JPH1081666A - Phthalimide derivative or salt thereof, its production and medicinal composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound to be used as an active ingredient for medicinal compositions, esp. having production-controlling effect on tumor necrotic factors and vascularization inhibitory activity and/or aminopeptidase N inhibitory activity. SOLUTION: This new compound (salt) is shown by formula I (R is adamanthyl or 2,6-diisopropylphenyl; X is nitro, amino, cyano, trifluoromethyl, hydroxy, a halogen or lower alkyl; Y and Z are each O or S; (m) is 0-4; (n) is 0 or 1), e.g. N-(2,6-diisopropylphenyl)isoindoline. The compound of formula I is obtained by reaction between a compound of formula II and a compound of the formula R-NH2 (when Y is O and (n) is zero). The other objective medicinal composition containing this new composition is useful for treating such immunological diseases as graft rejection, rheumatic fever, Behcet's disease and aphthous ulcer, and for prophylaxis/treatment of inflammatory diseases and allergic diseases.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel 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 In order to find an excellent pharmaceutical composition, the present inventors have developed tumor necrosis factor (TN) which is considered to be one of the factors causing various diseases.
Focusing on regulation of F-α) production, inhibition of angiogenesis and inhibition of aminopeptidase N (APN), the present inventors completed the present invention as a result of various studies. That is, the present invention provides a compound represented by the general formula (I):

[0004]

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[Wherein, R represents an adamantyl group or 2,6-
X is a nitro group, amino group, cyano group, trifluoromethyl group, hydroxy group, halogen atom or lower alkyl group, and Y and Z
Is an oxygen atom or a sulfur atom (which may be the same or different), and m is an integer of 0 to 4 (when m is 2 or more,
X may be the same or different), and n is 0 or 1
Wherein (1) R is a 2,6-diisopropylphenyl group, Y and Z are oxygen atoms, n is 1 and m is 0, (2) R is 2, A 6-diisopropylphenyl group, X is a halogen atom,
Y and Z are oxygen atoms, n is 1 and m is 4
Wherein (3) R is a 2,6-diisopropylphenyl group, X is a nitro group, amino group or hydroxy group, Y and Z are oxygen atoms, n is 1, and m is 1 and (4) R is an adamantyl group, Y and Z are oxygen atoms, n is 1, and m
Phthalimide derivative or a salt thereof, a method for producing them, and a pharmaceutical composition containing them.

In the general formula (I), examples of the halogen atom contained in X include fluorine, chlorine, bromine and iodine atoms, and the lower alkyl group contained in X has 1 to 6 carbon atoms. Desirable are straight-chain or branched ones such as methyl, ethyl, propyl, isopropyl, butyl, tertiary-butyl, pentyl, hexyl and the like. In the general formula (I), when m is 2 or more, Xs may be the same or different.

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

The phthalimide derivative represented by the general formula (I) or a salt thereof (hereinafter abbreviated as the compound of the present invention) is prepared by a method such as the following reactions [A] to [C] and a usual salt formation reaction. Can be manufactured.

[0009]

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[0010]

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[0011]

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The reaction [A] will be described below.
In the reaction [A], R, X and m are as described above. The reaction [A] is usually carried out in the presence of an acidic substance. Examples of the acidic substance include one or two kinds of organic acids such as acetic acid and toluenesulfonic acid; and inorganic acids such as sulfuric acid and hydrochloric acid. The above is appropriately selected.

The reaction [A] is carried out in the presence of a solvent, if necessary. As the solvent, any solvent may be used as long as it 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] is usually from 0 to 80 ° C, preferably from 20 to 40 ° C, and the reaction time is usually from 0.1 to
4 hours, desirably 0.2 to 2 hours.

The reaction [B] is described below.
In the reaction [B], R, X and m 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) is usually 100 to 200 ° C,
The temperature is desirably 140 to 200 ° C.
４4 hours, preferably 1-2 hours.

