JPH0673020A - Pyridazinone derivative and its production - Google Patents

Abstract

PURPOSE:To obtain a new pyridazinone derivative having excellently protecting action on endotoxin shock and treating action on nephritis. CONSTITUTION:A compound of formula I (R<1> is 1-10C alkyl, 3-6C cycloalkyl, lower alkenyl, heterocyclic group containing N, O or S as a hetero atom or camphor-10-yl; R<3> is H, lower alkyl, lower alkenyl or R<1> and R<3> are bonded at ends to form lower alkylene; R<2> is H, lower alkyl, aryl or lower alkenyl; A-B is ethylene or vinylene which may be replaced with one or two groups selected from lower alkyl and phenyl; (n) is 1 or 2; D is halogen) or its pharmacologically acceptable salt such as 2-methylsulfonylamino-5-[4,5- dihydropyridazin-3(2H)-on-6-yl]indane. The compound is obtained by reacting a compound of formula II (R<4> is H or lower alkyl) or its salt with a hydrazine compound of formula III.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pyridazinone derivative having endotoxin shock-protecting activity and nephritis therapeutic activity, and a process for producing the same.

[0002]

2. Description of the Related Art In Japanese Patent Laid-Open No. 63-23853, 6-
(2-benzenesulfonamide-indan-5-yl)
It has been disclosed that benzenesulfonamidoindanyl compounds such as 4,5-dihydro-pyridazin-3 (2H) -one exhibit antithrombotic activity.

On the other hand, as a therapeutic agent for endotoxin shock which develops in patients with severe infections of Gram-negative bacteria, it has been conventionally used
Steroid hormones, aprotinin (protease inhibitor), dobutamine (cardiotonic drug), etc. are used.

Further, as a therapeutic drug for nephritis, conventionally, prednisolone (steroid drug), cyclophosphamide (immunosuppressive drug), dipyridamole, dilazep (antiplatelet drug), heparin (anticoagulant), etc. have been used. .

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a novel compound having an excellent endotoxin shock protective activity and nephritis therapeutic activity, and a method for producing the same.

[0006]

The pyridazinone derivative according to the present invention has the general formula [I]

[0007]

[Chemical 16]

[In the formula, R ¹ 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 nitrogen atom, an oxygen atom or sulfur as a hetero atom. A heterocyclic group containing an atom (the heterocyclic group may have a substituent) or a camphor-10-yl group, R ³ is a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl Represents a group, or R ¹ and R ³
Form a lower alkylene group by being bonded at the terminal, R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group, and —AB— represents a lower alkyl group and a phenyl group. Represents an ethylene group or a vinylene group which may be substituted with 1 to 2 groups selected from
Represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] Is shown.

More specifically, R ¹ is a phenyl group optionally substituted by ¹ to 2 halogen atoms, a lower alkylthio group, a phenylamino group and a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom. An alkyl group having 1 to 10 carbon atoms which may be substituted with a group selected from the group;
6 cycloalkyl group; lower alkenyl group; heterocyclic group containing nitrogen atom, oxygen atom or sulfur atom as a hetero atom
(The heterocyclic group may have a substituent); a camphor-10-yl group, R ³ is a hydrogen atom; a phenyl group and a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom. A lower alkyl group optionally substituted with a group selected from the group (the heterocyclic group may have a substituent);
A lower alkenyl group, or R ¹ and R ³ combine at the terminal to form a lower alkylene group, and R ² represents a hydrogen atom; groups 1 to 3 selected from a halogen atom and a lower alkoxy group.
Optionally substituted with a phenyl group, a carboxyl group, a heterocyclic group containing a nitrogen atom as a hetero atom, an oxygen atom or a sulfur atom (the heterocyclic group may have a substituent), A lower alkyl group which may be substituted with a group selected from a cyano group, a di-lower alkylcarbamoyl group, a lower alkoxycarbonyl group and a di-lower alkylamino group; an aryl group; a lower alkenyl group, -AB-
Is a group 1-2 selected from a lower alkyl group and a phenyl group.
Examples thereof include an ethylene group or a vinylene group which may be substituted with one, n is 1 or 2, and D is a hydrogen atom or a halogen atom.

Further, R ¹ has ¹ to 10 carbon atoms substituted with a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom.
When it is an alkyl group of, a C 1-10 alkyl group substituted with a pyridyl group or a thienyl group is mentioned as such a group, and R ¹ is a nitrogen atom as a hetero atom,
In the case of a heterocyclic group containing an oxygen atom or a sulfur atom (the heterocyclic group may have a substituent), such a group includes a thienyl group which may be substituted with a pyridyl group. , A pyridyl group, a di-lower alkylthiazolyl group, a di-lower alkylisoxazolyl group, a quinolyl group or a di-lower alkylhalogenopyrazolyl group, and R ² represents a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. When it is a lower alkyl group substituted with a heterocyclic group containing (the heterocyclic group may have a substituent), such a group may be substituted with a lower alkoxycarbonyl group. Good piperazinyl group, imidazolyl group, thienyl group,
Examples thereof include a lower alkyl group substituted with a pyridyl group, a tetrazolyl group or a morpholino group, and when R ² is an aryl group, such a group includes a phenyl group. When R ³ is a lower alkyl group substituted with a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom (the heterocyclic group may have a substituent), such a group Include a lower alkyl group substituted with a piperazinyl group optionally substituted with a phenyl group, a thienyl group or a pyridyl group, and when D is a halogen atom, such a group includes a chlorine atom. To be

Another specific example of the object [I] is R ¹
Is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenylamino lower alkyl group or a camphor-10-yl group, and R ² is a hydrogen atom, a lower alkyl group, a phenyl group or a phenyl lower alkyl group. , R ³ is a hydrogen atom, —AB— is an ethylene group or vinylene group which may be substituted with 1 to 2 groups selected from a lower alkyl group and a phenyl group, n is 1, and D is An example is a compound that is a hydrogen atom.

Among the object [I], preferable compounds include compounds in which D is a hydrogen atom.

As the pharmaceutically effective compound, R ¹ in the object [I] is an alkyl group having 1 to 10 carbon atoms which may be substituted with a group selected from a phenyl group, a thienyl group and a pyridyl group, and a carbon atom. A cycloalkyl group, a lower alkenyl group or a camphor-10-yl group of the formulas ³ to 6, R ³ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, or R ¹ and R ³ are bonded at the terminal. A lower alkylene group which forms a lower alkylene group and R ² is a lower alkyl group or a lower alkenyl group which may be substituted with a group selected from a hydrogen atom, a cyano group, a tetrazolyl group, a carboxyl group and a di-lower alkylcarbamoyl group; Examples include compounds in which -B- is an ethylene group or a vinylene group, n is 1 or 2, and D is a hydrogen atom.

As a more pharmaceutically effective compound, R ¹ in the target compound [I] is an alkyl group having 1 to 5 carbon atoms, a benzyl group, a cyclohexyl group, a lower alkenyl group or a camphor-10-yl group, R ² is a lower alkyl group or a lower alkenyl group which may be substituted with a group selected from a hydrogen atom, a cyano group, a tetrazolyl group, a carboxyl group and a di-lower alkylcarbamoyl group, and R ³ is a hydrogen atom, a lower alkyl group. Or a lower alkenyl group, -AB- is an ethylene group or a vinylene group, n is 1 or 2, and D is a hydrogen atom. In particular, R ¹ has ¹ to 5 carbon atoms. R ² is a hydrogen atom, a tetrazolyl lower alkyl group, a carboxyl lower alkyl group or a lower alkyl group, And R ³ is a hydrogen atom or a lower alkyl group, —AB— is an ethylene group or a vinylene group, n is 1 or 2, and D is a hydrogen atom.

The object [I] of the present invention may have two kinds of optical isomers based on an asymmetric carbon atom, and the present invention includes both these optical isomers and a mixture thereof.

The object [I] of the present invention can be in the form of its pharmacologically acceptable salt. Examples of the pharmacologically acceptable salt include inorganic acid salts such as hydrochloride, sulfate and hydrobromide, and organic acid salts such as fumarate, oxalate and maleate. .

The object [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. . Further, the pharmaceutical preparation may be a solid preparation such as a tablet, a capsule or a powder, or a liquid preparation such as a solution, a suspension or an emulsion. Further, for parenteral administration, it can be used in the form of injection.

Although the dose varies depending on the age, weight, condition of the patient or the degree of disease, the daily dose is usually 1 to 200 mg / kg, especially 10 to 100 mg / kg in the case of oral administration. For parenteral administration,
0.1-30 mg / kg, especially 1-20 mg / kg
Is preferred.

According to the present invention, the target compound [I] or a pharmaceutically acceptable salt thereof is, for example, a compound represented by the general formula [II]

[0020]

[Chemical 17]

(In the formula, R ⁴ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above.) A compound represented by the general formula [III]

[0022]

[Chemical 18]

The compound can be produced by reacting with a hydrazine compound represented by the formula (wherein the symbols have the same meanings as described above) to form a pharmacologically acceptable salt, if desired.

