JPH10231285A - Phthalimide derivative or its salt, their production and pharmaceutical composition containing the derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound producible by reacting a specific dialdehyde compound with an amine compound and subjecting the product to salt-forming reaction and useful e.g. as an active component of a pharmaceutical composition for controlling the production of tumor necrosis factor inducing various diseases. SOLUTION: This new phthalimide derivative (salt) is expressed by formula I [X is =CY- (Y is H, nitro, amino, cyano, CF3 , OH, a halogen or an alkyl) or =N-Y; Z1 and Z2 are each O or S; (1) is 1, 2 or 3; (m) and (n) are each 0 or 1; Q1 and Q2 are each H or an alkyl; R is a (substituted)biphenyl or a (substituted)indanyl], e.g. 2-(3,5-dimethylisoxazol-4-ylmethyl)-4,5,6,7-tetrafluoro-1H- isoindol-1,3-dione. The compound is useful e.g. as an agent for controlling the production of tumor necrosis factor. The compound can be produced by reacting a dialdehyde compound of formula II with an amine compound of formula III and optionally subjecting the product to salt-forming reaction.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a phthalimide derivative or a salt thereof, a method for producing them, and a pharmaceutical composition containing them.

[0002]

2. Description of the Related Art Japanese Patent Laid-Open Publication No. Sho 50-112432 discloses that
A phthalimide derivative as an active ingredient of an agricultural and horticultural fungicide is disclosed, and JP-A-62-2760 discloses an isoindoline derivative as an active ingredient of an agricultural and horticultural fungicide. The phthalimide derivative of the present invention has a different chemical structure. In the field of pharmaceuticals, Chemical & Pharmaceutical Buretin (CHEMICAL & PHARMACEUT)
ICAL BULLETIN) Vol. 43, No. 1, 177-1
79, 1995, N-alkylphthalimides, and furthermore, Biological Pharmaceutical Buretin (BIOLOGICAL PHARMA).
CEUTICAL BULLETIN) Volume 18, Issue 9, 1
The chemical structure of the phthalimide derivative of the present invention is also distinguished from benzylphthalimide and phenethylphthalimide disclosed in pages 228 to 1233, 1995.

[0003]

SUMMARY OF THE INVENTION The present inventors have determined that certain phthalimide derivatives or salts thereof regulate the production of tumor necrosis factor (TNF-α), which is considered to be one of the factors causing various diseases. The present invention was completed as a result of intensive studies to find an excellent pharmaceutical composition. That is, the present invention provides a compound represented by the general formula (I):

[0004]

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[Wherein X is = CY- or = N-,
Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group, and l is 1, 2 or 3 (X is = CY- and l is 1 or more. And X is = N- and l
Is 2 or more, Y may be the same or different)
Wherein Z ₁ and Z ₂ are each independently an oxygen atom or a sulfur atom, m is 0 or 1, Q ₁ and Q ₂ are each independently a hydrogen atom or an alkyl group, and n is 0 Or 1
Wherein R is an optionally substituted isoxazolyl group, an optionally substituted biphenyl group or an optionally substituted indanyl group] or a salt thereof, a method for producing them, and a medicament containing them. Composition.

In the above general formula (I), examples of the halogen atom contained in Y include fluorine, chlorine, bromine and iodine atoms, and are included in the alkyl group represented by Q ₁ or Q ₂ or Y. As the alkyl group, a linear or branched one having 1 to 6, preferably 1 to 4 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tertiary butyl group, a pentyl And a hexyl group. In the general formula (I), X is = C
When Y- and l is 1 or more, and when X is = N- and 1 is 2 or more, Y may be the same or different.

In the general formula (I), the substituents of the optionally substituted isoxazolyl group, the optionally substituted biphenyl group and the optionally substituted indanyl group are alkyl having 1 to 6 carbon atoms. A linear or branched C1-C4 group, for example, a methyl group,
Examples include an ethyl group, a propyl group, an isopropyl group, a butyl group, a tertiary butyl group, a pentyl group, and a hexyl group.

