JPH07233072A - Medicine composition - Google Patents

Abstract

PURPOSE:To obtain a medicine composition useful as a preventive and therapeutic agent for hepatitis, an endotoxin shock protecting action agent, having excellent endotoxin shock protecting action, treating action on hepatitis and inhibitory action on aggregation of blood platelet, comprising a specific pyridazinone derivative as an active ingredient. CONSTITUTION:A medicine composition comprises a compound of formula I [R<1> is a (substituted) 1-10C alkyl, a 3-6C cycloalkyl, a lower alkenyl, etc.; R<3> is H, a (substituted) lower alkyl, a lower alkyl, etc.; R<2> is H, a (substituted) lower alkyl, an aryl, etc.; A-B are (<=2 lower alkyl-or phenyl-substituted) ethylene or vinylene; D is H or a halogen; n is 1 or 2] or its salt such as 2- methylsulfonylamino-5-[4,5-dihydropyridazin-3(2H)-on-6-yl]indane as an active ingredient. The compound of formula I, for example, is obtained by reacting a compound of formula II (R<4> is H or a lower alkyl) with a compound of formula III.

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, a platelet aggregation inhibitor and / or an endotoxin shock protective agent.

[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, endotoxin causes platelet aggregation, leukocyte activation, bronchoconstriction, gastrointestinal mucosal damage, cardiac function suppression, renal function decline, etc., and damages important organs such as kidney, lung and liver. Known to cause. Conventionally, steroid hormones have been used as therapeutic agents for endotoxin shock that develops in patients with severe infections of Gram-negative bacteria.
Aprotinin (protease inhibitor), dobutamine (cardiotonic drug), etc. have been used.

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

[0005]

DISCLOSURE OF THE INVENTION The present invention provides a pharmaceutical composition comprising a novel pyridazinone derivative having an excellent endotoxin shock protective activity, nephritis therapeutic activity and / or platelet aggregation inhibitory activity as an active ingredient.

[0006]

The present invention has the general formula [I]

[0007]

[Chemical 2]

[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 represents that it is 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,
-AB- represents 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 represents 1 or 2 and D represents a hydrogen atom or a halogen atom. Represents ] It is related with the pharmaceutical composition which uses the pyridazinone derivative shown by these or its pharmacologically acceptable salt as an active ingredient.

The pyridazinone derivative [I] or a pharmacologically acceptable salt thereof which is the active ingredient of the present invention has an excellent endotoxin shock protective activity, a nephritis therapeutic activity and / or a platelet aggregation inhibitory activity, and is useful for preventing nephritis. It is useful as a therapeutic drug, a platelet aggregation inhibitor and / or an endotoxin shock protective drug, especially as a prophylactic / therapeutic drug for nephritis.

Specific examples of the pyridazinone derivative [I] which is the active ingredient of the present invention include phenyl group in which R ¹ may be substituted with ¹ to 2 halogen atoms, lower alkylthio group, phenylamino group and different groups. An alkyl group having 1 to 10 carbon atoms which may be substituted with a group selected from heterocyclic groups containing a nitrogen atom or a sulfur atom as a term atom; 3 carbon atoms
A cycloalkyl group of 6 to 6; a lower alkenyl 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); or camphor- 10-yl group, R ³ is a hydrogen atom; 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 optionally substituted with;
Or a lower alkenyl group, or R ¹ and R ³ are bonded at the terminal to form a lower alkylene group, and R ² is substituted with a hydrogen atom; 1 to 3 groups selected from a halogen atom and a lower alkoxy group Optionally a phenyl group, 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 diene A lower alkyl group which may be substituted with a group selected from a lower alkylcarbamoyl group, a lower alkoxycarbonyl group and a di-lower alkylamino group; an aryl group; or a lower alkenyl group,
-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 or 2, and D is a hydrogen atom or a halogen atom. The compound is

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

Among the pyridazinone derivatives [I], preferred compounds include compounds in which D is a hydrogen atom.

