JPH06312978A - New phthalimide derivative having inhibiting activity against phospholipase a2 - Google Patents

Abstract

PURPOSE:To obtain a new compound, having inhibiting action on phospholipase A2 and useful for treating, etc., inflammatory diseases, allergic diseases, anaphylactic shock, arthritis, chronic articular rheumatism, etc. CONSTITUTION:The compound is expressed by formula I [X is (substituted)lower alkyl, (substituted)heteroaryl, etc.; (n) is 2-20; Y is O or S; (m) is 0 or 1; Z is CH3, formula II, etc.], e.g. 4-acetoxy-2-(4-phenylbutyl)-1H-isoindol-1,3(2H)-dione. Furthermore, this compound expressed by formula I is obtained by reacting a compound expressed by formula III with a compound expressed by formula IV. The compound expressed by formula III is a new substance.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel phthalimide derivative having a phospholipase A ₂ inhibitory activity, a drug containing these derivatives as an active ingredient, and an intermediate compound useful for the production of these derivatives.

[0002]

2. Description of the Related Art It has been speculated that various chemical mediators are involved in inflammatory reactions, and such chemical mediators include prostaglandins, leukotrienes, platelet aggregation inhibitor (PAF) and the like. Traditionally,
It is known that an enzyme called phospholipase A ₂ liberates and produces arachidonic acid from cell membrane phospholipids, resulting in the production of chemical mediators of various inflammatory reactions. Phospholipase A ₂ is a rate-limiting enzyme in the arachidonic acid cascade and excises arachidonic acid bound to the 2-position of phospholipids. Downstream of arachidonic acid, there are enzymes such as cyclooxygenase and 5-lipoxygenase, and by inhibiting these enzymes, the production of chemical mediators such as prostaglandins, thromboxane, and leukotriene that are produced in the subsequent stage is produced. Can be suppressed. Drugs that specifically inhibit cyclooxynase and 5-lipoxygenase have been developed, but these conventional drugs have gastrointestinal disorders,
It has side effects such as kidney damage, and its action is weaker than that of steroids. On the other hand, steroids are often limited in clinical application due to their serious side effects.

Recently, phospholipase A ₂ includes type I and type II
The presence of type ₂ phospholipase A ₂ has been confirmed, and the idea that the type present in gastric mucosa is type I phospholipase, and the enzyme involved in inflammation is type II phospholipase. Therefore, paying attention to the fact that the production of prostaglandins, thromboxane, and leukotrienes is suppressed by selectively inhibiting type II phospholipase, and drugs having such action are treated as inflammatory diseases, allergic diseases, anaphylactic shock. Attempts have been made to apply it to such diseases. Indeed, high type II phospholipase A ₂ activity was found in rheumatoid arthritis, anaphylactic shock pancreatitis and psoriasis, suggesting the importance of phospholipase A ₂ in the field of inflammation. Conventionally known inhibitors of phospholipase A ₂ are mepacrine, p-bromophenacyl bromide, manolide and its derivatives, but their activity is generally weak and their effectiveness in experimental animals has been confirmed. Very few things.

[0004]

Therefore, based on the above-mentioned findings, the present inventors have conducted diligent research to find out a compound having a phthalimide derivative as a basic skeleton and having a type II phospholipase A ₂ inhibitory action. It was found that the novel phthalimide derivative represented by the following general formula [I] has a selective and strong type II phospholipase A ₂ inhibitory action, and completed the present invention.

[0005]

That is, the object of the present invention is to:
The following general formula [I]

[0006]

[Chemical 5]

[Wherein X is a lower alkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or

[0008]

[Chemical 6]

(Wherein R ¹ and R ² are a hydrogen atom, a hydroxyl group or a lower alkoxy group), n is an integer of 2 to 20, and Y is —O— or —S—. Yes, m
Is an integer from 0 to 1 and Z is

[0010]

[Chemical 7]

[Wherein R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a carboxyl group or a lower alkoxy group]] Another object of the present invention is to provide a phthalimide derivative and a pharmaceutically acceptable salt.

[0012]

[Chemical 8]

A phthalimide derivative represented by the formula: wherein Y, Z, n, m, R ³ , R ⁴ and R ⁵ are the same as defined above. Another object of the present invention is to provide a drug having a phospholipase A ₂ inhibitory action, especially an anti-inflammatory agent, containing these phthalimide derivatives [I].

Definitions of various substituents used in the present specification are as follows. The "lower alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butyl group, Isobutyl group, s
ec-butyl group, tert-butyl group, n-pentyl group, cyclopentyl group, 1-methylbutyl group, 2,2-
Dimethylpropyl group, 2,2-dimethylbutyl group, n-
Hexyl group, cyclohexyl group and the like, particularly preferably methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group and isobutyl group. The "lower alkoxy group" is one that is alkoxylated with the above alkyl group, and specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, an n-butoxy group, an isobutoxy group, a sec-butoxy group, a tert-butoxy group,
Pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, 1-methylbutoxy group, 2-methylbutoxy group, 1,2-dimethylpropoxymethyl group, 1-ethylpropoxy group, hexyloxy group , Isohexyloxy group, neohexyloxy group, 1-methylpentyloxy group, 2-methylpentyloxy group, 3-methylpentyloxy group, 1,1-dimethylbutoxy group, 1,2-dimethylbutoxy group, 2,
2-dimethylbutoxy group, 1,3-dimethylbutoxy group, 2,3-dimethylbutoxy group, 1-ethylbutoxy group, 2-ethylbutoxy group, 1-ethyl-2-methylpropoxy group, 1-ethyl-2- Methylpropoxy group and the like, particularly preferably methoxy group, ethoxy group, propoxy group, isopropoxy group, n-butoxy group and isobutoxy group. The “halogen atom” is chlorine, bromine, fluorine or iodine. The “lower alkyl group which may be substituted” means the above lower alkyl group substituted with a hydroxyl group, a halogen group, a lower alkoxy group, a nitro group, an amino group, a cyano group or a carboxyl group. For example, chloromethyl group, bromomethyl group, fluoromethyl group, trifluoromethyl group, trifluoroethyl group, difluoromethyl group, hydroxymethyl group, 2-methoxyethyl group, 2-ethoxyethyl group, 2,2-dimethoxyethyl group, 2,2-diethoxyethyl group, 2-isopropoxyethyl group, 2-nitroethyl group, 3-nitropropyl group, 2-aminoethyl group, 3-aminopropyl group,
A 2-cyanoethyl group, a 3-cyanopropyl group, a 2-carboxyethyl group, a 2-methoxybutyl group and the like. The "aryl group which may be substituted" is a lower alkyl group which may be substituted with a plurality of halogen atoms, a halogen atom, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a di-lower alkylamino group, acetyl or propionyl. , A phenyl group, a biphenyl group or a naphthyl group, which may have 1 to 3 substituents which may be the same or different and are selected from acyl groups such as, butyryl and benzoyl. The "optionally substituted heteroaryl group" is a lower alkyl group which may be substituted with a plurality of halogen atoms, a halogen atom, a lower alkoxy group, a hydroxyl group, a nitro group, an amino group, a di-lower alkylamino group, acetyl, Thiophen ring, furan ring, imidazole ring, pyrazole ring, thiazole ring, oxazole ring, pyridine which may have 1 to 3 substituents which may be the same or different and are selected from acyl groups such as propionyl, butyryl, benzoyl etc. Ring, pyrazine ring,
A group consisting of a pyrimidine ring, an indole ring, a quinoline ring, an isoquinoline ring, a thianaphthene ring, or the like. "Pharmaceutically acceptable salts thereof" include various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, nitrate; acetate, propionate, succinate. , Glycolate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-
Various organic acid addition salts such as toluene sulfonate and ascorbate; salts with various amino acids such as aspartate and glutamate are included, but are not limited thereto.