Among the target compounds [I], the general formula [I-
a]

[0025]

[Chemical 19]

(However, R ⁵ 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. Represents a heterocyclic group (which may have a substituent) or a camphor-10-yl group, and R ⁶ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower group. Which represents an alkenyl group, and other symbols have the same meanings as defined above.) The pyridazinone derivative represented by the formula or a pharmacologically acceptable salt thereof is represented by the general formula [IV]

[0027]

[Chemical 20]

[Wherein the symbols have the same meanings as defined above] or a salt thereof, and a compound of the general formula [V]

[0029]

[Chemical 21]

(Wherein X ¹ represents a reactive residue, and other symbols have the same meanings as described above), and the compound is reacted to form a pharmacologically acceptable salt, if desired. It can be manufactured.

Among the target compounds [I], the general formula [Ic]

[0032]

[Chemical formula 22]

(In the formula, R ⁷ 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 nitrogen atom, an oxygen atom or sulfur as a hetero atom. Represents a heterocyclic group containing an atom (the heterocyclic group may have a substituent) or a camphor-10-yl group, and R ⁸ represents an optionally substituted lower alkyl group or lower alkenyl group. And other symbols have the same meanings as described above.) The pyridazinone derivative represented by the formula) or a pharmaceutically acceptable salt thereof is represented by the general formula [Ib]

[0034]

[Chemical formula 23]

[Wherein the symbols have the same meanings as defined above] or a salt thereof, and a compound of the general formula [VI]

[0036]

[Chemical formula 24]

(Wherein, X ² represents a reactive residue, and other symbols have the same meanings as described above), and the compound is reacted to form a pharmacologically acceptable salt, if desired. It can be manufactured.

Of the desired product [I], the general formula [Ie]

[0039]

[Chemical 25]

(In the formula, R ⁹ represents an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group,
Other symbols have the same meanings as above. ) The pyridazinone derivative represented by the formula) or a pharmaceutically acceptable salt thereof has the general formula [Id]

[0041]

[Chemical formula 26]

[Wherein the symbols have the same meanings as defined above] or a salt thereof, and a compound of the general formula [VI
I]

[0043]

[Chemical 27]

(Wherein X ³ represents a reactive residue, and other symbols have the same meanings as described above), and by reacting with a compound represented by the formula, a pharmacologically acceptable salt is obtained. It can be manufactured.

Of the desired product [I], a compound of the general formula [Ig]

[0046]

[Chemical 28]

(Wherein R ¹⁰ and R ¹¹ are the same or different and each represents a hydrogen atom, a lower alkyl group or a phenyl group, and other symbols have the same meanings as described above), or a pharmacologically effective compound thereof. Acceptable salts have the general formula [If]

[0048]

[Chemical 29]

(In the formula, symbols have the same meanings as described above.) The compound can be produced by oxidizing the compound to obtain a pharmacologically acceptable salt, if desired.

In the above production method of the present invention, the compound [I
The reaction of I] with the hydrazine compound [III] can be appropriately carried out in a suitable solvent or in the absence of a solvent.

The solvent may be an inert solvent which does not adversely influence the reaction, and examples thereof include lower fatty acids such as lower alcohol, acetic acid and propionic acid, aromatic hydrocarbons such as toluene and xylene, ethers such as tetrahydrofuran and dioxane. Kind and the like.

The hydrazine compound [III] may be a hydrate.

The reaction can be carried out over a wide range from room temperature to the boiling point of the reaction mixture, for example from 10 ° C to 200 ° C, especially 20 ° C.
It can be suitably carried out at a temperature of from 150 ° C to 150 ° C.

The condensation reaction between compound [IV] and compound [V] can be appropriately carried out in a suitable solvent in the presence or absence of a deoxidizing agent.

The reactive residue (X ¹ ) of the compound [V] is a nucleophilic leaving group such as a halogen atom or an alkoxy group, and when the compound [V] is a symmetrical sulfonic acid anhydride. A lower alkyl sulfonyloxy group, a benzene sulfonyloxy group, a lower alkyl group-substituted benzene sulfonyloxy group, etc. can be suitably used.

Examples of the deoxidizing agent include tri-lower alkylamine, N-lower alkylmorpholine, pyridine,
Organic bases such as 2,6-lutidine, inorganic bases such as alkali metal hydroxides, alkali metal hydrogen carbonates, alkali metal carbonates and alkali metal hydrides can be preferably used.

The solvent may be an inert solvent which does not adversely influence the reaction, for example, a halogen-based solvent such as chloroform, dichloromethane, dichloroethane, toluene,
Aromatic hydrocarbons such as xylene, tetrahydrofuran, ethers such as dioxane, ketone solvents such as acetone and methyl ethyl ketone, esters such as ethyl acetate, acetonitrile, pyridine, 2,6-lutidine, dimethylformamide, dimethyl sulfoxide, 1, 3-dimethyl-2-imidazolidinone and the like, and combinations of these solvents with water can be mentioned.

The present condensation reaction can be carried out over a wide range from -78 ° C to the boiling point of the reaction mixture, for example, -10 ° C to 150 ° C, especially -10 ° C to 60 ° C.

Further, the compound [Ib] and the compound [VI]
The condensation reaction of and the condensation reaction of the compound [Id] with the compound [VII] can be appropriately carried out in the presence of a base in a suitable solvent.

The reactive residues (X ² and X ³ ) of the compound [VI] and the compound [VII] are, for example, groups which are nucleophilically separated, for example, a halogen atom, an alkoxy group, a lower alkylsulfonyloxy group, benzenesulfonyl. Oxy group,
A lower alkyl group-substituted benzenesulfonyloxy group, a trifluoromethanesulfonyloxy group and the like can be preferably used.

Examples of the base include lower alkyl metals such as butyl lithium, alkali metal alkoxides, alkali metal hydroxides, alkali metal carbonates, alkali metal hydrides and the like.

The solvent may be an inert solvent which does not adversely influence the reaction, and examples thereof include ethers such as dimethoxyethane, tetrahydrofuran and dioxane, alcohols such as methanol, ethanol, 2-methoxyethanol, propanol and butanol, and the like. Ketone solvents such as acetone and methyl ethyl ketone, esters such as ethyl acetate, dimethylformamide, dimethylacetamide,
Examples thereof include amide solvents such as 1,3-dimethyl-2-imidazolidinone, acetonitrile, dimethyl sulfoxide, and the like.

This condensation reaction can be suitably carried out under cooling to heating, especially at 0 ° C to 150 ° C.

Oxidation of compound [If] can be carried out by a conventional method. For example, compound [I-f] in a suitable solvent can be used.
f] is treated with sodium 3-nitrobenzenesulfonate under basic conditions, or is reacted redox using dimethyl sulfoxide under acidic conditions, or
It can be suitably carried out with hydrogen bromide-acetic acid or the like.

As the solvent, water, acetic acid, trifluoroacetic acid, methanesulfonic acid, acetic acid solution of hydrobromic acid, or the like can be preferably used.

In the reaction of the present invention, starting compounds [II], [IV], [Ib], [Id] or [I] are used.
If an optically active substance is used as -f], the corresponding optically active target compound [I], [Ia], without racemization,
[Ic], [Ie] or [Ig] can be obtained, respectively.

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

[0068]

[Chemical 30]

(Wherein the symbols have the same meanings as described above) and the sulfone compound [V] or the general formula [IX].

[0070]

[Chemical 31]

(Wherein E is a lower alkylene group, and X ⁴ and X ⁵ are reactive residues) are reacted with each other, and if necessary, the compound represented by the general formula [X ]

[0072]

[Chemical 32]

(Wherein the symbols have the same meanings as described above) and a compound of the general formula [XI]

[0074]

[Chemical 33]

(Wherein the symbols have the same meanings as described above) or the general formula [XII].

[0076]

[Chemical 34]

(In the formula, X ⁶ represents a reactive residue, and other symbols have the same meanings as described above.). The starting compound [IV] of the present invention has the general formula [XIII]

[0078]

[Chemical 35]

(Wherein the symbols have the same meanings as described above) and a hydrazine compound [III]
When -AB- is an ethylene group, it can be produced by further oxidizing and converting the ethylene group to a vinylene group, if desired.

The starting material compound [XIII] for the above reaction
Is, for example, if necessary, after protecting the amino group of the compound [VIII], the compound [XI] or [XI] is added to the compound.
It can be produced by a method of reacting I] and then removing the protecting group, a method described in Examples below, or the like.

In the present specification, the lower alkyl group, the lower alkoxy group and the lower alkylene group have 1 to 1 carbon atoms.
6, especially those having 1 to 5 carbon atoms, and examples of the lower alkenyl group include those having 2 to 7 carbon atoms.
Moreover, examples of the aryl group include a phenyl group and the like.

