JPH0971535A - Pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a pharmaceutical composition having excellent nephritis remedying action and/or endotoxin shock protecting action. SOLUTION: This composition contains a new indane derivative of formula I (R is a lower alkyl, a lower alkenyl or a monocyclic heteroaromatic group; R<2> is H or a lower alkyl; A is a lower alkylene) or its salt as an active component. It can be administered by oral or parenteral administration at a dose of 1-300mg/kg, preferably 3-100mg/kg for oral administration and 0.01-50mg/kg, preferably 0.1-20mg/kg for parenteral administration. The agent is effective for the prevention and treatment of nephritis such as glomerular nephritis, immunoglobulin A nephropathy, nephrotic syndrome, lupus erythematosus nephritis, etc., and the prevention and treatment of endotoxin shock in a patient of grave infection with Gram-negative bacteria. The compound of formula I can be produced by reacting an amine compound of formula II with a sulfonic acid compound of formula R<1> -SO2 X (X is a reactive residue).

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art In Japanese Patent Laid-Open No. 63-23853, 6-
(2-benzenesulfonamide-indan-5-yl)
It has been disclosed that benzenesulfonamidoindane compounds such as 4,5-dihydro-pyridazin-3 (2H) -one exhibit antithrombotic activity. Also, WO92 /
No. 15558, 6- [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl]-
It is disclosed that benzenesulfonaminoalkylindan compounds such as 3-oxo-2,3,4,5-tetrahydropyridazine have a thromboxane A ₂ antagonistic action.

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), 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 pharmaceutical composition comprising a novel indane derivative having an excellent therapeutic activity for nephritis and / or endotoxin shock protection activity as an active ingredient.

[0006]

The present invention has the general formula [I]

[0007]

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(In the formula, R ¹ is a lower alkyl group, a lower alkenyl group or a monocyclic heteroaromatic group which contains a nitrogen atom as a hetero atom and may have a substituent, and R ² is a hydrogen atom or Lower alkyl group, A represents a lower alkylene group.)
The present invention relates to a pharmaceutical composition comprising an indane derivative or a pharmacologically acceptable salt thereof as an active ingredient.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION The indane derivative [I] or a pharmacologically acceptable salt thereof, which is the active ingredient of the present invention, has an excellent therapeutic activity for nephritis and / or an endotoxin shock-protective activity, and is useful for preventing / treating nephritis. It is useful as a drug and / or an endotoxin shock protective drug, especially as a prophylactic / therapeutic drug for nephritis.

In the indane derivative [I] which is the active ingredient of the present invention, examples of the monocyclic heteroaromatic group which contains a nitrogen atom as a hetero atom and may have a substituent include, for example, methyl group and ethyl group. Group, lower alkyl group such as propyl group; halogeno lower alkyl group; lower alkoxy group such as methoxy group, ethoxy group, propoxy group; lower alkylthio group such as methylthio group; hydroxyl group; mercapto group; cyano group; amino group; substituted amino Group (for example, mono-lower alkylamino group, di-lower alkylamino group, acylamino group); halogen atom; carboxy group; lower alkoxycarbonyl group such as methoxycarbonyl group; lower alkylcarbonyloxy group; lower alkylcarbonyl group; carbamoyl group; 1 selected from a di-lower alkylcarbamoyl group; and a phenoxy group Optionally substituted with four groups pyridyl group, and the like also.

As preferred compounds, in the general formula [I], R ¹ is an alkyl group having 1 to 4 carbon atoms, a vinyl group or a pyridyl group, R ² is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and A is a carbon atom. Examples thereof include compounds having an alkylene group of the numbers 1 to 4.

More preferred compounds include R ¹ being a vinyl group, R ² being a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, and A
Is a compound having 1 to 4 carbon atoms.

The indane derivative [I], which is an active ingredient of the present invention, has two optical isomers based on an asymmetric carbon atom, and the present invention includes both of these optical isomers and a mixture thereof. It includes.