Of these pyridazinone derivatives [I],
The efficacy on preferred compounds, R ¹ is a phenyl group, a thienyl group and an alkyl group having 1 to 10 carbon atoms which may be substituted by a group selected from a pyridyl group, a cycloalkyl group having 3 to 6 carbon atoms, lower alkenyl Group, camphor-1
A 0-yl group, a thienyl group or a di-lower alkylhalogenopyrazolyl group, 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 to form a lower alkylene 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 -A
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.

R ¹ is a more preferable compound in terms of efficacy.
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, a carboxyl group or a di-lower alkylcarbamoyl group. A lower alkyl group or a lower alkenyl group which may be substituted with a selected group, R ³ represents a hydrogen atom, a lower alkyl group or a lower alkenyl group, and —AB— represents an ethylene group or a vinylene group; n is 1 or 2,
Examples thereof include compounds in which D is a hydrogen atom, and among them, R ¹
Is an alkyl group or a lower alkenyl group having 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,
R ³ is a hydrogen atom or a lower alkyl group, and -AB-
Is an ethylene group or a vinylene group, n is 1 or 2, and D is a hydrogen atom.

Further, as other more preferable compounds in terms of efficacy, R ¹ is an alkyl group having 1 to 5 carbon atoms, a benzyl group,
A cyclohexyl group, a lower alkenyl group, a thienyl group or a di-lower alkylhalogenopyrazolyl group, 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 ends to form a lower alkylene group. And R ² is a hydrogen atom or a lower alkyl 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. Among them, R ¹ is an alkyl group having 1 to 5 carbon atoms, a lower alkenyl group or A benzyl group, R ³ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, or R ¹ and R ³
Are bonded to each other to form an ethylene group, R ² is a hydrogen atom, —AB— is an ethylene group or a vinylene group, n is 1 or 2, and D is a hydrogen atom. can give.

Further preferred compounds in view of their efficacy are R ¹
Is a C 1-5 alkyl group or a lower alkenyl group, R ² is a hydrogen atom or a C 1-5 alkyl group, R ³ is a hydrogen atom or a C 1-5 alkyl group, -AB- is an ethylene group or a vinylene group, and n
And 1 is D, and D is a hydrogen atom. Among them, R ¹ is an ethyl group, a propyl group, a butyl group or a vinyl group, R ² is a hydrogen atom or a methyl group, and R is
³ is a hydrogen atom or a propyl group, -AB- is an ethylene group or a vinylene group, n is 1, and D is a hydrogen atom.

The most preferable compound in terms of efficacy is R ¹
Is an alkyl group having 1 to 5 carbon atoms or a lower alkenyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom or an alkyl group having 1 to 5 carbon atoms, and -AB- is a vinylene group. And n is 1, and D is a hydrogen atom. Among them, R ¹ is a propyl group or a vinyl group, R ² is a hydrogen atom, and R ³ is a hydrogen atom or a propyl group. A compound in which -AB- is a vinylene group, n is 1 and D is a hydrogen atom.

The pyridazinone derivative [I] which is the active ingredient of the present invention includes both two kinds of optical isomers based on asymmetric carbon atoms and a mixture thereof.

The pyridazinone derivative [I], which is the active ingredient of the present invention, can be used in medicinal use either in the free form or 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 anti-nephritis, platelet aggregation inhibitor and / or endotoxin shock-protecting agent of the present invention can be administered orally or parenterally, and can be administered in a conventional manner, for example, tablets, granules, capsules. Agent, powder, solution, suspension,
It can be used as an appropriate pharmaceutical preparation such as an injection and a drip injection.

The dose of the pyridazinone derivative [I] or a pharmacologically acceptable salt thereof varies depending on the administration method, the age / weight / condition of the patient or the degree of the disease, but usually the daily dose is oral administration. In the case of, 1-200m
g / kg, especially 10 to 100 mg / kg, in the case of parenteral administration, 0.1 to 30 mg / kg, especially 1 to
It is preferably 20 mg / kg.

The pyridazinone derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, can be prepared, for example, by the general formula [II]

[0023]

[Chemical 3]

(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]

[0025]

[Chemical 4]

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.