[0082]

[Action]

Experimental Example 1 (Protective effect against lethality of mice induced by endotoxin) Male ddy mice that had been fasted for about 24 hours were orally administered with a specimen dissolved or suspended in a 0.25% sodium carboxymethylcellulose (CMC) aqueous solution (100 mg). / Kg). After 30 minutes, 100 mg / 10 ml / kg of E. coli-derived endotoxin (lipopolysaccharide) dissolved in physiological saline was intraperitoneally administered.
The survival rate of the sample-administered group was calculated when the survival rate of the control group to which the CMC aqueous solution was orally administered reached 20% (about 20 hours after the endotoxin administration). As a result, 2-methylsulfonylamino-5- [4,5-dihydropyridazine-
The survival rate of 3 (2H) -on-6-yl] indan is 10
It was 0%.

Experimental Example 2 (Nephritis therapeutic effect) Male WKY rats (8 weeks old, 1 group 6)
Anti-rat glomerular basement membrane rabbit serum was diluted 50 times with physiological saline, and 2.5 ml / kg was intravenously administered to induce nephritis so that the dose was 30 mg / kg / 10 ml. A sample suspended in purified water using Tween 80 (manufactured by Nacalai Tesque) was orally administered twice a day for 8 days.

Urine was collected on the 8th day after the induction of nephritis for 24 hours. The amount of urine was measured, the urinary protein concentration was measured by the sulfosalicylic acid method, and the urinary protein excretion amount was calculated. As a result, 2-
Propylsulfonylamino-5- [pyridazine-3 (2
H) -on-6-yl] indan suppressed urinary protein excretion on day 8 after nephritis induction to 50 to 55% of that of the control group.

[0085]

【Example】

Example 1 2-Amino-5- [4,5-dihydropyridazine-3
To a solution of (2H) -on-6-yl] indane (1.15 g) in ethyl acetate (40 ml) -tetrahydrofuran (20 ml) was added potassium carbonate (1.4 g) in water (20 ml), and then,
Add 0.57 g of methanesulfonyl chloride and stir for 2 hours. The organic layer is separated, dried and the solvent is distilled off. The obtained crystals were recrystallized from tetrahydrofuran-isopropyl ether to give 2-methylsulfonylamino-5- [4,5-dihydropyridazine-3 (2H).
1.08 g of -on-6-yl] indan are obtained. m. p. : 218-220 ° C.

Example 2 2-Amino-5- [4,5-dihydropyridazine-3
To 50 ml of a chloroform suspension containing 5.61 g of (2H) -on-6-yl] indane and 4.1 g of triethylamine, 6.3 g of n-butanesulfonyl chloride was added under ice cooling, and the mixture was stirred for 1 hour. Dilute hydrochloric acid is added to the reaction solution, the chloroform layer is separated, washed and dried, and then the solvent is distilled off. By recrystallizing the obtained crystal from tetrahydrofuran-isopropyl ether, 2-n-butylsulfonylamino-5- [4,5-dihydropyridazine-3 (2
6.40 g of H) -on-6-yl] indan are obtained. m. p. 183-185 ° C.

Example 3-28 The corresponding starting material compound was treated as in Example 2 to give the following first compound:
The compounds listed in Tables 5 to 5 are obtained.

[0088]

[Table 1]

[0089]

[Table 2]

[0090]

[Table 3]

[0091]

[Table 4]

[0092]

[Table 5]

Example 29 (1) 8.41 g of 2-amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan was dissolved in 1400 ml of ethanol to give (+) camphorsulfonic acid. Add 8.52 g. By recrystallizing the obtained salt several times from ethanol, optically active 2-amino-
5.20 g of 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan. (+) Camphor sulfonate are obtained. m. p. : 256-257 ° C. (dec) [α] _D ²⁰ -13.4 ° (c = 1.00, H ₂ O).

(2) This product was treated in the same manner as in Example 2,
(+)-2-n-Butylsulfonylamino-5- [4,
5-Dihydropyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. 173-174 ° C. [α] _D ²⁰ + 33.2 ° (c = 1.00, DMF).

Example 30 (1) The mother liquor of Example 29- (1) is wholly recovered, neutralized with an aqueous potassium carbonate solution, and ethanol is distilled off. After extracting the residue with ethyl acetate, the solvent is distilled off. Residual 5.2
3 g was dissolved in 1000 ml of ethanol, 5.29 g of (-) camphorsulfonic acid was added, and the obtained salt was recrystallized several times from ethanol to give optically active 2-amino-5- [4,5-dihydropyridazine- 3 (2H)-
4.99 g of on-6-yl] indan. (−) Camphor sulfonate are obtained. m. p. : 257-258 ° C. (dec) [α] _D ²⁰ + 13.1 ° (c = 1.00, H ₂ O).

(2) This product was treated in the same manner as in Example 2,
(-)-2-n-Butylsulfonylamino-5- [4,
5-Dihydropyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 173-174 ° C. [α] ^{_{D 20 -33.4 ° (c = 1.00}} , DMF).

Example 31 (1) 66.43 g of triethylamine was added to a solution of 87.44 g of 2-aminoindan in 800 ml of methylene chloride, and n-butylsulfonyl chloride 102.8 was added under ice cooling.
g, and the mixture is stirred at the same temperature for 1 hour. The reaction solution is washed with diluted hydrochloric acid, dried and the solvent is distilled off. By recrystallizing the obtained crystal from isopropyl ether, 2-n-
151.12 g of butylsulphonylaminoindan are obtained. m. p. : 60-62 ° C.

(2) 29.22 g of this product and succinic anhydride 2
To 300 ml of a suspension of 3.05 g of dichloroethane, 62.96 g of anhydrous aluminum chloride was added under ice cooling, and the mixture was stirred at room temperature for 1 hour.
Stir for hours. Next, 10% hydrochloric acid 2 was added to the reaction solution under ice cooling.
After adding 00 ml, 700 ml of ethyl acetate is added.
The organic layer is separated, washed and dried, and then the solvent is distilled off. By recrystallizing the obtained crystals from ethyl acetate, 2-
29.77 g of n-butylsulfonylamino-5- (3-carboxypropionyl) indane are obtained. m. p. : 138.5-139.5 ° C.

(3) 17.30 g of this product was added to 20 parts of ethanol.
Dissolve in 0 ml, add 12.5 g of hydrazine monohydrate, and heat to reflux for 2.5 hours. The solvent was distilled off from the reaction solution, the residue was washed with water, dried and recrystallized from tetrahydrofuran-isopropyl ether to give 2-n-
Butylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane 12.
04 g are obtained. m. p. 183-185 ° C.

Examples 32-34 In the same manner as in Example 31, 2-n-butylsulfonylamino-5- (3-carboxypropionyl) indane is reacted with a substituted hydrazine to give compounds shown in Table 6 below.

[0101]

[Table 6]

Example 35 (1) 26.4 g of 2-aminoindane and phthalic anhydride 4
4.5 g is added to 200 ml of acetic acid and heated under reflux for 17 hours. The reaction solution was poured into ice water, the precipitated crystals were collected by filtration, washed and dried, and the obtained crystals were recrystallized from ethyl acetate to give 2- (1,3-isoindolinedione-2).
-Yl) Indan 45.04 g are obtained. m. p. : 200-202 ° C.

(2) 1.60 g of anhydrous aluminum chloride was suspended in 30 ml of carbon disulfide, and 580 mg of dimethyl succinic anhydride and then 790 mg of 2- (1,3-isoindolinedione-2-yl) indan under ice cooling. In addition, 0 ℃
~ Stir at room temperature for 3 hours and heat to reflux for 4 hours. The reaction mixture is poured into ice water, hydrochloric acid is added, the mixture is extracted with dichloromethane-tetrahydrofuran (3: 1), dried and the solvent is evaporated. The obtained crystals are washed with ethyl acetate and then dried to give 2- (1,3-isoindolinedione-2.
580 mg of -yl) -5- (3-carboxy-3,3-dimethylpropionyl) indane are obtained. m. p. : 238-240 ° C.

(3) 9.80 g of this product was added to 300 parts of methanol.
suspended in ml, added with 5.06 g of hydrazine monohydrate,
Heat to reflux for 3 hours. After cooling, insoluble materials are removed and the solvent is distilled off. Then, the residue is dissolved in chloroform to remove insoluble matter, and the solvent is distilled off. The obtained crystals were recrystallized from chloroform-n-hexane to give 2-amino-5- [4,4-dimethyl-4,5-dihydropyridazin-3 (2H) -on-6-yl] indane 5. .04 g
To get m. p. 175-177 ° C.

