JP2757352B2 - Indane derivative, its production method and its synthetic intermediate - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel indane derivative having an endotoxin shock protective effect and / or a therapeutic effect on nephritis, a process for producing the same and a synthetic intermediate thereof.

[0002]

2. Description of the Related Art Japanese Patent Laid-Open Publication No.
It has been disclosed that benzenesulfonamidoindanyl compounds such as-(2-benzenesulfonamido-indan-5-yl) -4,5-dihydro-pyridazin-3 (2H) -one exhibit an antithrombotic effect. I have. In addition, WO
No. 92/15558 discloses 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 thromboxane A ₂ antagonism.

On the other hand, as a remedy for endotoxin shock which occurs in patients with severe infections of Gram-negative bacteria,
Steroid hormones, aprotinin (a protease inhibitor), dobutamine (a cardiotonic) and the like are used.

[0004] Prednisolone (steroid), cyclophosphamide (immunosuppressant), dipyridamole, dilazep (antiplatelet agent), heparin (anticoagulant) and the like have been used as therapeutic agents for nephritis. .

[0005]

SUMMARY OF THE INVENTION The present invention provides a novel indane derivative having an excellent endotoxin shock protective effect and / or a therapeutic effect on nephritis, a process for producing the same, and a synthetic intermediate thereof.

[0006]

The present invention provides a compound of the general formula [I]

[0007]

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(Wherein R ¹ is an optionally substituted aryl group, lower alkyl group, cycloalkyl group having 3 to 6 carbon atoms, halogeno lower alkyl group, lower alkenyl group, phenyl-substituted lower alkenyl group) A nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, a monocyclic or bicyclic heteroaromatic group which may have a substituent, and a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom Optionally substituted monocyclic or bicyclic heteroaromatic group-substituted lower alkyl group, optionally substituted lower alkoxy group, 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 the dotted line represents the presence or absence of a double bond. ) Or a pharmaceutically acceptable salt thereof.

In the object [I] of the present invention, examples of the aryl group which may have a substituent include a lower alkoxy group, a phenyl-substituted lower alkoxy group, a halogen atom, a hydroxyl group, a trifluoromethyl group, and a nitro group. Selected from the group consisting of a group, a lower alkyl group and a di-lower alkylamino group
A phenyl group which may be substituted with up to 3 groups is mentioned, and a halogeno lower alkyl group is, for example, a trifluoromethyl group. Examples of the phenyl-substituted lower alkenyl group include a styryl group. As 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, for example, a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group 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), halogen atom, phenoxy group, carboxy group, lower alkoxy A carbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a pyridyl group optionally substituted with 1 to 4 groups selected from a carbamoyl group and a di-lower alkylcarbamoyl group, a furyl group, a thienyl group, a pyrazyl group, Pyrimidyl group, quinolyl group, isoquinolyl group, etc .; Atom, oxygen atom or containing a sulfur atom which may have a substituent monocyclic or bicyclic heteroaromatic cyclic group-substituted lower alkyl group, for example, 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 target compounds [I] 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, a substituted amino group (for example, a mono-lower alkylamino group, Lower alkylamino group, acylamino group), halogen atom,
A pyridyl group optionally having one or two 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) A pyridyl group in which R ¹ may have one or two substituents selected from a lower alkyl group and an amino group; a lower alkyl group; a lower alkenyl group; or a lower alkoxy group.

(1C) A pyridyl group in which R ¹ may have one or two substituents selected from a methyl group and an amino group.

In the "pyridyl group optionally having substituent (s)" for R ¹ , there are no particular restrictions on the substitution position of the substituent 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. Preferred examples of the pyridyl group having a substituent include a 2- or 4-position monosubstituted or 2,4-disubstituted pyridin-3-yl group of a pyridine ring. Among these, more preferred examples include an unsubstituted pyridin-3-yl group and a 2-substituted pyridin-3-yl group.

Another preferred group of compounds includes, for example,
A group consisting of compounds having the following characteristics is given.

(2) X is a carbonyl group.

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

(3) Alk is a lower alkylene group.

Another preferred compound group includes, 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 preferred compound group, there can be mentioned, for example, a group consisting of compounds having the characteristics of the above (1A) and (2).

As another particularly preferred compound group, there can be mentioned, for example, a group consisting of compounds having the characteristics of the above (2) and (4).

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

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

The object [I] of the present invention may have two types of optical isomers based on asymmetric carbon atoms, and the present invention includes both these optical isomers and mixtures thereof.