Among the phthalimide derivatives represented by the above general formula (I), the compound wherein Y is an amino group or a hydroxy group can form a salt, and the salt is a pharmacologically acceptable one. Any salt is included, for example, inorganic acid salts such as hydrochloride, sulfate and nitrate; organic acid salts such as acetate and methanesulfonate; alkali metal salts such as sodium and potassium salts Alkaline earth metal salts such as magnesium salts and calcium salts; and organic amine salts such as triethanolamine salts and tris (hydroxymethyl) aminomethane salts.

Constituents in the general formula (I)

[0010]

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Has one asymmetric carbon atom, and when Q ₁ and Q ₂ are not the same, an S-form or an R-form exists as an optically active substance. In the present invention, the phthalimide derivative represented by the general formula (I) or a salt thereof includes a racemic form, the S-form or the R-form unless otherwise specified.

The phthalimide derivative represented by the general formula (I) or a salt thereof can be produced by a method such as the following reactions [A] to [C] and a usual salt forming reaction.

[0013]

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[0014]

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[0015]

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Formula (III)

[0017]

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Since the amine represented by the formula (1) has one asymmetric carbon atom, when Q ₁ and Q ₂ are not the same, an S-form or an R-form exists as an optically active substance. Unless otherwise specified, racemic, S- or R-forms are included. The reaction [A] will be described below. In the reaction [A], X, Y, Q ₁ , Q ₂ , R, l and n are as described above. The reaction (A) is usually performed in the presence of an acidic substance,
As the acidic substance, one or more kinds are appropriately selected from, for example, organic acids such as acetic acid and toluenesulfonic acid; and inorganic acids such as sulfuric acid and hydrochloric acid.

The reaction [A] is carried out in the presence of a solvent, if necessary. The solvent may be any one which is inert to the reaction, for example, benzene, toluene, xylene, chlorobenzene. And aromatic hydrocarbons such as carbon tetrachloride, methylene chloride, chloroform, dichloromethane, dichloroethane, trichloroethane, hexane, and cyclohexane; dioxane, ethers; dimethyl sulfoxide, dimethylacetamide , Dimethylformamide, N
One or more kinds are appropriately selected from polar aprotic solvents such as -methylpyrrolidone; organic acids such as acetic acid. The reaction temperature of the reaction [A] varies depending on the reaction conditions and cannot be specified unconditionally, but is usually 0 to 80 ° C, preferably 20 to 40 ° C, and the reaction time is usually 0.1 to 4 hours.
Desirably, it is 0.2 to 2 hours.

The reaction (B) will be described below.
In reaction [B], X, Y, Q ₁ , Q ₂ , R, l and n are as described above. The reaction (B) is carried out in the presence of a solvent, if necessary. The solvent may be any solvent as long as it is inert to the reaction, for example, benzene, toluene, xylene, and chlorobenzene. One or more kinds are appropriately selected from aromatic hydrocarbons; ethers such as dioxane; polar aprotic solvents such as dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone. The reaction temperature of the reaction [B] varies depending on the reaction conditions and cannot be specified unconditionally.
The reaction is carried out at a temperature of 00 ° C, preferably 140 to 200 ° C, and usually for 1 to 4 hours, preferably 1 to 2 hours.

The reaction [C] will be described below.
In the reaction [C], X, Y, Q ₁ , Q ₂ , R, 1, m and n are as described above, and Z ₂ is an oxygen atom or a sulfur atom. The reaction (C) is carried out in the presence of a solvent, if necessary, and any solvent may be used as long as it is inert to the reaction. Examples of the solvent include benzene, toluene, xylene, and chlorobenzene. One or more kinds are appropriately selected from aromatic hydrocarbons; ethers such as dioxane; polar aprotic solvents such as dimethylsulfoxide, dimethylacetamide and N-methylpyrrolidone.

The reaction temperature of the reaction [C] varies depending on the reaction conditions and cannot be specified unconditionally.
The reaction temperature is desirably 120 to 180 ° C, and the reaction time is usually 0.5 to 40 hours, desirably 1 to 40 hours.
In the reaction [C], diphosphorus pentasulfide itself, a dimer thereof, or the like can be used as diphosphorus pentasulfide. In the reaction (C), it is possible to selectively produce only a monothio type or to produce a mixture of a monothio type and a dithio type depending on arbitrary reaction conditions. When a dithio-type mixture is obtained, both can be separated by purification means such as column separation.

