JPH10109975A - Medicinal composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicinal composition capable of regulating a production of tumor necrosis factors and inhibiting vascularization and activity of aminopeptidase N by making the composition contain a cyclic imide derivative. SOLUTION: This medicinal composition contains a compound or its salt expressed by the formula [Q1 is a single bond, CH2 , O, S or NH; Q2 and Q3 are each C(O), C(S) or CH2 ; Z is a single bond or a lower alkanediyl; R is a substitutable aryl or a cycloalkyl; X is nitro, an amino capable of being acylated, cyano, triflurormethyl, hydroxy, a halogen, an alkyl, etc.; (m) is 0-4] as an effective ingredient. The medicine which regulates the production of tumor necrosis factors is useful as a biological response regulator, an immune activator, an immunosuppressor, etc. The medicine which inhibits activity of aminopeptidase N is useful for preventing and curing cancers, metastases of cancers, inflammatory diseases, autoimmune diseases and allergic diseases. The medicine which inhibits vascularization-activity is useful for preventing and curing cancers, metastases of cancers, benign tumors, chronic inflammations, psoriasis, vascularization-related eye diseases, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a pharmaceutical composition containing a cyclic imide derivative or a salt thereof. The cyclic imide derivative or a salt thereof includes the above-mentioned isoindole derivative or a salt thereof, a certain N-phenylimide-based compound or a salt thereof, a certain phthalimide derivative or a salt thereof, and an N-phenylphthalimide derivative or a salt thereof. You. In particular, the present invention relates to an aminopeptidase N enzyme inhibitor or an angiogenesis inhibitor containing the cyclic imide derivative or a salt thereof as an active ingredient. The present invention also relates to a novel isoindole derivative or a salt thereof, a production method thereof, and a pharmaceutical composition containing the same. Also, the present invention relates to a medicament for regulating the production of tumor necrosis factor (TNF-α), comprising a novel isoindole derivative or a salt thereof as an active ingredient.

[0002]

BACKGROUND ART Japanese Patent Application Laid-Open No. Sho 50-121432 discloses a phthalimide derivative as an active ingredient of an agricultural and horticultural fungicide. Japanese Patent Application Laid-Open No. 62-22760 discloses an agricultural and horticultural fungicide. Are disclosed as active ingredients, but each has a different chemical structure from the cyclic imide derivative of the present invention. In the field of pharmaceuticals, Chemical and Pharmaceutical Buretin (CHEMICAL
& PHARMACEUTICAL BULLETIN) Volume 43 Issue 1 Numbers 177-179
P., N-alkylphthalimides disclosed in 1995, as well as BIOLOGICAL PHARMACEUTICAL BULLETIN 18 vol. 9
Pp. 1228-1233, 1995, the cyclic imide derivatives of the present invention are distinguished by their chemical structures from both benzylphthalimide and phenethylphthalimide.

[0003]

SUMMARY OF THE INVENTION Tumor necrosis factor (TNF-) is considered to be one of the factors causing various diseases.
Pharmaceuticals that regulate (enhance or suppress) the production of α) are also useful as biological response modifiers, and can be expected to be used widely as immunostimulants and immunosuppressants. ing. In addition, aminopeptidase N (APN) is widely distributed on epithelial cells of the kidney and small intestine, monocytes and granulocytes, cancerous cells, and other cell membrane surfaces such as placenta, liver, and pancreas, and digests and absorbs amino acids, peptide hormones, It discusses various physiological functions such as biosynthesis and degradation of bioactive substances such as growth factors and autakoids, and degradation of extracellular matrix. Drugs that inhibit the activity of APN include cancer, cancer metastasis, and inflammatory It is expected as a prophylactic or therapeutic agent for diseases, autoimmune diseases, allergic diseases and the like, and development of a drug that is an aminopeptidase N inhibitor is required. It is known that the pathological increase in angiogenesis is involved in the onset or progression of various diseases, and there is a need for the development of a drug that is an angiogenesis inhibitor useful as a preventive or therapeutic agent for such diseases. I have. Furthermore, it is significant to find excellent pharmaceutical compositions for certain novel and characteristic isoindole derivatives or salts thereof.

[0004]

In order to find an excellent pharmaceutical composition for certain isoindole derivatives or salts thereof, the present inventors have developed tumor necrosis factor (TNF), which is considered to be one of the factors causing various diseases. Note that it regulates the production of -α). Further, by using an optically active substance among the isoindole derivatives or salts thereof, TN
The present invention has been completed based on the finding that the control of F-α production can be separated into an enhancing action and an inhibiting action, and a compound having only one action can be obtained. In addition, they have found that a cyclic imide derivative having a certain chemical structure or a salt thereof has an aminopeptidase N inhibitory action or an angiogenesis inhibitor, and completed the present invention.

That is, the present invention provides: [1] General formula (I):

Embedded image Wherein Q ₁ is a single bond, -CH _2- , -O-, -S- or -NH-, and Q ₂ and Q ₃ are each independently
—C (O) —, —C (S) — or —CH ₂ —, and Q
_At least one of ₂ and Q ₃ is -C (O)-or -C
(S)-, Z is a single bond or a lower alkanediyl group, R is an optionally substituted aryl group or an optionally substituted cycloalkyl group, and X is a nitro group or an acylated group. An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group;
An aminopeptidase N enzyme inhibitor comprising a cyclic imide derivative or a salt thereof and a pharmaceutically acceptable carrier; and an integer of 4 (when m is 2 or more, Xs may be the same or different).

[2] The above-mentioned [1], wherein Q _{1 of the} cyclic imide derivative is a single bond or —CH ₂ —, and Z is a single bond.
Aminopeptidase N inhibitor of; [3] Q ₁ is a single bond or -CH ₂ cyclic imide derivatives
-, Z is a single bond, and R is a phenyl group which may be substituted; the aminopeptidase N enzyme inhibitor of the above [1]; [4] Q _{1 of the} cyclic imide derivative is -CH _2- Yes,
The aminopeptidase N enzyme inhibitor of the above-mentioned [1], wherein Z is a single bond and R is a phenyl group which may be substituted;

[5] General formula (I):

Embedded image Wherein Q ₁ is a single bond, -CH _2- , -O-, -S- or -NH-, and Q ₂ and Q ₃ are each independently
—C (O) —, —C (S) — or —CH ₂ —, and Q
_At least one of ₂ and Q ₃ is -C (O)-or -C
(S)-, Z is a single bond or a lower alkanediyl group, R is an optionally substituted aryl group or an optionally substituted cycloalkyl group, and X is a nitro group or an acylated group. An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group;
4 (when m is 2 or more, X may be the same or different), provided that when Z is a single bond, R is an optionally substituted aryl group. An angiogenesis inhibitor comprising a derivative or a salt thereof and a pharmaceutically acceptable carrier;

[0008] [6] to Q ₁ cyclic imide derivative is a single bond or -CH ₂ - is, angiogenesis inhibitors of [5]; [7] Q ₁ is a single bond or -CH ₂ cyclic imide derivatives
Wherein R is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted; [5] the angiogenesis inhibitor according to the above [5]; ₁ is a single bond or -CH ₂
Wherein Z is a single bond or a 1,1-ethanediyl group, and R is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, [5] Angiogenesis inhibitors;

[9] Q _{1 of the} cyclic imide derivative is a single bond or -CH ₂
Wherein Z is a single bond or a 1,1-ethanediyl group, R is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, and X is a fluorine atom [5], wherein m is 4.
Angiogenesis inhibitors;

[10] General formula (I '):

Embedded image Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different), Y is an oxygen atom or a sulfur atom,
Q ₃ is —C (O) —, —C (S) — or —CH ₂ —] or a salt thereof;

[11] The cyclic imide derivative of the above-mentioned [10], wherein the compound of the formula (I ′) is an S-form or an R-form of an optically active form, or a salt thereof; 10] or [1
[1] the cyclic imide derivative or salt thereof; [13] the cyclic imide derivative of the above-mentioned [10] or [11], wherein Z ′ is a methyl group, X is a fluorine atom, and m is 4, or a salt thereof; 14] a pharmaceutical composition comprising the cyclic imide derivative or salt thereof of the above [10] and a pharmaceutically acceptable carrier; [15] a tumor comprising the cyclic imide derivative or salt thereof of the above [10] and a pharmaceutically acceptable carrier Necrosis factor production regulator;

[16] General formula (I ″):

Embedded image [In the formula, Z ′ is an alkyl group, and R ″ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group (where the substituent is nitro X ′ is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group. , Y and A are each independently an oxygen atom or a sulfur atom, 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.] The cyclic imide derivative of the above [10], which is an isoindole derivative or a salt thereof, or a salt thereof; [17] Z' Is a methyl group, R '' is a phenyl group,
A naphthyl group or a cyclohexyl group, X ′ is a fluorine atom, Y and A are oxygen atoms, m is 0 or 4, and n is 1, the cyclic imide derivative of the above [16] or a salt thereof;

[18] General formula (I ″):

Embedded image [In the formula, Z ′ is an alkyl group, and R ″ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group (where the substituent is nitro X ′ is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group. , Y and A are each independently an oxygen atom or a sulfur atom, 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 the isoindole derivative or a salt thereof is contained as an active ingredient.
4) a pharmaceutical composition;

[19] a regulator of tumor necrosis factor production, characterized in that the pharmaceutical composition of [18] contains the isoindole derivative or a salt thereof as an active ingredient; [20] the isoindole derivative or a salt thereof Is the S-form or the R-form of the optically active substance; the tumor necrosis factor production regulator of the above-mentioned [19]; A factor production inhibitor; [22] the isoindole derivative or a salt thereof, wherein Z ′ is a methyl group, R ″ is a phenyl group, a naphthyl group or a cyclohexyl group, and X ′ is a fluorine atom;
The tumor necrosis factor production inhibitor according to the above [21], wherein Y and A are oxygen atoms, m is 0 or 4, and n is 1;

[23] Formula (I'-1):

Embedded image Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different). A phthalaldehyde corresponding to the cyclic imide derivative represented by the general formula (III):

[0015]

Embedded image Wherein Z ′ and R ′ are as defined above, and then, if desired, a salt-forming reaction is carried out, wherein the method for producing the cyclic imide derivative or a salt thereof is performed;

[24] Formula (I'-2):

Embedded image Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different) when the cyclic imide derivative or a salt thereof is produced, wherein the general formula (II):

[0017]

Embedded image Wherein X and m are as defined above, and a compound represented by the general formula (III):

[0018]

Embedded image Wherein Z ′ and R ′ are as defined above, and then, if desired, a salt-forming reaction is carried out. as well as

[25] Formula (I'-3):

Embedded image Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
And Q is an integer of 4 or more (when m is 2 or more, Xs may be the same or different), and Q ₃ is -C (O)-, -C (S)-
Or —CH ₂ —), or a salt thereof, which is represented by the general formula (I′-4):

[0020]

Embedded image Wherein Z ′, R ′, X and m are as described above,
Wherein ₄ is —C (O) — or —CH ₂ —), and diphosphorus pentasulfide, and then, if desired, a salt forming reaction. The present invention relates to a method for producing the salt.