Next, the novel phthalimide compound represented by the general formula [I] according to the present invention can be produced, for example, according to the reaction steps shown below. It goes without saying that the method for producing the compound of the present invention is not limited to the exemplified production method. Hereinafter, a flow will be shown and will be described in more detail.

[0016]

[Chemical 9]

Each of the above reaction steps will be further described. The symbols Y, Z, n and m are the same as above.

Reaction (A): Production of Compound [3] Although some of the bromine compounds [3] are known, they can generally be obtained by the following reaction. The starting material dibromoalkane compound [2] was treated with sodium hydroxide, potassium hydroxide, sodium hydride,
Compound [3] can be obtained by reacting with compound [4] in the presence of a base such as potassium hydride. This reaction is carried out by using sodium hydroxide, potassium hydroxide, or in some cases tetra-n-butylammonium halide (nBu ₄ NX) in a solvent such as dimethylformamide (DMF), tetrahydrofuran (THF), dimethylsulfoxide (DMSO) and the like. , Sodium iodide, potassium iodide, and the like can be added. Alternatively, it can be carried out in a two-layer system of methylene chloride-water, using sodium hydroxide, potassium hydroxide or the like as a base in the presence of a catalytic amount of a quaternary ammonium salt.

Reaction (B); Production of compound [6] N-substituted phthalimide compound [6] by a known method or by heating compound [3] which can be synthesized according to the above reaction (A) with potassium phthalimide.
Can be obtained. This reaction can be carried out, for example, in a solvent such as DMF or in the absence of a solvent at room temperature to reflux temperature, and preferably in DMF at a reaction temperature of about 80 ° C.

Reaction (C); Production of Compound [6] Compound [4] (provided that R ³ , R ⁴ and R ⁵ exclude a carboxyl group or a hydroxyl group) is reacted with Compound [5] in the presence of a base, The N-substituted phthalimide compound [6] can be obtained. This reaction is carried out, for example, in DMF, THF, DMS.
Sodium hydroxide, potassium hydroxide in a solvent such as O,
Depending on the case, it can be carried out by adding an additive such as nBu ₄ NX, sodium iodide, potassium iodide, etc., and the reaction temperature is suitably from room temperature to about 60 ° C.

Reaction (D): Production of Compound [7] The compound [6] obtained according to the above is prepared by a known method, for example, in methanol, ethanol, methylamine,
The amino compound [7] can be obtained by reacting in the presence of hydrazine or a strong acid (hydrochloric acid, sulfuric acid, etc.) or a strong base (sodium hydroxide, potassium hydroxide, etc.),
The reaction temperature is suitably from 0 ° C. to room temperature or around the reflux temperature.

Reaction (E): Production of compound [8] Amino compound [7] is heated with 3-hydroxyphthalic anhydride or 4-hydroxyphthalic anhydride in a solvent such as chloroform, methylene chloride, benzene or toluene. By refluxing, the compound [8] that is an N-substituted phthalimide can be obtained.

Reaction (F): Production of Compound [10] Compound

The compound [10], which is an acid chloride, can be obtained by halogenating [9] by a known method. This reaction can be carried out, for example, with phosphorus pentachloride (PCl ₅ ), thionyl chloride (SOCl ₂ ) or oxalyl chloride (COCl) _{2 in a} suitable solvent or without solvent, optionally in the presence of catalytic amounts of DMF. It is possible to carry out the reaction at a reaction temperature of 0 ° C. to around the reflux temperature. However, the compound

When X is a phenolic substituent in [9], in the presence of an appropriate base (eg, pyridine or a tertiary amine such as triethylamine), an appropriate solvent (eg, chloroform or methylene chloride)
In the middle or in some cases, this reaction is carried out after protection with an acetyl group or a chloroacetyl group in advance without a solvent.