(4) 1.29 g of this product in dichloromethane
A solution of 1.38 g of potassium carbonate in 20 ml of water is added to a solution of 60 ml of tetrahydrofuran (2: 1), and then a solution of 1.12 g of methanesulfonyl chloride in 20 ml of dichloromethane is added dropwise thereto, followed by stirring at room temperature for 1 hour. The organic layer is separated, dried and the solvent is distilled off. By recrystallizing the obtained crystals with tetrahydrofuran-isopropyl ether, 2-methylsulfonylamino-5-
[4,4-Dimethyl-4,5-dihydropyridazine-3
1.46 g of (2H) -on-6-yl] indan are obtained. m. p. : 215-216 [deg.] C.

Example 36 (1) To a suspension of 8.00 g of anhydrous aluminum chloride in 100 ml of dichloroethane, a solution of 3.20 g of 2-methylpropanoyl chloride in 50 ml of dichloroethane was added dropwise under ice cooling. Then, 5.27 g of 2- (1,3-isoindolinedione-2-yl) indan is added and stirred for 3 hours. The reaction solution was poured into ice water containing hydrochloric acid, the organic layer was separated, washed with water and dried, and then the solvent was distilled off to recrystallize the resulting crystal to obtain 2 -(1,3-isoindolinedione-2-yl) -5- (2-methylpropionyl) indan 4.9
2 g are obtained. m. p. 138-140 ° C.

(2) 1.78 g of 1,1,1,3,3,3-hexamethylsilazane and n-butyllithium (1.6
Tetrahydrofuran 50 of lithium bis (trimethylsilyl) amide prepared from M hexane solution 6.9 ml)
The ml solution is cooled to −40 ° C. and 2- (1,3-isoindolinedione-2-yl) -5- (2-methylpropionyl) indane 3.30 g tetrahydrofuran 50
The ml solution is added dropwise over 15 minutes. Stir for 20 minutes at 0 ° C., cool to −30 ° C., and add bromoacetic acid methyl ester
A solution of 68 g of tetrahydrofuran in 10 ml is added dropwise, and the mixture is stirred at room temperature for 2.5 hours. A saturated ammonium chloride solution is added to the reaction solution, extracted with ethyl acetate, dried and the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 4: 1), and the crystals obtained were recrystallized from ethyl acetate-n-hexane to give 2- (1, 3-isoindolinedione-2-yl) -5- (2,2-dimethyl-
3-methoxycarbonylpropionyl) indane 2.0
6 g are obtained. m. p. : 115-117 ° C.

(3) 5.55 g of methanol 100
25 ml of 1N potassium hydroxide aqueous solution is added to the ml suspension, and the mixture is stirred at room temperature for 2 hours. Methanol is distilled off, and the residue is acidified by adding 5% hydrochloric acid and extracted with ethyl acetate.
The organic layer is washed with water and dried, and then the solvent is distilled off to obtain 2
-(1,3-isoindolinedione-2-yl) -5-
5.07 g of (2,2-dimethyl-3-carboxypropionyl) indane is obtained.

(4) To a solution of 5.07 g of this product in 200 ml of isopropanol was added 3.4 g of hydrazine monohydrate, and the mixture was heated under reflux overnight. The insoluble matter formed is removed and the solvent is distilled off. The residue was washed with water and dried to give 2-amino-5- [5,5-dimethyl-4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 3.01.
get g.

(5) A suspension of 3.01 g of this product and 1.7 g of triethylamine in 100 ml of methylene chloride was cooled while cooling.
2.4 g of butylsulfonyl chloride is added, and the mixture is stirred at the same temperature for 2 hours and then at room temperature for 2 hours. The reaction solution is poured into ice water, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. The crystal obtained by purifying the residue by silica gel column chromatography (elution solvent; chloroform: ethyl acetate = 3: 1) is recrystallized from chloroform-isopropyl ether to give 2-n-butylsulfonylamino- 2.33 g of 5- [5,5-dimethyl-4,5-dihydropyridazin-3 (2H) -on-6-yl] indan are obtained. m. p. 159-161 ° C.

Example 37 (1) 2- (1,3-isoindolinedione-2-yl) indan 1.00 g and anhydrous aluminum chloride 1.2
A suspension of 7 g of dichloroethane in 5 ml of a solution of phenylacetic acid chloride 0.70 g of dichloroethane in 5 ml under ice cooling.
1 is added, and the mixture is stirred at the same temperature for 2 hours and then at room temperature for 1 hour. The reaction solution is poured into ice water and extracted with chloroform.
The organic layer was washed with water and dried, and then the solvent was distilled off to recrystallize the resulting crystal to obtain 2
-(1,3-isoindolinedione-2-yl) -5-
1.05 g of (2-phenylacetyl) indane is obtained. m. p. : 162-164 ° C.

(2) 1.35 g of 60% sodium hydride
To 100 ml of dimethylformamide suspension under ice-cooling,
A solution of 11.64 g of the compound obtained above in 50 ml of dimethylformamide is added dropwise with stirring. 10 minutes later,
A solution of 5.16 g of bromoacetic acid methyl ester in 50 ml of dimethylformamide is added dropwise, and the mixture is stirred for 1.5 hours.

The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried, and then the solvent is distilled off. The obtained crystals were recrystallized from ethyl acetate-n-hexane to give 2- (1,3-isoindolinedione-2-yl) -5- (2-phenyl-3-methoxycarbonylpropionyl) indane 11. 14 g are obtained. m. p. : 163-165 ° C.

(3) 4.0 m of this product, 40 m of ethanol
2.21 g of hydrazine monohydrate was added to the 1 l solution, and 20
Heat to reflux for minutes. The solvent is distilled off, and 80 ml of chloroform is added to the residue to remove insoluble matter. The organic layer is washed with water and dried, and then the solvent is distilled off to give 2-amino-5- (2
2.90 g of -phenyl-3-methoxycarbonylpropionyl) indane are obtained as an oil. IR (neat) cm ⁻¹ : 3370, 1735, 167
5 Mass (m / z): 323 (M ⁺ ).

(4) To a solution of 2.90 g of this product and 1.78 g of triethylamine in 30 ml of chloroform was added 2.07 g of butylsulfonyl chloride under ice cooling, and the mixture was stirred at room temperature for 30 minutes.
Stir for minutes. The reaction solution is poured into ice water and extracted with ethyl acetate. After washing and drying the organic layer, the solvent is distilled off. By purifying the residue by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 2: 1),
2-n-butylsulfonylamino-5- (2-phenyl-3-methoxycarbonylpropionyl) indane 2.
66 g are obtained as an oil. IR (neat) cm ⁻¹ : 3280, 1735, 167
5 Mass (m / z): 443 (M ⁺ ).

(5) 2.66 g of this product in 30 m of methanol
To the 1 solution, 15 ml of 1N sodium hydroxide aqueous solution is added, and the mixture is heated under reflux for 30 minutes. Methanol is distilled off from the reaction solution, 5% hydrochloric acid is added to the residue to acidify it, and the mixture is extracted with ethyl acetate. After washing and drying the organic layer, the solvent is distilled off to give 2-n-butylsulfonylamino-5- (2
2.57 g of -phenyl-3-carboxypropionyl) indane are obtained.

(6) 2.57 g of ethanol 30 m of this product
1.46 g of hydrazine monohydrate was added to the solution 1.
Heat to reflux for 5 hours. The solvent was distilled off from the reaction solution, and the obtained crystals were recrystallized from methanol to give 2-n.
-Butylsulfonylamino-5- [5-phenyl-4,
1.65 g of 5-dihydropyridazin-3 (2H) -on-6-yl] indane are obtained. m. p. 158-160 ° C.

Example 38 (1) By treating 2-n-butylsulfonylaminoindan and acetyl chloride in the same manner as in Example 31- (2), 2-n-butylsulfonylamino-5-acetylindane was obtained. obtain. m. p. : 90-92 ° C.

(2) 1.45 g of water 1 of sodium hydroxide
3 ml-100 ml ethanol solution under cooling with 2-n
-Butylsulfonylamino-5-acetylindane 4.
00 g and benzaldehyde 1.92 g are added, and the mixture is stirred at room temperature for 16 hours. Ethanol is distilled off from the reaction solution, the residue is neutralized with 10% hydrochloric acid, and extracted with chloroform.

After washing the organic layer with water and drying, the solvent was distilled off, and the resulting crystals were recrystallized from isopropanol to obtain 4.47 g of 2-n-butylsulfonylamino-5- (3-phenylacryloyl) indane. obtain. m. p. 119-120 ° C.

(3) To a solution of 7.70 g of this product and 17.0 g of acetone cyanohydrin in 500 ml of methanol was added a solution of 1.05 g of sodium carbonate in 10 ml of water, and overnight.
Heat to reflux. Methanol is distilled off from the reaction solution, and the residue is extracted with ethyl acetate. The organic layer is washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography (elution solvent; n-hexane: ethyl acetate = 2: 1) to give 2-n-butylsulfonylamino-.
6.56 g of 5- (3-cyano-3-phenylpropionyl) indane are obtained as an oil. IR (neat) cm ⁻¹ : 3270, 2320, 168
0 Mass (m / z): 410 (M ⁺ ).