In another embodiment, the present invention provides a compound represented by the general formula (I):

Embedded image Wherein R ₁ or R ₂ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group, Y is an oxygen atom or a sulfur atom, and X ₁ or X ₂ is a halogen atom, a nitro group, a cyano group. A trifluoromethyl group, a hydroxy group, an amino group which may be acylated, an alkyl group, an alkoxy group or an alkylthio group;
Or an integer of 1 to 4 (when m is 2 or more, X ₁ may be the same or different), and p is an integer of 0 or 1 to 6 (when p is 2 or more, X ₂ is the same Wherein Q ₅ is —C (O) — or —CH ₂ —), or a salt thereof and a pharmaceutically acceptable carrier. 1] the aminopeptidase N enzyme inhibitor;

[27] The amino acid of the above-mentioned [26], wherein R ₁ and R ₂ are both isopropyl groups, Y is an oxygen atom, m or p is 0, and Q ₅ is —C (O) —. A peptidase N enzyme inhibitor;

[28] Formula (I ″ ′ − 1) or (I ″ ″-2):

Embedded image Wherein R ₁ or R ₂ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group, Y is an oxygen atom or a sulfur atom, and X ₁ or X ₂ is a halogen atom, a nitro group, a cyano group. A trifluoromethyl group, a hydroxy group, an amino group which may be acylated, an alkyl group, an alkoxy group or an alkylthio group;
Or p is an integer of 1 to 4 (when m is 2 or more, X ₁ may be the same or different), and p is 0 or an integer of 1 to 6 (when p is 2 or more, X ₂ is the same And Q ₅ is —C (O) — or —CH ₂ —), or a salt thereof and a pharmaceutically acceptable carrier. 5] an angiogenesis inhibitor;

[29] The blood vessel of the above-mentioned [28], wherein R ₁ and R ₂ are both isopropyl groups, Y is an oxygen atom, m or p is 0, and Q ₅ is —C (O) —. Neogenesis inhibitors;

[30] Formula (I ″ ″):

Embedded image Wherein R ″ ″ is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower alkylthiophenyl group, and X is a nitro group, an amino group which may be acylated, a cyano group, Methyl group, hydroxy group,
Halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q ₃
-C (O) is -, - C (S) - or -CH ₂ -,
m is an integer of 0 to 4 (when m is 2 or more, Xs may be the same or different)] and the phthalimide derivative or a pharmaceutically acceptable carrier thereof; Aminopeptidase N enzyme inhibitors; and

[31] Formula (I ″ ″):

Embedded image Wherein R ″ ″ is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower alkylthiophenyl group, and X is a nitro group, an amino group which may be acylated, a cyano group, Methyl group, hydroxy group,
Halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q ₃
-C (O) is -, - C (S) - or -CH ₂ -,
m is an integer of 0 to 4 (when m is 2 or more, Xs may be the same or different), the phthalimide derivative or a pharmaceutically acceptable carrier thereof, Angiogenesis inhibitors; and

[32] N-phenylphthalimide, N
-Phenylthiophthalimide, N- (2,6-diisopropylphenyl) -phthalimide, N- (2,6-diisopropylphenyl) -4,5,6,7-tetrafluoro-phthalimide, N- (2,6-diisopropyl) It comprises at least one N-phenylphthalimide derivative selected from the group consisting of phenyl) -4-nitrophthalimide and N- (2,6-diisopropylphenyl) -5-nitrophthalimide, or a salt thereof, and a pharmaceutically acceptable carrier. An angiogenesis inhibitor according to the above [5]; [33] a pharmaceutical composition according to the above [18] which exhibits an effect of enhancing the production of tumor necrosis factor (TNF-α); [34] a tumor necrosis factor (TNF) -The pharmaceutical composition of [18], which has an effect of inhibiting the production of -α); [35] cytotoxicity against tumor cells, T Cell activation, activation of tumor cytotoxic macrophages, activation of neutrophils, at least one of the physiological activity selected from the group consisting of production induction and stimulation of the immune system of the interferon-beta ₂ by fibroblasts The pharmaceutical composition of the above [18], which has a favorable effect on

[36] A physiological action selected from the group consisting of promoting cancer metastasis and angiogenesis, inducing endotoxin shock, inducing tissue inflammation, inhibiting lipoprotein lipase of fat globules and inducing replication of human immunodeficiency virus. [37] The pharmaceutical composition of the above [18], which inhibits at least one of the above; [37] The pharmaceutical composition of the above [18], which exhibits an inflammation-suppressing or immunomodulating effect; [38] Rheumatic fever, rheumatism The pharmaceutical composition of the above-mentioned [18], which is a preventive or therapeutic agent for autoimmune diseases such as rheumatoid arthritis, erythema nodosum leprosum, Behcet's disease, lupus erythema or aphthous ulcer;

[39] Cachexia in cancer and infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, inflammatory bowel disease, multiple organ failure, malaria, meningitis, hepatitis, The pharmaceutical composition of the above-mentioned [18], which is a preventive or therapeutic agent for diabetes or acquired immunodeficiency syndrome; [40] The above-mentioned [1] which suppresses the side effect of TNF-α.
[18] The pharmaceutical composition of [18], wherein the pharmaceutical composition of [18] contains the isoindole derivative or a salt thereof as an active ingredient; A biological response modifier comprising the above-mentioned isoindole derivative or a salt thereof as an active ingredient as a pharmaceutical composition; [43] the above-mentioned isoindole derivative or a salt thereof as an active ingredient as the pharmaceutical composition of the above [18]. [44] the agent of the above-mentioned [43], which is a therapeutic agent for a cancer disease; [45] the above-mentioned isoindole derivative or a salt thereof as a pharmaceutical composition of the above-mentioned [18] as an active ingredient [46] The above-mentioned [4] which is a therapeutic agent for transplant rejection, graft-versus-host syndrome, or a disease of the immune system. Agents];

[47] cancer; cancer metastasis; benign tumors including hemangiomas, acoustic neuromas, neurofibromas, trachoma, purulent granuloma, granulation; various chronic inflammations including rheumatoid arthritis; psoriasis; diabetic retinopathy; Ocular diseases involving angiogenesis, including retinopathy of prematurity, macular degeneration, glaucoma, posterior lens fibroplasia, central retinal vein atresia; angiogenesis associated with corneal transplantation; hypertrophic scars; atherosclerosis; Edema sclerosis;
And a prophylactic or therapeutic agent for at least one of the diseases selected from the group consisting of:
[48] at least one of the physiological functions selected from the group consisting of digestion and absorption of amino acids; biosynthesis or degradation of physiologically active substances including peptide hormones, growth factors or autakoids; and degradation of extracellular matrix [49] The agent of the above [1], which exerts a favorable effect on cancer cells; [49] The agent of the above [1], which exhibits an immune function regulating action; [51] The above-mentioned [1], which is a prophylactic or therapeutic agent for at least one of diseases selected from the group consisting of cancer, cancer metastasis, inflammatory disease, autoimmune disease and allergic disease. [52] the substituent of the optionally substituted aryl group or the optionally substituted cycloalkyl group contained in R is a nitro group or an optionally acylated amino group; An agent of the above-mentioned [1], which is selected from the group consisting of: a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group and an alkylthio group; An optionally substituted aryl group or an optionally substituted cycloalkyl group has a nitro group, an optionally acylated amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group The agent of the above-mentioned [5], which is selected from the group consisting of an alkoxy group and an alkylthio group; [54] a phenyl group which may be substituted, a naphthyl group which may be substituted or A substituent of the cyclohexyl group which may be substituted is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, A cyclic imide derivative of the above [10] or a salt thereof, which is selected from the group consisting of a hydroxy group, a halogen atom, an alkyl group, an alkoxy group and an alkylthio group; [55] the general formula (I ′) of the above [30] In the phthalimide derivative represented by “″), (1) R ″ ″ is 2,6
A diisopropylphenyl group, Y is an oxygen atom, Q ₃ is —C (O) — and m is 0, (2) R ″ ″ is a 2,6-diisopropylphenyl group X is a halogen atom, Y is an oxygen atom, Q ₃ is —C (O) —, and m is 4, (3) R ″ ″ is 2,6- A diisopropylphenyl group, X is a nitro group, amino group or hydroxy group, Y is an oxygen atom, Q ₃ is —C (O) —,
And (4) R ″ ″ is an adamantyl group, Y is an oxygen atom, Q ₃ is —C (O) —, and m is 0, excluding those in which m is 1 [30] the aminopeptidase N enzyme inhibitor of the above [30], which comprises a compound or a salt thereof; and [56] the phthalimide derivative represented by the general formula (I "") of the above [31], wherein (1) R '''' Is 2,6
A diisopropylphenyl group, Y is an oxygen atom, Q ₃ is —C (O) — and m is 0, (2) R ″ ″ is a 2,6-diisopropylphenyl group X is a halogen atom, Y is an oxygen atom, Q ₃ is —C (O) —, and m is 4, (3) R ″ ″ is 2,6- A diisopropylphenyl group, X is a nitro group, amino group or hydroxy group, Y is an oxygen atom, Q ₃ is —C (O) —,
And (4) R ″ ″ is an adamantyl group, Y is an oxygen atom, Q ₃ is —C (O) —, and m is 0, excluding those in which m is 1 Or a salt thereof, wherein the angiogenesis inhibitor of the above [31] is provided.

In one preferred embodiment, the present invention provides a compound of the general formula (I ′):

Embedded image Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different), Y is an oxygen atom or a sulfur atom,
Q ₃ are -C (O) -, - C (S) - or -CH ₂ - cyclic imide derivative or a salt thereof represented by a is], provides a process for their preparation and pharmaceutical compositions containing them It is.

In particular, in one of the more preferred embodiments, the present invention provides compounds of the general formula (I ''):

Embedded image [In the formula, Z ′ is an alkyl group, and R ″ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group (where the substituent is nitro X ′ is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group. , Y and A are oxygen atoms or sulfur atoms (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)
Wherein n is 0 or 1.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention provides a cyclic imide derivative represented by the general formula (I) or a salt thereof (pharmaceutically acceptable salt).
A pharmaceutical composition having an aminopeptidase N enzyme inhibitory action, comprising, as an active ingredient, a cyclic imide derivative represented by the general formula (I) or a salt thereof (pharmaceutically acceptable salt) as an active ingredient, an angiogenesis inhibitory action Embedded image and a cyclic imide derivative represented by the general formula (I) or a salt thereof, and a novel cyclic imide derivative represented by the general formula (I ′) or a salt thereof ( A pharmaceutically acceptable salt). In addition, the present invention provides a cyclic imide derivative represented by the general formula (I ') or a salt thereof, a method for producing the same, and a pharmaceutical composition having a tumor necrosis factor production regulating action comprising the derivative or a salt thereof as an active ingredient. provide.