Reaction (G); Production of Compound [I] Compound [I] can be obtained by reacting acid chloride [10] with compound [8] in a suitable solvent. This reaction can be carried out, for example, in a solvent such as chloroform or methylene chloride and using a tertiary amine such as pyridine or triethylamine as the base. The reaction temperature is suitably from 0 ° C to around room temperature. It should be noted that instead of the acid chloride compound [10], acylation may be carried out using an acid anhydride such as acetic anhydride. However, in the case where Z is substituted with a hydroxyl group or a carboxyl group in the compound [8], this reaction is carried out after protection with benzyl or paramethoxybenzyl in advance. Removal of the protecting group of the product is carried out by reacting in the presence of a suitable catalyst (eg, palladium carbon, palladium black or Raney nickel) in a suitable solvent (eg, methanol, ethanol, ethyl acetate or acetic acid) under a hydrogen atmosphere. By doing so, the final product [I] can be obtained. In the compound [10], when X is a phenolic substituent protected by an acetyl group or a chloroacetyl group, after carrying out this reaction, a suitable base (for example, aqueous sodium hydrogen carbonate or a tertiary amine such as trimethylamine) is used. ) In the presence of a suitable solvent (eg, methanol, ethanol, ethyl acetate or acetic acid, etc.)
The protecting group can be removed under a medium hydrogen atmosphere to obtain the final product [I].

The object compound of the present invention represented by the general formula [I] produced by the above method can form a pharmacologically acceptable salt. Examples of these salts include acid addition salts with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid, or acid addition salts with organic acids such as tartaric acid, maleic acid, fumaric acid, succinic acid and sulfonic acid. Examples include salt. Furthermore, when the phthalimide derivative or a salt thereof according to the present invention is used as a pharmaceutical preparation, it can be administered to a patient in a suitable dosage form containing this as an active ingredient by an oral or parenteral administration method. Is. Examples of the oral administration form include tablets, capsules, granules, powders, liquids and the like. Examples of parenteral administration forms include injections, suppositories, ointments, solutions and the like. In order to adjust these various preparations, excipients, stabilizers, preservatives, buffers and other additives can be appropriately selected and used according to a conventional method in the field. The dose can be appropriately increased or decreased according to the age, sex, weight, and degree of symptoms of the patient, and the administration method. Usually 1 to 1000 mg of the compound of the present invention per adult per day
The daily dose is set, but is not limited thereto.

[0026]

EXAMPLES The present invention will be further described below with reference to examples.

Example 1 4-acetoxy-2- (4-phenylbutyl) -1H-
Isoindol-1,3 (2H) -dione (Compound 1) Under a nitrogen stream, a suspension of 3-hydroxyphthalic anhydride (1.0 g) in chloroform (30 ml) was added to commercially available 4-phenyl-
1-Butylamine (0.909g) was added dropwise at 100 ° C for 28
Stir for hours. The solvent was distilled off, and the resulting oily substance was dissolved in chloroform (2 ml) and pyridine (2 ml), acetic anhydride (1.5 g) was added, and the mixture was stirred at 100 ° C. for 24 hours. Further, toluene (10 ml) was added, and the mixture was stirred at 120 ° C for 5 hours. The reaction solution was concentrated to give an oily substance (2.5 g), which was poured into water (100 ml) and extracted three times with chloroform (50 ml). The extract was washed twice with water (25 ml) and once with saturated brine (25 ml), dried over sodium sulfate and concentrated. The obtained oil (2.5 g) was purified by silica gel column chromatography (eluent: ethyl acetate-hexane) to obtain a colorless solid (1.436 g), which was recrystallized (ethyl acetate-hexane).
The title compound (1.129 g) was obtained (see Table 1).

Example 2 4-acetoxy-2-octadecyl-1H-isoindole-1,3 (2H) -dione (Compound 2) In the same manner as in Example 1, 3-hydroxyphthalic anhydride was used. (1.0 g), commercially available octadecylamine (1.64
g) and acetic anhydride (1.5g) and colorless solid (2.87g)
Got This is silica gel column chromatography
(Eluent: ethyl acetate-chloroform-hexane) to give a colorless solid (1.642 g) which was then recrystallized (hexane) to give the title compound (1.47 g) (see Table 1).

Example 3 4-benzoyloxy-2- (4-phenylbutyl)-
1H-isoindole-1,3 (2H) -dione (compound 3) a) 4-hydroxy-2- (4-phenylbutyl) -1
H-isoindole-1,3 (2H) -dione 3-hydroxyphthalic anhydride (10.0 g) under nitrogen stream
4-Phenylbutylamine (9.09 g) was added dropwise to the toluene suspension (50 ml) of and the mixture was stirred at 120 ° C for 3 days. The reaction mixture was concentrated, and the obtained solid (19 g) was recrystallized (ether-hexane-ethanol) to give the title compound (14.0 g).

B) 4-benzoyloxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2
H) -dione A solution of 4-hydroxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2H) -dione (1.00 g) in pyridine (5 ml) under a stream of argon and commercially available benzoyl chloride. (0.524 g) was added dropwise, and the mixture was stirred at room temperature for 18 hours. The reaction solution was diluted with ethyl acetate (30 ml), the insoluble material was filtered off, toluene (30 ml) was added, and the mixture was concentrated. The obtained oil (1.60 g) was purified by silica gel column chromatography (ethyl acetate-hexane) to give the title compound (1.357 g) (see Table 1).

Example 4 4- (2,2-dimethylpropionyloxy) -2-
(4-phenylbutyl) -1H-isoindole-1,
3 (2H) -dione (Compound 4) 4-Hydroxy-2- (4-) prepared in a) of Example 3
Phenylbutyl) -1H-isoindole-1,3 (2
H) -dione (0.90 g) in pyridine (4 ml) was added dropwise with commercially available pivaloyl chloride (0.41 ml) under ice cooling.
The mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into 1M-hydrochloric acid aqueous solution (50 ml) and extracted with ethyl acetate (40 ml). The organic layer was washed successively with water (30 ml) and saturated brine (30 ml), dried over anhydrous sodium sulfate, and concentrated. The title compound (0.58 g) was obtained by recrystallizing the residual solid (0.94 g) from ether-hexane (see Table 1).

Example 5 4- (2-Methylpropionyloxy) -2- (4-phenylbutyl) -1H-isoindole-1,3 (2
H) -dione (Compound 5) In the same manner as described in Example 4, 4-hydroxy-2
-(4-phenylbutyl) -1H-isoindole-
Light yellow solid (1.25 g) from 1,3 (2H) -dione (1.00 g) and commercially available isobutyryl chloride (0.39 ml).
Got This was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give a colorless powder (1.19 g) and recrystallized from ethyl acetate-hexane to give the title compound (0.93 g) ( See Table 2).