The compound of the present invention is useful as an active ingredient of a pharmaceutical composition. In particular, the compound of the present invention can regulate (enhance or suppress) the production of tumor necrosis factor (TNF-α). Effectively used for prevention. TNF-α
Is cytotoxic to tumor cells, activation of T cells, which is one of the immune system cells, activation of tumor cytotoxic macrophages, activation of neutrophils, production induction of interferon-beta ₂ by fibroblasts, immune While having favorable effects such as stimulation of the system, its overproduction promotes cancer metastasis and angiogenesis, induces endotoxin shock, induces tissue inflammation,
It is a cytokine involved in various biological functions such as inhibition of fat globule lipoprotein lipase and undesired effects such as induction of human immunodeficiency virus replication. It is known. The pharmaceutical composition containing the compound of the present invention is a biological response modifier that enables the regulation of the amount of TNF-α in a living body, and is used as an immunostimulant effective for treating diseases such as cancer, It can be used as an immunosuppressant having a therapeutic effect on rejection, graft-versus-host syndrome, diseases of the immune system, etc., and also has a therapeutic effect on other diseases involving TNF-α . Examples of the aforementioned diseases of the immune system include autoimmune diseases such as rheumatic fever and rheumatoid arthritis, erythema nodosum leprosum, Behcet's disease, lupus erythema, aphthous ulcer and the like, and other diseases involving TNF-α. As cachexia in cancer and infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, diabetes, acquired And immunodeficiency syndrome. Furthermore, when the amount of TNF-α increases remarkably in cancer treatment or the like, it is possible to suppress the induced side effects and the like due to excessive TNF-α by using the pharmaceutical composition containing the compound of the present invention in combination. (Inhibition of angiogenesis) It is known that a pathological increase in angiogenesis is involved in the onset or progression of various diseases. Specific examples of these diseases include cancer and cancer metastases; benign tumors such as hemangiomas, acoustic neuromas, neurofibromas, trachoma, suppurative granulomas, granulations; various chronic inflammations such as rheumatoid arthritis; psoriasis; diabetic retina Ocular diseases such as retinopathy, retinopathy of prematurity, macular degeneration, glaucoma, posterior lens fibrosis, central retinal vein atresia; angiogenesis associated with corneal transplantation; hypertrophic scar; atherosclerosis Disease; edema sclerosis; nephropathy. The pharmaceutical composition containing the compound of the present invention can be used as an angiogenesis inhibitor, and is useful as a prophylactic or therapeutic agent for the above-mentioned diseases. (Inhibition of Aminopeptidase N) Aminopeptidase N
Is an enzyme that hydrolyzes as a substrate a peptide having an amino terminus such as alanine, leucine, phenylalanine, tyrosine, arginine, methionine, lysine, tryptophan, glycine, serine, histidine, etc. It is widely distributed on the surface of cell membranes such as granulocytes, cancerous cells, and other placenta, liver, and pancreas. (Physiology and Oncology, Vol. 29, 288-296, 19
1994). It has also been suggested that this enzyme is involved in immune functions (Japanese Journal of Cancer).
AND CHEMOTHERAPY; JAPANESE JOURN
al of Cancer and Chemothe
rapy, 9, 1019-1024, 1982
Year). In addition, it has been reported that this inhibition of aminopeptidase N suppresses metastasis of cancer cells (Cancer Research, Cancer Research, vol. 46,
455-5510, 1986). The pharmaceutical composition containing the compound of the present invention can be used as an aminopeptidase N inhibitor, and is useful as a preventive or therapeutic agent for cancer, cancer metastasis, inflammatory disease, autoimmune disease, allergic disease and the like. is there. In particular, the following embodiments are desirable.

(1) A biological response modifier containing a phthalimide derivative represented by the above general formula (I) as an active ingredient. (2) An immunostimulant containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (3) An immunosuppressant containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (4) A tumor necrosis factor production enhancer containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (5) A tumor necrosis factor production inhibitor containing the phthalimide derivative represented by the general formula (I) as an active ingredient.