The target compound [I] of the present invention can be used in a free form or a pharmaceutically acceptable salt thereof for pharmaceutical use. Pharmaceutically acceptable salts include:
Inorganic acid salts such as hydrochloride, phosphate, hydrobromide and the like, and organic acid salts such as acetate, succinate, fumarate, methanesulfonate and the like can be mentioned.

The object [I] of the present invention can be administered orally or parenterally, and can be used as a pharmaceutical preparation by mixing with an excipient suitable for oral or parenteral administration. . 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. In the case of parenteral administration, it can be used in the form of injection.

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

According to the present invention, (A) the target compound [I] is, for example, a compound represented by the general formula [II]:

[0030]

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(Wherein the symbols have the same meanings as described above) or a salt thereof, and a compound represented by the general formula [III]:

[0032]

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(Wherein the symbols have the same meanings as described above), a salt thereof or a reactive derivative thereof, and if desired, a pharmacologically acceptable salt can be produced. .

(B) Of the target product [I], a compound represented by the general formula [I-
a)

[0035]

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Wherein R ¹¹ is a lower alkyl group, a lower alkenyl group or a phenyl group, Z represents an oxygen atom or a sulfur atom, and other symbols have the same meanings as described above. Compound [II] and general formula [IV]

[0037]

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(Wherein the symbols have the same meanings as described above), and if desired, a pharmacologically acceptable salt can be prepared to produce the compound.

(C) Of the target compound [I], a compound whose dotted line indicates the presence of a double bond, that is, a compound of the general formula [Ib]

[0040]

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(Wherein the symbols have the same meanings as described above) or a pharmaceutically acceptable salt thereof is a compound of the object [I] wherein the dotted line represents the absence of a double bond. That is, the general formula [I-c]

[0042]

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

In the above production method (A), the compound [II
When compound [I] is produced using I] or a salt thereof, the reaction can be carried out in a suitable solvent in the presence of a condensing agent.

As the condensing agent, conventional condensing agents such as 1,3-dicyclohexylcarbodiimide, carbonyldiimidazole, 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide, diethyl cyanophosphonate and the like can be used. As the salt of the compound [III], conventional salts such as alkali metal salts, alkaline earth metal salts and organic amine salts can be used. When reacting with compound [II], these salts are preferably subjected to the reaction in advance as a free compound.

In the production method (A), the compound [II
When the compound [I] is produced using the reactive derivative of I], the reaction can be appropriately carried out in a suitable solvent in the presence or absence of a deoxidizing agent. As reactive derivatives,
For example, any of those commonly used for condensation, such as acid halides (including halogenoformate), mixed acid anhydrides and active esters, can be used. Examples of the deoxidizing agent include alkali metal carbonates such as potassium carbonate and sodium carbonate, alkali metal carbonates such as potassium hydrogen carbonate and sodium hydrogen carbonate, alkali metal hydroxides such as sodium hydroxide and potassium hydroxide, triethylamine, tributylamine, Tri-lower alkylamines such as diisopropylethylamine, 1,4-diazabicyclo [2.2.2] octane, 1,5-diazabicyclo [4.3.0] nona-
Examples include tertiary amines such as 5-ene and 1,8-diazabicyclo [5.4.0] undec-7-ene, and aromatic amines such as pyridine, lutidine, collidine and dimethylaniline.

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

The solvent used in the above production methods (A) and (B) may be any inert solvent which does not adversely affect the reaction in any of the production methods (A) and (B). Halogen solvents such as chloroform, dichloromethane and dichloroethane; aromatic hydrocarbons such as toluene and xylene; ether solvents such as tetrahydrofuran, dioxane, diethyl ether and 1,2-dimethoxyethane; ketone solvents such as acetone and methyl ethyl ketone; acetic acid Ester solvents such as ethyl, alcohol solvents such as 2-methoxyethanol, 2-propanol and tert-butanol, acetonitrile, pyridine, 2,6
-Lutidine, dimethylformamide, dimethylsulfoxide, 1,3-dimethyl-2-imidazolidinone, and the like; a mixed solvent of these solvents; and a combination of these solvents and water.

The production methods (A) and (B) are performed under cooling.
It can be carried out under heating, for example, -30 ° C to 150
C, especially at -10C to room temperature.

