JPH0971534A - Pharmaceutical composition - Google Patents

Abstract

(57) Abstract: A pharmaceutical composition useful as a prophylactic / therapeutic agent for nephritis and / or a prophylactic / therapeutic agent for endotoxin shock. SOLUTION: The general formula [I] (In the formula, R ¹ is a lower alkyl group, a lower alkenyl group or the like,
R ² represents a hydrogen atom or a lower alkyl group, X represents a carbonyl group or a thiocarbonyl group, Alk represents a single bond or a lower alkylene group, and a dotted line represents the presence or absence of a double bond. )
A pharmaceutical composition containing the indane derivative or a pharmaceutically acceptable salt thereof represented by the following as an active ingredient.

Description

Detailed Description of the Invention

[0001]

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

[0002]

2. Description of the Related Art Japanese Unexamined Patent Publication No. 63-23853 discloses that
It has been disclosed that benzenesulfonamidoindanyl compounds such as-(2-benzenesulfonamido-indan-5-yl) -4,5-dihydro-pyridazin-3 (2H) -one exhibit antithrombotic activity. There is. Also, WO
92/15558, benzenesulfonaminoalkylindanes such as 6- [2-[(4-chlorophenyl) sulfonylaminomethyl] indan-5-yl] -3-oxo-2,3,4,5-tetrahydropyridazine. It is disclosed that the derivative has a thromboxane A ₂ antagonism.

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 an aryl group which may have a substituent, a lower alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, a halogeno lower alkyl group, a lower alkenyl group, a phenyl-substituted lower alkenyl group. A monocyclic or bicyclic heteroaromatic cyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom and optionally having a substituent, and a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. Monocyclic or bicyclic heteroaromatic cyclic group optionally substituted, lower alkyl group, lower alkoxy group optionally substituted, phenoxy group, lower alkylamino group, lower alkenylamino group Represents a phenylamino group or a lower alkenyloxy group, R ² represents a hydrogen atom or a lower alkyl group, X represents a carbonyl group or a thiocarbonyl group,
Alk represents a single bond or a lower alkylene group, and a dotted line represents the presence or absence of a double bond. And 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, the aryl group which may have a substituent includes, for example, a lower alkoxy group, a phenyl-substituted lower alkoxy group, a halogen atom, a hydroxyl group and trifluoro. Examples thereof include a phenyl group which may be substituted with 1 to 3 groups selected from a methyl group, a nitro group, a lower alkyl group and a di-lower alkylamino group. Examples of the halogeno lower alkyl group include a trifluoromethyl group. can give.
Examples of the phenyl-substituted lower alkenyl group include a styryl group. Examples of the monocyclic or bicyclic heteroaromatic cyclic group containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom and optionally having a substituent include, for example, a lower alkyl group, a halogeno lower alkyl group and a lower alkoxy. Group, lower alkylthio group, hydroxyl group, mercapto group, cyano group,
Amino group, substituted amino group (for example, mono-lower alkylamino group, di-lower alkylamino group, acylamino group),
It may be substituted with 1 to 4 groups selected from a halogen atom, a phenoxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a di-lower alkylcarbamoyl group, Examples thereof include a pyridyl group, a furyl group, a thienyl group, a pyrazyl group, a pyrimidyl group, a quinolyl group, an isoquinolyl group, and the like, which may have a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. Alternatively, the lower alkyl group substituted with a bicyclic heteroaromatic group includes, for example, a pyridylmethyl group. Examples of the lower alkoxy group which may have a substituent include a lower alkoxy group which may be substituted with a phenyl group.

Among the indane derivatives [I] which are the active ingredients of the present invention, a preferable compound group includes, for example, a group consisting of compounds having the following characteristics.

(1A) R ¹ is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, a cyano group, an amino group or a substituted amino group (for example, a mono-lower alkylamino group, a dialkyl group). Lower alkylamino group, acylamino group), halogen atom,
A pyridyl group optionally having 1 or 2 substituents selected from a phenoxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a di-lower alkylcarbamoyl group; Pyridyl lower alkyl group; lower alkyl group; cycloalkyl group having 3 to 6 carbon atoms; lower alkenyl group; or lower alkoxy group.

(1B) R ¹ is a pyridyl group optionally having 1 or 2 substituents selected from lower alkyl group, lower alkylamino group and amino group; lower alkyl group; lower alkenyl group; or lower An alkoxy group.

(1C) R ¹ is a pyridyl group which may have 1 or 2 substituents selected from a methyl group, a methylamino group and an amino group.

In the "pyridyl group which may have a substituent (s)" for R ¹ , there are no particular restrictions on the substitution position of the substituent (s) on the pyridine ring and the bonding position with the partial structure --X--. Preferred examples include those bonded to the partial structure: -X- at the 3-position on the pyridine ring, that is, a substituted or unsubstituted pyridin-3-yl group. Further, when the pyridyl group having a substituent is preferable, a 2- or 4-position mono-substituted or 2,4-di-substituted pyridin-3-yl group of the pyridine ring can be mentioned. Among these, a more preferable example is an unsubstituted pyridin-3-yl group or a 2-position-substituted pyridin-3-yl group.

Another preferable group of compounds is, for example,
An example is a group consisting of compounds having the following characteristics.

(2) X is a carbonyl group.

Still another preferable compound group is, for example, a group consisting of compounds having the following characteristics.