Further, among the pyridazinone derivatives [I],
General formula [I-a]

[0028]

[Chemical 5]

(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 described above.), Or a pharmaceutically acceptable salt thereof is a compound represented by the general formula [IV]

[0030]

[Chemical 6]

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

[0032]

[Chemical 7]

(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 pyridazinone derivatives [I], the general formula [Ic]

[0035]

[Chemical 8]

(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 defined above.) Is a compound represented by the formula [Ib].

[0037]

[Chemical 9]

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

[0039]

[Chemical 10]

(Wherein, X ² represents a reactive residue, and other symbols have the same meanings as described above), and the compound represented by the formula (1) is reacted to form a pharmacologically acceptable salt, if desired. It can be manufactured.

Among the pyridazinone derivatives [I], the general formula [Ie]

[0042]

[Chemical 11]

(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. ) Or a pharmacologically acceptable salt thereof has the general formula [Id]

[0044]

[Chemical 12]

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

[0046]

[Chemical 13]

(Wherein, X ³ 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 pyridazinone derivatives [I], the general formula [Ig]

[0049]

[Chemical 14]

(In the formula, 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.) Acceptable salts have the general formula [If]

[0051]

[Chemical 15]

(In the formula, symbols have the same meanings as described above.) The compound can be produced by oxidizing the compound to give 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 (eg lower alcohol etc.) or in the absence of a solvent.

The hydrazine compound [III] may be a hydrate.

The condensation reaction of compound [IV] and compound [V] can be carried out in an appropriate solvent (eg chloroform).
It can be appropriately carried out in the presence or absence of a deoxidizing agent (for example, tri-lower alkylamine etc.).

The reactive residue (X ¹ ) of the compound [V] is a nucleophilic leaving group such as a halogen atom, an alkoxy group, a lower alkylsulfonyloxy group, a benzenesulfonyloxy group or a lower alkyl group-substituted benzene. A sulfonyloxy group and the like can be preferably used.

Further, compound [Ib] and compound [VI]
The condensation reaction of and the condensation reaction of the compound [Id] with the compound [VII] may be appropriately performed in the presence of a base (eg, sodium hydride) in a suitable solvent (eg, dimethylformamide). it can.

As the reactive residues (X ² and X ³ ) of the compound [VI] and the compound [VII], the same groups as the reactive residue (X ¹ ) of the compound [V] are preferably used. it can.

The compound [If] can be oxidized according to a conventional method, for example, a suitable solvent (eg, water).
In the above, compound [If] is treated with sodium 3-nitrobenzenesulfonate under basic conditions, or is reacted under acidic conditions, for example, redox using dimethyl sulfoxide in hydrogen bromide-acetic acid. Can be more suitably performed.

Starting compounds [II], [IV],
When an optically active substance is used as [Ib], [Id] or [If], the corresponding optically active active ingredient [I], [Ia], [I-] can be obtained without racemization. c], [I-
e] or [Ig] can be obtained respectively.

The starting compound [II] has the general formula [VII]
I]

[0062]

[Chemical 16]

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

[0064]

[Chemical 17]

(Wherein E is a lower alkylene group and X ⁴ and X ⁵ are reactive residues) are reacted with each other and, if necessary, ring-closed in the molecule of the general formula [X ]

[0066]

[Chemical 18]

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

[0068]

[Chemical 19]

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

[0070]

[Chemical 20]

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

[0072]

[Chemical 21]

(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.
I] can be reacted, and then the protecting group can be removed, or the method described in the reference example described below can be used for the production.

In the present specification, examples of the lower alkyl group, lower alkoxy group and lower alkylene group include methyl group, ethyl group, n-propyl group, isopropyl group and n.
-Butyl group, sec-butyl group, tert-butyl group,
n-pentyl group, isopentyl group, neopentyl group, n
-Hexyl group, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, pentyloxy group, isopentyloxy group methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group,
1 to 6 carbon atoms such as hexamethylene group, especially 1 carbon atom
5 to 5, and examples of the lower alkenyl group include a vinyl group, a 1-propenyl group, an allyl group, a 1-methylallyl group, a 1 or 2 or 3-butenyl group, a 1 or 2 or 3 or a 4-pentenyl group. Examples thereof include those having 2 to 7 carbon atoms such as 1 or 2 or 3 or 4 or 5-hexenyl group. Moreover, examples of the aryl group include a phenyl group and the like.