The oxidation in the production method (C) can be carried out according to a conventional method. For example, the compound [I-
c) is treated with sodium 3-nitrobenzenesulfonate under basic conditions, or reacted under redox conditions with dimethylsulfoxide in hydrogen bromide-acetic acid under acidic conditions, or with bromine, chlorine or the like. After halogenation,
It can be suitably carried out by immediately subjecting it to a dehydrohalogenation reaction.

As the solvent, water, acetic acid, propionic acid,
Trifluoroacetic acid, methanesulfonic acid or a hydrogen bromide-acetic acid solution can be suitably used.

In the reaction of the present invention, if an optically active compound is used as the starting compound [II] or [Ic],
The corresponding optically active target compound [I], [Ia] or [Ib] can be obtained without racemization.

In the starting compound [II] of the present invention, R ²
Is a hydrogen atom, Alk is a single bond, and the dotted line is a compound representing the absence of a double bond, is described in JP-A-63-23853, but other compounds are novel compounds,
General formula [V]

[0054]

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[0055] (wherein, R ²¹ represents a hydrogen atom or a lower alkyl group and the other symbols. The same as defined above) by reacting the compound with hydrazine represented by, if R ²¹ represents a hydrogen atom, If desired, further amino groups can be added, for example, to the corresponding aldehyde compound and sodium borohydride (Na
BH ₄ ), sodium triacetoxyborohydride [N
aB (OCOCH ₃ ) ₃ H], alkylation by a method such as subjecting to a reductive alkylation reaction in the presence of a suitable reducing agent, and if the dotted line indicates the absence of a double bond, further oxidation if desired. Can be produced.

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

The solvent may be any inert solvent which does not adversely affect the reaction, for example, lower alcohols such as methanol and ethanol, lower fatty acids such as acetic acid and propionic acid, aromatic hydrocarbons such as toluene and xylene, and tetrahydrofuran. And ethers such as dioxane. The reaction can be carried out widely from room temperature to the boiling point of the reaction mixture, for example from 10 ° C. to 200 ° C., especially from 2 ° C.
It can be suitably carried out at 0 ° C to 150 ° C.

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

The starting compound [V] is, for example, optionally a compound of the general formula [VI]

[0060]

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

[0062]

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Wherein R ³ represents an ester residue and Y represents a halogen atom.
Then removing the ester residues and / or protecting groups,
Alternatively, it can be produced by the method described in the below-mentioned embodiment.

In the present specification, examples of the lower alkyl group include a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, a sec-butyl group and a tert-butyl group.
t-butyl group, n-pentyl group, isopentyl group, neopentyl group, n-hexyl group and the like having 1 to 6, preferably 1 to 4, especially 1 to 3 carbon atoms, and as the lower alkoxy group, For example, a methoxy group, an ethoxy group,
A C 1-6 carbon atom such as a propoxy group, an isopropoxy group, a butoxy group, a pentyloxy group, an isopentyloxy group,
Particularly, the lower alkylene group includes 1 to 4 carbon atoms such as a methylene group, an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. Lower alkenyl groups such as vinyl group, 1-propenyl group, allyl group,
2 to 7 carbon atoms such as methyl allyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4 or 5-hexenyl, especially 2
~ 5.

In the present specification, a 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. An amino group, an N-lower alkyl-N-thiocarbamoylamino group (a nitrogen atom in the carbamoyl group or the thiocarbamoyl group may be further substituted with one or two lower alkyl groups), a lower alkylcarbamoyl group; And a pyrrolidino group, a piperidino group, a perhydroazepin-1-yl group, a morpholino group, a thiomorpholino group, a piperazino group (the nitrogen atom at the 4-position of the piperazino group is a lower alkyl group, a lower alkenyl group, and an acyl group. , Which may be substituted with an aryl group, 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 and a hexanoyl group;
Preferably a lower alkylcarbonyl group having 2 to 4 carbon atoms such as a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group, a butoxycarbonyl group, a tert-butoxycarbonyl group, a pentyloxycarbonyl group, and a hexyloxycarbonyl group; Preferably 2
And 4 lower alkoxycarbonyl groups.

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

[0068]

[Action]

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

[0069]

[Table 1]

Experimental Example 2 (Effects on Rat Glomerulonephritis) Rabbit glomerular basement membrane fraction obtained from WKY rats was immunized to rabbits several times with adjuvant, and then whole blood was collected to obtain nephrotoxin serum (NTS). I got This NTS was diluted 50-fold with physiological saline, and 2.5 ml / kg body weight was intravenously injected once into 8-week-old male WKY rats to induce nephritis. The normal group received the same amount of physiological saline intravenously.