(6) An anticancer agent containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (7) An anti-inflammatory agent containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (8) An antidiabetic agent containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (9) An angiogenesis inhibitor containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (10) An antirheumatic agent containing the phthalimide derivative represented by the general formula (I) as an active ingredient. (11) An aminopeptidase N inhibitor comprising the phthalimide derivative represented by the general formula (I) as an active ingredient.

When the compound of the present invention is administered as a pharmaceutical composition as described above, it is usually used alone or mixed with various pharmacologically acceptable adjuvants to prepare tablets, capsules, powders, granules, and injections. Or liquid, syrup, suspension, eye drop, inhalant, ointment, suppository, etc., in the form of a pharmaceutical preparation suitable for oral, parenteral, topical or rectal use. .

Examples of preparations suitable for oral use include solid compositions such as tablets, capsules, powders, granules and troches, and liquid compositions such as solutions, syrups and suspensions. No. When preparing the solid composition, binders such as carboxymethylcellulose, gum arabic, powdered tragacanth, calcium carbonate, gelatin, polyvinylpyrrolidone, water, ethanol, glucose solution, and starch solution; Excipients such as lactose, sucrose, glucose, sodium chloride, calcium carbonate, carboxymethylcellulose, silicic acid; disintegrating agents such as alginic acid, starch, carboxymethylcellulose, sodium carboxymethylcellulose; magnesium stearate, light anhydrous silicic acid, urea. Surfactants such as polyoxyethylene sorbitan fatty acid esters and alkyl sulfates; capsule bases such as gelatin; other sweeteners, flavoring agents, disintegration inhibitors, absorption promoters, stabilizers, Preservative, thickener It can be used. When preparing the liquid composition as a preparation, sorbitol, gelatin,
In addition to methylcellulose, carboxymethylcellulose, and vegetable oil, emulsifiers, sweeteners, flavors, absorption enhancers, stabilizers, preservatives, and the like can be used. These preparations are usually prepared so as to contain 0.1 to 95% by weight of the compound of the present invention.

Preparations suitable for parenteral use include, for example, injections. When preparing an injection, a solution, suspension,
It is prepared in an injectable form such as an emulsion. In this case, it may contain a pharmacologically acceptable buffer such as benzyl alcohol as a preservative, ascorbic acid as an antioxidant, or a reagent for adjusting osmotic pressure. This injection is usually prepared so as to contain about 0.1 to 10% by weight of the compound of the present invention.

[0030] Formulations suitable for topical or rectal use include, for example, eye drops, inhalants, ointments, suppositories and the like. The eye drops are prepared by a conventional method using a pharmacologically acceptable carrier. The inhalant can be dissolved in a solution for aerosol or nebulizer together with the compound of the present invention or a pharmacologically acceptable inert carrier, or can be administered to the respiratory tract as a fine powder for inhalation. An ointment is prepared by a conventional method by adding a commonly used base and the like, and usually 0.1 to 30% by weight of the compound of the present invention.
It is prepared to contain a certain amount. Suppositories are prepared by a conventional method using carriers well known in the art, for example, polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride and the like, and usually contain about 0.1 to 95% by weight of the compound of the present invention. Is prepared.

[0030]

EXAMPLES Next, examples of the present invention will be described, but the present invention is not limited to these examples. First, synthesis examples of the compound of the present invention will be described.

Synthesis Example 2- (3,5-dimethylisoxazol-4-ylmethyl) -4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione (Compound No. 22) Synthesis 2.0 g of tetrafluorophthalic anhydride and 1.90 g of 3,5-dimethyl-4-aminomethylisoxazole were charged into a 50 ml eggplant-shaped flask, and the mixture was heated at 190 to 200 ° C.
For 1.5 hours. After cooling, the reaction product was dissolved in chloroform and subjected to silica gel chromatography (eluent: methylene chloride: methanol = 20: 1v /
Purified in v) and recrystallized with a mixed solvent of n-hexane-ethyl acetate to obtain 1.29 g of the desired product as pale yellow needles. 43% yield. m. p. 144-146 ° C; MS
(FAB +) m / z: 329 (M + H ⁺ )

Next, Table 1 shows typical examples of the compounds of the present invention which are synthesized based on the above-mentioned synthesis examples or the method for producing the compounds of the present invention.