[0076]

[Action]

Experimental Example 1 (Protective effect against mouse lethality induced by endotoxin) Male ddY mice fasted for about 24 hours were orally administered with a sample 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.

When the survival rate of the control group which was orally administered with the CMC aqueous solution became 20% (about 2% after the administration of endotoxin)
After 0 hour), the survival rate of the sample-administered group was determined. The results are as shown in Table 1 below.

[0078]

[Table 1]

Experimental Example 2 (Glamor nephritis therapeutic action) Male WKY rats (8 weeks old, 1
Anti-rat glomerular basement membrane rabbit serum was diluted 50-fold with physiological saline to 6 animals per group, and 2.5 ml / kg was intravenously administered to induce nephritis, resulting in a dose of 30 mg / kg / 10 ml. As described above, 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 to calculate the urinary protein excretion amount, and the urinary protein excretion rate relative to the control group was determined. The results are as shown in Table 2 below.

[0081]

[Table 2]

Experimental Example 3 (Platelet aggregation inhibitory effect) 9 volumes of blood collected from a healthy person was mixed with 1 volume of 3.8% (W / V) trisodium citrate aqueous solution and then centrifuged to obtain a platelet suspension ( PRP) was prepared. The residual blood was further centrifuged to prepare platelet-depleted plasma (PPP). PRP was diluted with PPP to adjust the platelet count to about 4 × 10 ⁵ cells / mm ³ . Then, add 25 μl of the sample solution to 200 μl of PRP,
After stirring at 37 ° C. for 2 minutes, U-46619 solution (final concentration of about 0.2 μg / ml) was added to cause platelet aggregation. Platelet aggregation is bone's method [Nature, No. 1
94, p. 927 (1962)] to examine the inhibitory effect on platelet aggregation of the sample. The inhibitory action on platelet aggregation of the test compound is IC ₅₀ (concentration required to inhibit 50% of platelet aggregation induced by U-46619: μg / m
l). The results are as shown in Table 3 below.

[0083]

[Table 3]

[0084]

Production Example Production 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.

Production 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.

Production Example 3-28 The corresponding starting compound was treated in the same manner as in Production Example 2 to give the following 4th compound.
~ 8 The compounds listed in Table 8 are obtained.

[0087]

[Table 4]

[0088]

[Table 5]

[0089]

[Table 6]

[0090]

[Table 7]

[0091]

[Table 8]

Production Example 29 (1) 2-Amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane (8.41 g) was dissolved in ethanol (1400 ml) 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. (decomposition) [α] _D ²⁰ -13.4 ° (c = 1.00, H ₂ O).

(2) This product was treated in the same manner as in Production 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, dimethylformamide).

Production Example 30 (1) The mother liquor of Production 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. (decomposition) [α] _D ²⁰ + 13.1 ° (c = 1.00, H ₂ O).

(2) This product was treated in the same manner as in Production 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}} , dimethylformamide).

Production Example 31 (1) 66.43 g of triethylamine was added to a solution of 87.44 g of 2-aminoindane 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.

Production Examples 32-34 In the same manner as in Production Example 31, 2-n-butylsulfonylamino-5- (3-carboxypropionyl) indane is reacted with a substituted hydrazine to give compounds shown in Table 9 below.

[0100]

[Table 9]

Production Example 35 (1) 26.4 g of 2-aminoindan 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.

Production 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) 1,1,1,3,3,3-hexamethylsilazane 1.78 g 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 1.
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.

Production Example 37 (1) 1.00 g of 2- (1,3-isoindolinedione-2-yl) indan 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) 4.00 g 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) This product 2.66 g of methanol 30 m
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.