(3) Alk is a lower alkylene group.

Still another preferable compound group is, for example, a group consisting of compounds having the following characteristics.

(4) The dotted line indicates the presence of a double bond.

Further, as a particularly preferable compound group, for example, a group consisting of compounds having the features of the above (1A) and (2) can be mentioned.

Another particularly preferred group of compounds is, for example, a group consisting of compounds having the features of (2) and (4) above.

As a more preferable compound group, there can be mentioned, for example, a group consisting of compounds having the features (1B), (2), (3) and (4).

As a particularly preferred compound group, there can be mentioned, for example, a group consisting of compounds having the features of (1C), (2), (3) and (4).

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

The indane derivative [I] can be used for medicinal purposes in the free form or in the form of its pharmacologically acceptable salt. As the pharmacologically acceptable salt,
Examples thereof include inorganic acid salts such as hydrochloride, phosphate and hydrobromide, and organic acid salts such as acetate, succinate, fumarate and methanesulfonate.

Furthermore, 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 especially as a prophylactic / therapeutic agent for nephritis and / or an endotoxin shock-protecting 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 more excellent nephritis. Preventive / therapeutic action and /
Or, it has an endotoxin shock protective action. For example, as described in Experimental Examples below, the active ingredient of the present invention is
When administered to rats with glomerulonephritis, urinary protein excretion rate is significantly suppressed compared to controls.

Further, the indane derivative [I] and its pharmaceutically acceptable salts, which are the active ingredients of the present invention, have low toxicity and, for example, 2- [2- (2
-Methylpyridin-3-ylcarbonylamino) ethyl] -5- [pyridazin-3 (2H) -on-6-yl] indane was orally administered to mice at a dose of 300 mg / kg and observed for 3 days. No deaths were observed.

Therefore, the pharmaceutical composition of the present invention is useful as a prophylactic / therapeutic drug for nephritis (eg, glomerulonephritis, immunoglobulin A (IgA) nephropathy, nephrotic syndrome, lupus nephritis, etc.). In addition, when administered to endotoxin-induced mice, the survival rate is improved as compared with the control. Therefore, the pharmaceutical composition of the present invention is useful as a prophylactic / therapeutic drug for endotoxin shock that develops in patients with severe infections of Gram-negative bacteria.

(A) The indane derivative [I] or a pharmaceutically acceptable salt thereof, which is the active ingredient of the present invention, can be obtained by, for example, the formula [II]

[0036]

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

[0038]

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(Where the symbols have the same meanings as described above), a salt thereof or a reactive derivative thereof is reacted to obtain a pharmaceutically acceptable salt, if desired. .

(B) Of the indane derivatives [I] which are the active ingredients of the present invention, the general formula [Ia]

[0041]

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(In the formula, R ¹¹ is a lower alkyl group, a lower alkenyl group or a phenyl group, Z is an oxygen atom or a sulfur atom, and other symbols have the same meanings as described above.) Or its pharmacology. Acceptable salts include the starting compound [II] and the general formula [IV]

[0043]

[Chemical 6]

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

(C) In the indane derivative [I] which is the active ingredient of the present invention, a compound in which the dotted line indicates the presence of a double bond, that is, the general formula [Ib]

[0046]

[Chemical 7]

(Where the symbols have the same meaning as described above) or a pharmaceutically acceptable salt thereof is a compound of the indane derivative [I] in which the dotted line represents the absence of a double bond. That is, the general formula [Ic]

[0048]

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It can also be prepared by oxidizing a compound represented by the formula (wherein the symbols have the same meanings as described above) to form a pharmacologically acceptable salt, if desired.

In the above production method (A), the compound [II
I] or a salt thereof is used to produce compound [I], the reaction is carried out in the presence of an ordinary condensing agent (eg, 1,3-dicyclohexylcarbodiimide) in a suitable solvent (eg,
Dimethylformamide, etc.).

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

As the salt of the compound [III], conventional salts such as alkali metal salts and organic amine salts can be used. When these salts are reacted with the compound [II],
It is preferable to provide the compound as a free compound in advance.

In the production method (A), the compound [II
When the compound [I] is produced using the reactive derivative of I], the reaction is 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, an alkali metal carbonate or the like).

As the reactive derivative, for example, acid halide (including halogenoformic acid ester), mixed acid anhydride, active ester and the like which are commonly used for condensation can be used.

In the production method (B), the reaction of the compound [II] and the compound [IV] can be carried out according to a conventional method, for example, the compound [I].
It can be easily carried out by mixing I] and compound [IV] in a solvent (for example, 2-methoxyethanol or the like) or without a solvent.

Oxidation in the production method (C) can be carried out according to a conventional method, for example, a suitable solvent (eg, water).
In the above, compound [Ic] is treated with sodium 3-nitrobenzenesulfonate under basic conditions, or is reacted redox using dimethyl sulfoxide in acetic acid under hydrogen bromide-acetic acid, or It can be suitably carried out by immediately subjecting it to a dehydrohalogenation reaction after halogenating it with bromine, chlorine or the like.

In the reaction, the starting compound [II]
Alternatively, when an optically active substance is used as [Ic], the corresponding optically active indane derivative [I], [Ia] or [Ib] can be obtained without racemization.