In the experiment, each 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. Oral administration. The same amount of purified water was orally administered to the normal group and the control group. On the 7th day, the rats were placed in metabolic cages, urine was collected for 24 hours, urine protein concentration was measured by the sulfosalicylic acid method, and protein excretion (mg /
D) and the protein excretion inhibition rate was calculated by the following equation.

[0072]

(Equation 1)

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

[0074]

[Table 2]

[0075]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited thereto. The starting compounds were described in Examples 1 to 10 and Examples 92 to 104, and the target compounds were described in Examples 11 to 91 and Examples 105 to 159.

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 the solvent is distilled off. The resulting crude crystals were recrystallized from acetone to give 2-propylamino-5- [4,5-dihydropyridazine-3.
(2H) -On-6-yl] indane (7.78 g) is obtained.

M. p. 146-148 ° C Example 2 2-amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane (8.02 g) in 25
The suspension was suspended in 70% hydrogen bromide-acetic acid solution (70 ml), and dimethylsulfoxide (2.96 g) was added thereto under ice cooling, followed by stirring at room temperature for 1.5 hours. Then, 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] indane hydrobromide 8.5
5 g are obtained.

M. p. Example: 2-Propylamino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane was prepared in Example 2.
To give 2-propylamino-5- [pyridazin-3 (2H) -one-6-yl] indan.

M. p. 137-139 ° C Example 4 (1) 46.4 g of oxalyl chloride and 2 drops of dimethylformamide are added to a dichloroethane solution (840 ml) of 48.3 g of methyl hydrogen succinate, and the mixture is stirred at room temperature for 5 hours. Then, a solution of 34.6 g of 2- (acetylaminomethyl) indane in 280 ml of dichloroethane and 97.6 g of anhydrous aluminum chloride 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 was separated, washed with water and dried, and then the solvent was 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 are suspended in 10 N 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
Hydrazine monohydrate (30 g),
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% aqueous sodium hydroxide solution.
Extract with chloroform. After the organic layer is washed with water and dried, the solvent is distilled off. The residue was recrystallized from methanol to give 2-aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indan 35.3.
g.

M. p. : 170-171 ° C (3) 2-aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane 4.9
0 g was suspended in 20 ml of acetic acid, and 30% hydrogen bromide-acetic acid 5
0 ml and 2.8 g of dimethyl sulfoxide are added and stirred for 3 hours. Add 300 ml of isopropyl ether,
The precipitated crystals are collected by filtration. By recrystallizing the obtained crude crystals from methanol, 2-aminomethyl-5-
5.11 g of [pyridazin-3 (2H) -one-6-yl] indane hydrobromide are obtained.

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

[0083]

[Table 3]

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

[0085]

[Table 4]

Example 9 (1) 2-Aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane 6.1
A methanol solution (5 ml) of propanal (1.51 g) was dropped into a methanol solution (60 ml) of 5 g,
Stir at room temperature for 30 minutes. Then, under ice-cooling, 1.03 g of sodium borohydride was added, and the mixture was added at the same temperature for 20 minutes and at room temperature for 1 minute.
Stir for hours. Methanol is distilled off, water is added to the residue,
Extract with ethyl acetate. After the organic layer is washed with water and dried, the solvent is distilled off. The residue was 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] indane (5.22 g) is obtained.

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

M. p. 144-146 ° C. Example 10 In the same manner as in Example 9- (1), 2-
[2- (Propylamino) ethyl] -5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane is obtained.

M. p. : 123-124 ° C Example 11 2-amino-5- [4,5-dihydropyridazine-3
(2H) -on-6-yl] indane (7.26 g) and triethylamine (7.05 g) in 1,3-dimethyl-2-imidazolidinone (70 ml) were added dropwise with a solution of 4.09 g of butyryl chloride in 20 ml of tetrahydrofuran. 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-dihydropyridazine-3 (2H) -one-6
-Yl] indane, 7.47 g.

M. p. : 214-215 ° C Examples 12-28 The corresponding starting compounds are treated in the same manner as in Example 11, to give the compounds shown in Tables 5 to 7.

[0091]

[Table 5]

[0092]

[Table 6]

[0093]

[Table 7]

Example 29 2-amino-5- [4,5-dihydropyridazine-3
(2H) -On-6-yl] indane 5.13 g of 2-
2.38 g of propyl isocyanate is added dropwise to the 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) -one-6-yl] indan4. .91 g are obtained.