[0033]

[Table 1]

[0034]

[Table 2]

[0035]

[Table 3]

[0036]

[Table 4]

Next, the NMR data of typical examples of the compound of the present invention are shown in Table 2. Is the first
Compound No. in the table. Is the same as

[0038]

[Table 5]

In Table 1, Compound No. 5, 6, 1
The results of elemental analysis of 0, 12, 14, 19, 22 and 30 were as follows. Compound No. 5: Theoretical value C; 61.31, H; 4.04, N; 10.21 Actual value C: 61.56, H; 4.00, N; 10.27 Compound no. 6: Theoretical value C; 61.31, H; 4.04, N; 10.21 Actual value C: 61.18, H; 3.98, N; 10.18 Compound No. 6 10: Theoretical value C; 55.82, H; 3.68, N; 13.95 Actual value C: 55.60, H; 3.57, N; 13.74 Compound no. 12: Theoretical value C; 80.25, H; 4.38, N; 4.68 Actual value C: 80.32, H; 4.58, N; 4.63 Compound No. 12 14: Theoretical value C; 64.70, H; 2.44, N; 3.77 Actual value C: 64.63, H; 2.61, N; 3.97 Compound No. 19: Theoretical value C; 49.70, H; 1.92, N; 8.92 Actual value C: 49.40, H; 2.07, N; 9.22 Compound no. 17: Theoretical value C; 64.46, H; 4.16, N; 11.56 Actual value C: 64.62, H; 4.18, N; 11.37 Compound No. 22: Theoretical value C; 51.23, H; 2.46, N; 8.53 Actual value C: 51.24, H; 2.26, N; 8.64 30: Theoretical value C; 60.90, H; 2.71, N; 4.18 Actual value C: 60.98, H; 2.63, N; 4.28 Compound no. 36: Theoretical value C; 60.70, H; 4.31, N; 16.33 Actual value C: 60.63, H; 4.25, N; 16.11

Next, test examples of the present invention will be described. Human leukemia cell HL-60 is okadaic acid (9,10-Deepit).
hio-9,10-didehydroacanthi
folicin) or 12-O-tetradecanoylphorbol-13-acetate (TPA) to produce tumor necrosis factor (TNF-α), the effect of the compounds of the invention on their TNF-α production or secretion I saw Test Example 1 (Effect of the Compound of the Present Invention on TNF-α Production or Secretion by Okadaic Acid Stimulation) Human leukemia cells (HL-60) were cultured in a carbon dioxide incubator using RPMI1640 medium (containing 5% fetal bovine serum) ( 5% CO ₂ , humidified at 37 ° C). The cells are then pre-cultured in RPMI 1640 medium (containing 10% fetal bovine serum), and Okada is adjusted to a final concentration of 50 nM with respect to HL-60 cells (5 × 10 ⁵ cells / ml) in the logarithmic growth phase. An acid (available from Hirota Fujiki, Saitama Prefectural Cancer Center) was added, and the compound of the present invention was further added to a desired concentration to form a cell suspension, which was then placed in a carbon dioxide incubator (5% CO ₂ , humidified, 37%). C). In this culture, a 24-well multiplate (manufactured by Corning Incorporated) was used, and the cells were cultured by dispensing 0.5 ml of the cell suspension described above per well. After 16 hours of culture, centrifuge (1000
rpm × 10 min. )) To remove the cells,
The amount of NF-α was measured using a human TNF-α ELISA system (manufactured by Amersham) according to the method of Amersham. Table 3 shows the measurement results.
The numerical values in the table are the values when the amount of TNF-α in the medium supernatant when treated with only okadaic acid at a final concentration of 50 nM is 100%.

[0041]

[Table 6]

Test Example 2 (Effect of Compound of the Present Invention on TNF-α Production or Secretion by TPA Stimulation) Test Example 2 was repeated except that okadaic acid at a final concentration of 50 nM was replaced by TPA at a final concentration of 3 nM (manufactured by Sigma). The procedure was performed in the same manner as in Method 1. The measurement results are shown in Table 4, and the numerical values in the table are values when the amount of TNF-α in the medium supernatant when treated with only TPA at a final concentration of 3 nM is 100%.