Among the raw material compounds [II], compounds in which R ² represents a hydrogen atom, Alk represents a single bond and a dotted line represents the absence of a double bond are described in JP-A-63-23853. The other compounds are novel compounds and have the general formula [V]

[0059]

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(Wherein R ²¹ represents a hydrogen atom or a lower alkyl group and other symbols have the same meanings as described above) and hydrazine are reacted, and when R ²¹ represents a hydrogen atom, If desired, an amino group may be further added, for example, with a corresponding aldehyde compound and sodium borohydride (Na
BH ₄ ) is alkylated by a method such as subjecting to a reductive alkylation reaction in the presence of a suitable reducing agent, and when the dotted line represents the absence of a double bond, if desired, the method may be followed by the same method as in the method (C). It can be manufactured by oxidizing it.

In the above reaction, the reaction of compound [V] with hydrazine can be appropriately carried out in a suitable solvent (eg acetic acid etc.) or in the absence of a solvent.

The starting compound [V] is, for example, if necessary, the compound of the general formula [VI]

[0063]

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(Where the symbols have the same meanings as described above), after protecting the amino group of the compound, the compound of the general formula [VII]

[0065]

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(Wherein R ³ represents an ester residue and Y represents a halogen atom),
A method of subsequently removing the ester residue and / or the protecting group,
Alternatively, it can be produced by the method described in the production example below.

In the present specification, examples of the lower alkyl group include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, sec-butyl group and ter.
Examples of the lower alkoxy group include a t-butyl group, an n-pentyl group, an isopentyl group, a neopentyl group, an n-hexyl group and the like having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, especially 1 to 3 carbon atoms. For example, methoxy group, ethoxy group,
1 to 6 carbon atoms such as a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, an isopentyloxy group,
Among them, those having 1 to 4 are mentioned, and examples of the lower alkylene group include, for example, methylene group, ethylene group, trimethylene group, tetramethylene group, pentamethylene group, hexamethylene group and the like, having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. In particular, those of 1 to 4 are mentioned, and examples of the lower alkenyl group include 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, and the like, having 2 to 7 carbon atoms, especially 2
~ 5 can be mentioned.

In the present specification, the substituted amino group means a mono-lower alkylamino group, a di-lower alkylamino group, an acylamino group, an N-lower alkyl-N-lower alkoxycarbonylamino group, an N-lower alkyl-N-carbamoyl group. An amino group, an N-lower alkyl-N-thiocarbamoylamino group (the nitrogen atom in the carbamoyl group or the thiocarbamoyl group may be further substituted with 1 or 2 lower alkyl groups), a lower alkylcarbamoyl group Also including any, further pyrrolidino group, piperidino group, perhydroazepin-1-yl group, morpholino group, thiomorpholino group, piperazino group (the 4-position nitrogen atom of the piperazino group is further lower alkyl group, lower alkenyl group, acyl group , Optionally substituted with aryl groups, etc.) Two substituents also include those forms a ring structure to each other at an end.

Examples of the acyl group include a formyl group; an acetyl group, a propionyl group, a butyryl group, an isobutyryl group, a pivaloyl group, a hexanoyl group and the like having 2 to 7 carbon atoms,
Preferably a lower alkylcarbonyl group having 2 to 4; a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, a hexyloxycarbonyl group and the like having 2 to 7 carbon atoms, Preferably 2
To lower alkoxycarbonyl groups and the like.

The lower alkyl group, lower alkoxy group, lower alkylene group and lower alkenyl group include straight chain and branched chain groups.

[0071]

[Experimental Example 1] (Protective action against lethality of mice induced by endotoxin) Male ddY mice (1 group: 10 mice) fasted for about 24 hours were dissolved in a 0.25% sodium carboxymethylcellulose (CMC) aqueous solution. Alternatively, the suspended sample was orally administered (100 mg / kg). 30 minutes later,
Escherichia coli-derived endotoxin (lipopolysaccharide) dissolved in physiological saline was intraperitoneally administered at 100 mg / 10 ml / kg. When the survival rate of the control group, which was orally administered with the CMC aqueous solution, reached 20% (about 2% after administration of endotoxin).
After 0 hour), the survival rate of the sample-administered group was determined. The result is first
It is as described in the table.

[0072]

[Table 1]

Experimental Example 2 (Effects on rat glomerulonephritis) The kidney glomerular basement membrane fraction obtained from WKY rats was immunized with an adjuvant several times in rabbits, and then whole blood was collected and nephrotoxin serum (NTS). Got 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.

[0075]

[Equation 1]

The results are shown in Table 2. As is clear from Table 2, protein excretion in the sample-administered group was suppressed by about 6%.
It was suppressed at a high rate of 0 to 99%.

[0077]

[Table 2]

[0078]

[Production example]

Production Example 1 2- (N-methoxycarbonyl-N-propylamino)
9 ml of iodotrimethylsilane was added to 130 ml of a chloroform solution of 13.16 g of -5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan,
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. The resulting crude crystals were recrystallized from acetone to give 2-propylamino-5- [4,5-dihydropyridazine-3.
7.78 g of (2H) -on-6-yl] indan are obtained.

M. p. 146-148 ° C Production Example 2 2-Amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane (25%)
% Hydrogen bromide-acetic acid solution (70 ml), and dimethylsulfoxide (2.96 g) is added under ice cooling, and the mixture is stirred at room temperature for 1.5 hr. Next, 140 ml of diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration and recrystallized from methanol to give 2-amino-5- [pyridazine-3 (2
H) -On-6-yl] indan hydrobromide 8.5
5 g are obtained.