(4) 6.56 g of this product dioxane 300
300 ml of 10N hydrochloric acid is added to the ml solution, and the mixture is heated under reflux for 5 hours. 300 ml of water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed with water and dried, and then the solvent is distilled off to give 2-n-butylsulfonylamino-5- (3-
Carboxy-3-phenylpropionyl) indane 6.
5 g are obtained.

(5) This product 6.5 g ethanol 120 m
To the 1 solution, 3.50 g of hydrazine monohydrate is added and heated under reflux for 4 hours. After cooling, the precipitated crystals were collected by filtration to give 2-n-butylsulfonylamino-5- [4-
Phenyl-4,5-dihydropyridazine-3 (2H)-
4.71 g of on-6-yl] indan are obtained. m. p. : 216-217 ° C.

Example 39 (1) 5.7 g of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, 150 ml of a tetrahydrofuran solution containing 18.9 g of 2-propionylaminoindane was added dropwise, and the mixture was heated under reflux for 2 hours. After cooling
Excess lithium aluminum hydride is treated with a saturated aqueous solution of ammonium chloride, and the insoluble matter is filtered. The filtrate was concentrated, chloroform was added to the residue, washed with water, dried, and the solvent was distilled off to give 2-propylaminoindan 1
7.5 g are obtained. This product 17.5g, triethylamine 1
2.12 g is dissolved in 200 ml of tetrahydrofuran,
With cooling, 17.8 g of methyl chlorocarbonate is added dropwise. After stirring at room temperature for 2 hours, tetrahydrofuran was distilled off, ethyl acetate was added to the residue, washed with water and dried, and then the solvent was distilled off to give 2- (N-methoxycarbonyl-N-propyl) aminoindan 21. 0.6 g is obtained. IR (neat) cm ^{< -1} >: 1660 Mass (m / z): 233 (M ^<+> ).

(2) To a solution of 21.6 g of this product and methylsuccinyl chloride (prepared from 24.68 g of methyl hydrogen succinate and 23.75 g of oxalyl chloride) in 300 ml of dichloromethane under ice cooling, anhydrous aluminum chloride 5
Add 9.85 g and stir at room temperature for 2 hours. The reaction solution was poured into ice water, the organic layer was separated, washed with water and dried, and then the solvent was distilled off to give 2- (N-methoxycarbonyl-N).
33.72 g of -propyl) amino-5- (3-methoxycarbonylpropionyl) indane are obtained. This product 33.
12.75 g of hydrazine monohydrate and 24 ml of acetic acid are added to a solution of 72 g of xylene in 400 ml, and the mixture is heated under reflux for 4 hours. The reaction solution is poured into ice water, extracted with ethyl acetate, washed with water and dried, and then the solvent is distilled off. By solidifying the residue in a diisopropyl ether-hexane mixed solution, 2- (N-
Methoxycarbonyl-N-propyl) amino-5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] indan 28.96 g is obtained. IR (neat) cm ⁻¹ : 3200, 1680, 166
0 Mass (m / z): 329 (M ⁺ ).

(3) To 130 ml of a chloroform solution of 13.16 g of this product was added 9 ml of iodotrimethylsilane,
Heat to reflux for 2 hours. After cooling, aqueous ammonia is added, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. By recrystallizing the obtained crude crystal from acetone, 2-propylamino-5- [4,5-dihydropyridazine-3
7.78 g of (2H) -on-6-yl] indan are obtained. m. p. 146-148 ° C.

(4) This product and n-butylsulfonyl chloride were treated in the same manner as in Example 2 to give 2- (N-
n-Butylsulfonyl-N-propyl) amino-5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] indan 28.96 g is obtained. m. p. 137-139 ° C.

Example 40 (1) 2-Aminoindane and 3-chloropropanesulfonyl chloride are treated in the same manner as in Example 31- (1) to give 2- (3-chloropropanesulfonyl) aminoindan. m. p. : 79-80 ° C.

(2) A solution of 9.94 g of the above compound in 90 ml of tetrahydrofuran was added dropwise to a suspension of 62.6% sodium hydride 2.11 g in 50 ml of tetrahydrofuran at room temperature. The reaction solution is heated to 50-55 ° C. and stirred for 10 hours. The reaction solution is poured into ice water and extracted with ethyl acetate. The organic layer is washed with water and dried, and then the solvent is distilled off. By purifying the residue by silica gel column chromatography [solvent: ethyl acetate-hexane (1: 2)], 2-
7.77 g of (thiazolidine-1,1-dioxide-2-yl) indane are obtained. m. p. : 101-102 ° C.

(3) By treating the above compound in the same manner as in Example 31- (2), 2- (thiazolidine-1,
1-Dioxido-2-yl) -5- (3-carboxypropionyl) indane is obtained, then Example 31-
By treating with hydrazine hydrate in the same manner as in (3), 2- (thiazolidin-1,1-dioxide-2-yl) -5- [4,5-dihydropyridazine-3 (2H)
-On-6-yl-] indan is obtained. m. p. : 210-212 ° C.

Example 41 2-Amino-5- [4,5-dihydropyridazine-3
2-Vinylsulfonylamino-5- [4,5-dihydro by treating (2H) -on-6-yl-] indane in the presence of 2 equivalents of triethylamine with chloroethanesulfonyl chloride as in Example 2. Pyridazin-3 (2H) -on-6-yl-] indane is obtained. m. p. 168-170 ° C.

Example 42 2-Amino-5- [4,5-dihydropyridazine-3
2- (Thiazetidin-1,1-dioxido-2-yl) -5- [4,5] was prepared by treating (2H) -on-6-yl-] indane with ethylenesulfonyl fluoride in the same manner as in Example 2. -Dihydropyridazine-3 (2H)
-On-6-yl-] indan is obtained. m. p. : 206-209 ° C.

Example 43 2-n-butylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 1.0 g of a solution of 1.0 g of dimethylformamide in 15 ml of dimethylformamide was cooled with ice. 118 mg of 62.6% sodium hydride was added,
Stir for 20 minutes. A solution of 544 mg of propyl iodide in 5 ml of dimethylformamide is added and the mixture is stirred at room temperature overnight.
The reaction solution is poured into ice water, extracted with ethyl acetate, washed with water and dried, and then the solvent is distilled off. The residue was subjected to silica gel column chromatography (elution solvent; chloroform: ethyl acetate =
By purification with 5: 1), 690 mg of 2- (N-n-butylsulfonyl-N-propyl) amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan is obtained. obtain. This compound is obtained in Example 39-
It showed the same physical properties as the compound obtained in (4).

Examples 44-52 The corresponding starting materials were used and treated in the same manner as in Example 43, to give compounds as shown in Tables 7 and 8.

[0135]

[Table 7]

[0136]

[Table 8]

Example 53 2-n-butylsulfonylamino-5- [2-methyl-
4,5-dihydropyridazin-3 (2H) -one-6-
Il] indan and methyl iodide were treated as in Example 43 to give 2- (N-n-butylsulfonyl-
N-methyl) amino-5- [2-methyl-4,5-dihydropyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. 137-138 ° C.

Example 54 2-n-butylsulfonylamino-5- {2- [3-
(1-Imidazolyl) propyl] pyridazine-3 (2
H) -on-6-yl} indane and propyl iodide were treated as in Example 43 to give 2- (Nn-
Butylsulfonyl-N-propyl) amino-5- {2-
[3- (1-imidazolyl) propyl] pyridazine-3
(2H) -on-6-yl} indan is obtained. IR (neat) cm ^{< -1} >: 1670 FABMS (m / z): 498 (MH ^<+> ).

Example 55 (1) 8.02 g of 2-amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane was suspended in 70 ml of a 25% hydrogen bromide-acetic acid solution. Turbid, under ice cooling,
Add 2.96 g of dimethyl sulfoxide and stir at room temperature for 1.5 hours. Next, add 140m of diethyl ether to the reaction mixture.
2-amino-5- [pyridazine-3 was obtained by adding l and collecting the precipitated crystals by filtration and recrystallizing from methanol.
8.55 g of (2H) -on-6-yl] indane hydrobromide is obtained. m. p. :> 300 ° C. This product is treated with sodium hydroxide to give 2-amino-5- [pyridazin-3 (2H) -on-6-yl] indane. m. p. : 228-229 ° C.

(2) 2-Amino-5- [pyridazine-3
1.14 g of (2H) -on-6-yl] indane and 0.8 g of triethylamine were added to 50 ml of dimethylformamide.
, Then n-butanesulfonyl chloride 1.2
After adding 5 g and stirring at 50 ° C. for 30 minutes, the mixture is stirred at room temperature overnight. The solvent is distilled off, water is added to the residue, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from methanol to give 2-n-butylsulfonylamino-5- [pyridazin-3 (2H) -on-6-yl] indan.1.
27 g are obtained. m. p. : 195-196 ° C.