M. p. : 214-216 ° C Example 30 2-amino-5- [4,5-dihydropyridazine-3
(2H) -On-6-yl] indan and butyl isocyanate were treated in the same manner as in Example 29 to give 2- (butylcarbamoyl) amino-5- [4,5-dihydropyridazin-3 (2H) -one. -6-yl] indane.

M. p. : 206-207 ° C Example 31 2-amino-5- [4,5-dihydropyridazine-3
(2H) -On-6-yl] indan and phenyl isocyanate were treated in the same manner as in Example 29 to give 2- (phenylcarbamoyl) amino-5- [4,5-dihydropyridazin-3 (2H) -one. -6-yl] indane.

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

[0098]

[Table 8]

Example 35 4.07 g of 2-propylamino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane
To a chloroform solution (40 ml) of 2.02 g of triethylamine and 2.02 g of tributylamine, 2.46 g of isobutyl chloroformate was added under ice cooling, followed by stirring for 1 hour. After the organic layer is washed with water and dried, the solvent is distilled off. The resulting 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 are obtained.

M. p. 161-162 ° C Examples 36-39 The corresponding starting compounds are treated in the same manner as in Example 35, to give the compounds described in Table 9.

[0101]

[Table 9]

Example 40 2-butyrylamino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane 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 aqueous ethanol to give 2-butyrylamino-5- [pyridazine-3.
(2H) -On-6-yl] indane (3.50 g) is obtained.

M. p. : 228-229 ° C Examples 41-48 The corresponding starting compounds were treated in the same manner as in Example 40 to give
The compounds shown in the table are obtained.

[0104]

[Table 10]

Example 49 2-amino-5- [pyridazin-3 (2H) -one-6
-Yl] indane hydrobromide 5.03 g in ethyl acetate suspension (150 ml) was added to potassium carbonate (4.52 g).
An aqueous solution (150 ml) was added, and then a solution of 3.0 g of acrylic acid chloride in 50 ml of tetrahydrofuran was added dropwise under ice-cooling, followed by stirring 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) -one-6-yl] indan are obtained.

M. p. : 235-237 ° C Example 50 2-amino-5- [pyridazin-3 (2H) -one-6
-Yl] indane hydrobromide and vinyl chloroformate were treated in the same manner as in Example 49 to give 2-vinyloxycarbonylamino-5- [pyridazin-3 (2H) -one-6-yl] indan. obtain.

M. p. : 205-206 ° C Example 51 2-propylamino-5- [pyridazine-3 (2H)-
To a suspension of 3.00 g of [on-6-yl] indan hydrobromide in 30 ml of dichloromethane was added 2.01 g of triethylamine, followed by stirring for 20 minutes. 1.66 g of phenyl chloroformate is added and stirred at room temperature for 2 hours. After the organic layer is washed with water and dried, the solvent is distilled off.

The resulting crude crystals were recrystallized from ethyl acetate-hexane to give 2- (N-propyl-N-phenoxycarbonylamino) -5- [pyridazine-3
(2H) -On-6-yl] indane (3.47 g) is obtained.

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

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

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

M. p. : 204-205 ° C Examples 55-64 The corresponding starting compounds are treated in the same manner as in Example 54, to give the compounds described in Tables 11 and 12.

[0113]

[Table 11]

[0114]

[Table 12]

Example 65 3.06 g of 2-aminomethyl-5- [pyridazin-3 (2H) -one-6-yl] indane hydrobromide and 3
To a suspension of methylcrotonic acid (1.15 g) in dimethylformamide (80 ml) was added 1.71 g of diethylphosphoric acid cyanide under ice-cooling, followed by triethylamine (2.8).
9 g of a 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, the residue was recrystallized from ethyl acetate-methanol to give 2-[(3-methylcrotonoyl) amino] methyl-5- [pyridazin-3 (2H) -one-6-yl].
2.45 g of indane are obtained.

M. p. Example 204: 2-aminomethyl-5- [pyridazin-3 (2H) -one-6-yl] indane hydrobromide 2.70 g of 2-
1.05 g of triethylamine is added to the methoxyethanol suspension (40 ml), and the mixture is stirred at room temperature for 10 minutes. 1.10 g of allyl isocyanate is added and stirred at room temperature for 1.5 hours. Pour into ice water and filter out the precipitated crystals. The obtained crystals were washed with water, dried, and recrystallized from methanol to give 2.35 g of 2-[(allylcarbamoyl) amino] methyl-5- [pyridazin-3 (2H) -one-6-yl] indane. obtain.