M. p. :> 300 ° C. Production Example 3 2-propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane Production Example 2
Treated in a similar manner to give 2-propylamino-5- [pyridazin-3 (2H) -on-6-yl] indane.

M. p. 137-139 ° C. Production Example 4 (1) To a solution of 48.3 g of methyl hydrogen succinate in dichloroethane (840 ml), 46.4 g of oxalyl chloride and 2 drops of dimethylformamide are added, and the mixture is stirred at room temperature for 5 hours. Then, a solution of 2- (acetylaminomethyl) indane (34.6 g) in dichloroethane (280 ml) and anhydrous aluminum chloride (97.6 g) are added to the reaction mixture under ice cooling. 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- (acetylamino) methyl-5-
(3-methoxycarbonylpropionyl) indane 5
1.8 g are obtained.

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) 2-aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 4.9
0 g was suspended in 20 ml of acetic acid and 30% hydrogen bromide-acetic acid 5
Add 0 ml and 2.8 g of dimethyl sulfoxide and stir for 3 hours. Add 300 ml of isopropyl ether,
The precipitated crystals are collected by filtration. By recrystallizing the obtained crude crystal from methanol, 2-aminomethyl-5-
5.11 g of [pyridazin-3 (2H) -on-6-yl] indane hydrobromide are obtained.

M. p. :> 300 ° C. Production Example 5-6 The corresponding starting material compound is treated in the same manner as in Production Examples 4- (1) and 4- (2) to obtain the compounds shown in Table 3.

[0085]

[Table 3]

Production Example 7-8 The compounds shown in Table 4 are obtained by treating the compounds obtained in Production Examples 5 and 6 in the same manner as in Production Example 4- (3).

[0087]

[Table 4]

Production Example 9 (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 is purified by silica gel column chromatography [solvent; chloroform-methanol (15: 1)] to give 2- (propylamino) methyl-5.
-[4,5-dihydropyridazin-3 (2H) -one-
6-yl] indan 5.22 g is obtained.

M. p. : 82-84 ° C (2) 2- (propylamino) methyl-5- [4,5-
5.08 g of dihydropyridazin-3 (2H) -on-6-yl] indane was treated in the same manner as in Production Example 4- (3) to give 2-propylaminomethyl-5- [pyridazin-3 (2.
H) -On-6-yl] indane hydrobromide (4.5
2 g) and then treated with 10% aqueous sodium hydroxide solution to give 2- (propylamino) methyl-
3.13 g of 5- [pyridazin-3 (2H) -on-6-yl] indan are obtained.

M. p. 144-146 ° C. Production Example 10 From the corresponding starting material compound in the same manner as in Production Example 9- (1),
[2- (Propylamino) ethyl] -5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane is obtained.

M. p. : 123-124 ° C Production Example 11 2-amino-5- [4,5-dihydropyridazine-3
To a 1,3-dimethyl-2-imidazolidinone suspension (70 ml) of 7.26 g of (2H) -on-6-yl] indane and 7.05 g of triethylamine, a solution of 4.09 g of butyryl chloride in 20 ml of tetrahydrofuran was added dropwise. And stir at room temperature for 4 hours. Pour the reaction solution into ice water,
The precipitated crystals are collected by filtration, washed with water and dried. By recrystallizing from ethyl acetate, 2-butyrylamino-5-
[4,5-Dihydropyridazin-3 (2H) -one-6
-Yl] indane 7.47 g are obtained.

M. p. : 214-215 ° C. Production Example 12-28 The corresponding starting material compound is treated in the same manner as in Production Example 11 to obtain the compounds shown in Tables 5 to 7.

[0093]

[Table 5]

[0094]

[Table 6]

[0095]

[Table 7]

Production Example 29 2-Amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indan 5.13 g of 2-
2.38 g of propyl isocyanate is added dropwise to a methoxyethanol suspension (60 ml), and the mixture is stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration and recrystallized from a mixed solution of methanol-acetonitrile to give 2- (propylcarbamoyl) amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 4 This gives 0.91 g.

M. p. : 214-216 ° C Production Example 30 2-Amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane and butyl isocyanate were treated as in Preparation Example 29 to give 2- (butylcarbamoyl) amino-5- [4,5-dihydropyridazin-3 (2H) -one. -6-yl] Indane is obtained.

M. p. : 206-207 ° C Production Example 31 2-Amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane and phenylisocyanate were treated as in Preparation 29 to give 2- (phenylcarbamoyl) amino-5- [4,5-dihydropyridazin-3 (2H) -one. -6-yl] Indane is obtained.

M. p. : 249-251 ° C Production Example 32-34 2-amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane and the corresponding isothiocyanate are treated in the same manner as in Production Example 29 to obtain the compounds shown in Table 8.

[0100]

[Table 8]

Production Example 35 2-Propylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 4.07 g
And 2.46 g of isobutyl chloroformate are added to a chloroform solution (40 ml) of 2.02 g of triethylamine under ice cooling, and the mixture is stirred for 1 hour. The organic layer is washed with water and dried, and then the solvent is distilled off. The obtained crude crystals were recrystallized from ethyl acetate to give 2- (N-propyl-N-isobutoxycarbonylamino) -5- [4,5-dihydropyridazin-3 (2H) -one-6-yl. ] 3.75 g of indane is obtained.