Example 56 (1) 2-Propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane was treated as in Example 55- (1). , 2-propylamino-5- [pyridazin-3 (2H) -on-6-yl]
Get Indan. m. p. 137-139 ° C.

(2) This product and n-butylsulfonyl chloride were treated in the same manner as in Example 2 to give 2- (N-
n-Butylsulfonyl-N-propyl) amino-5-
[Pyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 142-143 ° C.

Example 57 2-Propylamino-5- [pyridazine-3 (2H)-
2- (N-vinylsulfonyl-N-propyl) amino-5- [pyridazine-3 was obtained by treating on-6-yl] indane and chloroethanesulfonyl chloride in the presence of 2 equivalents of triethylamine in the same manner as in Example 2. (2
H) -on-6-yl] indane is obtained. m. p. : 153-154 ° C.

Example 58 (1) 2-Propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan and chloroethanesulfonyl chloride in the presence of 2 equivalents of triethylamine. By performing the same processing as in 2,
-(N-Vinylsulfonyl-N-propyl) amino-5
-[4,5-dihydropyridazin-3 (2H) -one-
6-yl] indane is obtained. m. p. : 135-136 ° C.

(2) 1.16 g of this product was added to 25% hydrogen bromide-
Suspended in 10 ml of acetic acid solution and added dimethyl sulfoxide.
Add 25 ml and stir at room temperature for 1.5 hours. Hydrogen bromide-acetic acid was distilled off, and 30 ml of ethanol was added to the residue,
Next, 15% methyl mercaptan sodium aqueous solution 10
After adding ml, the mixture is stirred at 50 ° C. for 2.5 hours. Ethanol is distilled off, ethyl acetate is added to the residue, washed with water and dried, and then the solvent is distilled off. By recrystallizing the obtained crude crystal from methanol, 2- [N- (2-methylthio)] was obtained.
Ethylsulfonyl-N-propyl] amino-5- [pyridazin-3 (2H) -on-6-yl] indan 1.1
2 g are obtained. m. p. : 130-131 ° C.

Example 59 2-Vinylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane was treated as in Example 58- (2) to give 2-
[(2-Methylthio) ethylsulfonylamino] -5-
[Pyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 209-210 [deg.] C. Example 60 2-n-butylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane 17.44 g in 25% hydrobromide-acetic acid solution 100 ml
The mixture is suspended in, 3.6 ml of dimethyl sulfoxide is added, and the mixture is stirred at room temperature for 1 hour. Then, the reaction solution was poured into ice water, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 2-n-butylsulfonylamino-5- [pyridazin-3 (2H) -on-6-yl] indane. 14.6
Get 0 g. m. p. : 195-196 ° C.

Examples 61 to 85 The compounds shown in Tables 9 to 12 are obtained from the corresponding starting materials by treating in the same manner as in Example 60.

[0148]

[Table 9]

[0149]

[Table 10]

[0150]

[Table 11]

[0151]

[Table 12]

Example 86 (1) 2-Propylamino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl-] indane and 2-thiophenesulfonyl chloride were prepared in the same manner as in Example 2. By the treatment, 2- [N-propyl-N- (2-
Thiophenesulfonyl)] amino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl-] indane is obtained. m. p. 129-130 ° C.

(2) The above compound was treated in the same manner as in Example 60 to give 2- [N-propyl-N- (2-thiophenesulfonyl)] amino-5- [pyridazine-3.
(2H) -on-6-yl-] indane is obtained. m. p. : 192-193 ° C.

Example 87 2- (thiazolidin-1,1-dioxide-2-yl)
By treating -5- [4,5-dihydropyridazin-3 (2H) -one-6-yl-] indane as in Example 60, 2- (thiazolidin-1,1-dioxide-2-yl) was obtained. ) -5- [Pyridazin-3 (2H) -on-6-yl-] indane is obtained. m. p. : 277-279 ° C (decomposition).

Example 88 2.45 g of 2-n-butylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan and 1.40 g of sodium hydroxide were added to 55 m of water.
1 solution, then add 2.66 g of sodium 3-nitrobenzenesulfonate and heat to reflux for 5 hours. After cooling, acidify with 10% hydrochloric acid, extract with ethyl acetate, dry and evaporate the solvent. By recrystallizing the obtained crystal from methanol, 2-n-butylsulfonylamino-5- [pyridazin-3 (2H) -one-6-
Ill] indan 1.62 g is obtained. m. p. : 195-196 ° C.

Examples 89-90 The corresponding starting compounds were treated in the same manner as in Example 88 to give the 13th example.
The compounds listed are obtained.

[0157]

[Table 13]

Example 91 2-n-butylsulfonylamino-5- [pyridazine-
3 (2H) -on-6-yl] indane (1.0 g) in dimethylformamide (30 ml) was added with potassium carbonate 828.
mg and 547 mg of benzyl bromide are added, and the mixture is stirred at room temperature for 2 hours. 2-n- was obtained by adding water to the reaction solution, collecting the precipitated crude crystals by filtration, drying and recrystallizing from ethanol.
Butylsulfonylamino-5- [2-benzylpyridazin-3 (2H) -on-6-yl] indan 1.15 g
To get This compound had the same physical properties as the compound obtained in Example 85.

Examples 92-105 The corresponding starting material compounds were treated as in Example 91 to give the first
The compounds listed in Table 4 and Table 15 are obtained.

[0160]

[Table 14]

[0161]

[Table 15]

Example 106 2-n-butylsulfonylamino-5- {2- [2-
(4-t-butoxycarbonylpiperazin-1-yl)
6 ml of trifluoroacetic anhydride was added dropwise to a solution of 3.3 g of ethyl] pyridazin-3 (2H) -on-6-yl} indane in 30 ml of dichloroethane and the mixture was stirred at room temperature for 3 hours. A 10% aqueous sodium hydroxide solution is added to the reaction solution, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. Hydrogen chloride-ethanol was added to the residue, and the obtained crude crystals were recrystallized from methanol to give 2-n-butylsulfonylamino-5-{[2- (2-piperazin-1-yl) ethyl] pyridazine. -3 (2H) -on-6-yl} indan dihydrochloride 2.77 g is obtained. m. p. : 108-110 ° C.

Example 107 2-n-butylsulfonylamino-5- [2-ethoxycarbonylmethylpyridazin-3 (2H) -one-6-
50 ml of a suspension of 3.25 g of indane in methanol
Then, under ice cooling, 1N sodium hydroxide aqueous solution 11.3 m
1 is added dropwise and the mixture is stirred at room temperature for 5 hours. Methanol was distilled off, water was added to the residue, the mixture was acidified with 10% hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water, and recrystallized from ethanol-water to give 2-n-butylsulfonylamino-5- [. 2.50 g of 2-carboxymethylpyridazin-3 (2H) -on-6-yl] indane are obtained. m. p. 186-188 ° C.

Example 108 2-n-butylsulfonylamino-5- [2-cyanomethylpyridazin-3 (2H) -on-6-yl] indan 2.23 g of dimethylformamide 45 ml solution was added with sodium nitride 1.8 g, 1.5 g of ammonium chloride are added and the mixture is stirred for 3.5 hours at 95 ° C. After cooling, water was added to the reaction solution, acidified with 10% hydrochloric acid, and the precipitated crystals were collected by filtration, dried and recrystallized from methanol to give 2-n-butylsulfonylamino-5- [2- (5
2.19 g of -tetrazolyl) methylpyridazin-3 (2H) -on-6-yl] indane are obtained. m. p. : 192-194 ° C.

Example 109 (1) 2- (Nn-butylsulfonyl-N-methyl)
2- (N-n-butylsulfonyl-N-methyl) amino was prepared by reacting amino-5- [pyridazin-3 (2H) -on-6-yl] indane with ethyl bromoacetate in the same manner as in Example 91. -5- [2-Ethoxycarbonylmethylpyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 82-84 ° C.

(2) This product was treated in the same manner as in Example 107 to give 2- (Nn-butylsulfonyl-N-).
Methyl) amino-5- [2-carboxymethylpyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 120-122 ° C.

Example 110 2- [N-n-butylsulfonyl-N- (3-pyridyl) methyl] amino-5- [pyridazine-3 (2H)-
By treating on-6-yl] indane and 3-picolyl chloride in the same manner as in Example 91, 2- [Nn-
Butylsulfonyl-N- (3-pyridyl) methyl] amino-5- [2- (3-pyridyl) methylpyridazine-3
(2H) -on-6-yl] indane is obtained. m. p. : 162-164 ° C.