Example 6 4-acetoxy-2- [5- (4-chlorophenoxy)
Pentyl] -1H-isoindole-1,3 (2H)-
Dione (Compound 6) a) 2- [5- (4-chlorophenoxy) pentyl]-
1H-isoindole-1,3 (2H) -dione, Journal of Pharmaceutical Sciences, Vol. 65, 1
After adding potassium phthalimide (14.70 g) to a solution of 5- (4-chlorophenoxy) pentyl bromide (19.92 g) in DMF (60 ml), which can be produced by a similar method described on page 074 (1976), 90 ° C. It was stirred for 1 hour. The mixture was returned to room temperature, added to water (400 ml) and extracted with dichloromethane (200, 100, 100 ml). The organic layer was mixed with 0.2 M sodium hydroxide aqueous solution, water (200 ml) and saturated saline solution (2
00ml) and then dried over anhydrous sodium sulfate.
Concentrated. The obtained solid (33.15 g) was recrystallized from ethyl acetate-hexane to give the title compound (22.14 g)
Was obtained as colorless crystals.

B) 5- (4-chlorophenoxy) pentylamine hydrochloride 2- [5- (4-chlorophenoxy) pentyl] -1H
-Isoindole-1,3 (2H) -dione (21.95g)
Ethanol (150 ml) in hydrazine monohydrate (3.
7 ml) was added and the mixture was stirred and refluxed for 2 hours. After returning to room temperature and adding concentrated hydrochloric acid (7.4 ml) dropwise, the mixture was stirred for 2 hours. The white solid deposited was filtered off and the filtrate was concentrated. Water (50 ml) was added to the residue, the insoluble material was filtered off, and the filtrate was concentrated. The residue was dissolved in ethanol (50 ml), diethyl ether (50 ml) was added for crystallization, and the mixture was filtered to give the title compound (12.13).
g) was obtained as a colorless solid.

C) 2- [5- (4-chlorophenoxy)
Pentyl] -4-hydroxy-1H-indole-1,
3 (2H) -dione 5- (4-chlorophenoxy) pentylamine hydrochloride (2.00 g) was dissolved in 2M aqueous sodium hydroxide solution (50 ml) and extracted with ethyl acetate (70, 50, 50 ml). The organic layer was washed successively with water (80 ml) and saturated brine (80 ml), dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in toluene (15 ml) and 3-hydroxyphthalic anhydride (1.
15 g) was added and the mixture was stirred and refluxed for 8 hours. The reaction mixture was concentrated to give a yellow solid (2.57g). Recrystallization from ethyl acetate-hexane gave the title compound (1.76 g) as pale yellow crystals.

D) 4-acetoxy-2- [5- (4-chlorophenoxy) pentyl] -1H-isoindole-
1,3 (2H) -dione 2- [5- (4-chlorophenoxy) pentyl] -4-
Hydroxy-1H-isoindole-1,3 (2H)-
Pyridine (0.32 ml) and acetic anhydride (0.28 ml) were added dropwise to a solution of dione (0.70 g) in dichloromethane (2.5 ml) under ice cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated, the residue was added to a 1 M aqueous hydrochloric acid solution (20 ml), and the mixture was extracted with dichloromethane (30 ml). The organic layer was saturated brine (20
ml), dried over anhydrous sodium sulfate, and concentrated. The residual oil (0.81 g) was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give a colorless solid (0.68 g). Further recrystallization from ethyl acetate-hexane gave the title compound (0.61 g
) Was obtained (see Table 2).

Example 7 2- [5- (4-chlorophenoxy) pentyl] -4-
(2-Methylpropionyloxy) -1H-isoindole-1,3 (2H) -dione (Compound 7) 2- [5- (4-chlorophenoxy) pentyl] -4 obtained in Example 6-C). -Hydroxy-1H-indole-1,3 (2H) -dione (0.87g) in pyridine (4m
l) Isobutyryl chloride (0.28ml) under ice cooling
Was added dropwise, and the mixture was stirred at room temperature for 18 hours. 1M reaction mixture
-Addition in hydrochloric acid aqueous solution (50 ml) and extraction with ethyl acetate (30 ml) three times. The organic layer was mixed with water (60 ml) and saturated saline (60
ml), and the extract was dried over anhydrous sodium sulfate and then concentrated. The obtained oil (1.11 g) was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give a colorless solid (0.95 g). The title compound (0.62 g) was obtained by recrystallization from ethyl acetate-hexane (see Table 2).

Example 8 2- [5- (4-chlorophenoxy) pentyl] -4-
(2,2-Dimethylpropionyloxy) -1H-indole-1,3 (2H) -dione (Compound 8) In the same manner as in Example 7, 2- [5- (4-chlorophenoxy) pentyl]- A yellow oil (1.17 g) was obtained from 4-hydroxy-1H-indole-1,3 (2H) -dione (0.87 g) and pivaloyl chloride (0.33 ml). Silica gel column chromatography (eluent:
Purified with hexane-ethyl acetate), colorless solid (0.98g
) Got. The crystals were recrystallized from ethyl acetate-hexane to give the title compound (0.86 g) (see Table 2).

Example 9 4-acetoxy-2- [5- (9H-carbazol-9
-Yl) pentyl] -1H-isoindole-1,3
(2H) -dione (Compound 9) a) 9- (5-Bromopentyl) -9H-carbazol DME of sodium hydride (1.20 g) under a stream of argon.
Carbazol (5.0 g) was added to the suspension (150 ml) over 10 minutes, and the mixture was stirred at 60 ° C for 2 hours. Cool to room temperature,
5-dibromopentane (6.88 g) was added all at once, at room temperature,
Stirred all day and night. The reaction solution was diluted with ethyl acetate (150 ml), washed with water (100 ml) and saturated saline (100 ml),
After drying over sodium sulfate, the solvent was concentrated. The obtained oil (9.8 g) was purified twice by medium pressure silica gel column chromatography (toluene-hexane) to give the title compound (3.57 g).