M. p. : 161-162 ° C Production Examples 36-39 The corresponding starting material compounds are treated in the same manner as in Production Example 35 to obtain the compounds shown in Table 9.

[0103]

[Table 9]

Production Example 40 2-butyrylamino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 4.00 g
20 ml of a 25% hydrogen bromide-acetic acid solution was added to an acetic acid suspension (45 ml) of dimethyl sulfoxide 1.1.
Add 4 ml and stir at room temperature for 3.5 hours. Hydrogen bromide-
The acetic acid was distilled off, and the residue was recrystallized from hydrous ethanol to give 2-butyrylamino-5- [pyridazine-3.
3.50 g of (2H) -on-6-yl] indan are obtained.

M. p. : 228-229 [deg.] C. Production Examples 41-48 The corresponding starting compound was treated in the same manner as in Production Example 40 to give the 10th example.
The compounds listed are obtained.

[0106]

[Table 10]

Production Example 49 2-Amino-5- [pyridazin-3 (2H) -one-6
-Yl] indan hydrobromide 5.03 g in ethyl acetate suspension (150 ml), potassium carbonate (4.52 g)
An aqueous solution (150 ml) is added, then a tetrahydrofuran solution (50 ml) of 3.0 g of acrylic acid chloride is added dropwise under ice cooling, and the mixture is stirred for 3 hours. The precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from methanol-acetonitrile to give 2-acryloylamino-5-
3.69 g of [pyridazin-3 (2H) -on-6-yl] indan are obtained.

M. p. : 235-237 ° C Production Example 50 2-Amino-5- [pyridazin-3 (2H) -one-6
2-yl] indane Hydrobromide and vinyl chloroformate were treated as in Preparation 49 to give 2-vinyloxycarbonylamino-5- [pyridazin-3 (2H) -on-6-yl] indane. obtain.

M. p. : 205-206 ° C Production Example 51 2-Propylamino-5- [pyridazine-3 (2H)-
2.06 g of triethylamine is added to a dichloromethane suspension (30 ml) of 3.00 g of on-6-yl] indane hydrobromide and stirred for 20 minutes. Add 1.66 g of phenyl chloroformate and stir at room temperature for 2 hours. The organic layer is washed with water and dried, and then the solvent is distilled off. By recrystallizing the obtained crude crystal from ethyl acetate-hexane, 2
-(N-propyl-N-phenoxycarbonylamino)
3.47 g of -5- [pyridazin-3 (2H) -on-6-yl] indan are obtained.

M. p. : 140-141 ° C Production Example 52 2-propylamino-5- [pyridazine-3 (2H)-
On-6-yl] indane hydrobromide and isobutyl chloroformate were treated as in Preparation 51 to give 2-
(N-propyl-N-isobutoxycarbonylamino)
-5- [Pyridazin-3 (2H) -on-6-yl] indane is obtained.

M. p. 178-179 ° C Production Example 53 2-Amino-5- [pyridazin-3 (2H) -one-6
-Yl] indan hydrobromide 5.04 g of 2-methoxyethanol suspension (60 ml) was added with 2.0 g of triethylamine and stirred for 10 minutes, and then 2.33 g of propyl isothiocyanate was added dropwise. Stir at ℃ for 7 hours. After cooling, water (100 ml) -isopropyl ether (300 ml) is added to the reaction solution and stirred, and the precipitated crystals are collected by filtration, washed with water and dried. By recrystallizing the obtained crystal from ethanol, 2-[(propyl) thiocarbamoyl] amino-5- [pyridazine-3 (2
4.53 g of H) -on-6-yl] indan are obtained.

M. p. 197-199 ° C Production Example 54 2-Aminomethyl-5- [pyridazin-3 (2H) -on-6-yl] indane hydrobromide 3.50 g of ethyl acetate suspension (100 ml) in potassium carbonate. (3.30
g) An aqueous solution (100 ml) was added, and then, under ice-cooling, a solution of 2.30 g of butyryl chloride in tetrahydrofuran (30
ml) and stirred for 3 hours. The precipitated crystals are collected by filtration, washed with water, dried, and recrystallized from methanol to obtain 2.75 g of 2- (butyrylamino) methyl-5- [pyridazin-3 (2H) -on-6-yl] indane. .

M. p. : 204-205 ° C Production Examples 55-64 The corresponding starting material compounds are treated in the same manner as in Production Example 54 to obtain the compounds shown in Tables 11 to 12.

[0114]

[Table 11]

[0115]

[Table 12]

Production Example 65 2-Aminomethyl-5- [pyridazin-3 (2H) -on-6-yl] indane Hydrobromide 3.06 g and 3
To a suspension of 1.15 g of methylcrotonic acid in dimethylformamide (80 ml) was added 1.71 g of diethyl phosphoric acid cyanide under ice cooling, and then triethylamine 2.8.
9 g of dimethylformamide solution (20 ml) is added dropwise, and the mixture is stirred at the same temperature for 2.5 hours. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration. The obtained crystals are washed with water,
After drying, it was recrystallized from ethyl acetate-methanol to give 2-[(3-methylcrotonoyl) amino] methyl-5- [pyridazin-3 (2H) -on-6-yl].
2.45 g of indane is obtained.