In the above general formulas (I), (I ′) and (I ″ ″), and the following general formula (I ″ ″ ″), the halogen atom contained in X is fluorine, chlorine, Each atom of bromine and iodine is mentioned, and as the alkyl group contained in X, a lower alkyl group is mentioned, and a linear or branched C1-C6, preferably C1-C4 alkyl group. Those such as methyl, ethyl, propyl, isopropyl,
Examples include a butyl group, a tertiary butyl group, a pentyl group, and a hexyl group. Examples of the alkoxy group contained in X include a lower alkoxy group, which has 1 to 1 carbon atoms.
6, desirably a straight-chain or branched one having 1 to 4 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, tert-butoxy, pentoxy, hexyloxy, etc. And
Further, as the alkylthio group, a lower alkylthio group can be mentioned, which has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Linear or branched, such as methylthio, ethylthio, propylthio, isopropylthio, butylthio, tertiarybutylthio, pentylthio, hexylthio and the like. The amino group contained in X may be substituted with an acyl group. Examples of the acyl group include those having an alkyl group residue, and the alkyl group portion includes those described above. The alkyl group portion of the above group may be substituted with the above halogen atom. In the general formulas (I ′ ″-1) and (I ″ ″-2), the halogen atom, alkyl group, alkoxy group, and alkylthio group contained in X ₁ or X ₂ are the same as those described above for X. It is. The optionally acylated amino group contained in X ₁ or X ₂ is also the same as that of X described above. X ₁ or X ₂
Is preferably fluorine. In the general formula (I), the lower alkanediyl group contained in Z has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms.
Linear or branched, for example, a methylene group, an ethylene group, a propylene group, a —CH (CH ₃ ) — group, a —C (C
H _{3) 2} - _{group, -CH (CH 3) -CH 2} - group, -C
(CH ₃ ) ₂ —CH ₂ — group, —CH (CH ₃ ) —CH
(CH ₃ ) — group, —C (CH ₃ ) ₂ —CH ₂ —CH ₂ —
And the like. Similarly, in the general formula (I ′),
As the alkyl group for Z ′, those similar to the alkyl groups contained in X described above can be mentioned.

In the above general formulas (I) and (I ′), the aryl part of the optionally substituted aryl group contained in R and R ′ is a monocyclic or bicyclic aryl moiety, Heterocyclic compounds containing one or more hetero atoms such as nitrogen atom, sulfur atom, oxygen atom, for example,
Examples include a phenyl group, a naphthyl group, a pyridyl group, a thenyl group, a furanyl group, a pyrimidyl group, an oxazole group, and an imidazole group.Examples of the substituent of the optionally substituted aryl group include those similar to the above X. And preferably a straight-chain or branched alkyl group, preferably a lower alkyl group having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group and an ethyl group. ,
Examples include a propyl group, an isopropyl group, a butyl group, a tertiary butyl group, a pentyl group, and a hexyl group.
Further preferred substituents include a nitro group, an amino group which may be acylated, for example, an amino group, an alkanoylamino group, preferably a straight-chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms. Or an alkylthio group such as a branched alkanoylamino group, preferably having 1 to 1 carbon atoms
6, desirably a linear or branched alkylthio group having 1 to 4 carbon atoms. The cycloalkyl portion of the optionally substituted cycloalkyl group contained in R and R ′ is a monocyclic, bicyclic or tricyclic one,
For example, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclohexyl group, an adamantyl group, and the like can be mentioned. As the substituent of the optionally substituted cycloalkyl group, those similar to the above X can be mentioned, and it is preferable. Is an alkyl group, preferably a lower alkyl group, having a straight or branched chain having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, such as a methyl group, an ethyl group,
Examples include a propyl group, an isopropyl group, a butyl group, a tertiary butyl group, a pentyl group, and a hexyl group.
In the general formulas (I ′ ″-1) and (I ′ ″-2), R ₁
And included in R _2, an amino group, a lower alkyl group and the lower alkoxy group and a lower alkylthio group, the X
Are described. Incidentally, the general formula (I),
(I ′), (I ″), (I ′ ″ −1) and (I ″ ″)
When m is 2 or more, X may be the same or different, and X ′ and X ₁ may be the same or different. Further, in the general formula (I ″ ′ − 2), when p is 2 or more,
X ₂ may be the same or different. The general formula (I ″)
Wherein R '' is an optionally substituted phenyl group;
Examples of the substituents of the optionally substituted naphthyl group or the optionally substituted cyclohexyl group include the same as those described above for R and R′.The lower acylamino group includes, for example, carbon Examples thereof include a linear or branched lower alkanoylamino group having 1 to 6, preferably 1 to 4 carbon atoms.

In the cyclic imide derivative represented by the general formula (I), the compound in which X is an amino group or a hydroxy group (and / or a compound having an amino group or a hydroxy group as a substituent in R) is a salt. And salts thereof include any pharmacologically acceptable salts, for example, inorganic salts such as hydrochloride, sulfate and nitrate; acetate, methanesulfone Organic acid salts such as acid salts; alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as magnesium salts and calcium salts; triethanolamine salts;
Organic amine salts such as tris (hydroxymethyl) aminomethane salt and the like can be mentioned. Of the isoindole derivatives represented by the general formulas (I ′) and (I ″),
A compound in which X or X ′ is an amino group or a hydroxy group (and / or a compound having an amino group or a hydroxy group as a substituent in R ′ or R ″) can similarly form a salt. The salts include all salts that are pharmacologically acceptable, and include, for example, the salts exemplified above.

In the above general formulas (I ') and (I "),

Embedded image Has one asymmetric carbon atom, and therefore has an S-form or an R-form as an optically active substance. In the present invention, the isoindole derivative represented by the general formulas (I ′) and (I ″) or a salt thereof includes a racemic form, the S-form or the R-form unless otherwise specified.

In the above-mentioned formula (I '), the following compounds are preferably racemic, S-form or R-form of an optically active compound. (1) Z ′ is a methyl group, R ′ is a phenyl group, a naphthyl group or a cyclohexyl group, X is a nitro group, a halogen atom, Y is an oxygen atom, and Q ₃ is —C
(O)-or -C (S)-, wherein m is 0, 1 or 4. (2) Z ′ is a methyl group, R ′ is a phenyl group, a naphthyl group or a cyclohexyl group, X is a fluorine atom, Y is an oxygen atom, and Q ₃ is —C (O) — or —. C
(S)-, wherein m is 0 or 4. (3) Z ′ is a methyl group, R ′ is a phenyl group, a naphthyl group or a cyclohexyl group, X is a fluorine atom, Y is an oxygen atom, and Q ₃ is —C (O) —. ,
A compound wherein m is 0 or 4. In addition, the general formula (I ″)
Among them, racemic forms of the following compounds and S-forms or R-forms of optically active forms are more desirable. (1) Z ′ is a methyl group, R ″ is a phenyl group, a naphthyl group or a cyclohexyl group, X ′ is a nitro group,
A compound wherein a halogen atom, Y is an oxygen atom, A is an oxygen atom or a sulfur atom, m is 0, 1 or 4, and n is 1. (2) Z ′ is a methyl group, R ″ is a phenyl group, a naphthyl group or a cyclohexyl group, X ′ is a fluorine atom, Y is an oxygen atom, A is an oxygen atom or a sulfur atom. , M is 0 or 4, and n is 1. (3) Z ′ is a methyl group, R ″ is a phenyl group, a naphthyl group or a cyclohexyl group, X ′ is a fluorine atom, Y and A are oxygen atoms, and m is 0 or 4. , N is 1.

In the general formula (I '), the following compounds are more preferable. (4) (R) -2- (1-phenylethyl) -1H-isoindole-1,3-dione, (R) -2- (1-naphthylethyl) -1H-isoindole-1,3-dione , (R) -2- (1-phenylethyl) -4,5,
6,7-tetrafluoro-1H-isoindole-1,
3-dione, (R) -2- (1-naphthylethyl)-
4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione, (R) -2- (1-cyclohexylethyl) -1H-isoindole-1,3-dione,
(R) -2- (1-cyclohexylethyl) -4,5
6,7-tetrafluoro-1H-isoindole-1,
3-dione, (R) -2- (1-phenylethyl) -1
H-isoindole-1-thio-3-one, (R) -2
-(1-Naphthylethyl) -1H-isoindole-1
-Thio-3-one, (R) -2- (1-phenylethyl) -4,5,6,7-tetrafluoro-1H-isoindole-1-thio-3-one, (R) -2- (1-naphthylethyl) -4,5,6,7-tetrafluoro-1
H-isoindole-1-thio-3-one, (R) -2
-(1-cyclohexylethyl) -1H-isoindole-1-thio-3-one or (R) -2- (1-cyclohexylethyl) -4,5,6,7-tetrafluoro-
1H-isoindole-1-thio-3-one.

Further, among the above-mentioned general formula (I '), the following compounds are most desirable. (5) (R) -2- (1-phenylethyl) -1H-isoindole-1,3-dione, (R) -2- (1-naphthylethyl) -1H-isoindole-1,3-dione , (R) -2- (1-phenylethyl) -4,5,
6,7-tetrafluoro-1H-isoindole-1,
3-dione, (R) -2- (1-naphthylethyl)-
4,5,6,7-tetrafluoro-1H-isoindole-1,3-dione, (R) -2- (1-cyclohexylethyl) -1H-isoindole-1,3-dione or (R)- 2- (1-cyclohexylethyl) -4,
5,6,7-tetrafluoro-1H-isoindole-
1,3-dione.

The above-mentioned general formula (I "'-1) or (I"'-
Preferred examples of the N-phenylimide-based compound of 2) or a salt thereof are exemplified. (1) R ₁ and R ₂ are both isopropyl groups. (2) X ₁ or X ₂ is a fluorine or nitro group. (3) m and p are 0 or 1. (4) Q ₅ is —C (O) —.

The cyclic imide derivative of the general formula (I) or a salt thereof (hereinafter, simply referred to as "the compound of the present invention") of the present invention can be produced by various methods. For example, the compound of the present invention can be produced by a method such as the following reactions [A] to [C] and a usual salt forming reaction.
Further, if necessary, the compound thus obtained can be modified into a compound having a corresponding substituent, for example, by modifying a substituent of the compound or replacing it with another substituent. Examples of such treatment include acylation of an amino group and reduction of a nitro group. [A] Q ₂ is —C (O) —, and Q ₃ is —CH ₂
Or Q ₂ is —CH ₂ —, and Q ₃ is —C
(O)-

Embedded image (In the above reaction [A], Q ₁ , Z, R, X and m are as described above.)

[B] Q ₂ is —C (O) — and Q
_{When 3} is -C (O)-

Embedded image (In the above reaction [B], Q ₁ , Z, R, X and m are as described above.)

[C] When Q ₂ is —C (S) —

Embedded image (In the above reaction [C], Q ₃ , Z, R, X and m are as described above, and Q ₆ is —C (O) — or —CH ₂ —.) Describe in. The reaction [A] is usually carried out in the presence of an acidic substance. Examples of the acidic substance include organic acids such as acetic acid and toluenesulfonic acid;
One or more kinds are appropriately selected from inorganic acids such as sulfuric acid and hydrochloric acid.

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 Aromatic hydrocarbons such as carbon tetrachloride, methylene chloride, chloroform, dichloromethane, dichloroethane, trichloroethane, hexane, and cyclohexane; ethers such as dioxane; dimethyl sulfoxide; One or more of a polar aprotic solvent such as dimethylacetamide, dimethylformamide, and N-methylpyrrolidone; and an organic acid such as acetic acid are appropriately selected. 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 ° C.
Time, preferably 0.2 to 2 hours.

