyridazinyl group, a pyrrolyl group which may be substituted with 1 to 4 groups selected from a carbamoyl group, a lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group; , Imidazolyl, pyrazolyl, quinolyl, isoquinolyl, indolyl, isoindolyl, thiazolyl, isoxazolyl, oxazolyl, quinazolinyl, thienopyrimidinyl, triazinyl, tetrazolyl, quinoxalinyl, benzothienyl, benzothiazolyl , benzoxazolyl group, benzoimidazolyl group, isothiazolyl group, phthalazyl group or benzofuryl group, R ¹ is a hydrogen atom; a phenyl group, a halogenophenyl group, a thienyl group, a pyridyl group, a morpholino group, low Alkylamino group, di-lower alkylamino group, piperazinyl group which may be substituted with lower alkyl group, imidazolyl group, lower alkoxycarbonyl group, cyano group, di-lower alkylcarbamoyl group or hydroxycarbonyl group A lower alkyl group; or a lower alkenyl group, R ³ is a hydrogen atom; or a phenyl group, a halogenophenyl group, a thienyl group, a pyridyl group, a morpholino group, a lower alkylamino group, a di-lower alkylamino group, or a lower alkyl group. The pharmaceutical composition according to claim 1, which is a lower alkyl group optionally substituted with a piperazinyl group, an imidazolyl group, a lower alkoxycarbonyl group, a cyano group, a di-lower alkylcarbamoyl group or a hydroxycarbonyl group. 3. The pharmaceutical composition according to claim 2, wherein X is a hydrogen atom, a lower alkoxy group or a halogen atom, R ¹ is a hydrogen atom or a lower alkyl group, and R ³ is a hydrogen atom or a lower alkyl group. 4. Y is a single bond or an oxygen atom, A is a linear or branched alkylene group having 2 to 6 carbon atoms, R ² is a lower alkyl group; a lower alkenyl group; or a lower alkyl group, a halogeno lower alkyl group, Lower alkoxy group, lower alkylthio group, hydroxyl group, mercapto group, cyano group, amino group, lower alkylamino group, di-lower alkylamino group,
1-4 groups selected from an acylamino group, 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 lower alkylcarbamoyl group and a di-lower alkylcarbamoyl group The pharmaceutical composition according to claim 3, which is a pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group, or an indolyl group which may be substituted with: 5. R ¹ is selected from a lower alkyl group; a lower alkenyl group; or a lower alkyl group and an amino group.
The pharmaceutical composition according to claim 4, which is a pyridyl group, a pyrazinyl group, a pyrrolyl group, an isoxazolyl group, or an indolyl group which may be substituted with four groups. 6. A pyridyl group, wherein B is a carbonyl group, and R ² is optionally substituted with 1-4 groups selected from a lower alkyl group; a lower alkenyl group; or a lower alkyl group and an amino group. A pyrazinyl group, a pyrrolyl group, an isoxazolyl group or an indolyl group, or
B is a sulfonyl group, a pharmaceutical composition according to claim 5, wherein R ² is a lower alkyl group or a lower alkenyl group,. 7. X is a hydrogen atom, Y is a single bond, B and R
² is a pyridyl group, wherein B is a carbonyl group and R ² is optionally substituted with one or two groups selected from a lower alkyl group and an amino group, or B is a sulfonyl group; ² is a lower alkenyl group, R ¹ is a hydrogen atom,
The pharmaceutical composition according to claim 6, wherein R ³ is a hydrogen atom, R ⁴ is a hydrogen atom, and R ⁵ is a hydrogen atom. 8. The pharmaceutical composition according to claim 7, wherein B is a carbonyl group, and R ² is a pyridyl group optionally substituted with one or two groups selected from a lower alkyl group and an amino group. 9. 6- [4- [4- (pyridin-3-ylcarbonylamino) butyl] phenyl] pyridazine-3
A pharmaceutical composition comprising (2H) -one or a pharmaceutically acceptable salt thereof as an active ingredient. 10. The pharmaceutical composition according to claim 1, which is a prophylactic / therapeutic agent for nephritis and / or an endotoxin shock protective agent. 11. The method according to claim 1, which is a prophylactic or therapeutic agent for nephritis.
10. The pharmaceutical composition according to any one of 9 above. 12. The pharmaceutical composition according to claim 1, which is a prophylactic / therapeutic agent for glomerulonephritis. 13. The pharmaceutical composition according to any one of claims 1 to 9, which is a prophylactic / therapeutic agent for immunoglobulin A nephropathy, nephrotic syndrome and / or lupus nephritis.