M. p. : 204-205 ° C Production Example 66 2-Aminomethyl-5- [pyridazin-3 (2H) -on-6-yl] indane hydrobromide 2.70 g of 2-
1.05 g of triethylamine is added to a methoxyethanol suspension (40 ml), and the mixture is stirred at room temperature for 10 minutes. Add 1.10 g of allyl isocyanate and stir at room temperature for 1.5 hours. Pour into ice water and collect the precipitated crystals by filtration. The obtained crystals were washed with water, dried and then recrystallized from methanol to give 2.35 g of 2-[(allylcarbamoyl) amino] methyl-5- [pyridazin-3 (2H) -on-6-yl] indan. obtain.

M. p. : 208-209 ° C. Production Example 67 2- {2-[(propyl) thiocarbamoylamino] ethyl} -5- [pyridazine-3 was prepared by treating the corresponding starting material compound and propyl isothiocyanate in the same manner as in Production Example 66. (2H) -on-6-yl] indane is obtained.

M. p. 155-157 ° C Production Example 68 2-Aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 1.57 g of 1,3-dimethyl-2-imidazolidinone. Suspension (15
ml) and triethylamine (1.47 g) were added, and the mixture was stirred at room temperature for 1
Stir for 0 minutes. Then, a tetrahydrofuran solution (8 ml) of butyryl chloride 0.83 g is added dropwise, and the mixture is stirred for 1 hour. The reaction solution is poured into ice water, and the precipitated crystals are collected by filtration. The obtained crystals were washed with water, dried and then recrystallized from ethyl acetate-methanol to give 2- (butyrylamino) methyl-5- [4,5-dihydropyridazine-3.
1.47 g of (2H) -on-6-yl] indan are obtained.

M. p. 172-173 ° C. Production Examples 69-72 The corresponding starting material compounds are treated in the same manner as in Production Example 68 to obtain the compounds shown in Table 13.

[0121]

[Table 13]

Production Example 73 2- (Butyrylamino) methyl-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indane 3.13 g of acetic acid suspension (20 ml) in 30% odor. Hydrogen chloride-acetic acid (25 ml) and dimethyl sulfoxide (1 ml) are added, and the mixture is stirred at room temperature for 3 hours. Diisopropyl ether was added, and the precipitated crystals were collected by filtration, washed with water, dried, and recrystallized from methanol to give 2- (butyrylamino) methyl-5- [pyridazin-3 (2H) -on-6-yl] indan 2 Obtain 80 g.

M. p. : 204-205 ° C Production Examples 74-77 The corresponding starting material compounds are treated in the same manner as in Production Example 73 to obtain the compounds shown in Table 14.

[0124]

[Table 14]

Production Examples 78-88 The corresponding starting materials were treated in the same manner as in Production Example 11 to obtain the compounds shown in Tables 15 to 16.

[0126]

[Table 15]

[0127]

[Table 16]

Production Example 89 (1) 8.41 g of 2-amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan was dissolved in 1400 ml of ethanol to give (+) camphorsulfonic acid. Add 8.52 g. By recrystallizing the obtained salt several times from ethanol, optically active 2-amino-
5.20 g of 5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan. (+)-Camphor sulfonate are obtained.

M. p. : 256-257 ° C. (decomposition) [α] _D ²⁰ -13.4 ° (c = 1.00, H ₂ O) (2) All the mother liquor of (1) above was recovered and neutralized with an aqueous potassium carbonate solution. , The ethanol is distilled off. After extracting the residue with ethyl acetate, the solvent is distilled off. 5.23 g of the residue 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-Dihydropyridazin-3 (2H) -one-6
-Yl] indan. (-)-Camphor sulfonate 4.99 g is obtained.

M. p. : 257-258 ° C. (decomposition) [α] _D ²⁰ + 13.1 ° (c = 1.00, H ₂ O) (3) Optical activity 2-amino-5- [4,5-dihydropyridazine-3 (2H ) -On-6-yl] Indane
138.8 g of (-)-camphor sulfonate was dissolved in 1.65 l of warm water, and sodium hydroxide 13.0 was added under cooling.
5 g / 130 ml of water is added dropwise and left to cool for 2 hours. The precipitated crystals were collected by filtration, dried, and recrystallized from methanol to give (+)-2-amino-5- [4,5-dihydropyridazin-3 (2H) -on-6-yl] indan 6
6.6 g are obtained.

M. p. 197-198 ° C. [α] _D ²⁰ + 35.9 ° (c = 1.00, dimethylformamide) (4) This product, 4.50 g of a tetrahydrofuran suspension 10
20 ml of THF solution of 1.26 g of propanal in 0 ml
Was added dropwise, and the mixture was stirred at room temperature for 3.5 hours. Then, the reaction mixture was cooled with ice and mixed with 1.48 g of NaBH ₄ and 8.94 g of acetic acid, sodium triacetoxyborohydride [N.
aB (OCOCH ₃ ) ₃ H] is added dropwise to 100 ml of a tetrahydrofuran suspension, and the mixture is stirred for 1 hour. 4 reaction solvents
Concentrate to 1/10 volume, pour into ice water, neutralize, and extract with chloroform. The organic layer was washed with water and dried, then the solvent was distilled off, the obtained residue was purified by silica gel column chromatography [solvent: chloroform: methanol (15: 1)], and the obtained crystal was recrystallized from ethyl acetate. By doing so, (+)-2-propylamino-5- [4,5-
4.14 g of 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 ) (5) By treating this product in the same manner as in Production Example 11,
(+)-2- (N-propyl-N-butyrylamino)-
5- [4,5-Dihydropyridazin-3 (2H) -on-6-yl] indane is obtained.