The reaction (B) will be described below.
Reaction (B) is carried out in the presence of a solvent as necessary.
The solvent may be any solvent as long as it is inert to the reaction, for example, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; ethers such as dioxane; dimethylsulfoxide, dimethylacetamide , N-methylpyrrolidone, or a polar aprotic solvent or the like, and one or more are appropriately selected. The reaction temperature of the reaction [B] varies depending on the reaction conditions and cannot be specified unconditionally, but is usually 100 to 200 ° C, preferably 140 to 200 ° C, and the reaction time is usually 1 to 4
Time, preferably 1-2 hours.

The reaction [C] is described below.
Reaction (C) 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, aromatic hydrocarbons such as benzene, toluene, xylene and chlorobenzene; ethers such as dioxane; dimethylsulfoxide, dimethylacetamide , N-methylpyrrolidone, or a polar aprotic solvent or the like, and one or more are appropriately selected. The reaction temperature of the reaction [C] varies depending on the reaction conditions and cannot be specified unconditionally.
４０40 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 isoindole 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.

[A ′] when Y is an oxygen atom and Q ₃ is —CH ₂ —

Embedded image

[B ′] When Y is an oxygen atom and Q ₃ is —C (O) —

Embedded image

[C '] When Y is a sulfur atom

Embedded image

Formula (III):

Embedded image Since the amines represented by the formula (1) have one asymmetric carbon atom, S-forms or R-forms exist as optically active forms, but the amines include racemic forms, S-forms or R-forms unless otherwise specified.

The reaction [A '] can be carried out in the same manner as in the reaction [A]. Reaction [A ']
Wherein Z ′, R ′, X and m are as described above. The reaction [B '] can be carried out in the same manner as in the reaction [B]. In the reaction [B '], Z', R ', X
And m are as described above. The reaction [C '] can be carried out in the same manner as in the reaction [C]. 'During, Z reaction (C)', R ', X and m are as defined above, Q ₃ is -C (O) -, - C (S) - or -C
H ₂ —, and Q ₄ is —C (O) — or —CH ₂ —.

The N-phenylimide-based compound of the general formula (I ""-1) or (I ""-2) of the present invention or a salt thereof can be produced by various methods. The N-phenylimide type or a salt thereof of the present invention can be produced by the following reaction.

[0055]

Embedded image (Wherein R ₁ , R ₂ , X ₁ , X ₂ , m, and p are as described above, Q ₇ is —C (O) — or —CH ₂ —, and Q ₈ is —C (O) — Or —CH ₂ —.)

The formula (I ′ ″-1) or (I ″ ′ −)
In the N-phenylimide-based compound represented by 2), those in which Y is an oxygen atom are produced by the former reaction, and those in which Y is a sulfur atom are produced by the latter reaction. In this subsequent reaction, compounds represented by the following general formula can be produced in addition to the general formula (I ""-3) or (I ""-4). It can be produced selectively according to any reaction conditions or as a mixture. When manufactured as a mixture, each can be separated by purification means such as column separation.

[0057]

Embedded image

The reaction between the compound represented by the general formula (IX) or (XI) and the aniline-based compound represented by the general formula (XIII) is carried out in the same manner as in the above reaction [A].
The reaction between the compound represented by the general formula (IX), (X), (XI) or (XII) and the aniline compound represented by the general formula (XIII) may be carried out in an inert solvent. It may be carried out under melting without using. Examples of the inert solvent include aromatic hydrocarbons such as benzene, toluene, xylene, and chlorobenzene; ethers such as dioxane; and polar aprotic solvents such as dimethyl sulfoxide, dimethylacetamide, and N-methylpyrrolidone.
The species or two or more species are appropriately selected. In addition, the reaction of the imide compound represented by the general formula (XIV) or (XV) with phosphorus pentasulfide or a dimer thereof is usually performed in an inert solvent, and the inert solvent is, for example, the aromatic hydrocarbon described above. Is mentioned. The compound of the general formula (I ′ ″-2) forms a salt in the same manner as the compound of the general formula (I ″ ″-1) of the present invention. It is useful as a component and exhibits the same biological activity as described with respect to the compounds of the above general formula (I ″ ′-1), as described below.

The phthalimide derivative represented by the above general formula (I ″ ″) or a salt thereof can be obtained by, for example, R ′ ″ as R—Z—NH ₂ in the above methods [A] to [C]. '-N
It can be manufactured using H ₂ . The N-phenylphthalimide derivative can be produced by various methods. Among them, N-phenylphthalimide can be produced by reacting aniline with phthalic anhydride, for example, as in [A], N-phenylthiophthalimide can be used for this N-phenylimide, for example, as in [C].
It can be produced by reacting phenylphthalimide with diphosphorus pentasulfide, or a dimer thereof, which has a similar function. In this case, the reaction (A) may be carried out in the presence of an acidic substance as described above,
Also, phthalic anhydride may be used in excess. When a solvent is used in the reaction, those described above such as aromatic hydrocarbons, ethers, and polar aprotic solvents are preferably used. In this case, the reaction temperature of the reaction [A] varies depending on the reaction conditions and cannot be specified unconditionally.
The temperature is 0 ° C, preferably 140 to 200 ° C, and the reaction time is usually 1 to 4 hours, preferably 1 to 2 hours.

In this case, when a solvent is used in the reaction [C],
The same one as in the case of the reaction [A] can be preferably used. The reaction temperature of the reaction [C] varies depending on the reaction conditions and cannot be specified unconditionally.
The reaction temperature is 0 ° C, preferably 120 to 180 ° C, and the reaction time is usually 0.5 to 40 hours, preferably 1 to 40 hours.

In another embodiment, the present invention provides a compound of the general formula (I ″ ″ ′):

Embedded image [Wherein, R is an optionally substituted aryl group, for example, an optionally substituted phenyl group (wherein the substituent is, for example,
A nitro group, an amino group which may be acylated, for example, an alkoxy group, an alkylthio group or an alkyl group such as an amino group or a lower acylamino group);
Is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, and m is an integer of 0 to 4 (m is 2 In the above case, X may be the same or different)), a N-phenylphthalimide derivative or a salt thereof, a production method thereof, and a pharmaceutical composition containing the same. According to the present invention, an aminopeptidase N enzyme inhibitor or angiogenesis inhibitor comprising the N-phenylphthalimide derivative represented by the general formula (I ′ ″ ″) or a salt thereof and a pharmaceutically acceptable carrier, Further, the present invention provides a tumor necrosis factor production regulator, for example, a tumor necrosis factor production inhibitor, a tumor necrosis factor production enhancer, and the like.

The compound of the present invention is useful as an active ingredient of a pharmaceutical composition. In particular, it has an effect of regulating (enhancing or suppressing) 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. Among them, among the compounds of the general formula (I ') or salts thereof, the optically active R-form is effectively used for the treatment and prevention of various diseases, since it favorably suppresses the production of tumor necrosis factor. (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 the pathological increase in angiogenesis is involved in the onset or progress of various diseases. Specific examples of these diseases include cancer and cancer metastasis; benign tumors such as hemangiomas, acoustic neuromas, neurofibromas, trachoma, purulent granuloma, granulation; various chronic inflammations such as rheumatoid arthritis; psoriasis; diabetic retina Disease, retinopathy of prematurity, macular degeneration, glaucoma, posterior lens fibroplasia,
Eye diseases involving angiogenesis such as central retinal vein occlusion; angiogenesis associated with corneal transplantation; hypertrophic scars; atherosclerosis; edema sclerosis; and 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 a peptide having an amino terminus such as alanine, leucine, phenylalanine, tyrosine, arginine, methionine, lysine, tryptophan, glycine, serine or histidine as a substrate. It is widely distributed on epithelial cells of the kidney and small intestine, monocytes and granulocytes, cancerous cells, and other cell membrane surfaces such as placenta, liver, and pancreas. Various physiological functions such as biosynthesis and degradation of active substances and degradation of extracellular matrix are discussed (Hematology / Oncology, Vol. 29, 288-29).
6, 1994). It has also been suggested that this enzyme is involved in immune functions (Japanese Journal of Cancer and Chemotherapy;
Journal of Cancer and Che
Therapy, vol. 9, p. 1019-1024, 1
982). In addition, it has been reported that the inhibition of aminopeptidase N suppresses metastasis of cancer cells (Cancer Research; Cancer Research,
46, 4505-4510, 1986). The pharmaceutical composition containing the compound of the present invention comprises aminopeptidase N
It can be used as an inhibitor and is useful as a preventive or therapeutic agent for cancer, cancer metastasis, inflammatory disease, autoimmune disease, allergic disease and the like.

Particularly, the following embodiments are desirable. (1) An angiogenesis inhibitor containing the cyclic imide derivative represented by the general formula (I) as an active ingredient. (2) An aminopeptidase N inhibitor containing the cyclic imide derivative represented by the above general formula (I) as an active ingredient. (3) A biological response modifier containing the isoindole derivative represented by the general formula (I ′) as an active ingredient. (4) An immunostimulant containing the isoindole derivative represented by the general formula (I ') as an active ingredient. (5) An immunosuppressant containing the isoindole derivative represented by the general formula (I ') as an active ingredient. (6) A tumor necrosis factor production enhancer containing the isoindole derivative represented by the general formula (I ′) as an active ingredient. (7) A tumor necrosis factor production inhibitor comprising, as an active ingredient, the isoindole derivative represented by the general formula (I ′).

(8) An anticancer agent containing the isoindole derivative represented by the above general formula (I ') as an active ingredient. (9) An anti-inflammatory agent containing the isoindole derivative represented by the general formula (I ') as an active ingredient. (10) An antidiabetic agent containing the isoindole derivative represented by the general formula (I ') as an active ingredient. (11) An angiogenesis inhibitor containing the isoindole derivative represented by the general formula (I ′) as an active ingredient. (12) An antirheumatic agent comprising the isoindole derivative represented by the general formula (I ') as an active ingredient.

(13) An angiogenesis inhibitor containing, as an active ingredient, an N-phenylimide compound represented by the above general formula (I ′ ″-1) or (I ″ ″-2). (14) The general formula (I ′ ″ − 1) or (I ″ ″-2)
An aminopeptidase N inhibitor comprising, as an active ingredient, an N-phenylimide-based compound represented by the formula: (15) An angiogenesis inhibitor comprising, as an active ingredient, the phthalimide derivative represented by the general formula (I ″ ″). (16) Aminopeptidase N containing a phthalimide derivative represented by the above general formula (I ″ ″) as an active ingredient
Inhibitors. (17) An angiogenesis inhibitor comprising an N-phenylphthalimide derivative represented by the above general formula (I ″ ″) as an active ingredient. (18) An aminopeptidase N inhibitor comprising, as an active ingredient, an N-phenylphthalimide derivative represented by the above general formula (I ″ ″).

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 and the like. 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.

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.