The reaction [C] will be described below.
In the reaction [C], R, X, m and n are as described above,
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. Aromatic hydrocarbons; ethers such as dioxane; dimethyl sulfoxide, dimethylacetamide, N
One or more kinds are appropriately selected from polar aprotic solvents such as -methylpyrrolidone.

The reaction temperature of the reaction [C] is usually 100 to 2
The reaction temperature is usually 00 ° C, preferably 120 ° C to 180 ° C, and the reaction time is generally 0.5 to 40 hours, preferably 1 to 40 hours. In the reaction (C), as phosphorus pentasulfide,
The dimer or the like can be used. The reaction [C]
In, 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, and to obtain a mixture of a monothio type and a dithio type. In this case, both can be separated by a purification means such as column separation.

The compound of the present invention is useful as an active ingredient of a pharmaceutical composition. In particular, it acts to regulate (enhance or suppress) the production of tumor necrosis factor (TNF-α), angiogenesis inhibitory activity and / or aminopeptidase. Since it has N inhibitory activity, it is effectively used for treatment and prevention of various diseases. (Action to regulate TNF-α production) TNF-α is cytotoxic to tumor cells, activates T cells that are one of immune system cells, activates tumor-inducing macrophages, and activates neutrophils , Interferon-β ₂ by fibroblasts
It has favorable effects such as induction of the production of blood cells and stimulation of the immune system, while its overproduction promotes cancer metastasis and angiogenesis, induction of endotoxin shock, induction of tissue inflammation, inhibition of lipoprotein lipase of fat globules, human immunodeficiency It is known to be a cytokine involved in inflammatory and immunological reactions and widely involved in the control of biological reactions, showing versatile actions such as having undesirable effects such as inducing virus replication. The pharmaceutical composition containing the compound of the present invention can be used for TN in vivo.
It is a biological response regulator that enables the regulation of the amount of F-α, and can be used as an effective immunostimulant for the treatment of diseases such as cancer, rejection of grafts, graft-versus-host syndrome, diseases of the immune system, etc. It can be used as an immunosuppressant having a therapeutic effect on the other hand, and also has a therapeutic effect on other diseases involving TNF-α. The aforementioned diseases of the immune system include rheumatic fever, autoimmune diseases such as rheumatoid arthritis, erythema nodosum leprosy, Behcet's disease, lupus erythema,
Other diseases in which TNF-α is involved, such as aphthous ulcer, include cachexia in cancer and infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, and inflammatory bowel disease , Multiple organ failure, malaria, meningitis, hepatitis, diabetes, acquired immunodeficiency syndrome and the like. 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 above 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 aminopeptidase N inhibitor comprising the phthalimide derivative represented by the general formula (I) as an active ingredient. (11) An antirheumatic agent containing the phthalimide derivative represented by the general formula (I) as an active ingredient.

When the compound of the present invention is administered as the above-mentioned pharmaceutical composition, it is usually used alone or mixed with various pharmacologically acceptable adjuvants, and tablets, capsules, powders, granules, injections, etc. 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.

Preparations 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.

[0024]

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 1 Synthesis of N- (2,6-diisopropylphenyl) isoindoline (Compound No. 44) 0.5 g of o-phthalaldehyde and 0.661 g of 2,6-diisopropylaniline are dissolved in 20 ml of dichloromethane. Then, 1 ml of acetic acid was added thereto and reacted at room temperature for 25 minutes. After completion of the reaction, the reaction mixture was washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and then washed with a saturated saline solution, dried over anhydrous magnesium sulfate, and filtered.
The obtained filtrate was concentrated, dried and solidified. Thereafter, the mixture was recrystallized from a mixture of hexane and dichloromethane to obtain 0.7 of the desired product having a melting point of 130.9 to 132.0 ° C.
92 g were obtained.