The indane 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. The pharmacologically acceptable salt, hydrochloride, phosphate, inorganic acid salts such as hydrobromide or acetate, succinate, fumarate,
Organic acid salts such as methanesulfonic acid salts can be mentioned.

Further, the indane derivative [I] and its pharmaceutically acceptable salts, which are the active ingredients of the present invention, include any of its inner salts, addition salts, solvates, hydrates and the like. Should be interpreted.

The indane derivative [I] or a pharmaceutically acceptable salt thereof which is the active ingredient of the present invention can be administered orally or parenterally (eg, intravenously, intramuscularly, subcutaneously). It can be used as a pharmaceutical preparation together with a pharmaceutical carrier 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. Such pharmaceutical carriers include, for example, binders (syrup, gum arabic, gelatin, sorbite, tragacanth, polyvinylpyrrolidone, etc.), excipients (lactose, sugar, corn starch, potassium phosphate, sorbit, glycine, etc.), lubricants Any of conventional materials such as (magnesium stearate, talc, polyethylene glycol, silica, etc.), disintegrant (potato starch, etc.) or wetting agent (sodium lauryl sulfate, etc.) can be used. In the case of parenteral administration, distilled water for injection, physiological saline, glucose aqueous solution and the like can be used in the form of injections or drip injections.

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

The pharmaceutical composition of the present invention can be preferably used as a prophylactic / therapeutic agent for nephritis and / or an endotoxin shock protective agent.

That is, the indane derivative [I] and its pharmacologically acceptable salt, which are the active ingredients of the present invention, have less side effects on the circulatory system, such as less influence on heart rate and blood pressure, and excellent nephritis. It has a preventive / therapeutic action and / or an endotoxin shock protective action. For example, as described in Experimental Examples below, the active ingredient of the present invention, when administered to a rat in which glomerulonephritis is induced, significantly suppresses the urinary protein excretion rate as compared with the control.

The indane derivative [I] and its pharmacologically acceptable salts, which are the active ingredients of the present invention, have low toxicity, and for example, 2- [3- (vinylsulfonylamino) which is the active ingredient of the present invention. ) Propyl] -5- [pyridazin-3 (2H) -on-6-yl] indan 300 mg
Even when the mice were orally administered at a dose of / kg and observed for 3 days, no deaths were observed.

Therefore, the pharmaceutical composition of the present invention is useful as a prophylactic / therapeutic agent for nephritis (eg, glomerulonephritis, immunoglobulin A (IgA) nephropathy, nephrotic syndrome, lupus nephritis, etc.). In addition, the pharmaceutical composition of the present invention is useful as a prophylactic / therapeutic agent for endotoxin shock that develops in patients with severe infections of Gram-negative bacteria.

The indane derivative [I] or a pharmaceutically acceptable salt thereof which is the active ingredient of the present invention can be prepared by the method (A): general formula [II]

[0023]

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

[0025]

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(Wherein, X represents a reactive residue, and other symbols have the same meanings as described above) or by reacting with a sulfonic acid compound represented by the formula (B): the general formula [IV]

[0027]

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(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.

Examples of the reactive residue (X) of the sulfonic acid compound [III] include a nucleophilic leaving group such as a halogen atom and an alkoxy group.

As the salt of the amine compound [II], for example, a salt with an inorganic acid such as hydrochloric acid or a salt with an organic acid such as succinic acid can be used.

Method (A): The reaction of the amine compound [II] or a salt thereof with the sulfonic acid compound [III] can be carried out by a conventional method.

For example, the reaction of an amine compound [II] or a salt thereof with a sulfonic acid compound [III] is carried out in a solvent (eg ethyl acetate etc.) if necessary with a deoxidizing agent (eg
It can be carried out in the presence of alkali metal carbonate, etc.).

Method (B): Oxidation of compound [IV] can be carried out by a conventional method. For example, compound [IV] is treated with 3-nitrobenzene in a suitable solvent (eg, water) under basic conditions. Treated with sodium sulfonate, or
It is preferably carried out in a hydrogen bromide-acetic acid solution by reacting it redox using dimethyl sulfoxide under acidic conditions or by halogenating it with bromine, chlorine and the like and then subjecting it to a dehydrohalogenation reaction. be able to.