M. p. : 208-209 ° C Example 67 By treating the corresponding starting compound and propyl isothiocyanate in the same manner as in Example 66, 2- {2-[(propyl) thiocarbamoyl] aminoethyl} -5- [pyridazine-3 (2H) -On-6-yl] indane is obtained.

M. p. 155-157 ° C Example 68 2-Aminomethyl-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane 1.57 g of 1,3-dimethyl-2-imidazolidinone Suspension (15
ml), and 1.47 g of triethylamine was added thereto.
Stir for 0 minutes. Next, a solution of 0.83 g of butyryl chloride in tetrahydrofuran (8 ml) 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 recrystallized from ethyl acetate-methanol to give 2- (butyrylamino) methyl-5- [4,5-dihydropyridazine-3.
(2H) -On-6-yl] indane 1.47 g are obtained.

M. p. 172-173 ° C Examples 69-72 The corresponding starting compounds are treated in the same manner as in Example 68, to give the compounds listed in Table 13.

[0120]

[Table 13]

Example 73 A suspension of 3.13 g of 2- (butyrylamino) methyl-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane in acetic acid (20 ml) was treated with 30% odor. 25 ml of hydrogen chloride-acetic acid and 1 ml of dimethyl sulfoxide 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) -one-6-yl] indan 2 .80 g are obtained.

M. p. : 204-205 ° C Examples 74-77 By treating the corresponding starting compounds in the same manner as in Example 73, the compounds shown in Table 14 are obtained.

[0123]

[Table 14]

Examples 78 to 88 By treating the corresponding starting compounds in the same manner as in Example 11, the compounds shown in Tables 15 to 16 are obtained.

[0125]

[Table 15]

[0126]

[Table 16]

Example 89 (1) Dissolve 8.41 g of 2-amino-5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane in 1400 ml of ethanol, and add (+) camphorsulfonic acid. 8.52 g are added. By recrystallizing the obtained salt from ethanol several times, optically active 2-amino-
5.20 g of 5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indan. (+)-Camphorsulfonate are obtained.

M. p. : 256-257 ° C (decomposition) [α] _D ²⁰ -13.4 ° (c = 1.00, H ₂ O) (2) Collect all of the mother liquor of (1) above and neutralize with an aqueous potassium carbonate solution , Ethanol is distilled off. After the residue is extracted 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 from ethanol several times to give optically active 2-amino-5-amino acid.
[4,5-dihydropyridazine-3 (2H) -one-6
-Yl] indane. (-)-Camphorsulfonate 4.99 g are obtained.

M. p. : 257-258 ° C. (decomposition) [α] ^{_{D 20 + 13.1 ° (c =}} 1.00, H 2 O) (3) optically active 2-amino-5- [4,5-dihydro-pyridazin -3 (2H ) -On-6-yl] indane
138.8 g of (-)-camphorsulfonic acid salt was dissolved in 1.65 l of warm water, and sodium hydroxide 13.0 was cooled.
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) -one-6-yl] indane 6
6.6 g are obtained.

M. p. 197-198 ° C. [α] _D ²⁰ + 35.9 ° (c = 1.00, dimethylformamide) (4) A suspension of 4.50 g of this product in tetrahydrofuran 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 adjusted with 1.48 g of NaBH ₄ and 8.94 g of acetic acid, and sodium triacetoxyborohydride [N
aB (OCOCH ₃ ) ₃ H] in 100 ml of tetrahydrofuran suspension and stirred for 1 hour. 4 reaction solvents
Concentrate to 1/100, pour into ice water, neutralize and extract with chloroform. The organic layer is washed with water, dried and then the solvent is distilled off. The obtained residue is purified by silica gel column chromatography [solvent: chloroform: methanol (15: 1)], and the obtained crystal is recrystallized from ethyl acetate. By doing so, (+)-2-propylamino-5- [4,5-
4.14 g of dihydropyridazin-3 (2H) -one-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 Example 11,
(+)-2- (N-propyl-N-butyrylamino)-
This gives 5- [4,5-dihydropyridazin-3 (2H) -one-6-yl] indane.