Synthesis Example 2 Synthesis of N- (2,6-diisopropylphenyl) -5-tert-butylphthalimide (Compound No. 73) 4-tert-butylphthalic anhydride 0.605 g and 2,6-diisopropylaniline 0.630 g, and reacted at 200 ° C. for 1 hour. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and then washed with saturated saline. Then, it was dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Thereafter, the mixture was recrystallized using a mixture of hexane and dichloromethane to give a melting point of 23.
0.7055 g of the target product at 4.0 to 234.8 ° C. was obtained.

Synthesis Example 3 N- (2,6-diisopropylphenyl) thiophthalimide (Compound No. 74 described below)
(1) 7.41 g of phthalic anhydride and 8.86 g of 2,6-diisopropylaniline were mixed and reacted at 180 ° C. for 2 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and then washed with saturated saline. Then, it was dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Thereafter, the mixture was recrystallized from a mixture of hexane and dichloromethane to give N- (2,6-
9.06 g (yield 62.5%) of diisopropylphenyl) phthalimide was obtained.

(2) 0.3 g of N- (2,6-diisopropylphenyl) phthalimide is dissolved in 10 ml of xylene, 0.217 g of diphosphorus pentasulfide (dimer) is added thereto, and the mixture is refluxed for 1.5 hours. Reacted. After completion of the reaction, the reaction mixture was purified by silica gel column chromatography (developing solvent: ethyl acetate / hexane = 1/15) to obtain 0.164 g of the target product having a melting point of 130.5 to 131.6 ° C.
0.033 g of (2,6-diisopropylphenyl) dithiophthalimide was obtained.

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

[0030]

[Table 1]

[0031]

[Table 2]

[0032]

[Table 3]

[0033]

[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

[0035]

[Table 5]

The compound No. in Table 1 was used. The results of the 80 instrumental analysis were as follows. Mass: M / Z 395 (M ⁺ ), 362 (M-3
3 .: MS), 320 (M-75: M-4F) Elemental analysis: Theory C: 60.75, H; 4.33, N; 3.54 Found C: 60.50 H; 73N; 3.38

Next, test examples of the present invention will be described. (Action of regulating TNF-α production) Human leukemia cell H
L-60 is okadaic acid (9,10-Deepitio-
9,10-didehydroacantifoli
cin) or 12-O-tetradecanoylphorbol-13-acetate (TPA) to produce tumor necrosis factor (TNF-α),
The effect of the compound of the present invention on α production or secretion was examined. 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%. As is apparent from Table 3, these compounds of the present invention suppressed the production or secretion of TNF-α by HL-60 cells stimulated with okadaic acid.

[0038]

[Table 6]

Test Example 2 (Effect of the 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 with 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%. As is evident from Table 4, these compounds of the present invention showed that TNF-α by TPA-stimulated HL-60 cells
Increased production or secretion.

[0040]

[Table 7]

Test Example 3 (Effect of the Compound of the Present Invention on Subcutaneous Angiogenesis in Mice) A mixture of Matrigel and recombinant Human Fibroblast Growth Factor-Basic was injected subcutaneously into the back of the mouse, whereby angiogenesis was induced in the subcutaneous mouse. Angiogenesis can be quantified by measuring the amount of hemoglobin in Matrigel. Therefore, the effect of the compound of the present invention on angiogenesis was examined. Matrigel (registered trademark; basement membrane matrix free of phenol,
Becton Dickinson Loveware; Becto
n Dickinson Labware) from Dulbecco's modified Eagles
e's medium; purchased from Sigma) plus 9m
g / ml and recombined
Human fibroblast growth factor
Basic; Recombinant Human F
ibroblast Growth Factor-b
asic (b-FGF, Intergen; Inter
gen) (2 μg / 700 μl). The mixture was injected subcutaneously into the back of 6-week-old BALB / c male mice (Charles River, Japan) at 700 μl / animal. Each day after the injection of Matrigel, 0.8% Tween 80 (Tween 80;
(Purchased from Nacalai Tesque) was administered a suspension containing the compound of the present invention at a desired concentration. On the 8th day after the injection of Matrigel, Matrigel taken out from the back of the mouse was placed in 200 µl of 1% NH ₄ OH at room temperature for 4 hours to extract hemoglobin. This extract was centrifuged together with Matrigel (10000 rpm, 5 minutes), and 100 μl of the obtained supernatant was added to Drakin's Reagent (Dr.
akin's reagent, Sigma; Shigm
(purchased from a)) and mixed at room temperature. After standing for more than 15 minutes, Spectrophotometer SPECTR
A max 250 (manufactured by Molecular Devices, Inc .;
The absorbance at 540 nm of the supernatant was measured using Molecular Devices). The amount of hemoglobin in the supernatant was determined using standard hemoglobin (hemoglobin).
in standard, purchased from Sigma), and the amount of hemoglobin per Matrigel obtained from one mouse was calculated. The results are shown in Table 5, and the hemoglobin amount of each treatment group was b-F
Matrigel without the addition of GF was injected into mice, and 0.8% Tween 80 (Tween 80) as a solvent was used.
Corrected by the amount of hemoglobin in Matrigel when only daily was administered. The compound of the present invention inhibited angiogenesis occurring in the subcutaneous mouse.