In the reaction, the starting compound [II]
Alternatively, if an optically active substance is used as [IV], the corresponding optically active indane derivative [I] can be obtained without racemization.

The starting compound [II] is a novel compound, for example, a compound of the general formula [V]

[0036]

[Chemical 6]

(Wherein R ²¹ represents a hydrogen atom or a lower alkyl group, and other symbols have the same meanings as described above), the amino group of the compound represented by Formula [VI]

[0038]

[Chemical 7]

(Wherein R ³ is an ester residue and Z is a halogen atom) is reacted to remove the ester residue and the amino-protecting group from the product, and then hydrazine is added. When R ²¹ is a hydrogen atom, the amino group may be further optionally converted into, for example, a corresponding aldehyde compound and sodium borohydride (NaBH ₄ ).
Alkylation by a method such as subjecting to a reductive alkylation reaction in the presence of a suitable reducing agent such as

[0040]

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(Wherein the symbols have the same meanings as described above), and the compound can be produced by oxidizing the compound in the same manner as in the method (B).

Starting compound [IV] is compound [VII]
The compound [III] can be produced in the same manner as in the method (A).

In the present specification, the lower alkyl group means
For example, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group, tert-
Butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group and the like having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms Means The lower alkylene group is, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene,
It means one having 1 to 10 carbon atoms such as hexamethylene, heptamethylene and octamethylene, preferably one having 6 carbon atoms. The lower alkenyl group is, for example, vinyl group, 1
-Propenyl group, allyl group, 1-methylallyl group, 1 or 2 or 3-butenyl group, 1 or 2 or 3 or 4-pentenyl group, 1 or 2 or 3 or 4 or 5-hexenyl group, etc. It means 7 things, preferably 2-5 things. The acyl group means one having 2 to 7 carbon atoms, preferably one having 2 to 4 carbon atoms. The lower alkyl group, lower alkylene group, lower alkenyl group and acyl group include
Included are straight and branched chains.

[0044]

[Action]

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

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

[0046]

[Equation 1]

The results are shown in Table 1. As is clear from Table 1, protein excretion in the sample-administered group was suppressed by about 6%.
It was suppressed at a high rate of 1 to 91%.

[0048]

[Table 1]

[0049]

[Production example]

Production Example 1 3.22 g of 2-aminomethyl-5- [pyridazin-3 (2H) -on-6-yl] indane hydrobromide was suspended in a mixed solution of 30 ml of ethyl acetate and 30 ml of tetrahydrofuran. An aqueous solution of sodium carbonate (5.
(30 g / 30 ml of water), and then 10 m of tetrahydrofuran containing 3.32 g of ethanesulfonyl chloride under ice cooling.
l solution is added and stirred for 3 hours. 300 ml of ethyl acetate
Is added, the organic layer is separated, washed with water and dried, and then the solvent is distilled off. The residue was purified by silica gel column chromatography [chloroform-methanol (100: 3)] to give 2
2.75 g of-(ethylsulfonylaminomethyl) -5- [pyridazin-3 (2H) -on-6-yl] indan
Get.

M. p. : 170-172 ° C.

Production Example 2-12 By treating the corresponding starting material compound in the same manner as in Production Example 1, the compounds shown in Table 2 are obtained.

[0052]

[Table 2]

Production Example 13 2- (Propylsulfonylaminomethyl) -5- [4,
5-dihydropyridazin-3 (2H) -on-6-yl] indan 5.24 g of acetic acid in 60 ml suspension was added with 30
% Hydrogen bromide-acetic acid 25 ml, dimethyl sulfoxide 1.
Add 3 ml and stir at room temperature for 2 hours. 150 ml of isopropyl ether was added, and the precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from methanol to give 2- (propylsulfonylaminomethyl) -5- [pyridazine-
3.82 g of 3 (2H) -on-6-yl] indane are obtained. The physicochemical properties of this product were consistent with those of Production Example 2.