[0072]

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 (R) -2- (1-phenylethyl) -4,5,6,7
-Tetrafluoro-1H-isoindole-1,3-di
Synthesis of ON (Compound No. 18) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 121 mg of (R) -α-methylbenzylamine were charged, and heated and stirred at 180 ° C. for 2 hours. After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), recrystallized with a mixed solvent of n-hexane / ethyl acetate, and 210 mg of the desired product was obtained. Was obtained as colorless needles. Yield 65%. m. p. 95.5
９６96 ° C .; [α] ²⁰ _D = 41.5 ° (C = 0.348)
AcOEt); MS (E1 +) 323 (M) ⁺

Synthesis Example 2 : (S) -2- (1-phenylethyl) -4,5,6,7
-Tetrafluoro-1H-isoindole-1,3-di
Synthesis of ON (Compound No. 17) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 121 mg of (S) -α-methylbenzylamine were charged and heated and stirred at 180 ° C. for 2 hours. After allowing to cool, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), recrystallized with a mixed solvent of n-hexane-ethyl acetate, and purified to give 240 mg of the objective compound. Was obtained as colorless needles. Yield 74%. m. p. 95-9
6 ° C .; [α] ²⁰ _D = −42.2 ° (C = 0.386 A
cOEt); MS (E1 +) 323 (M) ⁺

Synthesis Example 3 (R) -2- (1-naphthylethyl) -4,5,6,7
-Tetrafluoro-1H-isoindole-1,3-di
Synthesis of ON (Compound No. 50) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 121 mg of (R) -α-methylbenzylamine were charged and heated and stirred at 180 ° C. for 2 hours. After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), and further purified by Kugelrohr distillation to obtain 290 mg of the desired product as a yellow oil. (Solidified upon standing at room temperature). Yield 78
%. b. p. 240 ° C. (1 mmHg); [α] ²⁰ _D = 4
0.9 [deg.] (C = 0.089 EtOH); MS (E1
+) 373 (M) ⁺

Synthesis Example 4 : (S) -2- (1-naphthylethyl) -4,5,6,7
-Tetrafluoro-1H-isoindole-1,3-di
Synthesis of ON (Compound No. 49) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 121 mg of (S) -α-methylbenzylamine were charged and heated and stirred at 180 ° C. for 2 hours. After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), and further purified by Kugelrohr distillation to obtain 280 mg of the desired product as a yellow oil. (Solidified upon standing at room temperature). Yield 75
%. b. p. 240 ° C. (1 mmHg); [α] ²⁰ _D = −
42.1 ° (C = 0.097 EtOH); MS (E1
+) 373 (M) ⁺

Synthesis Example 5 : (R) -2- (1-cyclohexylethyl) -4,5
6,7-tetrafluoro-1H-isoindole-1,
Synthesis of 3-dione (Compound No. 69) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 127 mg of (R) -α-methylbenzylamine were charged and heated and stirred at 180 ° C. for 1.5 hours. . After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), recrystallized with a mixed solvent of n-hexane / ethyl acetate, and 210 mg of the desired product was obtained. Was obtained as a colorless powder. Yield 64%. m. p. 147 ~
148 ° C .; [α] ²⁰ _D = −5.13 ° (C = 0.65)
8, AcOEt); MS (E1 +) 329 (M) ⁺

Synthesis Example 6 : (S) -2- (1-cyclohexylethyl) -4,5
6,7-tetrafluoro-1H-isoindole-1,
Synthesis of 3-dione (Compound No. 68) In a 50 ml eggplant-shaped flask, 220 mg of tetrafluorophthalic anhydride and 127 mg of (S) -α-methylbenzylamine were charged and heated and stirred at 180 ° C. for 1.5 hours. . After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), and recrystallized with a mixed solvent of n-hexane / ethyl acetate to obtain 215 mg of the objective compound. Was obtained as a colorless powder. Yield 65%. m. p. 147 ~
148 ° C .; [α] _D ²⁰ = 5.26 ° (C = 0.618,
AcOEt); MS (E1 +) 329 (M) ⁺

Synthesis Example 7 : (R) -2- (1-phenylethyl) -4-nitro-1
H-isoindole-1,3-dione (Compound No. 8
Synthesis of 4) 386 mg of 3-nitrophthalic anhydride and (R) -α-methylbenzylamine 24 in a 50 ml eggplant-shaped flask
2 mg was charged and heated and stirred at 180 ° C. for 1.5 hours. After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), recrystallized with a mixed solvent of n-hexane / ethyl acetate, and 430 mg of the desired product was obtained. Was obtained as a slightly yellow powder. 73% yield. m. p. 115-
117 ° C .; MS (E1 +) 296 (M) ⁺

Synthesis Example 8 : (S) -2- (1-phenylethyl) -4-nitro-1
H-isoindole-1,3-dione (Compound No. 8
Synthesis of 3) 386 mg of 3-nitrophthalic anhydride and (S) -α-methylbenzylamine 24 in a 50 ml eggplant-shaped flask
2 mg was charged and heated and stirred at 180 ° C. for 1.5 hours. After cooling, the reaction product was dissolved in chloroform, purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v), recrystallized with a mixed solvent of n-hexane-ethyl acetate, and 443 mg of the desired compound was obtained. Was obtained as a slightly yellow powder. Yield 75%. m. p. 115-
117 ° C .; MS (E1 +) 296 (M) ⁺

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 above-mentioned method for producing the compounds of the present invention.

[0082]

[Table 1]

[Table 2]

[Table 3]

[0083]

[Table 4]

[0084]

[Table 5]

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

[0086]

[Table 6]

In Table 1, Compound No. 17-18,
No. 49 to 50 and No. The results of elemental analysis of Nos. 68 to 69 were as follows. Compound No. 17: Theoretical value C; 59.45, H; 2.81, N; 4.33 Actual value C: 59.50, H; 2.81, N; 4.36 Compound No. 18: Theoretical value C; 59.45, H; 2.81, N; 4.33 Actual value C: 59.41, H; 2.88, N; 4.45 Compound No. 49: Theoretical value C; 64.35, H; 2.97, N; 3.75 Actual value C: 64.35, H; 2.92, N; 3.90 Compound no. 50: Theoretical value C; 64.35, H; 2.97, N; 3.75 Actual value C: 64.35, H; 2.92, N; 3.82 Compound no. 68: Theoretical value C; 58.36, H; 4.59, N; 4.25 Actual value C: 58.51, H; 4.69, N; 4.25 Compound no. 69: Theory C: 58.36, H; 4.59, N; 4.25 Found C: 58.32, H; 4.40, N; 4.35

Synthesis Example 9 N- (2,6-diisopropylphenyl) isoindoli
Synthesis of o-phthalaldehyde ( 0.5 g) and 2,6-diisopropylaniline (0.661 g ) in dichloromethane (20 ml), acetic acid (1 ml) was added thereto, and the mixture was 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 10 N- (2,6-diisopropylphenyl) -5-tert
Butylphthalimide (Compound No. 173 described below)
Mixing 0.605g of synthetic 4-tert-butyl phthalic anhydride with a 2,6-diisopropyl aniline 0.630 g, it was reacted at 200 ° C.. 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 11 N- (2,6-diisopropylphenyl) thiophthalate
Synthesis of Mid (Compound No. 174) (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 was dissolved in 10 ml of xylene, and 0.217 g of diphosphorus pentasulfide (dimer) was added thereto. The mixture was 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 3 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.

[0093]

[Table 7]

[Table 8]

[Table 9]

[Table 10]

[0094]

[Table 11]

Next, the NMR data of typical examples of the compounds of the present invention are shown in Table 4. Is the third
Compound No. in the table. Is the same as

[0096]

[Table 12]

In Table 3, compound No. The results of the 180 instrumental analysis were as follows. Mass: M / Z 395 (M ⁺ ), 362 (M-33: MS), 320 (M-75: M-
4F) Elemental analysis: theoretical C; 60.75, H; 4.33, N; 3.54 found C; 60.50 H; 4.73 N; 3.38.

Synthesis Example 12 : N-phenylphthalimide (Compound No. 201 described below)
Under synthetic ice cooling, 1.48 g of aniline 0.93 phthalic anhydride
1 g, and reacted at 180 ° C. for 2 hours. After completion of the reaction, the resultant was dissolved in ethyl acetate, washed with an aqueous solution of sodium hydrogen carbonate, washed with water, and then washed with a saturated saline solution. Then, it was dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Then, recrystallization was performed using ethanol to obtain 1.10 g of the target compound. The product had the following physical properties and analysis values. mp. 209 to 211 ° C ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.96 (2H, m), 7.80 (2H, m), 7.
52 (2H, m), 7.43 (3H, m) C ₁₄ H ₉ NO ₂ elemental analysis Experimental value: C 75.22 H 4.16 N 6.55 Theoretical value: C 75.33 H 4.06 N 6.27

[0099]Synthesis Example 13:N- (2,6-diisopropylphenyl) -phthalimime
(Compound No. 202 described below) 7.41 g of phthalic anhydride and 2,6-diisopropylani
8.86 g of phosphorus was mixed and reacted at 180 ° C. for 2 hours.
Was. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate,
After washing with an aqueous solution of sodium hydrogen carbonate and washing with water,
Washed with a saline solution. Then, with anhydrous magnesium sulfate
It was dried, filtered, concentrated, dried and solidified. So
After that, the target compound was recrystallized using ethanol.
9.06 g (62.5% yield) was obtained. This one is below
The physical properties and analytical values of the compound were shown. mp. 172 ° C ¹ H-NMR (60MHz, CDCl_Three): δ 7.87 (4H, m), 7.26 (3H, m), 2.72
(2H, q, J = 8.8Hz), 1.21 (12H, d, J = 8.8Hz) C₂₀H_{twenty one}NO_Two Elemental analysis Experimental value: C 78.17 H 6.74 N 4.57 Theoretical value: C 78.15 H 6.89 N 4.56

Synthesis Example 14 : N- (2,6-diisopropylphenyl) -4,5
6,7-tetrafluoro-phthalimide (Compound N
o. Synthesis of 203) 0.2 g of 3,4,5,6-tetrafluorophthalic anhydride and 0.161 g of 2,6-diisopropylaniline were mixed, melted at 150 ° C. for 2 hours, and reacted. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Thereafter, the mixture was recrystallized using a mixture of hexane and dichloromethane to obtain 0.198 g (yield: 57%) of the target compound. The product had the following physical properties and analysis values. mp. 167.0 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 7.48 (1 H, t, J = 7.73 Hz), 7.30
(2H, d, J = 7.73Hz), 2.63 (2H, 7 split, J = 6.90Hz), 1.17 (12H,
_{d, J = 6.90Hz) C 20} H 17 F 4 NO 2 Elemental analysis Found: C 63.04 H 4.42 N 3.77 F 20.02 theory: C 63.32 H 4.52 N 3.69 F 20.03