Production Example 38 (1) 2-n-butylsulfonylamino-5-acetylindane was obtained by treating 2-n-butylsulfonylaminoindan and acetyl chloride in the same manner as in Production Example 31- (2). 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 obtained crystals were recrystallized from isopropanol to give 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 of 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.

Production Example 39 (1) 5.7 g of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, 150 ml of a tetrahydrofuran solution of 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.

17.5 g of this product, 12.
12 g is dissolved in 200 ml of tetrahydrofuran, and 17.8 g of methyl chlorocarbonate is added dropwise under cooling. 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-propylamino) indane 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.
To a solution of 72 g of xylene in 400 ml, 12.75 g of hydrazine monohydrate and 24 ml of acetic acid are added, 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-propylamino) -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 Production Example 2 to give 2- (N-
n-Butylsulfonyl-N-propylamino) -5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] indan 28.96 g is obtained. m. p. 137-139 ° C.

Production Example 40 (1) By treating 2-aminoindane and 3-chloropropanesulfonyl chloride in the same manner as in Production Example 31- (1), 2- (3-chloropropanesulfonyl) aminoindane is obtained. 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 Production Example 31- (2), 2- (thiazolidine-1,
1-Dioxido-2-yl) -5- (3-carboxypropionyl) indane is obtained, then Preparation 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.

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

Production 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 Production Example 2. -Dihydropyridazine-3 (2H)
-On-6-yl-] indan is obtained. m. p. : 206-209 ° C.

Production 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-propylamino) -5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan is obtained. obtain. This compound was produced in Production Example 39-
It showed the same physical properties as the compound obtained in (4).

Production Examples 44-52 The corresponding starting materials were used and treated in the same manner as in Production Example 43, to give the compounds shown in Tables 10 to 11.

[0135]

[Table 10]

[0136]

[Table 11]

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

Production Example 54 2-n-butylsulfonylamino-5- {2- [3-
(1-Imidazolyl) propyl] pyridazine-3 (2
H) -on-6-yl} indane and propyl iodide were treated in the same manner as in Production Example 43 to give 2- (Nn-
Butylsulfonyl-N-propylamino) -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 ^<+> ).

Production 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.

Production Example 56 (1) Treating 2-propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane in the same manner as in Production Example 55- (1). 2-propylamino-5- [pyridazin-3 (2H) -one-
6-yl] indane is obtained. m. p. 137-139 ° C.

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

Production Example 57 2-Propylamino-5- [pyridazine-3 (2H)-
On-6-yl] indane and chloroethanesulfonyl chloride were treated in the same manner as in Production Example 2 in the presence of 2 equivalents of triethylamine to give 2- (N-vinylsulfonyl-N-propylamino) -5- [pyridazine-3. (2
H) -on-6-yl] indane is obtained. m. p. : 153-154 ° C.

Production Example 58 (1) Production Example of 2-propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane and chloroethanesulfonyl chloride in the presence of 2 equivalents of triethylamine. By performing the same processing as in 2,
-(N-Vinylsulfonyl-N-propylamino) -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-propylamino] -5- [pyridazin-3 (2H) -on-6-yl] indan 1.1
2 g are obtained. m. p. : 130-131 ° C.

Production Example 59 2-Vinylsulfonylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane was treated in the same manner as in Production Example 58- (2) to give 2-
[(2-Methylthio) ethylsulfonylamino] -5-
[Pyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 209-210 ° C Production 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.

Production Examples 61-85 The corresponding starting materials were treated in the same manner as in Production Example 60 to give the compounds shown in Tables 12-15.

[0148]

[Table 12]

[0149]

[Table 13]

[0150]

[Table 14]

[0151]

[Table 15]

Production 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 Production 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 Production 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.

Production Example 87 2- (thiazolidin-1,1-dioxide-2-yl)
By treating -5- [4,5-dihydropyridazin-3 (2H) -one-6-yl-] indane in the same manner as in Production 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).

Production 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.

Production Examples 89-90 The corresponding starting compound was treated in the same manner as in Production Example 88 to give the 16th compound.
The compounds listed are obtained.