Example 111 2-Amino-6- [4,5-dihydropyridazine-3
(2H) -on-6-yl] -1,2,3,4-tetrahydronaphthalene hydroiodide 10.3 g of 1,3
To a 100 ml suspension of dimethyl-2-imidazolidinone, 26.7 ml of triethylamine was added at room temperature,
Stir for a minute. Butanesulfonyl chloride under ice cooling 12.
Add 6 ml dropwise and stir at room temperature for 4 hours. Ethanol 4
0 ml is added and the mixture is stirred for 30 minutes, ethyl acetate is added to the reaction solution, the organic layer is washed with water and dried, and then the solvent is distilled off. By recrystallizing the obtained crude crystal from isopropanol, 2-n-butylsulfonylamino-6- [4,5-
Dihydropyridazin-3 (2H) -one-6-yl]-
8.5 g of 1,2,3,4-tetrahydronaphthalene are obtained. m. p. 185-187 ° C.

Examples 112 to 114 The corresponding starting materials were treated in the same manner as in Example 111 to give compounds as shown in Table 16 below.

[0170]

[Table 16]

Example 115 2-n-butylsulfonylamino-6- [4,5-dihydropyridazin-3 (2H) -on-6-yl] -1,
2-n-Butylsulfonylamino-6- [pyridazine-3 (2H) was prepared by treating 2,3,4-tetrahydronaphthalene with dimethylsulfoxide-25% hydrobromide-acetic acid in the same manner as in Example 60. -On-6-yl] -1,2,3,4-tetrahydronaphthalene is obtained. m. p. : 195-197 ° C.

Example 116 2.40 g of the above compound, 1.10 g of dimethylaminoethyl chloride hydrochloride and 3.70 g of potassium carbonate were suspended in 60 ml of acetone and heated under reflux for 20 hours. Acetone is distilled off, the residue is dissolved in chloroform-water, and the organic layer is separated. After washing the organic layer with water and drying, the solvent was distilled off, the residue was treated with hydrogen chloride-ethanol to give the hydrochloride, and recrystallized from an ethanol-ethyl ether mixture to give 2
-N-butylsulfonylamino-6- [2- (2-dimethylaminoethyl) pyridazin-3 (2H) -one-6
-Yl] -1,2,3,4-tetrahydronaphthalene
2.1 g of hydrochloride are obtained. m. p. : 113-115 ° C (decomposition).

Example 117 2-Amino-6- [4,5-dihydropyridazine-3
(2H) -on-6-yl] -7-chloro-1,2,
By treating 3,4-tetrahydronaphthalene hydroiodide and butanesulfonyl chloride in the same manner as in Example 111, 2-n-butylsulfonylamino-6-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] -7-chloro-1,2,3,4-tetrahydronaphthalene is obtained. m. p. 183-185 ° C.

Example 118 2-n-Propylsulfonylamino-5- [pyridazin-3 (2H) -on-6-yl] indane was treated with methyl iodide in the same manner as in Example 91 to give 2-n −
Propylsulfonylamino-5- [2-methylpyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 182-183 ° C.

Reference Example 1 (1) To a suspension of 17.58 g of 2-methoxycarbonylaminosuccinic anhydride and 33.77 g of 4-chlorobenzene in 150 ml of dichloroethane was added 33.40 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature. Stir for 1 hour. Under ice cooling, 100 ml of 10% hydrochloric acid was added, and ethyl acetate was added to 500.
Add ml. The organic layer is separated, washed with water and dried, and then the solvent is distilled off. The obtained crude crystals are recrystallized from ethyl acetate to obtain 24.2 g of 3-carboxy-3-methoxycarbonylamino-4′-chloropropiophenone. m. p. : 141-142 ° C.

(2) 400 ml of tetrahydrofuran containing 45.57 g of the above compound and 16.97 g of triethylamine
To the solution, under ice cooling, 18.20 g of trimethylchlorosilane
Is added dropwise and the mixture is stirred at room temperature for 1.5 hours. The triethylamine hydrochloride formed is removed and the tetrahydrofuran is distilled off. The residue is dissolved in 400 ml of dichloromethane, 55.67 g of triethylsilane is added, 90.9 g of titanium tetrachloride is added dropwise under ice cooling, and the mixture is stirred at room temperature for 18 hours. The reaction solution is poured into concentrated hydrochloric acid (50 ml) -ice and extracted with 1000 ml of ethyl acetate. The organic layer is separated, washed with water and dried, the solvent is distilled off, and the residue is subjected to silica gel column chromatography [solvent: chloroform: methanol (10
0: 1)] to give 1-chloro-4-
39.68 g of (3-carboxy-3-methoxycarbonylaminopropyl) benzene are obtained. m. p. : 113-114 ° C.

(3) To a solution of 10.0 g of the above compound in 200 ml of dichloromethane, 3.9 ml of oxalyl chloride,
Add 1 drop of dimethylformamide and stir at room temperature for 30 minutes. Under ice cooling, 12.4 g of anhydrous aluminum chloride was added thereto, and the mixture was stirred at room temperature for 30 minutes. The reaction solution is poured into ice water and extracted with ethyl acetate (1000 ml). After washing the organic layer with water and drying, the solvent was distilled off, and the obtained crude crystals were recrystallized from a mixed solution of ethyl acetate-hexane to give 1-oxo-2.
-Methoxycarbonylamino-7-chloro-1,2,
7.30 g of 3,4-tetrahydronaphthalene are obtained. m. p. : 126-127 ° C.

(4) To a solution of 13.47 g of the above compound in 40 ml of trifluoroacetic acid, 24.1 g of triethylsilane was added, and the mixture was heated under reflux for 3 hours, and then trifluoroacetic acid was distilled off. The residue was dissolved in ethyl acetate, washed with water and dried, the solvent was distilled off, and the resulting crude crystals were recrystallized from a mixed solution of ethyl acetate-hexane to give 2-methoxycarbonylamino-7-chloro-1,2. 10.52 g of 3,3,4-tetrahydronaphthalene are obtained. m. p. : 99-101 ° C.

(5) Methyl hydrogen succinate 14.9 g
Oxalyl chloride (10.3 ml) and dimethylformamide (1 drop) are added to a dichloromethane (180 ml) solution of and the mixture is stirred at room temperature for 3 hours. Under ice cooling, 18.0 g of the above 2-methoxycarbonylamino-7-chloro-1,2,3,4-tetrahydronaphthalene and anhydrous aluminum chloride 4 were added.
Add 0.0 g and stir at room temperature for 18 hours. The reaction solution is poured into ice water and the organic layer is separated. After washing the organic layer with water and drying,
The solvent was distilled off, and the obtained crude crystals were recrystallized from a mixed solution of ethyl acetate-hexane to give 2-methoxycarbonylamino-6- (3-methoxycarbonylpropionyl) -7-chloro-1,2,3,3. 24.3 g of 4-tetrahydronaphthalene are obtained. m. p. : 86-89 ° C.

(6) To a solution of 30.0 g of the above compound in 600 ml of dimethylformamide, 60 ml of 90% formic acid,
7.5 g of 0% palladium-carbon is added, and the mixture is heated under reflux for 15 hours. The residue was dissolved in ethyl acetate, washed with water and dried, and the solvent was evaporated to give 2-methoxycarbonylamino-6- (3-methoxycarbonylpropionyl)-.
26.0 g of 1,2,3,4-tetrahydronaphthalene are obtained. m. p. : 109-111 ° C.

(7) 26.0 g of the above compound, xylene 2
Hydrazine monohydrate 20.0 g acetic acid 23 in 60 ml solution
Add ml and heat to reflux for 4 hours. Xylene is distilled off,
The obtained crude crystals were washed with water, dried, and recrystallized from isopropanol-diisopropyl ether to give 2-
Methoxycarbonylamino-6- [4,5-dihydropyridazin-3 (2H) -on-6-yl] -1,2
20.0 g of 3,4-tetrahydronaphthalene are obtained. m. p. : 197-198 ° C.

(8) A suspension of 9.5 g of the above compound in 100 ml of chloroform was added to 6.7 m of iodotrimethylsilane.
Add 1 and heat and stir for 1 hour. After cooling, methanol 3
Add ml and stir for 20 minutes. The precipitated crystals were collected by filtration to give 2-amino-6- [4,5-dihydropyridazin-3 (2H) -one-6-yl] -1,2,3,2.
4-Tetrahydronaphthalene ・ hydroiodide 11.5
get g. m. p. : 228-230 ° C.

Reference Example 2 (1) 2-Methoxycarbonylamino-6- (3-methoxycarbonylpropionyl) -7-chloro-1,2,2
By treating 3,4-tetrahydronaphthalene and hydrazine monohydrate in the same manner as in Reference Example 1- (7), 2-
Methoxycarbonylamino-6- [4,5-dihydropyridazin-3 (2H) -on-6-yl] -7-chloro-1,2,3,4-tetrahydronaphthalene is obtained. m. p. : 196-198 ° C.

(2) By treating the above compound and iodotrimethylsilane in the same manner as in Reference Example 1- (8), 2
-Amino-6- [4,5-dihydropyridazine-3 (2
H) -On-6-yl] -7-chloro-1,2,3,4
-Tetrahydronaphthalene / hydroiodide 11.5 g
To get m. p. :> 250 ° C.