Synthesis Example 15 N- (2,6-diisopropylphenyl) -4-nitro
Synthesis of phthalimide (Compound No. 204 described later) 0.386 g of anhydride obtained by dehydrating 3-nitrophthalic acid at about 220 ° C. and 0.3 of 2,6-diisopropylaniline 0.3
54 g and reacted at 180 ° C. for 4 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Thereafter, the mixture was recrystallized using a mixture of hexane and ethyl acetate to obtain 0.320 g of the target compound (yield: 45%). The product had the following physical properties and analysis values. mp. 157-158 ° C ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.23 (1H, d, J = 7.86 Hz), 8.21
(1H, d, J = 7.86Hz), 8.01 (1H, d, J = 7.86Hz), 7.48 (1H, t, J = 7.
83Hz), 7.30 (2H, d, J = 7.83Hz), 2.66 (2H, 7 split, J = 6.61H
z), 1.19 (6H, d , J = 6.61Hz), 1.18 (6H, d, J = 6.61Hz) C 20 H 20 N 2 O 4 Elemental analysis Found: C 68.32 H 5.74 N 8.07 theory: C 68.17 H 5.72 N 7.95

Synthesis Example 16 N- (2,6-diisopropylphenyl) -5-nitro
Synthesis of phthalimide (Compound No. 205 described later) 0.386 g of anhydride obtained by dehydrating 4-nitrophthalic acid (containing 20% of 3-nitrophthalic acid) at about 190 ° C. and 0.354 g of 2,6-diisopropylaniline And reacted at 180 ° C. for 4 hours. After completion of the reaction, the reaction mixture was dissolved in ethyl acetate, dried over anhydrous magnesium sulfate, filtered, concentrated, dried and solidified. Then, recrystallization was performed using a mixture of hexane and ethanol to obtain 0.352 g (yield: 50%) of the target compound. The product had the following physical properties and analysis values. mp. 161 to 162 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.81 (1 H, d, J = 2.14 Hz), 8.71
(1H, dd, J = 8.14,2.04Hz), 8.18 (1H, d, J = 8.14Hz), 7.49 (1H,
t, J = 7.73Hz), 7.32 (2H, d, J = 7.73Hz), 2.64 (2H, 7 split, J =
6.90Hz), 1.17 (12H, d , J = 6.90Hz) C 20 H 20 N 2 O 4 Elemental analysis Found: C 68.41 H 5.71 N 7.93 theory: C 68.17 H 5.72 N 7.95 Next, the synthesis example or Table 5 shows typical examples of the compound of the present invention synthesized based on the various methods for producing the compound of the present invention described above.

[0103]

[Table 13]

Synthesis Example 17 : N-phenyl-homophthalimide (Compound No. A-
Synthesis of 1) 0.871 g (5.37 mmol) of homophthalic anhydride and 0.4 g (4.30 mmol) of aniline were mixed,
Melted at 200 ° C. for 1 hour. The reaction was dissolved in ethyl acetate and washed with aqueous NaHCO ₃ , water and then brine,
After drying over anhydrous MgSO ₄ , pleating and filtering, concentrating and evaporating to dryness, the residue was recrystallized using a mixture of CH ₂ Cl ₂ and hexane.
g (68% yield). The product had the following physical properties and analysis values. mp. 186.7-187.9 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.25 (1H, dd, J = 7.63, 0.92),
7.65 (1H, dt, J = 7.63,1.42), 7.43-7.54 (4H, m), 7.35 (1H, d,
J = 7.32), 7.20-7.22 (2H, m), 4.24 (2H, s) C ₁₅ H ₁₁ NO ₂ elemental analysis Experimental value: C 75.88 H 4.63 N 6.00 Theoretical value: C 75.94 H 4.67 N 5.90

[0105]Synthesis Example 18:N- (2,6-dimethylphenyl) -homophthalimide
Synthesis of (Compound No. A-2) 0.67 g (4.13 mmol) of homophthalic anhydride and
0.4 g of 2.6-dimethylaniline (3.30 mmol
1) was mixed and melted at 200 ° C. for 1 hour. Reactant
Is dissolved in ethyl acetate and NaHCO_Three Aqueous solution, then water
Wash with saturated saline, anhydrous MgSO_Four Dry with folds
After filtration, concentration and drying, the residue is taken up in CH_Two Cl_Two And heki
Recrystallized using a mixture with sun
0.565 g (yield 68%) of colored granular crystals was obtained. This one
Indicates the following physical properties and analysis values. mp. 129.0-130.4 ° C ¹ H-NMR (500 MHz, CDCl_Three ): δ 8.27 (1H, d, J = 7.54), 7.67 (1
H, dt, J = 7.54,1.32), 7.49 (1H, t, J = 7.54), 7.38 (1H, d, J = 7.
54), 7.25 (1H, t, J = 7.33), 7.18 (2H, d, J = 7.33), 4.25 (2H,
s), 2.10 (6H, s) C₁₇H_FifteenNO_Two Elemental analysis Experimental value: C 77.03 H 5.68 N 5.23 Theoretical value: C 76.96 H 5.70 N 5.28

[0106]Synthesis Example 19:N- (2,6-diisopropylphenyl) -homophthal
Synthesis of imide (Compound No. A-3) 0.512 g (3.16 mmol) of homophthalic anhydride and
0.42 g (2.37) of 2,6-diisopropylaniline
mmol) and melted at 200 ° C. for 1 hour.
The reaction was dissolved in ethyl acetate and NaHCO_Three Aqueous solution, water
Then, wash with saturated saline and dry_Four And dry
The mixture was filtered, concentrated and dried to dryness._Two Cl_Two 
Recrystallized from a mixture of
As a result, 0.351 g (36% yield) of slightly purple tabular crystals were obtained.
The product had the following physical properties and analysis values. mp. 184.2-185.9 ° C ¹ H-NMR (500 MHz, CDCl_Three): δ 8.27 (1H, d, J = 7.66), 7.67 (1H,
dt, J = 7.66,1.32), 7.50 (1H, t, J = 7.66), 7.44 (1H, t, J = 7.8
3), 7.39 (1H, d, J = 7.66), 7.28 (2H, d, J = 7.83), 4.25 (2H, s),
2.64 (2H, 7 fission, J = 6.87), 1.15 (6H, d, J = 6.87), 1.14 (6H, d,
J = 6.87) C_{twenty one}H_{twenty three}NO_Two Elemental analysis Experimental value: C 78.32 H 7.14 N 4.55 Theoretical value: C 78.47 H 7.21 N 4.36

Synthesis Example 20 : N-phenyl-2,3-naphthalimide (Compound No. B
0.91 g of 2,3-naphthalenedicarboxylic anhydride (4.- 1)
59 mmol) and 5 ml of aniline.
Refluxed at C for 1 hour. The reaction was dissolved in CHCl ₃ and 1
After washing with N-HCl (more than equivalent), aqueous NaHCO ₃ solution, then water, and finally with saturated saline, drying over anhydrous MgSO ₄ , filtration with folds, concentration, and drying, the residue was washed with CHC.
white needles 0.36g purpose was recrystallized from l ₃
(Yield 29%) was obtained. The product had the following physical properties and analysis values. mp. 274.2-274.8 ° C. ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.47 (2H, s), 8.08-8.13 (2H,
m), 7.72-7.76 (2H, m ), 7.49-7.56 (4H, m), 7.41-7.45 (1H, m) C 18 H 11 NO 2 Elemental analysis Found: C 79.16 H 4.13 N 5.14 Theoretical: C, 79.11 H 4.06 N 5.13

Synthesis Example 21 N- (2,6-dimethylphenyl) 2,3-naphthalimi
Synthesis of 1,3- naphthalenedicarboxylic acid anhydride (5.0 g, 5.0 g)
5 mmol) and 5 ml of 2,6-dimethylaniline were mixed and stirred at 190 ° C. for 1 hour. CHCl
₃ in 1N-HCl (more than equivalent), NaHCO ₃
Aqueous solution, then with water, and finally with saturated saline, and anhydrous MgS
Dried O _4, pleated filtered, concentrated, white powder JoAkira 1.11 g (yield 73% as a mixture of the desired product was recrystallized with the residue CH ₃ OH and hexane after dryness ) Got. The product had the following physical properties and analysis values. mp. 180.1-180.7 ° C ¹ H-NMR (500 MHz, CDCl ₃ ): δ 8.48 (2H, s), 8.08-8.13 (2H,
m), 7.72-7.76 (2H, m), 7.29 (1H, t, J = 7.53), 7.21 (2H, d, J =
7.53), 2.20 (6H, s ) C 20 H 15 NO 2 Elemental analysis Found: C 79.81 H 5.11 N 4.55 theory: C 79.72 H 5.02 N 4.65

[0109]Synthesis Example 22:N- (2,6-diisopropylphenyl) 2,3-naph
Synthesis of Talimid (Compound No. B-3) 2,3-naphthalenedicarboxylic anhydride 1.0 g (5.0 g)
5 mmol) and 5 ml of 2,6-diisopropylaniline
And stirred at 190 ° C. for 1 hour. Reactant C
HCl_Three , 1N-HCl (more than equivalent), NaH
CO_Three Aqueous solution, then with water and finally with saturated saline solution, anhydrous
MgSO_Four Dried, filtered, folded and concentrated to dryness
After the residue_Three And C_Two H_Five Using a mixture with OH
And recrystallized to obtain 0.611 g of transparent granular crystals (yield
34%). It has the following physical properties and analytical values.
Indicated. mp. 251.0-252.3 ° C ¹ H-NMR (500 MHz, CDCl_Three): δ 8.49 (2H, s), 8.13-8.09 (2H,
m), 7.76-7.72 (2H, m), 7.48 (1H, t, J = 7.73), 7.32 (2H, d, J =
7.73), 2.77 (2H, 7 fission, J = 6.84), 1.18 (12H, d, J = 6.84) C_{twenty four}H_{twenty three}NO_Two Elemental analysis Experimental value: C 80.72 H 6.40 N 3.86 Theoretical value: C 80.64 H 6.49 N 3.92

Synthesis Example 23 N- (2,6-diethylphenyl) -homophthalimide (compound N
o. A-14) Homophthalic anhydride 16 in a 50 ml eggplant-shaped flask
2 mg (1.0 mmol) and 149 mg (1.0 mmol) of 2,6-diethylaniline were charged and heated and stirred at 180 ° C. for 2 hours. After cooling, the reaction product was dissolved in chloroform and purified by silica gel chromatography (eluent: methylene chloride: methanol = 30: 1 v / v).
Recrystallized with a mixed solvent of -hexane-ethyl acetate;
0 mg of the desired product was obtained as a slightly yellow powder. Yield 75%; mp 108-110 ° C; MS (EI +) m / z: 293
(M) ⁺ ; ¹ H-NMR (500 MHz, CDCl ₃ ) δ: 1.14 (6H, t, J = 7.33 Hz), 2.40
(4H, q, J = 7.33Hz), 4.25 (2H, s), 7.24 (2H, d, J = 7.83Hz),
7.36-7.40 (2H, m), 7.50 (1H, t, J = 7.83Hz), 7.67 (1H, dt, J =
7.83, 1.47Hz), 8.26 (1H, d, J = 6.85Hz); Anal calcd for C ₁₉ H ₁₉ NO ₂ (293.37): C, 77.79; H, 6.5
3; N, 4.77. Found: C, 77.69; H, 6.43; N, 4.56.