M. p. : 103-105 ° C. [α] ^{_{D 20 + 13.3 ° (c =}} 1.00, methanol) 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 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) 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 of 18.9 g of indane was added dropwise, and the mixture was refluxed for 2 hours. After cooling, excess lithium aluminum hydride is treated with an aqueous saturated ammonium chloride solution, and insolubles are filtered. The filtrate is concentrated, chloroform is added to the residue, washed with water, dried, and then the solvent is distilled off to obtain 17.5 g of 2- (propylamino) indane.

17.5 g of this product, triethylamine
12 g was dissolved in 200 ml of tetrahydrofuran, and 17.8 g of methyl chlorocarbonate was 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, dried, and the solvent was distilled off to give 2- (N-methoxycarbonyl-N-propylamino) indane 21. 0.6 g are obtained.

IR (neat) cm ^-1 : 1660 Mass (m / z): 233 (M ⁺ ) (2) 21.6 g of this product, methyl succinyl chloride (24.68 g of methyl hydrogen succinate and 23.75 g of oxalyl chloride) 300 ml of dichloromethane prepared from
59.85 g of anhydrous aluminum chloride is added to the solution under ice cooling, and the mixture is stirred at room temperature for 2 hours. Pour the reaction solution into ice water,
The organic layer was separated, washed with water and dried, and the solvent was 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 were added 12.75 g of hydrazine monohydrate and 24 ml of acetic acid, and the mixture was refluxed 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 mixed solution of diisopropyl ether-hexane to give 2- (N-methoxycarbonyl-N-propylamino) -5- [4,5-dihydropyridazine-3.
(2H) -On-6-yl] indan (28.96 g) is obtained.

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

[0138]

[Table 17]

Examples 99-101 By treating the corresponding starting compounds in the same manner as in Example 4- (3), the compounds shown in Table 18 are obtained.

[0140]

[Table 18]

Examples 102 to 104 By treating the corresponding starting compounds in the same manner as in Example 9- (2), the compounds shown in Table 19 are obtained.

[0142]

[Table 19]

Examples 105 to 122 By treating the corresponding starting compounds in the same manner as in Example 54, the compounds shown in Tables 20 to 22 are obtained.

[0144]

[Table 20]

[0145]

[Table 21]

[0146]

[Table 22]

Examples 123 to 157 The corresponding starting compounds were treated in the same manner as in Example 65, to give the compounds shown in Tables 23 to 28.

[0148]

[Table 23]

[0149]

[Table 24]

[0150]

[Table 25]

[0151]

[Table 26]

[0152]

[Table 27]

[0153]

[Table 28]

Examples 158 to 159 The corresponding starting compounds were treated in the same manner as in Example 68, to give compounds as shown in Table 29.

[0155]

[Table 29]

[0156]

The indane derivative [I] and the pharmaceutically acceptable salt thereof, which are the object of the present invention, have an excellent endotoxin shock protective effect and / or a therapeutic effect on nephritis. It is useful as a preventive / therapeutic agent for endotoxin shock or a preventive / therapeutic agent for nephritis which develops in patients with severe infection.

The objective compound [I] of the present invention has low toxicity and high safety as a medicine.

Continuation of the front page (51) Int.Cl. ⁶ identification code FI C07D 405/12 237 C07D 405/12 237 409/12 237 409/12 237 (58) Investigated field (Int.Cl. ⁶ , DB name) C07D 237/14 C07D 237/04 C07D 403/12 C07D 405/12 C07D 409/12 C07D 401/12 A61K 31/50 CA (STN) REGISTRY (STN) WPIDS (STN)

Claims (18)