M. p. : 103-105 ° C. [α] _D ²⁰ + 13.3 ° (c = 1.00, methanol) Production Example 90 (+)-2- (N-propyl-N-butyrylamino)-
By treating 5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane in the same manner as in Production Example 40, (+)-2- (N-propyl-N-butyrylamino)- 5- [pyridazine-3 (2H) -one-6-
Ill] get Indan.

M. p. 159-160 ° C. [α] _D ²⁰ + 16.3 ° (c = 1.00, methanol) Production Example 91 (1) 5.7 g of lithium aluminum hydride was suspended in 100 ml of tetrahydrofuran, and then 2- (propionylamino). ) 150 ml of a tetrahydrofuran solution containing 18.9 g of indane 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 is concentrated, chloroform is added to the residue, washed with water and dried, and then the solvent is distilled off to obtain 17.5 g of 2- (propylamino) indane.

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 MS (m / z): 233 (M ⁺ ) (2) 21.6 g of this product, methylsuccinyl chloride (24.68 g of methyl hydrogen succinate and 23.75 g of oxalyl chloride). Prepared from) 300 ml of dichloromethane
To the solution was added 59.85 g of anhydrous aluminum chloride under ice cooling, and the mixture was stirred at room temperature for 2 hours. Pour the reaction solution into ice water,
The organic layer is separated, washed with water and dried, and then the solvent is distilled off to give 2- (N-methoxycarbonyl-N-propylamino) -5- (3-methoxycarbonylpropionyl).
33.72 g of indane are obtained.

To a solution of 33.72 g of this product in 400 ml of xylene, 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, dried, and the solvent is distilled off. The residue was solidified in a diisopropyl ether-hexane mixed solution to give 2- (N-methoxycarbonyl-N-propylamino) -5- [4,5-dihydropyridazine-3.
28.96 g of (2H) -on-6-yl] indan are obtained.

IR (neat) cm ⁻¹ : 3200, 16
80, 1660 MS (m / z): 329 (M ⁺ ) Production Examples 92-98 The corresponding starting compounds were treated in the same manner as in Production Examples 4- (1) and 4- (2) to give the compounds shown in Table 17. Obtain the compound.

[0139]

[Table 17]

Production Examples 99-101 The corresponding starting material compounds were treated in the same manner as in Production Example 4- (3) to give compounds shown in Table 18.

[0141]

[Table 18]

Production Examples 102-104 The corresponding starting material compounds were treated in the same manner as in Production Example 9- (2) to give the compounds shown in Table 19.

[0143]

[Table 19]

Production Examples 105-122 The corresponding starting material compounds were treated in the same manner as in Production Example 54 to obtain the compounds shown in Tables 20 to 22.

[0145]

[Table 20]

[0146]

[Table 21]

[0147]

[Table 22]

Production Examples 123-157 The corresponding starting material compounds were treated in the same manner as in Production Example 65 to obtain the compounds shown in Tables 23 to 28.

[0149]

[Table 23]

[0150]

[Table 24]

[0151]

[Table 25]

[0152]

[Table 26]

[0153]

[Table 27]

[0154]

[Table 28]

Production Examples 158-159 The corresponding starting material compounds were treated in the same manner as in Production Example 68 to obtain the compounds shown in Table 29.

[0156]

[Table 29]

Production Example 160 The corresponding starting material compound was treated in the same manner as in Production Example 65 to give 2- [2- (2-methylaminopyridin-3-ylcarbonylamino) ethyl] -5- [pyridazine-3.
(2H) -On-6-yl] indane is obtained.

Production Example 161 The corresponding starting material compound was treated in the same manner as in Production Example 11 to give 2- [2- (4-methylpyridin-3-ylcarbonylamino) ethyl] -5- [4,5-dihydropyridazine. -3 (2H) -on-6-yl] indan,
Then, this was treated in the same manner as in Production Example 40 to give 2
-[2- (4-Methylpyridin-3-ylcarbonylamino) ethyl] -5- [pyridazin-3 (2H) -on-6-yl] indane is obtained.

Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number in the agency FI Technical display location C07D 405/12 237 C07D 405/12 237 409/12 237 409/12 237 (72) Inventor Fumika Okumura Minami Saitama Prefecture 675-1-C403, Kokuki, Shiraoka-cho, Saitama-gun

Claims (19)