Production Examples 14-18 The corresponding starting material compounds are treated in the same manner as in Production Example 13 to obtain the compounds shown in Table 3.

[0055]

[Table 3]

Production Examples 19-27 By treating the corresponding starting material compounds in the same manner as in Production Example 1, the compounds shown in Table 4 are obtained.

[0057]

[Table 4]

Reference Example 1 (1) Oxalyl chloride 4 was added to a dichloroethane solution (840 ml) containing 48.3 g of succinic acid monomethyl ester.
6.4 g and 2 drops of dimethylformamide are added and stirred at room temperature for 5 hours. The reaction mixture was then cooled to 2 under ice-cooling.
A solution of 34.6 g of-(acetylaminomethyl) indane in dichloroethane (280 ml) and 97.6 g of anhydrous aluminum chloride are added. After stirring for 1 hour, 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 to give 2- (acetylaminomethyl) -5- (3
-Methoxycarbonylpropionyl) indane 51.8
get g.

M. p. 139-140 ° C. (2) 51.8 g of this product is suspended in 10N hydrochloric acid (800 ml), and heated under reflux overnight. After concentrating the reaction solution and allowing it to cool,
The precipitated crystals (48.5 g) are collected by filtration. Acetic acid 3
Suspend in 00 ml, add 30 g of hydrazine monohydrate,
Heat to reflux for 4 hours. After cooling, diethyl ether is added, and the precipitated crystals are collected by filtration. The obtained crystals were suspended in water and adjusted to pH 9 with a 10% sodium hydroxide aqueous solution,
Extract with chloroform. The organic layer is washed with water and dried, and then the solvent is distilled off. The residue was recrystallized from methanol to give 2-aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 35.3.
get g.

M. p. : 170-171 ° C (3) Suspend 4.90 g of this product in 20 ml of acetic acid to give 30%
50 ml of hydrogen bromide-acetic acid and dimethyl sulfoxide 2.
Add 8 g and stir for 3 hours. Isopropyl ether 3
00 ml is added, and the precipitated crystals are collected by filtration. By recrystallizing the obtained crude crystal from methanol, 2-aminomethyl-5- [pyridazin-3 (2H) -one-6-
Ill] indane hydrobromide 5.11 g is obtained.

M. p. :> 300 ° C. Reference Example 2 (1) 2- [2- (acetylamino) ethyl] indane was treated in the same manner as in Reference Example 1- (1) to give 2-
[2- (Acetylamino) ethyl] -5- (3-methoxycarbonylpropionyl) indane is obtained.

M. p. : 96-97 ° C.

(2) By treating this product in the same manner as in Reference Example 1- (2), 2- (2-aminoethyl) -5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Ill] Get Indan.

M. p. 189-190 ° C.

(3) By treating this product in the same manner as in Reference Example 1- (3), 2- (2-aminoethyl) -5-
[Pyridazin-3 (2H) -on-6-yl] indane hydrobromide is obtained.

M. p. : 279-280 ° C (decomposition).

Reference Example 3 (1) A solution of 19.34 g of ethyl 2-indaneacetate in 200 ml of toluene was cooled to −78 ° C. under 1.5 M.
65 ml of a solution of diisobutylaluminum hydride (DIBAH) in 65 ml of toluene is added, and the mixture is stirred at the same temperature for 1.5 hours. A 15% sodium sulfite aqueous solution is added, the organic layer is separated, washed and dried, and then the solvent is distilled off. The residue is purified by silica gel column chromatography [hexane-ethyl acetate (10: 1)] to obtain 13.58 g of 2-indaneacetaldehyde.