B) 2- [5- (9H-carbazol-9]
-Yl) pentyl] -1H-isoindole-1,3
(2H) -dione 9- (5-bromopentyl) -9H- under an argon stream.
Potassium phthalimide (2.09 g) was added to a DMF (20 ml) solution of carbazol (3.57 g), and the mixture was stirred at 90 ° C for 2 hours. The reaction solution was diluted with water (200 ml), extracted with methylene chloride (50 ml) three times, washed with saturated potassium carbonate (50 ml) and saturated sodium chloride (50 ml), and dried over sodium sulfate. The solvent was concentrated to obtain a solid (4.50 g) and recrystallized (ethyl acetate-hexane) to give the title compound (3.66 g).

C) 9- (5-Aminopentyl) -9H-carbazol 2- [5- (9H-carbazol-9) under a stream of argon.
-Yl) pentyl] -1H-isoindole-1,3
41% -methylamine (10 ml) was added dropwise to a suspension of (2H) -dione (1.60 g) in methanol (40 ml) and the mixture was allowed to stand at room temperature for 2 hours.
It was stirred for a day. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (eluent: chloroform-methanol-ammonia water = 90: 10: 1) to obtain the title compound (0.484 g) as a colorless oil. .

D) 2- [5- (9H-carbazol-9]
-Yl) Pentyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione 9- (5-aminopentyl) -9H- under an argon stream.
Add 3 to a suspension of carbazol (0.33g) in toluene (20ml).
-Hydroxyphthalic anhydride (0.215g) was added and 110
Stir for 5 hours at ° C. The reaction solution was concentrated, and the residue was purified by silica gel chromatography (eluent: ethyl acetate-hexane = 1: 4) to give the title compound (0.
270 g) was obtained.

E) 4-acetoxy-2- [5- (9H-
Carbazol-9-yl) pentyl] -1H-isoindole-1,3 (2H) -dione In the same manner as in Example 3-b), 2- [5- (9H
-Carbazol-9-yl) pentyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione (0.260 g) and acetic anhydride (0.5 ml) using silica gel column chromatography- ( The title compound (0.260 g) was obtained by purification with an eluent: ethyl acetate-hexane = 1: 4) (see Table 3).

Example 10 2- [5- (9H-carbazol-9-yl) pentyl]
-4- (2,2-Dimethylpropionyl) -1H-isoindole-1,3 (2H) -dione (Compound 10) In the same manner as in Example 9-e), 2- [5- (9H
-Carbazol-9-yl) -pentyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione (0.900g) and pivaloyl chloride (0.238g) on a silica gel column. The title compound (0.650 g) was obtained by purification by chromatography (eluent: ethyl acetate-hexane = 1: 5) (see Table 3).

Example 11 4-acetoxy-2- [5- (diphenylmethyloxy) pentyl] -1H-isoindole-1,3 (2
H) -dione (compound 11) a) 5- (diphenylmethyloxy) pentyl bromide Diphenylcarbinol (10.0 g) was added to a suspension of sodium hydride (2.16 g) in dimethoxyethane (200 ml) under an argon stream. It was added little by little and stirred at 60 ° C. for 2 hours.
After cooling, 1,5-dibromopentane (6.88 g) in dimethoxyethane (5 ml) was added at once, and the mixture was stirred at room temperature for 24 hours. Dilute the reaction mixture with ethyl acetate (300 ml) and wash with water (150 m
l) and saturated saline (150 ml), the extract was dried over sodium sulfate and the solvent was concentrated. The obtained oily substance was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1.5: 98.5) to obtain the title compound (6.00 g) as a pale yellow oily substance.

B) 2- [5- (diphenyloxymethyl) pentyl] -1H-isoindole-1,3 (2
H) -dione In the same manner as in Example 9-b), silica gel column chromatography (eluent: acetic acid) was performed using 5- (diphenyloxymethyl) pentyl bromide (3.0 g) and potassium phthalimide (1.83 g). Ethyl-hexane =
The title compound (6.15 g) was obtained as a colorless oil by purification with 1: 6).

C) 5- (Diphenyloxymethyl) pentylamine 2- [5- (diphenyloxymethyl) pentyl] -1H-isoindo-in the same manner as in Example 9-c).
Silica gel column chromatography using eluate 1,3 (2H) -dione (6.15g) and 41% -methylamine (25ml) (eluent: chloroform-methanol-ammonia water = 90: 10: 1). By purifying in
The title compound (1.35 g) was obtained as a pale yellow oil.

D) 2- [5- (diphenyloxymethyl) pentyl] -4-hydroxy-1H-isoindo-
Ru-1,3 (2H) -dione In the same manner as in Example 9-d), 5- (diphenyloxymethyl) pentylamine (1.35 g) and 3-hydroxyphthalic anhydride (0.822 g) were used. The residue was purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 4) to give the title compound (1.52 g) as a pale yellow oil.

E) 4-acetoxy-2- [5- (diphenylmethyloxy) pentyl] -1H-isoindole-1,3 (2H) -dione In the same manner as in Example 9-e), 2 -[5- (Diphenylmethyloxy) pentyl] -4-hydroxy-1
H-isoindole-1,3 (2H) -dione (0.104
g) and acetic anhydride (0.5 ml), silica gel column chromatography (eluent: ethyl acetate-toluene =
1: 9) to give the title compound (0.112
g) was obtained (see Table 3).

Example 12 4-[(2,2-dimethylpropionyl) oxy] -2
-[5- (diphenylmethyloxy) pentyl] -1H
-Isoindole-1,3 (2H) -dione (Compound 1
2) 2- [5- (diphenylmethyloxy) pentyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione (0.900 g) obtained in Example 11-d) and pivaloyl. Silica gel column chromatography using chloride (0.299 g) (eluent: ethyl acetate-hexane =
1: 6) to give the title compound (0.730
g) was obtained (see Table 3).

Example 13 4-Cyclopropylcarbonyloxy-2- [5- (diphenylmethyloxy) pentyl] -1H-isoindole-1,3 (2H) -dione (Compound 13) Example 11-d) Using 2- [5- (diphenylmethyloxy) pentyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione (0.620 g) and cyclopropanecarbonyl chloride (0.162 g) obtained in hand,
The title compound (0.730 g) was obtained by purification by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 6, 1: 4) (see Table 4).

Example 14 4-Cyclopropylcarbonyloxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2H)
-Dione (compound 14) 4-hydroxy-2- (4- obtained in Example 3-a)
Phenylbutyl) -1H-isoindole-1,3 (2
H) -dione (0.900 g) and cyclopropanecarbonyl chloride (350 mg), silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 1).
The title compound (1.00 g) was obtained by purification in 5) (see Table 4).

Example 15 2- (4-phenylbutyl) -4- (3-pyridylcarbonyloxy) -1H-isoindole-1,3 (2
H) -dione hydrochloride (Compound 15) 4-Hydroxy-2- (4-) obtained in Example 3-a)
Phenylbutyl) -1H-isoindole-1,3 (2
H) -dione (0.900 g) and nicotinoyl chloride hydrochloride (542 mg) were purified by silica gel column chromatography (eluent: ethyl acetate-hexane = 1: 1) to give 2- (4- Phenylbutyl)-
4- (3-Pyridinecarbonyloxy) -1H-isoindole-1,3 (2H) -dione (1.15 g) was obtained.
Furthermore, dissolve in ether (20 ml) and use 1N hydrochloric acid / ether.
A colorless precipitate is obtained by treating with tel (3.5 ml),
The title compound (2.52 g) was obtained by filtering, washing with ether and drying (see Table 4).

Example 16 2- (4-phenylbutyl) -4- (2-thiophenylcarbonyloxy) -1H-isoindole-1,3
(2H) -dione (Compound 16) 4-hydroxy-2- (4-) obtained in Example 3-a)
Phenylbutyl) -1H-isoindole-1,3 (2
H) -dione (1.20g) and thenoyl chloride (1.07g)
Silica gel column chromatography-
2- (4-phenylbutyl) -4-by purifying twice with (eluent: ethyl acetate-hexane = 1: 6)
(3-Pyridinecarbonyloxy) -1H-isoindole-1,3 (2H) -dione (1.64 g) was obtained (Table 4)
reference).

Example 17 4- [3- (3,4-dihydroxyphenyl) propenoyloxy] -2- (4-phenylbutyl) -1H-isoindole-1,3 (2H) -dione (Compound 17) a) 3,4-Diacetoxycinnamic acid 3,4-Dihydroxycinnamic acid (3.27 g) in pyridine (8.8 ml) was added dropwise with acetic anhydride (5.7 ml) under ice cooling and stirred at room temperature for 24 hours. . The residue obtained by concentrating the reaction mixture was added to 1 M hydrochloric acid (100 ml), and the mixture was extracted with ethyl acetate (100, 50, 50 ml). The organic layer was washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous sodium sulfate and concentrated. The residual solid was recrystallized from ethyl acetate-hexane to give the title compound (3.30 g)
Was obtained as colorless crystals.

B) 3,4-diacetoxycinnamic acid chloride Under a nitrogen gas stream, 3,4-diacetoxycinnamic acid (0.79
g) was suspended in a dichloromethane (13 ml) solution and oxalyl chloride (0.92 ml) and DMF (1 drop) were added.
After stirring at room temperature for 1 hour, it was concentrated to give 3,4-
Diacetoxycinnamic acid chloride (0.85 g) was obtained as a pale yellow solid. c) 4- [3- (3,4-dihydroxyphenyl) propenoyloxy] -2- (4-phenylbutyl) -1
H-isoindole-1,3 (2H) -dione 3,4-diacetoxycinnamic acid chloride was dissolved in dichloromethane (3 ml) and prepared in Example 3-a) 4-
Hydroxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2H) -dione (0.80 g) in pyridine (5 ml) was added dropwise at 0 ° C. After stirring at room temperature for 19 hours, the mixture was added to 1M hydrochloric acid (80 ml) and extracted with ethyl acetate (80 ml). The organic layer was washed with water (70 ml) and saturated brine (70 ml), dried over anhydrous sodium sulfate and concentrated. Next, the residue (1.59 g) was dissolved in methanol (50 ml), saturated aqueous sodium hydrogen carbonate (3 ml) was added, and the mixture was stirred at room temperature for 1 hr. After adding 1M hydrochloric acid aqueous solution (6 ml) to make it weakly acidic,
The mixture was concentrated, the residue was added to a 1M aqueous hydrochloric acid solution (60 ml), and the mixture was extracted with ethyl acetate (60 ml). The organic layer was washed with water (50 ml) and saturated brine (50 ml), dried over anhydrous sodium sulfate and concentrated. The obtained foam (1.33 g) was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to obtain a colorless solid (0.64 g). Further, the title compound (0.51 g) was obtained by recrystallization from ethyl acetate-hexane (see Table 5).

Example 18 2- (4-phenylbutyl) -4-[(3,4,5-trihydroxyphenyl) carbonyloxy)]-1H-
Isoindole-1,3 (2H) -dione (Compound 1
8) a) 3,4,5-Triacetoxybenzoic acid In the same manner as in Example 17-a), gallic acid (10.0
g) was used to convert the crude product to ether-hexane (1:
Crystallization from 1) gave the title compound (12.84 g) as a colorless powder.

B) 2- (4-phenylbutyl) -4-
[(3,4,5-Trihydroxyphenyl) carbonyloxy)]-1H-isoindole-1,3 (2H)-
Dione was reacted with 3,4,5-triacetoxybenzoic acid (0.898g) using phosphorus pentachloride (0.649g) instead of oxalyl chloride in the same manner as in Examples 17-b) and c). The resulting compound was treated with 4-hydroxy-2- (4
-Phenylbutyl) -1H-isoindole-1,3
By reacting with (2H) -dione (0.896 g),
2- (4-phenylbutyl) -4-[(3,4,5-triacetoxyphenyl) carbonyloxy)]-1H-
Isoindole-1,3 (2H) -dione (2.00 g) was obtained. 1.8 g of this was treated with saturated aqueous sodium hydrogen carbonate (0.5 ml) and further subjected to silica gel column chromatography (eluent: chloroform: methanol: acetic acid = 95: 5: 1).
The title compound (0.460 g) was obtained by purification with (see Table 5).