[0042]

[Table 8]

Test Example 4 (Effect of the Compound of the Present Invention on the Activity of Aminopeptidase N) The activity of aminopeptidase N was determined by using L-alanine-7-amide-4-methylcoumarin trifluoroacetate as an enzyme substrate. It can be measured by measuring the fluorescence intensity of the generated dye (European Journal Immunology, Vol. 22, pp. 923-930, 1992). That is,
Acute lymphoblastic leukemia cells (MOLT-4), 5 × 1
0 for ^4, as an enzyme substrate L- alanine-7-amido-4-methylcoumarin trifluoroacetate (Sigma, No.A4302) was added to a final concentration of 0.2 mM, the present invention compound Together with a diluent (buffer for enzyme substrate reaction) prepared at a desired concentration at 37 ° C.
For 1 hour. As a control, only a buffer containing no compound of the present invention was added. 100 mM Hepes buffer pH 7.6 (containing 120 mM sodium chloride, 5 mM potassium chloride, 1.2 mM magnesium sulfate, and 0.5% bovine serum albumin) was used as a buffer for the enzyme substrate reaction. After the reaction, the fluorescence intensity was measured with an MTP-32 corona microplate reader (manufactured by Corona Electric Co., Ltd.) under the measurement conditions of an excitation wavelength of 380 nm and a fluorescence emission wavelength of 440 nm. Sixth
As is clear from the table, the compounds of the present invention inhibited aminopeptidase N. The values in the table indicate the enzyme inhibitory activity of the compound of the present invention, based on the fluorescence intensity of the control, as IC ₅₀ (μg
/ Ml).

[0044]

[Table 9]

[0045]

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

Continued on the front page (51) Int.Cl. ⁶ Identification code Agency reference number FI Technical display A61K 31/40 ABN A61K 31/40 ABN ADP ADP ADU ADU AED AED C07D 209/44 C07D 209/44 209/46 209 / 46

Claims (8)