IR (neat) cm ^-1 : 1725 FAB-MS (m / z): 161 (MH ⁺ ) (2) 63% sodium hydride (3.90 g) was suspended in tetrahydrofuran (60 ml) and cooled under water with diethylphosphono. Ethyl acetate 22.8 g of tetrahydrofuran 1
A 00 ml solution is added dropwise and the mixture is stirred at the same temperature for 30 minutes. A solution of 13.58 g of 2-indaneacetaldehyde in 100 ml of tetrahydrofuran is added dropwise to the mixture, and the mixture is stirred at the same temperature for 1 hour and further at room temperature for 1 hour. The reaction solution is poured into ice water and extracted with ethyl acetate. Wash the ethyl acetate layer,
After drying, the solvent is distilled off. The residue is subjected to silica gel column chromatography [hexane-ethyl acetate (20: 1)].
Purified with 2-indan crotonic acid ethyl ester 1
9.22 g are obtained.

IR (neat) cm ⁻¹ : 1700, 1655 FAB-MS (m / z): 231 (MH ⁺ ) (3) To a solution of 19.22 g of this product in 200 ml of ethanol was added 2.0 g of 10% palladium-carbon. In addition, catalytic hydrogenation is performed at room temperature and atmospheric pressure. After 1.5 hours, the catalyst was removed and ethanol was distilled off to give 2-indan butyric acid ethyl ester 1
9.24 g are obtained.

IR (neat) cm ^-1 : 1740 MS (m / z) 232 (M ⁺ ) (4) A solution of 19.21 g of this product in 50 ml of ethanol was added,
Aqueous sodium hydroxide solution (5.15 g / 30 ml of water) is added, and the mixture is stirred at room temperature for 1 hr. The ethanol is distilled off, the aqueous layer is made weakly acidic with 10% hydrochloric acid, and the mixture is extracted with ethyl acetate. The ethyl acetate layer was washed and dried, and the solvent was distilled off to give 2-
16.87 g of indanbutyric acid are obtained.

M. p. 74-75 ° C.

(5) To a solution of 16.84 g of this product and 11.67 g of oxalyl chloride in 200 ml of tetrahydrofuran was added 3 drops of dimethylformamide, and the mixture was stirred for 1.5 hours. The solvent and excess oxalyl chloride are distilled off. The residue was dissolved in 10 ml of tetrahydrofuran and cooled with ice, 2
Add dropwise to 100 ml of 8% aqueous ammonia solution. After stirring at the same temperature for 2 hours, the generated crystals are collected by filtration, washed with water and dried to obtain 14.46 g of 2-indanebutyric acid amide.

M. p. 116-118 ° C.

(6) Lithium aluminum hydride 3.2
Under ice-cooling, 14.42 g of 2-indanebutyric acid amide was added to a suspension of 3 g of tetrahydrofuran in 200 ml.
Heat to reflux for 5 hours. After cooling, 50% Rochelle salt aqueous solution is added, and the precipitated insoluble matter is collected by filtration. The filtrate is concentrated to dryness. The residue is dissolved in 50 ml of tetrahydrofuran, hydrogen chloride-dioxane is added, and the precipitated crystals are collected by filtration and 2
12.82 g of-(4-aminobutyl) indane hydrochloride are obtained.

M. p. 184-186 ° C.

(7) To a suspension of 12.74 g of this product and 13.91 g of triethylamine in 100 ml of dichloromethane,
Under ice cooling, 5.42 g of acetyl chloride in dichloromethane 20
Add the ml solution dropwise and stir at the same temperature for 1 hour. After washing and drying the reaction solution, the solvent is distilled off. The obtained crude crystals were recrystallized from ethyl acetate-isopropyl ether to give 2- (4
12.0 g of -acetylaminobutyl) indane are obtained.

M. p. 83-84 ° C.

(8) This product was treated in the same manner as in Reference Example 1- (1) to give 2- (4-acetylaminobutyl).
-5- (3-Methoxycarbonylpropionyl) indane is obtained.

M. p. : 94-95 ° C.

(9) This product was treated in the same manner as in Reference Example 1- (2) to give 2- (4-aminobutyl) -5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Ill] Get Indan.

M. p. 153-155 ° C.

(10) By treating this product in the same manner as in Reference Example 1- (3), 2- (4-aminobutyl) -5-
[Pyridazin-3 (2H) -on-6-yl] indane is obtained.