Example 19 4- [3- (4-hydroxy-3-methoxyphenyl)
Propenoyloxy] -2- (4-phenylbutyl)-
1H-isoindole-1,3 (2H) -dione (Compound 19) a) 4-acetoxy-3-methoxycinnamic acid In the same manner as in Example 18-b), 4-hydroxy-3-methoxycinnamic acid. Crustic acid (5.00 g) and acetic anhydride (4.85
ml) to give the title compound (6.19 g) as a white solid.

B) 4- [3- (4-Hydroxy-3-methoxyphenyl) propenoyloxy] -2- (4-phenylbutyl) -1H-isoindole 1,3 (2H)
-Dione 4-acetoxy-3-methoxycinnamic acid (1.00 g), phosphorus pentachloride (0.92) as in Example 18-b).
g) and 4-hydroxy-2- (4-phenylbutyl)
-1H-isoindole 1,3 (2H) -dione (1.25
g)) with 4- [3- (4-acetoxy-3-methoxyphenyl) propenoyloxy] -2- (4-phenylbutyl) -1H-isoindole-1,3 (2H).
-Dione (1.25 g) was obtained. Further treatment with saturated aqueous sodium hydrogen carbonate and purification by silica gel chromatography gave the title compound (0.15 g) (see Table 5).

Example 20 4- (2,2-Dimethylpropionyloxy) -2-
(3-phenoxypropyl) -1H-isoindole-
1,3 (2H) -dione (Compound 20) a) 2- (3-phenoxypropyl) -1H-isoindole 1,3 (2H) -dione In the same manner as in Example 6-a), 3- A colorless solid (32.79g) was obtained from phenoxypropyl bromide (25.12g) and potassium phthalimide (23.6g). By recrystallizing from ethyl acetate-hexane, the title compound (2
8.46g) was obtained.

B) 3-phenoxypropylamine hydrochloride In the same manner as in Example 6, b), 2- (3-phenoxypropyl) -1H-isoindole-1,3 (2
H) -dione (28.36g), hydrazine monohydrate (5.9ml)
) And concentrated hydrochloric acid (11.8 ml) to give a white solid (17.56 g). The title compound (7.68 g) was obtained by recrystallization from ethanol-water.

C) 4-Hydroxy-2- (3-phenoxypropyl) -1H-isoindole-1,3 (2H)
-Dione In the same manner as in Example 6-c), a white solid (2.55 g) was obtained from 3-phenoxypropylamine hydrochloride (1.95 g) and 3-hydroxyphthalic anhydride (1.40 g). The title compound (1.99 g) was obtained by recrystallizing from ethyl acetate-hexane (twice).

D) 4- (2,2-Dimethylpropionyloxy) -2- (3-phenoxypropyl) -1H-isoindole-1,3 (2H) -dione In the same manner as in Example 7, 4 -Hydroxy-2-
(3-phenoxypropyl) -1H-isoindole-
An oil (1.36 g) was obtained from 1,3 (2H) -dione (1.00 g) and pivaloyl chloride (0.45 ml). Purification by silica gel column chromatography (eluent: hexane-ethyl acetate) gave the title compound (1.26 g) (see Table 5).

Example 21 2- [3-[(3,5-di-tert-butyl-4-hydroxy) phenylthio] propyl] -4- (2,2-
Dimethylpropionyloxy) -1H-isoindole-1,3 (2H) -dione (Compound 21) a) 2- [3-[(3,5-di-tert-butyl-4
-Hydroxy) phenylthio] propyl] -1H-isoindole-1,3 (2H) -dione 3,5-di-tert-butyl-4-under a nitrogen gas stream.
Hydroxythiophenol (1.01g) in DMF (8ml)
Sodium hydride (0.17 g) was added to the solution under ice cooling, and the mixture was stirred at room temperature for 20 minutes. Under ice cooling again, 2- (3-bromopropyl) -1H-isoindole-1,3 (2H)-
A DMF (2 ml) solution of dione (1.12 g) was added dropwise, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was added to ice water (50 ml) and extracted with dichloromethane (25 ml) three times. The organic layer was washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and concentrated. The obtained oil (4.11 g) was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (1.15 g) as a yellow oil.

B) 3-[(3,5-Di-tert-butyl-4-hydroxy) phenylthio] propylamine 2- [3-[(3,5-di-tert-4-hydroxy) phenylthio] propyl] -1H-isoindole-1,3 (2H) -dione (0.97g) in methanol (10
hydrazine monohydrate (1.13 ml) was added to the
The mixture was stirred at 0 ° C for 1 hour. Concentrated hydrochloric acid (0.5 ml) with stirring under ice cooling
After the addition of, the insoluble matter that had precipitated was filtered off and the filtrate was concentrated.
The obtained pale yellow solid (1.42 g) was dissolved in 2M aqueous sodium hydroxide solution (50 ml) and extracted twice with ethyl acetate (50 ml). Water (80 ml) and saturated saline (80 m
l), dried over anhydrous sodium sulfate and concentrated to give the title compound (0.62 g) as a pale yellow solid.

C) 2- [3-[(3,5-di-tert)
-Butyl-4-hydroxy) phenylthio] propyl]
-4-Hydroxy-1H-indole-1,3 (2H)
-Dione 3-[(3,5-di-tert-butyl-4-hydroxy) phenylthio] propylamine (0.60 g) and 3
-Hydroxyphthalic anhydride (0.34g) in toluene (8m
l) The solution was stirred and refluxed for 14 hours. The reaction mixture was concentrated to give the title compound (0.98 g).

D) 2- [3-[(3,5-di-tert)
-Butyl-4-hydroxy) phenylthio] propyl]
-4- (2,2-dimethylpropionyloxy) -1H
-Indole-1,3 (2H) -dione In the same manner as in Example 7, 2- [3-[(3,5-
From di-tert-butyl-4-hydroxy) phenylthio] propyl] -4-hydroxy-1H-isoindole-1,3 (2H) -dione (0.97 g) and pivaloyl chloride (0.27 ml), a yellow compound ( 1.12g) was obtained. Purify by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (0.89 g
) Was obtained (see Table 6).