N- (2-methylthiophenyl) -phthalimide shown below was prepared in the same manner as in the synthesis of compound No. A-14.
(Compound No. A-15) was synthesized. Yield 81%; mp 106-108 ° C (n-Hexane-Ethyl a
cetate); MS (EI +) m / z: 283 (M) ⁺ ; ¹ H-NMR (500 MHz, CDCl ₃ )
δ: 2.41 (3H, s), 4.20 (1H, d, J = 2.5Hz), 4.30 (1H, d, J = 2.5
Hz), 7.17 (1H, d, J = 7.83Hz), 7.31 (1H, dt, J = 7.83,2.0H
z), 7.34 (1H, d, J = 7.34Hz), 7.40-7.47 (1H, m), 7.48 (1H,
t, J = 7.83Hz), 7.65 (1H, dt, J = 7.83,1.47Hz), 8.26 (1H, d
d, J = 7.83,1.47Hz); Anal calcd for C ₁₆ H ₁₃ NO ₂ S: C, 67.82; H, 4.62; N, 4.
94.Found: C, 67.86; H, 4.58; N, 4.70.

Next, specific examples of the N-phenylimide-based compound of the present invention are shown in Tables 6 and 7.

[0113]

[Table 14]

[0114]

[Table 15]

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 compound of the present invention on TNF-α production or secretion stimulated by okadaic acid) Human leukemia cell (HL-60)
Using an RPMI 1640 medium (containing 5% fetal bovine serum) in a carbon dioxide incubator (5% CO ₂ , humidified
(37 ° C.). The cells are then transformed into RPMI 164
0 culture medium (containing 10% fetal bovine serum) and okadaic acid (Saitama Prefectural Cancer Center) to a final concentration of 50 nM for HL-60 cells (5 × 10 ⁵ cells / ml) in logarithmic growth phase. , And furnished by Mr. Hirota Fujiki), 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. Culture 1
After 6 hours, centrifuge (1000-2000 rpm × 10 mi)
n. ), Cells were removed, and the amount of TNF-α in the supernatant was measured using a human TNF-α ELISA system (Amersham).
Was measured according to the method of Amersham. The measurement results are shown in Table 8, and the values in the table are values when the amount of TNF-α in the medium supernatant when treated with only a final concentration of 50 nM okadaic acid is 100%.

[0116]

[Table 16]

Test Example 2 (Effect of the Compound of the Present Invention on TNF-α Production or Secretion by TPA Stimulation) The test was conducted except that a final concentration of 10 nM TPA (manufactured by Sigma) was used instead of a final concentration of 50 nM okadaic acid. It carried out like the method of Example 1. The measurement results are shown in Table 9, and the numerical values in the table are TP at a final concentration of 10 nM.
The amount of TNF-α in the culture supernatant when treated with
It is a value when it is set to 00%.

[0118]

[Table 17]

Test Example 3 : Human leukemia cell HL-60 contained 1
Stimulated by 2-O-tetradecanoylphorbol-13-acetate (TPA) and stimulated by tumor necrosis factor (TNF-
α) was produced, and the effect of the compound of the present invention on TNF-α production was examined. (Production or enhanced secretion of TNF-α) Human leukemia cells (H
L-60) in RPMI1640 medium (containing 5% fetal calf serum) in a carbon dioxide incubator (5% CO2).
₂ , humidified at 37 ° C). The cells are then
Pre-cultured in PMI1640 medium (containing 10% fetal bovine serum), TPA was added to HL-60 cells (5 × 10 ⁵ cells / ml) in logarithmic growth phase to a final concentration of 10 nM
And further add the compound of the present invention to a desired concentration to form a cell suspension, which is then placed in a carbon dioxide incubator (5%
(CO ₂ , humidified, 37 ° C). In this culture 2
Using a 4-well multiplate (manufactured by Corning Incorporated), the cells were cultured by dispensing 0.5 ml of the above cell suspension per well. After 16 hours of culture, centrifugation (1000 rpm × 1
0 min. ) To remove cells and determine the TNF-α concentration in the supernatant using a human TNF-α ELISA system (Amers
(manufactured by ham) according to the method of Amersham, and the amount of TNF-α production was determined. The TNF-α production (%) is shown below as a measurement result, and the numerical value is the TNF-α when treated only with TPA at a final concentration of 10 nM.
This is the value when the production amount is 100%.

Compound No. Treatment concentration (μM) TNF production (%) A-3 10 258 B-3 10 134

Test Example 4 : (Inhibitory action of aminopeptidase N) The activity of aminopeptidase N was determined by using L-alanine-7-amido-4-methylcoumarin trifluoroacetate as an enzyme substrate and fluorescence of a dye formed after the reaction. It can be measured by measuring the intensity (European Journal Immunology, Vol. 22, 92
3-930, 1992). That is, 5 × 10 ⁴ acute lymphoblastic leukemia cells (MOLT-4)
As an enzyme substrate, L-alanine-7-amide-4-methylcoumarin trifluoroacetate (manufactured by Sigma, No. A4
302) was added to a final concentration of 0.2 mM, and the mixture was reacted at 37 ° C. for 1 hour with a diluent (enzyme-substrate reaction buffer) prepared by adjusting the compound of the present invention to a desired concentration. As a control, only a buffer containing no compound of the present invention was added. 100 mM Hepes buffer, pH 7.6 (120 mM sodium chloride, 5 m
M potassium chloride, 1.2 mM magnesium sulfate, 0.5
% Bovine serum albumin). After the reaction, M was measured under the measurement conditions of an excitation wavelength of 380 nm and a fluorescence emission wavelength of 440 nm.
The fluorescence intensity was measured with a TP-32 corona microplate reader (manufactured by Corona Electric). The measurement results are described below. The values in the table represent the enzyme inhibitory activity of the compound of the present invention in terms of IC ₅₀ (μg / ml) based on the fluorescence intensity of the control. The compound of the present invention inhibited aminopeptidase N.

Aminopeptidase N inhibitory activity IC ₅₀ value Compound No. (Μg / ml) A-2 14.1 A-3 <1.0 A-14 0.0025 A-15 0.2 A-16 27.8

Test Example 5 : [Platelet-derived vascular endothelial cell growth factor inhibitory activity (thymidine phosphorylase inhibitory activity) test] (1) 100 mmol / l thymidine (manufactured by Wako Pure Chemical Industries), 500 mmol / l K ₂ HPO ₄ (Nacalai) Chemical Co.) and 0.5 mol / l 2-morpholinoethanesulfonic acid monohydrate (pH 5.6; Dojindo Laboratories) were prepared. (2) The compound of general formula (I) was dissolved in a dimethyl sulfoxide solution having a concentration of 10% or less to prepare a test sample having a compound of general formula (I) having a concentration of 1.0 mg / ml. (3) 5 μg / ml human platelet-derived vascular endothelial cell growth factor (manufactured by Sigma) was prepared. (4) 20 μl of 100 mmol / l thymidine, 50
20 μl of 0 mmol / l K ₂ HPO ₄ , 0.5 mol
/ L 2-morpholinoethanesulfonic acid monohydrate (pH 5.6) in a tube containing 100 µl of the compound of the general formula (I) and 20 µl of a test sample having a concentration of 1.0 mg / ml in a total volume of 200 µl. Water (Milli-Q water autoclaved) and 5 μg / m
l of human platelet-derived vascular endothelial cell growth factor was added, and the final concentration of the compound of general formula (I) was 100 μg /
ml and reacted at 37 ° C. for 90 minutes. (5) 2N-NaO was added to 50 µl of the solution after the reaction.
Add 50 μl of H to make a measurement solution. (6) Measure the absorbance of the measurement solution with an absorptiometer (SPECTRA).
max250: manufactured by Molecular Devices) at a wavelength of 300 nm. (7) Total amount in 100 μl of 0.5 mol / l 2-morpholinoethanesulfonic acid monohydrate (pH 5.6) buffer and 20 μl of a test sample having a compound of general formula (I) having a concentration of 1.0 mg / ml Sterile water is added to 200 μl to prepare a compound solution of the general formula (I) so that the final concentration is 100 μg / ml. A solution obtained by adding 50 μl of 2N-NaOH to 50 μl of this solution was used as a sample for background measurement, and the absorbance at a wavelength of 300 nm was measured. The difference between the absorbance measured in (6) and the absorbance of the background measurement sample was taken as the measured absorbance (OD _sample ). (8) The same operation as in (1) to (7) was performed without using a test sample, and the resulting absorbance was used as a measured absorbance value (OD _control ) of a _control . (9) Platelet-derived vascular endothelial cell growth factor activity inhibition rate (thymidine phosphorylase activity inhibition rate) in a test sample having a compound concentration of 100 μg / ml of general formula (I)
Is the inhibition rate = (1−OD _sample / OD _control ) × 10
Obtained by the formula of 0 (%). (10) The concentration of the compound of the general formula (I) 0.1 μg / m
1, 1 μg / ml and 10 μg / ml of the test sample were subjected to the same operations as in the above (4) to (9), and the platelet-derived vascular endothelial cell growth factor activity inhibition rate (thymidine phosphorylase activity inhibition rate) was measured. . (11) From the results of (9) and (10), a 50% platelet-derived vascular endothelial cell growth factor activity inhibitory concentration (50% thymidine phosphorylase activity inhibitory concentration) of the compound test sample of general formula (I) was determined. Was defined as the platelet-derived vascular endothelial cell growth factor activity inhibition (thymidine phosphorylase activity inhibition) value (IC ₅₀ value) of the compound of the general formula (I).

Compound No. IC ₅₀ (μg / ml) ───────────────────────────────A-1 38 A- 2 61

Test Example 6 : The effect of the compound of the present invention on TNF-α production or secretion induced by okadaic acid was examined in the same manner as in Test Example 1. Table 10 shows the measurement results.
As is clear from Table 10, these compounds of the present invention showed that TNF-α by okadaic acid-stimulated HL-60 cells
Production or secretion was suppressed.

[0126]

[Table 18]

Test Example 7 : TP was performed in the same manner as in Test Example 2 above.
The effect of the compound of the present invention on TNF-α production or secretion by A stimulation was examined. The measurement results are shown in Table 11. As is clear from Table 11, these compounds of the present invention have a T
Increased TNF-α production or secretion by HL-60 cells stimulated with PA.

[0128]

[Table 19]

Test Example 8 : (Effect of the compound of the present invention on mouse subcutaneous angiogenesis) A mixture obtained by adding recombinant human fibroblast growth factor-basic to Matrigel was injected subcutaneously into the back of the mouse, whereby the blood vessel was subcutaneously injected into the mouse. Angiogenesis occurs and 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 (10000 rpm, 5 minutes) together with Matrigel, and 100 μl of the obtained supernatant was added to Drabkin's Reagent (D
rabkin's reagent, Sigma; Shi
(purchased from GMA) and mixed at room temperature. After standing for more than 15 minutes, SPECT spectrophotometer
The absorbance at 540 nm of the supernatant was measured using RA max 250 (manufactured by Molecular Devices, Inc .; Molecular Devices). The amount of hemoglobin in the supernatant was determined using standard hemoglobin (hemogl).
obbin standard, purchased from Sigma), and the amount of hemoglobin per Matrigel obtained from one mouse was calculated. The results are shown in Table 12. The hemoglobin amount in each treatment group was
Matrigel without b-FGF added was injected into mice, and the solvent, 0.8% Tween 80 (Tween
80) is corrected by the amount of hemoglobin in Matrigel when only daily administration is performed. The compound of the present invention inhibited angiogenesis occurring in the subcutaneous mouse.