[0157]

[Table 16]

Production 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 Production Example 85.

Production Examples 92-105 The corresponding starting compound was treated in the same manner as in Production Example 91 to give the first compound.
The compounds listed in Tables 7-18 are obtained.

[0160]

[Table 17]

[0161]

[Table 18]

Production 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.

Production 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.

Production Example 108 2-n-butylsulfonylamino-5- [2-cyanomethylpyridazin-3 (2H) -on-6-yl] indane 2.23 g was added to 45 ml of dimethylformamide in a solution of 1.8 g of sodium nitride. 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.

Production Example 109 (1) 2- (N-n-butylsulfonyl-N-methylamino) -5- [pyridazin-3 (2H) -on-6-yl] indane and ethyl bromoacetate were produced. 2- (N-n-butylsulfonyl-N-methylamino) -5- [2-ethoxycarbonylmethylpyridazin-3 (2H) -on-6-yl] indane is obtained by reacting in the same manner as in. m. p. : 82-84 ° C.

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

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

Production 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.

Production Examples 112-114 The corresponding starting material compounds were treated in the same manner as in Production Example 111 to obtain the compounds shown in Table 19 below.

[0170]

[Table 19]

Production Example 115 2-n-butylsulfonylamino-6- [4,5-dihydropyridazin-3 (2H) -on-6-yl] -1,
2,3,4-Tetrahydronaphthalene was treated with dimethyl sulfoxide-25% hydrobromide-acetic acid in the same manner as in Production Example 60 to give 2-n-butylsulfonylamino-6- [pyridazine-3 (2H). -On-6-yl] -1,2,3,4-tetrahydronaphthalene is obtained. m. p. : 195-197 ° C.

Production 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).

Production 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 Production 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.

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

Production Example 119 (1) Optically active 2-amino-obtained in Production Example 30- (1)
By treating 5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane. (−)-Camphorsulfonate and n-propanesulfonyl chloride in the same manner as in Production Example 2, ( +)-2-n-Propylsulfonylamino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane is obtained. m. p. 197-198 ° C. [α] _D ²⁰ + 34.0 ° (c = 1.00, dimethylformamide).

(2) This product was treated in the same manner as in Production Example 60 to give (+)-2-n-propylsulfonylamino-5- [pyridazin-3 (2H) -on-6-yl].
Get Indan. m. p. : 202-203 ° C. [α] _D ²⁰ + 34.8 ° (c = 1.00, dimethylformamide).

Production Example 120 (1) Optically active 2-amino-obtained in Production Example 29- (1)
By treating 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan. (+)-Camphorsulfonate and n-propanesulfonyl chloride in the same manner as in Production Example 2, ( -)-2-n-Propylsulfonylamino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane is obtained. m. p. : 197-198 ° C. [α] ^{_{D 20 -34.3 ° (c = 1.00}} , dimethylformamide).

(2) This product was treated in the same manner as in Production Example 60 to give (-)-2-n-propylsulfonylamino-5- [pyridazin-3 (2H) -on-6-yl].
Get Indan. m. p. : 202-203 ° C. [α] ^{_{D 20 -34.6 ° (c = 1.00}} , dimethylformamide).

Production Example 121 (1) Optically active 2-amino-obtained in Production Example 30- (1)
138.8 g of 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan. (−)-Camphorsulfonate was dissolved in 1.65 l of warm water, and sodium hydroxide 13 was added under cooling. 0.05 g / 130 ml of water was added dropwise,
Allow to cool for 2 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from methanol to give (+)-2-amino-
66.6 g of 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan are obtained. m. p. 197-198 ° C. [α] _D ²⁰ + 35.9 ° (c = 1.00, dimethylformamide).