M. p. : 279-281 ° C.

Reference Example 4 (1) 2-Aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 6.1
A methanol solution (5 ml) of propanal (1.51 g) was added dropwise to a 5 g methanol solution (60 ml),
Stir for 30 minutes at room temperature. Then, under cooling with ice, 1.03 g of sodium borohydride was added, the same temperature for 20 minutes, and room temperature for 1 minute.
Stir for hours. Methanol was distilled off, water was added to the residue,
Extract 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 [solvent; chloroform-methanol (15: 1)] to give 2- (propylaminomethyl) -5.
-[4,5-dihydropyridazin-3 (2H) -one-
6-yl] indan 5.22 g is obtained.

M. p. : 82-84 ° C.

(2) 5.08 g of this product was used in Reference Example 1- (3)
Treated in the same manner as in 2- (propylamino) methyl-5
2- [Propylaminomethyl)-[pyridazin-3 (2H) -on-6-yl] indane hydrobromide (4.52 g) was obtained, followed by treatment with 10% aqueous sodium hydroxide solution to give 2- (propylaminomethyl). -5- [pyridazine-3 (2H)
3.13 g of -on-6-yl] indan are obtained.

M. p. : 144-146 ° C.

Reference Example 5 (1) 2- (2-Aminoethyl) -5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane was used as in Reference Example 4- (1). Process to 2- [2-
(Propylamino) ethyl] -5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane is obtained.

M. p. : 123-124 ° C.

(2) This product was treated in the same manner as in Reference Example 1- (3) to give 2- [2- (propylamino) ethyl] -5-.
2- [2- (Propylamino) ethyl] -5 was obtained by obtaining [pyridazin-3 (2H) -on-6-yl] indane hydrobromide followed by treatment with 10% aqueous sodium hydroxide. -[Pyridazine-3 (2H) -one-
6-yl] indane is obtained.

M. p. : 150-151 ° C.

Reference Example 6 2-Aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane 6.03 g of 1,3-dimethyl-2-imidazolidinone 60 ml suspension To the suspension, 5.53 g of triethylamine is added, and then a solution of 5.10 g of propanesulfonyl chloride in 20 ml of tetrahydrofuran is added. The mixture is stirred at room temperature for 30 minutes. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration.
The precipitated crystals were recrystallized from methanol-acetonitrile to give 2- (propylsulfonylaminomethyl) -5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] 5.34 g of indane are obtained.

M. p. 158-159 ° C.

Reference Example 7-13 The corresponding starting material compound is treated in the same manner as in Reference Example 6 to obtain the compounds shown in Table 5.

[0095]

[Table 5]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Fumika Okumura 675-1-Kokuki Shiraoka-cho, Minami-Saitama-gun, Saitama Prefecture

Claims (8)

[Claims] 1. A compound of the general formula [I] (In the formula, R ¹ is a lower alkyl group, a lower alkenyl group or a monocyclic heteroaromatic group which contains a nitrogen atom as a hetero atom and may have a substituent, and R ² is a hydrogen atom or a lower alkyl group. , A represents a lower alkylene group), or a pharmacologically acceptable salt thereof as an active ingredient. 2. The pharmaceutical composition according to claim 1, wherein R ¹ is a lower alkyl group, a lower alkenyl group or a pyridyl group. 3. The pharmaceutical composition according to claim 1, wherein R ² is a hydrogen atom. 4. The pharmaceutical composition according to claim 1, wherein R ² is a lower alkyl group. 5. A pharmaceutical composition comprising a prophylactic / therapeutic drug for nephritis and / or
Alternatively, the pharmaceutical composition according to claim 1, 2, 3, or 4, which is an endotoxin shock-protecting drug. 6. The pharmaceutical composition according to claim 5, which is a prophylactic / therapeutic drug for nephritis. 7. The pharmaceutical composition according to claim 5, which is a prophylactic / therapeutic drug for glomerulonephritis. 8. A pharmaceutical composition comprising immunoglobulin A nephropathy,
The pharmaceutical composition according to claim 5, which is a prophylactic / therapeutic drug for nephrotic syndrome and / or lupus nephritis.