[0185]

INDUSTRIAL APPLICABILITY The pyridazinone derivative [I] and its pharmacologically acceptable salt, which are the objects of the present invention, have excellent endotoxin shock-protecting activity and nephritis therapeutic activity, and therefore, for example, severe infection of Gram-negative bacteria is possible. It is useful as a therapeutic agent for endotoxin shock or a therapeutic agent for nephritis that develops in patients with dementia. Further, the object [I] of the present invention has low toxicity and is highly safe as a medicine.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location C07D 409/14 213 8829-4C 413/12 237 8829-4C 417/12 237 9051-4C // A61K 31/50 ABN 9360-4C ACV 9360-4C (C07D 409/14 213: 00 237: 00 333: 00) (72) Inventor Yasuhiko Sasaki 85-1 Kanda, Urawa-shi, Saitama Urawa New Heights 410

Claims (13)

[Claims] 1. A compound represented by the general formula [I]: [In the formula, R ¹ contains 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group, R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group. Alternatively, R ¹ and R ³ are bonded at the terminal to form a lower alkylene group, and R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group, and -AB- Represents an ethylene group or vinylene group which may be substituted with 1 to 2 groups selected from a lower alkyl group and a phenyl group, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] The pyridazinone derivative shown by these, or its pharmacologically acceptable salt. 2. A phenyl group or a lower alkylthio group in which an alkyl group having 1 to 10 carbon atoms which may be substituted in R ¹ may be substituted with ¹ to 2 halogen atoms,
It is an alkyl group having 1 to 10 carbon atoms which may be substituted with a group selected from a phenylamino group and a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom, and may be substituted with R ³ . The lower alkyl group may be substituted with a group selected from a phenyl group and a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom (the heterocyclic group may have a substituent). A lower alkyl group, which is a lower alkyl group which may be substituted in R ² , is selected from a halogen atom and a lower alkoxy group 1
A phenyl group which may be substituted with 3 to 3, a carboxyl group, a heterocyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom (the heterocyclic group may have a substituent) ), A cyano group, a di-lower alkylcarbamoyl group,
The compound according to claim 1, which is a lower alkyl group which may be substituted with a group selected from a lower alkoxycarbonyl group and a di-lower alkylamino group. 3. An alkyl group having 1 to 10 carbon atoms which may be substituted with a heterocyclic group containing a nitrogen atom or a sulfur atom as a hetero atom in R ¹ may be substituted with a pyridyl group or a thienyl group. A heterocyclic group which is a good C1-10 alkyl group and contains a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom (the heterocyclic group may have a substituent) is a pyridyl group. in an optionally substituted thienyl group, a pyridyl group, a di-lower alkyl-thiazolyl group, a di-lower alkyl isoxazolyl group, a quinolyl group or a di-lower alkyl-halogeno-pyrazolyl group, the nitrogen in R ² as hetero atom A lower alkyl group that may be substituted with a heterocyclic group containing an atom, an oxygen atom or a sulfur atom (the heterocyclic group may have a substituent) is substituted with a lower alkoxycarbonyl group. Which may be a piperazinyl group,
A lower alkyl group which may be substituted with an imidazolyl group, a thienyl group, a pyridyl group, a tetrazolyl group or a morpholino group, an aryl group is a phenyl group, and a hetero atom containing a nitrogen atom or a sulfur atom as a hetero atom in R ³ . A lower alkyl group which may be substituted with a cyclic group (the heterocyclic group may have a substituent) may be substituted with a phenyl group, which may be substituted with a piperazinyl group, a thienyl group or a pyridyl group. The compound according to claim 2, which is an optionally substituted lower alkyl group. 4. The compound according to claim 1, wherein D is a hydrogen atom. 5. R ¹ is an alkyl group having 1 to 10 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, a phenylamino lower alkyl group or a camphor-10-yl group, and R ² is a hydrogen atom, a lower alkyl group, A phenyl group or a phenyl lower alkyl group, R ³ represents a hydrogen atom, and —AB— is an ethylene group or a vinylene group which may be substituted with 1 to 2 groups selected from a lower alkyl group and a phenyl group. , N is 1. The compound according to claim 4. 6. R ¹ has 1 carbon atom which may be substituted with a group selected from a phenyl group, a thienyl group and a pyridyl group.
An alkyl group having 10 to 10, a cycloalkyl group having 3 to 6 carbon atoms, a lower alkenyl group or a camphor-10-yl group, R ³ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, or R ¹ and R ³ is bonded at the terminal to form a lower alkylene group, and R ² is a lower alkyl group or a lower group which may be substituted with a group selected from a hydrogen atom, a cyano group, a tetrazolyl group, a carboxyl group and a di-lower alkylcarbamoyl group. The compound according to claim 4, which is an alkenyl group, and -AB- is an ethylene group or a vinylene group. 7. R ¹ is an alkyl group having 1 to 5 carbon atoms, a benzyl group, a cyclohexyl group, a lower alkenyl group or a camphor-10-yl group, and R ² is a hydrogen atom, a cyano group, a tetrazolyl group or a carboxyl group. And a lower alkyl group or a lower alkenyl group which may be substituted with a group selected from di-lower alkylcarbamoyl groups, R ³
The compound according to claim 6, wherein is a hydrogen atom, a lower alkyl group or a lower alkenyl group. 8. R ¹ is an alkyl group having 1 to 5 carbon atoms or a lower alkenyl group, R ² is a hydrogen atom, a tetrazolyl lower alkyl group, a carboxyl lower alkyl group or a lower alkyl group, and R ³ is a hydrogen atom. The compound according to claim 7, which is a lower alkyl group. 9. A compound represented by the general formula [II]: [In the formula, R ¹ contains 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group, R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group. Alternatively, R ¹ and R ³ are bonded at the terminal to form a lower alkylene group, R ⁴ represents a hydrogen atom or a lower alkyl group, and —AB— represents a group 1 to 1 selected from a lower alkyl group and a phenyl group. It represents an ethylene group or a vinylene group which may be substituted with two, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] The compound or salt thereof represented by the general formula [III] (R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group.), Which is optionally reacted to form a pharmacologically acceptable salt. General formula [I] (In the formula, symbols have the same meanings as described above.) A process for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof. 10. A compound represented by the general formula [IV]: (In the formula, R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group;
⁶ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group, and -AB- is an ethylene group optionally substituted by 1 to 2 groups selected from a lower alkyl group and a phenyl group. Alternatively, it represents a vinylene group, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. )
A compound represented by the formula: [In the formula, R ⁵ includes 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group,
X ¹ represents a reactive residue. ] It reacts with the compound shown by these, and if necessary, it makes a pharmacologically acceptable salt, General formula [Ia] embedded image (In the formula, symbols have the same meanings as described above.) A process for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof. 11. A compound represented by the general formula [Ib]: [In the formula, R ⁷ includes 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group,
R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group, -A-B
-Is a group 1 selected from a lower alkyl group and a phenyl group.
It represents an ethylene group or a vinylene group which may be substituted with two, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] The compound or its salt represented by the following general formula [VI] (Wherein R ⁸ represents an optionally substituted lower alkyl group or lower alkenyl group, and X ² represents a reactive residue), and the compound is optionally pharmacologically acceptable. A salt of the general formula [I-
c] (In the formula, symbols have the same meanings as described above.) A process for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof. 12. A compound represented by the general formula [Id]: [In the formula, R ¹ contains 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group, R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group. Or R ¹ and R ³ are bonded to each other at a terminal to form a lower alkylene group, and -AB- is an ethylene group which may be substituted with 1 to 2 groups selected from a lower alkyl group and a phenyl group, or It represents a vinylene group, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] The compound or its salt shown by these are shown by general formula [VI
I] (In the formula, R ⁹ is an optionally substituted lower alkyl group,
It represents an aryl group or a lower alkenyl group, and X ³ represents a reactive residue. And a compound represented by the formula (I), which is optionally converted into a pharmacologically acceptable salt. (In the formula, symbols have the same meanings as described above.) A process for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof. 13. A compound represented by the general formula [If]: [In the formula, R ¹ contains 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 nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. A heterocyclic group (the heterocyclic group may have a substituent) or a camphor-10-yl group, R ³ represents a hydrogen atom, an optionally substituted lower alkyl group or a lower alkenyl group. Alternatively, R ¹ and R ³ are bonded at the terminal to form a lower alkylene group, R ² represents a hydrogen atom, an optionally substituted lower alkyl group, an aryl group or a lower alkenyl group, and R ¹⁰ and R ¹¹ Are the same or different and each represents a hydrogen atom, a lower alkyl group or a phenyl group, n represents 1 or 2, and D represents a hydrogen atom or a halogen atom. ] The compound represented by the formula [Ig] embedded image is oxidized to form a pharmacologically acceptable salt, if desired. (In the formula, symbols have the same meanings as described above.) A process for producing a pyridazinone derivative or a pharmaceutically acceptable salt thereof.