[0130]

[Table 20]

Test Example 9 : The effect of the compound of the present invention on the activity of aminopeptidase N was examined in the same manner as in Test Example 4. The measurement results are shown in Table 13. As is clear from Table 13, the compound of the present invention inhibited aminopeptidase N. The values in the table represent the enzyme inhibitory activity of the compound of the present invention as IC ₅₀ (μg / ml) based on the fluorescence intensity of the control group.

[0132]

[Table 21]

Test Example 10 : The effect of the compound of the present invention on TNF-α production or secretion stimulated by okadaic acid was examined in the same manner as in Test Example 1. The measurement results are shown in Table 14. As is clear from Table 14, the N-phenylphthalimide derivative suppressed TNF-α production or secretion by HL-60 cells stimulated with okadaic acid.

[0134]

[Table 22]

Test Example 11 : The effect of the compound of the present invention on subcutaneous neovascularization in mice was examined in the same manner as in Test Example 8.
The measurement results are shown in Table 15. As is clear from Table 15, the compound of the present invention inhibited angiogenesis occurring in subcutaneous mice.

[0136]

[Table 23]

[0137]

According to the present invention, the cyclic imide derivative or a salt thereof can regulate the amount of TNF-α, inhibit angiogenesis and / or inhibit the activity of aminopeptidase N in a living body. Is effective in treating or preventing the above diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C07D 209/48 C07D 209/48 Z // C07M 7:00

Claims (30)

[Claims] 1. A compound of the general formula (I): Wherein Q ₁ is a single bond, -CH _2- , -O-, -S- or -NH-, and Q ₂ and Q ₃ are each independently
—C (O) —, —C (S) — or —CH ₂ —, and Q
_At least one of ₂ and Q ₃ is -C (O)-or -C
(S)-, Z is a single bond or a lower alkanediyl group, R is an optionally substituted aryl group or an optionally substituted cycloalkyl group, and X is a nitro group or an acylated group. An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group;
An aminopeptidase N enzyme inhibitor comprising a cyclic imide derivative or a salt thereof and a pharmaceutically acceptable carrier, wherein n is an integer of 4 (when m is 2 or more, X may be the same or different). Wherein to Q ₁ cyclic imide derivative is a single bond or -
The aminopeptidase N enzyme inhibitor according to claim 1, which is CH ₂ — and Z is a single bond. 3. The cyclic imide derivative wherein Q ₁ is a single bond or-
The aminopeptidase N enzyme inhibitor according to claim 1, which is CH ₂ —, Z is a single bond, and R is a phenyl group which may be substituted. 4. The aminopeptidase N enzyme inhibitor according to claim 1, wherein Q _{1 of the} cyclic imide derivative is —CH ₂ —, Z is a single bond, and R is a phenyl group which may be substituted. 5. A compound of the general formula (I): Wherein Q ₁ is a single bond, -CH _2- , -O-, -S- or -NH-, and Q ₂ and Q ₃ are each independently
—C (O) —, —C (S) — or —CH ₂ —, and Q
_At least one of ₂ and Q ₃ is -C (O)-or -C
(S)-, Z is a single bond or a lower alkanediyl group, R is an optionally substituted aryl group or an optionally substituted cycloalkyl group, and X is a nitro group or an acylated group. An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group;
4 (when m is 2 or more, X may be the same or different), provided that when Z is a single bond, R is an optionally substituted aryl group. An angiogenesis inhibitor comprising a derivative or a salt thereof and a pharmaceutically acceptable carrier. 6. The cyclic imide derivative wherein Q ₁ is a single bond or-
CH ₂ - in which angiogenesis inhibitor of claim 5. 7. The cyclic imide derivative wherein Q ₁ is a single bond or-
The angiogenesis inhibitor according to claim 5, which is CH ₂ —, wherein R is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group. 8. A to Q ₁ cyclic imide derivative is a single bond or -
CH ₂ —, Z is a single bond or a 1,1-ethanediyl group, and R is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group. 5. An angiogenesis inhibitor. 9. The cyclic imide derivative wherein Q ₁ is a single bond or-
CH ₂ —, Z is a single bond or 1,1-ethanediyl group, R is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group, and X is The angiogenesis inhibitor according to claim 5, which is a fluorine atom and m is 4. 10. A compound of the general formula (I ′): Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different), Y is an oxygen atom or a sulfur atom,
Q ₃ are -C (O) -, - C (S) - or -CH ₂ - cyclic imide derivative or a salt thereof represented by the a]. 11. The cyclic imide derivative or a salt thereof according to claim 10, wherein the compound of the formula (I ′) is an S-form or an R-form of an optically active form. 12. The cyclic imide derivative according to claim 10, wherein Z ′ is a methyl group, or a salt thereof. 13. The cyclic imide derivative according to claim 10 or 11, wherein Z ′ is a methyl group, X is a fluorine atom, and m is 4. 14. A pharmaceutical composition comprising the cyclic imide derivative of claim 10 or a salt thereof and a pharmaceutically acceptable carrier. 15. A tumor necrosis factor production regulator comprising the cyclic imide derivative or a salt thereof according to claim 10 and a pharmaceutically acceptable carrier. 16. A compound of the general formula (I ″): [In the formula, Z ′ is an alkyl group, and R ″ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group (where the substituent is nitro X ′ is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group. , Y and A are each independently an oxygen atom or a sulfur atom, 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.], or an isoindole derivative or a salt thereof. 17. Z ′ is a methyl group, R ″ is a phenyl group, naphthyl group or cyclohexyl group, X ′ is a fluorine atom, Y and A are oxygen atoms, and m is 0 or 4. And n is 1. The cyclic imide derivative of claim 16, or a salt thereof. 18. A compound of the general formula (I ″): [In the formula, Z ′ is an alkyl group, and R ″ is an optionally substituted phenyl group, an optionally substituted naphthyl group, or an optionally substituted cyclohexyl group (where the substituent is nitro X ′ is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom or an alkyl group. , Y and A are each independently an oxygen atom or a sulfur atom, 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.], or an isoindole derivative or a salt thereof as an active ingredient.
4. The pharmaceutical composition of 4. 19. An agent for regulating the production of tumor necrosis factor, comprising the isoindole derivative or a salt thereof as an active ingredient as the pharmaceutical composition of claim 18. 20. The tumor necrosis factor production regulator according to claim 19, wherein the isoindole derivative or a salt thereof is an S-form or an R-form of an optically active form. 21. The tumor necrosis factor production inhibitor according to claim 20, wherein the isoindole derivative or a salt thereof is an R-form of an optically active substance. 22. The isoindole derivative or a salt thereof, wherein Z ′ is a methyl group, R ″ is a phenyl group, a naphthyl group or a cyclohexyl group, X ′ is a fluorine atom, and Y and A are oxygen atoms. 22. The inhibitor of tumor necrosis factor production according to claim 21, which is an R-form of an optically active substance wherein m is 0 or 4, and n is 1. 23. The general formula (I′-1): Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different) when the cyclic imide derivative or its salt is represented by the general formula (I′-1) A phthalaldehyde corresponding to the cyclic imide derivative represented by the general formula (III): Wherein Z ′ and R ′ are as defined above, followed by a salt formation reaction if desired. 24. The general formula (I′-2): Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
(Where m is 2 or more, Xs may be the same or different) when the cyclic imide derivative or a salt thereof is produced, which is represented by the general formula (II): ] Wherein X and m are as defined above, and a compound represented by the general formula (III): [Wherein Z ′ and R ′ are as defined above], and then, if desired, a salt-forming reaction is carried out, if desired. 25. The general formula (I′-3): Wherein Z ′ is an alkyl group, R ′ is an optionally substituted phenyl group, an optionally substituted naphthyl group or an optionally substituted cyclohexyl group, X is a nitro group,
An amino group, a cyano group, a trifluoromethyl group, a hydroxy group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group which may be acylated;
And Q is an integer of 4 or more (when m is 2 or more, Xs may be the same or different), and Q ₃ is -C (O)-, -C (S)-
Or a salt of —CH ₂ —, or a salt thereof, which is represented by the general formula (I′-4): Wherein Z ′, R ′, X and m are as described above,
Wherein ₄ is —C (O) — or —CH ₂ —), and diphosphorus pentasulfide, and then, if desired, a salt forming reaction. A method for producing the salt. 26. The general formula (I ′ ″-1): Wherein R ₁ or R ₂ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group, Y is an oxygen atom or a sulfur atom, X ₁ is a halogen atom, a nitro group, a cyano group, Fluoromethyl group, hydroxy group, amino group which may be acylated, alkyl group,
M is 0 or 1;
And X is an integer of 4 or more (when m is 2 or more, X ₁ may be the same or different), and Q ₅ is —C (O) — or —CH ₂
Or a salt thereof and a pharmaceutically acceptable carrier.
Aminopeptidase N enzyme inhibitor. 27. The general formula (I ′ ″-1): Wherein R ₁ or R ₂ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a lower alkylthio group, Y is an oxygen atom or a sulfur atom, X ₁ is a halogen atom, a nitro group, a cyano group, Fluoromethyl group, hydroxy group, amino group which may be acylated, alkyl group,
M is 0 or 1;
And X is an integer of 4 or more (when m is 2 or more, X ₁ may be the same or different), and Q ₅ is —C (O) — or —CH ₂
Or a salt thereof and a pharmaceutically acceptable carrier.
Angiogenesis inhibitors. 28. The general formula (I ″ ″): Wherein R ″ ″ is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower alkylthiophenyl group, and X is a nitro group, an amino group which may be acylated, a cyano group, Methyl group, hydroxy group,
Halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q ₃
-C (O) is -, - C (S) - or -CH ₂ -,
m is an integer of 0 to 4 (when m is 2 or more, Xs may be the same or different)] or a pharmaceutically acceptable carrier thereof. Aminopeptidase N enzyme inhibitor. 29. The general formula (I ″ ″): Wherein R ″ ″ is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower alkylthiophenyl group, and X is a nitro group, an amino group which may be acylated, a cyano group, Methyl group, hydroxy group,
Halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q ₃
-C (O) is -, - C (S) - or -CH ₂ -,
m is an integer of 0 to 4 (when m is 2 or more, Xs may be the same or different)] or a phthalimide derivative thereof and a pharmaceutically acceptable carrier. Angiogenesis inhibitors. 30. N-phenylphthalimide, N-phenylthiophthalimide, N- (2,6-diisopropylphenyl) -phthalimide, N- (2,6-diisopropylphenyl) -4,5,6,7-tetrafluoro -Phthalimide, N- (2,6-diisopropylphenyl)
At least one N-phenylphthalimide derivative selected from the group consisting of -4-nitrophthalimide and N- (2,6-diisopropylphenyl) -5-nitrophthalimide or a salt thereof, and a pharmaceutically acceptable carrier. Item 5. An angiogenesis inhibitor according to Item 5.