(57) [Claims] 1. A compound of the general formula [I] (Wherein, 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, having a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom; A monocyclic or bicyclic heteroaromatic group, a monocyclic or bicyclic heteroaromatic group substituted with a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, which 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,
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, Indicates the presence or absence of a bond. Or a pharmacologically acceptable salt thereof. 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 and a di-lower alkylamino group. A phenyl group optionally substituted with 1 to 3 groups selected from the group consisting of: a halogeno lower alkyl group being a trifluoromethyl group; a phenyl substituted lower alkenyl group being a styryl group; a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom A monocyclic or bicyclic heteroaromatic group which may have a substituent includes 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 pyridyl group optionally substituted with 1 to 4 groups 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, furyl Group, thienyl group, pyrazyl group, pyrimidyl group, quinolyl group or isoquinolyl group; monocyclic or bicyclic heteroaromatic ring containing a nitrogen atom, oxygen atom or sulfur atom as a hetero atom and optionally having a substituent The compound according to claim 1, wherein the group-substituted lower alkyl group is a pyridylmethyl group; and 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, and a lower group. 1 to 2 selected from an alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a di-lower alkylcarbamoyl group
The compound according to claim 1, which is a pyridyl group optionally having a 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. 4. The method according to claim 1, wherein R ¹ is a pyridyl group, a lower alkyl group, a lower alkenyl group or a lower alkoxy group optionally having one or two substituents selected from a lower alkyl group and an amino group. A compound as described. 5. The compound according to claim 1, wherein R ¹ is a pyridyl group optionally having one or two substituents selected from a methyl group and an amino group. 6. The compound according to claim 1, wherein R ² is a hydrogen atom. 7. The compound according to claim 1, wherein R ² is a lower alkyl group. 8. The compound according to claim 1, wherein X is a carbonyl group. 9. The compound according to claim 1, wherein Alk is a lower alkylene group. 10. The dashed line indicates the presence of a double bond.
A compound as described. 11. R ¹ is a lower alkyl group, a halogeno lower alkyl group, a lower alkoxy group, a lower alkylthio group,
Selected from 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 alkoxycarbonyl group, a lower alkylcarbonyloxy group, a lower alkylcarbonyl group, a carbamoyl group and a 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; The compound according to claim 1, which is 12. R ¹ is a pyridyl group, a lower alkyl group, a lower alkenyl group or a lower alkoxy group optionally having one or two substituents selected from a lower alkyl group and an amino group, and X is a carbonyl group. 2. The compound according to claim 1, wherein Alk represents a lower alkylene group and a 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 optionally having one or two substituents, wherein R ¹ is selected from a lower alkyl group and an amino group, and R ² is hydrogen. An atom, X is a carbonyl group, A
The compound according to claim 1, wherein lk represents a lower alkylene group, and a dotted line represents the presence of a double bond. 14. R ¹ is a pyridyl group optionally having one or two substituents selected from a methyl group and an amino group, R ² is a hydrogen atom, X is a carbonyl group, Alk is a lower alkylene group, 2. The compound according to claim 1, wherein the dotted line indicates the presence of a double bond. 15. A compound of the general formula [II] (Wherein R ² represents a hydrogen atom or a lower alkyl group;
lk represents a single bond or a lower alkylene group, and the dotted line represents the presence or absence of a double bond. ) And a salt thereof and a compound of the general formula [III]: (Wherein, 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, having a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom; A monocyclic or bicyclic heteroaromatic group, a monocyclic or bicyclic heteroaromatic group substituted with a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, which 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,
X represents a phenylamino group or a lower alkenyloxy group, and X represents a carbonyl group or a thiocarbonyl group. )
Wherein the compound represented by the formula (I) is reacted with a salt thereof or a reactive derivative thereof to obtain a pharmaceutically acceptable salt if desired. (Wherein the symbols have the same meanings as described above.) Or a pharmaceutically acceptable salt thereof. 16. A compound of the general formula [II] (Wherein R ² represents a hydrogen atom or a lower alkyl group;
lk represents a single bond or a lower alkylene group, and the dotted line represents the presence or absence of a double bond. ) And a salt thereof and a general formula [IV] (Wherein, R ¹¹ represents a lower alkyl group, a lower alkenyl group or a phenyl group, and Z represents an oxygen atom or a sulfur atom). The compound is reacted to form a pharmaceutically acceptable salt if desired. General formula [I-
a) (Wherein the symbols have the same meanings as described above.) Or a pharmaceutically acceptable salt thereof. 17. A compound of the general formula [Ic] (Wherein, 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, having a substituent containing a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom; A monocyclic or bicyclic heteroaromatic group, a monocyclic or bicyclic heteroaromatic group substituted with a nitrogen atom, an oxygen atom or a sulfur atom as a hetero atom, which 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,
R ² represents a hydrogen atom or a lower alkyl group; X represents a carbonyl group or a thiocarbonyl group; and Alk represents a single bond or a lower alkylene group. ) Is converted to a pharmaceutically acceptable salt, if desired, to give a salt represented by the general formula [Ib]: (Wherein the symbols have the same meanings as described above), or a method for producing a pharmacologically acceptable salt thereof. 18. A compound of the general formula [II] (Wherein R ² represents a hydrogen atom or a lower alkyl group;
lk represents a single bond or a lower alkylene group, and the dotted line represents the presence or absence of a double bond. However, in the case where R ² is a hydrogen atom and Alk is a single bond, it is excluded that the dotted line indicates the absence of a double bond. )).