[Claims] 1. A compound of the general formula (I): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group, X is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group, and Y and Z Are each independently an oxygen atom or a sulfur atom, m is an integer of 0 to 4 (when m is 2 or more, X may be the same or different), and n is 0 or 1, provided that (1) R is a 2,6-diisopropylphenyl group, Y and Z are oxygen atoms, n is 1 and m is 0, (2) R
Is a 2,6-diisopropylphenyl group, X is a halogen atom, Y and Z are oxygen atoms, n is 1, and m is 4, (3) R is 2,6- A diisopropylphenyl group, X is a nitro group, an amino group or a hydroxy group, Y and Z are oxygen atoms,
excluding those wherein n is 1 and m is 1 and (4) R is an adamantyl group, Y and Z are oxygen atoms, n is 1 and m is 0] A phthalimide derivative represented by the following or a salt thereof. 2. A compound of the general formula (I): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group, X is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group, and Y and Z Are each independently an oxygen atom or a sulfur atom, m is an integer of 0 to 4 (when m is 2 or more, X may be the same or different), and n is 0 or 1, provided that (1) R is a 2,6-diisopropylphenyl group, Y and Z are oxygen atoms, n is 1 and m is 0, (2) R
Is a 2,6-diisopropylphenyl group, X is a halogen atom, Y and Z are oxygen atoms, n is 1, and m is 4, (3) R is 2,6- A diisopropylphenyl group, X is a nitro group, an amino group or a hydroxy group, Y and Z are oxygen atoms,
excluding those wherein n is 1 and m is 1 and (4) R is an adamantyl group, Y and Z are oxygen atoms, n is 1 and m is 0] A pharmaceutical composition comprising the represented phthalimide derivative or a salt thereof as an active ingredient. 3. A compound of the general formula (I): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group, X is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group, and Y and Z Are each independently an oxygen atom or a sulfur atom, m is an integer of 0 to 4 (when m is 2 or more, X may be the same or different), and n is 0 or 1, provided that (1) R is a 2,6-diisopropylphenyl group, Y and Z are oxygen atoms, n is 1 and m is 0, (2) R
Is a 2,6-diisopropylphenyl group, X is a halogen atom, Y and Z are oxygen atoms, n is 1, and m is 4, (3) R is 2,6- A diisopropylphenyl group, X is a nitro group, an amino group or a hydroxy group, Y and Z are oxygen atoms,
excluding those wherein n is 1 and m is 1 and (4) R is an adamantyl group, Y and Z are oxygen atoms, n is 1 and m is 0] An agent for regulating tumor necrosis factor production, comprising a phthalimide derivative or a salt thereof as an active ingredient. 4. An angiogenesis inhibitor comprising the phthalimide derivative or a salt thereof as an active ingredient as the pharmaceutical composition of claim 2. 5. An aminopeptidase N inhibitor comprising the phthalimide derivative or a salt thereof as an active ingredient as the pharmaceutical composition of claim 2. 6. A compound represented by the general formula (I-1): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group, X is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group; (Where m is 2 or more, Xs may be the same or different). A method for producing a phthalimide derivative represented by the general formula (I-1) A phthalaldehyde corresponding to the phthalimide derivative to be reacted with a compound represented by the general formula (III); R—NH ₂ ... (III), wherein R is as defined above. A method for producing the phthalimide derivative or a salt thereof, wherein a salt-forming reaction is carried out if desired. 7. A compound represented by the general formula (I-2): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group, X is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or a lower alkyl group; (Where m is 2 or more, Xs may be the same or different), provided that (1) R is a 2,6-diisopropylphenyl group and m is 0, (2) R is 2,6-
A diisopropylphenyl group wherein X is a halogen atom and m is 4, (3) R is a 2,6-diisopropylphenyl group, X is a nitro group, an amino group or a hydroxy group, and excluding those wherein m is 1 and (4) those wherein R is an adamantyl group and m is 0), or a salt thereof, which is represented by the general formula (II): 6] Wherein X and m are as described above, and a compound represented by the general formula (III): R-NH ₂ ... (III) wherein R is as described above. A method for producing the phthalimide derivative or a salt thereof, which comprises reacting the compound represented by the formula (I) with a compound represented by the formula (I) and then performing a salt-forming reaction as required. 8. A compound represented by the general formula (I-3): Wherein R is an adamantyl group or a 2,6-diisopropylphenyl group; X is a nitro group, amino group, cyano group, trifluoromethyl group, hydroxy group, halogen atom or lower alkyl group; M is an integer of 0 to 4 (when m is 2 or more, X may be the same or different), and n is 0 or 1), or a phthalimide derivative represented by the following formula: A method for producing a salt, comprising the general formula (I-4): Wherein R, X, m and n are as defined above, and diphosphorus pentasulfide, and then, if desired, a salt forming reaction. Or a method for producing a salt thereof.