(2) 1.26 g of THF was added to 100 ml of a tetrahydrofuran suspension containing 4.50 g of this product.
20 ml of the solution was added dropwise, and the mixture was stirred at room temperature for 3.5 hours. Then, the reaction mixture was cooled with ice, and sodium triacetoxyborohydride (Sodium triacetoxyboror) was prepared from 1.48 g of NaBH ₄ and 8.94 g of acetic acid.
tetrahydrofuran suspension of hydride) 100
Add dropwise to ml and stir for 1 hour. The reaction solvent is concentrated to 1/4 volume, poured into ice water, neutralized, and extracted with chloroform. The organic layer is washed with water and dried, and then the solvent is distilled off. The obtained residue is subjected to silica gel column chromatography [solvent:
Chloroform: methanol (15: 1)] and the obtained crystals were recrystallized from ethyl acetate.
4.14 g of (+)-2-n-propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan are obtained. m. p. : 137-138 ° C. [α] _D ²⁰ + 24.1 ° (c = 1.00, CHC
l ₃ ).

(3) This product was treated in the same manner as in Production Example 55- (1) to give (+)-2-n-propylamino-5- [pyridazin-3 (2H) -on-6-yl. ] Get Indan. m. p. : 144-145 ° C. [α] ^{_{D 20 + 39.3 ° (c =}} 1.00, dimethylformamide).

(4) This product was treated in the same manner as in Production Example 57 to give (+)-2- (N-vinylsulfonyl-N).
-Propylamino) -5- [pyridazine-3 (2H)-
On-6-yl] indane is obtained. m. p. 172-173 ° C. [α] _D ²⁰ + 11.0 ° (c = 1.00, dimethylformamide).

Production Example 122 (1) Production Example 29-Optically active 2-amino-obtained in (1)
By treating 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan. (+) Camphorsulfonate in the same manner as in Production Example 121- (1), (-)-2. -Amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane is obtained. m. p. : 197-198 ° C. [α] ^{_{D 20 -35.8 ° (c = 1.00}} , dimethylformamide).

(2) This product was treated in the same manner as in Production Example 121- (2) to give (-)-2-n-propylamino-5- [4,5-dihydropyridazine-3 (2H)-.
On-6-yl] indane is obtained. m. p. : 138-139 ° C. [α] ^{_{D 20 -23.8 ° (c = 1.00}} , CHC
l ₃ ).

(3) This product was treated in the same manner as in Production Example 55- (1) to give (-)-2-n-propylamino-5- [pyridazin-3 (2H) -on-6-yl. ] Get Indan. m. p. : 144-145 ° C. [α] ^{_{D 20 -38.6 ° (c = 1.00}} , dimethylformamide).

(4) This product was treated in the same manner as in Production Example 57 to give (-)-2- (N-vinylsulfonyl-N).
-Propylamino) -5- [pyridazine-3 (2H)-
On-6-yl] indane is obtained. m. p. : 171-172 ° C. [α] ^{_{D 20 -11.0 ° (c = 1.00}} , dimethylformamide).

Reference Example 1 (1) 2-Methoxycarbonylaminosuccinic anhydride 1
To a suspension of 7.58 g and 33.77 g of 4-chlorobenzene in 150 ml of dichloroethane, 33.40 g of anhydrous aluminum chloride is added under ice cooling, and the mixture is stirred at room temperature for 1 hour. Under ice cooling, 100 ml of 10% hydrochloric acid was added, and ethyl acetate was 500 m.
Add l. 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.

[0197]

INDUSTRIAL APPLICABILITY The pyridazinone derivative [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, have excellent endotoxin shock protective activity and nephritis therapeutic activity. For example, as described in the above experimental example, the active ingredient of the present invention, when administered to endotoxin-induced mice, improves the survival rate as compared with the control. Therefore, the active ingredient of the present invention is useful, for example, as a prophylactic / therapeutic drug for endotoxin shock that develops in patients with severe infections of Gram-negative bacteria. When administered to rats with glomerulonephritis, the urinary protein excretion rate is suppressed as compared with the control. Therefore, the active ingredient of the present invention includes nephritis (eg, immunoglobulin A (IgA) nephropathy, nephrotic syndrome,
It can be used as a prophylactic / therapeutic drug for lupus nephritis).

The active ingredient of the present invention also has a platelet aggregation inhibitory action and can be used as a platelet aggregation inhibitor.