[Claims] 1. A compound of the general formula [I] (In the formula, R ¹ is an aryl group which may have a substituent,
A lower alkyl group, a cycloalkyl group having 3 to 6 carbon atoms, a halogeno lower alkyl group, a lower alkenyl group, a phenyl-substituted lower alkenyl group, and a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom A monocyclic or bicyclic heteroaromatic group which may have a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom and may have a substituent An alkyl group, a lower alkoxy group which may have a substituent, a phenoxy group, a lower alkylamino group, a lower alkenylamino group,
Represents a phenylamino group or a lower alkenyloxy group, R ² represents a hydrogen atom or a lower alkyl group, X represents a carbonyl group or a thiocarbonyl group, Alk represents a single bond or a lower alkylene group, and a dotted line represents a double Indicates the presence or absence of a bond. The pharmaceutical composition which uses the indane derivative or its pharmacologically acceptable salt shown by these as an active ingredient. 2. An aryl group which may have a substituent is a lower alkoxy group, a phenyl-substituted lower alkoxy group, a halogen atom, a hydroxyl group, a trifluoromethyl group, a nitro group, a lower alkyl group or a di-lower alkylamino group. A phenyl group which may be substituted with 1 to 3 groups selected from: a halogeno lower alkyl group is a trifluoromethyl group; a phenyl substituted lower alkenyl group is a styryl group; and a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom. Containing a monocyclic or bicyclic heteroaromatic group which may have a substituent, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group,
Cyano group, amino group, mono-lower alkylamino group, di-lower alkylamino group, acylamino group, halogen atom,
A phenoxy group, a carboxy group, a lower alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a di-lower alkylcarbamoyl group, which may be substituted with 1 to 4 groups, a pyridyl group, Furyl group, thienyl group, pyrazyl group, pyrimidyl group, quinolyl group or isoquinolyl group; monocyclic or bicyclic heteroaromatic ring containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom and optionally having a substituent The pharmaceutical composition according to claim 1, wherein the lower alkyl group substituted with a formula group is a pyridylmethyl group; the lower alkoxy group which may have a substituent is a lower alkoxy group which may be substituted with a phenyl group. 3. R ¹ is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, a cyano group, an amino group, a substituted amino group, a halogen atom, a phenoxy group, a carboxy group, a lower group. 1 or 2 selected from an alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a di-lower alkylcarbamoyl group.
2. A pharmaceutical composition according to claim 1, which is a pyridyl group optionally having 1 substituent; a pyridyl lower alkyl group; a lower alkyl group; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; or a lower alkoxy group. Stuff. 4. A pyridyl group, a lower alkyl group, a lower alkenyl group or a lower alkoxy group, wherein R ¹ may have 1 or 2 substituents selected from a lower alkyl group, a lower alkylamino group and an amino group. The pharmaceutical composition according to claim 1, which is 5. The pharmaceutical composition according to claim 1, wherein R ¹ is a pyridyl group which may have 1 or 2 substituents selected from a methyl group, a methylamino group and an amino group. 6. The pharmaceutical composition according to claim 1, wherein R ² is a hydrogen atom. 7. The pharmaceutical composition according to claim 1, wherein R ² is a lower alkyl group. 8. The pharmaceutical composition according to claim 1, wherein X is a carbonyl group. 9. The pharmaceutical composition according to claim 1, wherein Alk is a lower alkylene group. 10. The method according to claim 1, wherein the dotted line represents the presence of a double bond.
The described pharmaceutical composition. 11. R ¹ is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group,
Hydroxyl group, mercapto group, cyano group, amino group, substituted amino group, halogen atom, phenoxy group, carboxy group, lower alkoxycarbonyl group, lower alkylcarbonyloxy group, lower alkylcarbonyl group, carbamoyl group and di-lower alkylcarbamoyl group A pyridyl group optionally having 1 or 2 substituents; a pyridyl lower alkyl group; a lower alkyl group; a cycloalkyl group having 3 to 6 carbon atoms; a lower alkenyl group; or a lower alkoxy group, and X being a carbonyl group. The pharmaceutical composition according to claim 1, which is 12. A pyridyl group, a lower alkyl group, a lower alkenyl group or a lower alkoxy group, in which R ¹ may have 1 or 2 substituents selected from a lower alkyl group, a lower alkylamino group and an amino group. , X is a carbonyl group, Alk is a lower alkylene group, and the dotted line represents the presence of a double bond. 13. A pyridyl group, a lower alkyl group, a lower alkenyl group or a lower alkoxy group, wherein R ¹ may have 1 or 2 substituents selected from a lower alkyl group, a lower alkylamino group and an amino group. , R ² is a hydrogen atom, X is a carbonyl group, Alk is a lower alkylene group, and the dotted line represents the presence of a double bond. 14. R ¹ is a methyl group, 1 to 2 substituents pyridyl group which may have a selected from methylamino group and an amino group, R ² is a hydrogen atom, X is a carbonyl group, Alk The pharmaceutical composition according to claim 1, wherein the lower alkylene group and the dotted line represent the presence of a double bond. 15. 2- [2- (Pyridin-3-ylcarbonylamino) ethyl] -5- [pyridazine-3 (2
H) -on-6-yl] indane or a pharmacologically acceptable salt thereof as an active ingredient. 16. A pharmaceutical composition which is a prophylactic / therapeutic drug for nephritis and / or an endotoxin shock protective drug, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 1.
The pharmaceutical composition according to 2, 13, 14 or 15. 17. The pharmaceutical composition according to claim 16, which is a prophylactic / therapeutic drug for nephritis. 18. The pharmaceutical composition according to claim 16, which is a prophylactic / therapeutic drug for glomerulonephritis. 19. A pharmaceutical composition for preventing immunoglobulin A nephropathy, nephrotic syndrome and / or lupus nephritis
The pharmaceutical composition according to claim 16, which is a therapeutic drug.