Example 22 5-acetoxy-2- (4-phenylbutyl) -1H-
Isoindole-1,3 (2H) -dione (Compound 2
2) a) 4-hydroxyphthalic anhydride 4-hydroxyphthalic acid (10.0 g) in acetic anhydride (10 ml)
The suspension was stirred and refluxed for 1.5 hours. The reaction mixture was concentrated and azeotroped with toluene (3 times) to give the title compound (6.94 g).

B) 5-Hydroxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2H) -dione 4-hydroxyphthalic anhydride (1.50 g) in a toluene suspension 4- Add phenylbutylamine (2.2 ml) dropwise,
The mixture was stirred and refluxed for 4 hours. The reaction mixture was concentrated, and the obtained yellow oil (3.95 g) was purified by silica gel column chromatography (eluent: hexane-ethyl acetate) to give the title compound (1.83 g).

C) 5-acetoxy-2- (4-phenylbutyl) -1H-isoindole-1,3 (2H) -dione In the same manner as in Example 6-d), 5-hydroxy-
2- (4-phenylbutyl) -1H-isoindole-
1,3 (2H) -dione (0.81g), pyridine (1.1ml)
) And acetic anhydride (1.2 ml) to give a colorless solid (0.89 g). The title compound (0.75 g) was obtained by recrystallization from ethyl acetate-hexane (see Table 6).

The physicochemical properties of these compounds 1 to 22 are shown in Tables 1 to 6.

[0073]

[Table 1]

[0074]

[Table 2]

[0075]

[Table 3]

[0076]

[Table 4]

[0077]

[Table 5]

[0078]

[Table 6]

Next, the in vitro phospholipase A ₂ inhibitory action of the novel phthalimide derivative represented by the above general formula [I] according to the present invention was tested. Test Example 1 (1) Phospholipase A ₂ Inhibitory Activity Rat inflammatory phospholipase A ₂ (type II) was used as a phospholipase A ₂ source. CaCl ₂ , Tris-HCl
The above enzyme solution (0.02 m) was added to a solution prepared by adjusting the buffer solution (pH 7.5) to the final concentration of (4 ml, 100 ml).
l: 0.03U) and a test solution prepared in advance (final concentration: 0.
It consists of 5 mM and 0.1 mM. ) Was added (0.02 ml) and preincubated at 37 ° C. for 1 hour. Next, a solution (L-3 phosphatidylcholine-2) adjusted to be 0.1 μmol (0.045 μCi) per test
- ^{[1-1 4} C] arachidonyl-1-stearoyl ethanol - le - toluene (1: 1) solution (Amersham) non label L-1-phosphatidylcholine (T
Substrate (0.01m) diluted with ype XI-E Sigma
l) is added to bring the total volume to (0.25 ml), the reaction is started,
Incubated at 37 ° C for 20 minutes. (2 ml) Dole's reagent was added to stop the reaction, and n-heptane and water (1 ml) were added to extract the free arachidonic acid.
) Each, and stirred for 30 seconds with a vortex mixer. After standing, the upper layer (1 ml) was transferred to a test tube containing (2 ml) of n-heptane and (100 ml) of silicic acid, stirred for 40 seconds with a vortex mixer, and rotated at room temperature at 2000 rpm /
Min, centrifuged for 10 minutes. The supernatant (1 ml) was placed in a vial, ACS-2 (manufactured by Amersham) (4 ml) was added, and the measurement was performed with a liquid scintillation counter. The test is 1
Group 2 vials were performed. The phospholipase A ₂ inhibition rate is

[0080]

[Equation 1]

Calculated from The results are shown in Table 7.

[0082]

[Table 7]

(2) Effect of carrageenin on pleurisy Male Donryu rats (around 170 g) were found to have a dose of 0.
Inject 5% carrageenin saline solution (0.3 ml),
After a lapse of time, the rat was exsanguinated to death, and the amount of exudate and the number of white blood cells stored in the thoracic cavity were measured. The test solution was orally administered 1 hour before carrageenin injection or as a physiological saline solution containing 2% DMSO (EtOH) and 2% Tween80 (1 m
l) was administered to the tail vein at the same time as carrageenin infusion. The suppression rate (%) was shown as a ratio to the control group (non-drug administration group). The results are shown in Table 8.

[0084]

[Table 8]

[0085]

The phthalimide derivative according to the present invention is
Since it specifically inhibits phospholipase A ₂ , it can be used as a therapeutic agent for inflammation such as inflammatory diseases, allergic diseases, anaphylactic shock, arthritis and rheumatoid arthritis.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/40 AED 7431-4C C07D 401/12 209 7602-4C 403/12 209 7602-4C 405 / 12 209 7602-4C 409/12 209 7602-4C 413/12 209 7602-4C 417/12 209 9051-4C (72) Inventor Kazuhiko Nishii 6 Umegaoka, Midori-ku, Yokohama-shi, Kanagawa Japan Tobacco Inc. Pharmaceutical Research (72) Inventor, Hitoshi Okamoto, 2 Umegaoka, 6 Midori-ku, Yokohama, Kanagawa Prefecture Japan Tobacco Inc. Pharmaceutical Research Institute (72) Inouo Uchida, 6 Umegaoka, Midori-ku, Yokohama, Kanagawa Prefecture Japan Tobacco Inc. Pharmaceutical Research In-house

Claims (3)

[Claims] 1. The following general formula [I]: [In the formula, X is a lower alkyl group which may be substituted, an aryl group which may be substituted, a heteroaryl group which may be substituted, or (Wherein R ¹ and R ² are a hydrogen atom, a hydroxyl group or a lower alkoxy group), n is an integer of 2 to 20, Y is —O— or —S—, and m is Is an integer from 0 to 1 and Z is (In the formula, R ³ , R ⁴ and R ⁵ are the same or different and each is a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a carboxyl group or a lower alkoxy group). A pharmaceutically acceptable salt. 2. The following general formula [II]: (In the formula, Y, Z, n, m, R ³ , R ⁴ and R ⁵ are the same as above). 3. A phospholipase A ₂ inhibitor containing the compound according to claim 1 as an active ingredient.