The active ingredient of the present invention has low toxicity and is highly safe as a medicine. For example, (+)-2-n-propylsulfonylamino-5- which is the active ingredient of the present invention.
[Pyridazin-3 (2H) -on-6-yl] indane was orally administered to rats and mice at a dose of 1000 mg / kg and observed for 4 days, but no death was observed.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 403/12 237 409/12 237 409/14 213 413/12 237 417/14 237 // (C07D 401/12 213: 16 237: 04) (C07D 401/12 215: 04 237: 04) (C07D 409/12 237: 04 333: 10) (C07D 409/14 213: 16 237: 04 333: 10) ( (C07D 413/12 237: 04 261: 08) (C07D 417/14 237: 04 277: 22) (72) Inventor Yasuhiko Sasaki 85-1 Kanda, Urawa-shi, Saitama Urawa New Heights 410

Claims (14)

[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. Or R ¹ and R ³ are bonded at the terminal to form a lower alkylene group, and R 1
² is a hydrogen atom, an optionally substituted lower alkyl group,
Represents an aryl group or a lower alkenyl group, -AB- represents 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, and n represents 1 or 2. And D represents a hydrogen atom or a halogen atom. ] The pharmaceutical composition which uses the pyridazinone derivative shown by these or its pharmacologically acceptable salt as an active ingredient. 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 pharmaceutical composition 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 pharmaceutical composition according to claim 2, which is an optionally substituted lower alkyl group. 4. A hydrogen atom as D, 1, 2, or 3.
The described pharmaceutical composition. 5. 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.
-10 alkyl group, C 3-6 cycloalkyl group, lower alkenyl group, camphor-10-yl group, thienyl group or di-lower alkylhalogenopyrazolyl group, 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 to form a lower alkylene group, and R ² is a hydrogen atom, a cyano group, a tetrazolyl group, a carboxyl group and The pharmaceutical composition according to claim 4, which is a lower alkyl group or a lower alkenyl group which may be substituted with a group selected from a di-lower alkylcarbamoyl group, and -AB- is an ethylene group or a vinylene group. 6. 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 a di-lower alkylcarbamoyl group, and R ³ is a hydrogen atom, a lower alkyl group or a lower alkenyl group. . 7. 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. Or a lower alkyl group, the pharmaceutical composition according to claim 6. 8. R ¹ is an alkyl group having 1 to 5 carbon atoms, benzyl group, cyclohexyl group, lower alkenyl group, thienyl group or di-lower alkylhalogenopyrazolyl group, and R ³ is hydrogen atom, lower alkyl group or lower alkenyl group. Or R ¹ and R ³ are terminally bonded to each other to form a lower alkylene group, and R ² is a hydrogen atom or a lower alkyl group. 9. R ¹ is an alkyl group having 1 to 5 carbon atoms, a lower alkenyl group or a benzyl group, R ³ is a hydrogen atom, a lower alkyl group or a lower alkenyl group, or R ¹ and R ³ are terminal. 9. The pharmaceutical composition according to claim 8, which is bonded to form an ethylene group and R ² is a hydrogen atom. 10. R ¹ is a propyl group or a vinyl group, R ² is a hydrogen atom, R ³ is a hydrogen atom or a propyl group, —AB— is a vinylene group, and n is 1. And D is a hydrogen atom, The pharmaceutical composition according to claim 7 or 9. 11. A pharmaceutical composition which is a prophylactic / therapeutic agent for nephritis, a platelet aggregation inhibitor and / or an endotoxin shock-protective agent, 1, 2, 3, 4, 5, 6, 7, 8,
The pharmaceutical composition according to 9 or 10. 12. The pharmaceutical composition according to claim 11, which is a prophylactic / therapeutic drug for nephritis. 13. The pharmaceutical composition according to claim 11, which is a prophylactic / therapeutic drug for glomerulonephritis. 14. A pharmaceutical composition for preventing immunoglobulin A nephropathy, nephrotic syndrome and / or lupus nephritis
The pharmaceutical composition according to claim 11, which is a therapeutic drug.