[0043]

[Table 7]

[0044]

According to the present invention, the phthalimide derivative or a salt thereof can regulate the amount of TNF-α, inhibit angiogenesis, or inhibit aminopeptidase N in a living body. It is effective in treating or preventing various diseases.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/42 ADU A61K 31/42 ADU 31/435 ABA 31/435 ABA ABC ABC C07D 209/44 C07D 209/44 209/46 209 / 46 413/04 209 413/04 209 413/06 209 413/06 209 471/04 104 471/04 104Z

Claims (6)

[Claims] 1. A compound of the general formula (I): Wherein X is ＝ CY- or ＮN-, Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group; 2 or 3 (X is = CY- and l is 1
And when X is = N- and 1 is 2 or more, Y may be the same or different), and Z
₁ and Z ₂ are each independently an oxygen atom or a sulfur atom, m is 0 or 1, Q ₁ and Q ₂ are each independently a hydrogen atom or an alkyl group, and n is 0 or 1. ,
R is an optionally substituted isoxazolyl group, an optionally substituted biphenyl group or an optionally substituted indanyl group], or a salt thereof. 2. A compound of the general formula (I): Wherein X is ＝ CY— or ＮN—, Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group; , 2 or 3 (X is = CY- and l
And when X is = N- and l is 2 or more, Y may be the same or different), and Z ₁ and Z ₂ are each independently an oxygen atom or a sulfur. An atom, m is 0 or 1, Q ₁ and Q ₂ are each independently a hydrogen atom or an alkyl group, n is 0 or 1, R is an optionally substituted isoxazolyl group, A biphenyl group or an indanyl group which may be substituted], or a salt thereof as an active ingredient. 3. An agent for regulating tumor necrosis factor production, which comprises the phthalimide derivative or a salt thereof as an active ingredient in the pharmaceutical composition of claim 2. 4. A compound of the general formula (I-1): Wherein X is ＝ CY— or ＮN—, Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group; , 2 or 3 (X is = CY- and l
Is 1 or more, and when X is = N- and 1 is 2 or more, Y may be the same or different), and Q ₁ and Q ₂ are each independently a hydrogen atom or an alkyl. And n is 0 or 1, and R is an optionally substituted isoxazolyl group, an optionally substituted biphenyl group or an optionally substituted indanyl group], or a salt thereof. A process comprising the general formula (II): Wherein X, Y and 1 are as defined above, and a compound represented by the general formula (III): Wherein R, Q ₁ , Q ₂ and n are as defined above, and then, if desired, a salt-forming reaction. Production method. 5. A compound of the general formula (I-2): Wherein X is ＝ CY- or ＮN-, Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group; 2 or 3 (X is = CY- and l is 1
And X is = N- and l is 2 or more, Y may be the same or different.
₁ and Q ₂ are each independently a hydrogen atom or an alkyl group, n is 0 or 1, and R is an optionally substituted isoxazolyl group, an optionally substituted biphenyl group or an optionally substituted indanyl group. Wherein the phthalimide derivative or a salt thereof is represented by the general formula (IV): Wherein X, Y and 1 are as defined above, and a compound represented by the general formula (III): Wherein R, Q ₁ , Q ₂ and n are as defined above, and then, if desired, a salt-forming reaction. Production method. 6. General formula (I-3): Wherein X is ＝ CY— or ＮN—, Y is a hydrogen atom, a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group; , 2 or 3 (X is = CY- and l
Is 1 or more, and when X is = N- and 1 is 2 or more, Y may be the same or different), Z ₂ is an oxygen atom or a sulfur atom, and m is 0 Or 1
Wherein Q ₁ and Q ₂ are each independently a hydrogen atom or an alkyl group, n is 0 or 1, and R is an optionally substituted isoxazolyl group, an optionally substituted biphenyl group or a substituted A phthalimide derivative or a salt thereof represented by the formula:
General formula (I-4); Wherein X, Y and l are as described above, and m is 0 or 1. The compound represented by the formula is reacted with diphosphorus pentasulfide, and then, if desired, a salt forming reaction is carried out. The method for producing a phthalimide derivative or a salt thereof described above.