The present invention relates to a pharmaceutical composition which comprises a cyclic imide derivative or its salt. The cyclic imide derivative or its salt includes the isoindole derivative or its salt, a certain N-phenylimide compound or its salt, a certain phthalimide derivative or its salt, and an N-phenylphthalimide derivative or its salt. Particularly, the present invention relates to an aminopeptidase N inhibitor or an angiogenesis inhibitor, which comprises, as an active ingredient, the cyclic imide derivative or its salt.
The present invention further relates to a novel isoindole derivative or its salt, a method for producing it, and a pharmaceutical composition comprising it. It also relates to a pharmaceutical which modulates production of tumor necrosis factor (TNF-xcex1) and which comprises, as an active ingredient, a novel isoindole derivative or its salt.
JP-A-50-121432 discloses phthalimide derivatives as active ingredients for agricultural and horticultural fungicides, and JP-A-62-22760 discloses isoindoline derivatives as active ingredients for agricultural and horticultural fungicides. However, they are respectively different in their chemical structures from the cyclic imide derivatives of the present invention.
Further, in the field of pharmaceuticals, the cyclic imide derivatives of the present invention differ in the chemical structures from N-alkylphthalimides disclosed in CHEMICAL and PHARMACEUTICAL BULLETIN vol. 43, 1, 177-179, 1995, and from benzylphthalimides and phenethylphthalimides disclosed in BIOLOGICAL PHARMACEUTICAL BULLETIN vol. 18, 9, 1228-1233, 1995.
A pharmaceutical which modulates (enhances or suppresses) production of tumor necrosis factor (TNF-xcex1) which is considered to be one of factors which cause various diseases, is useful also as a biological response modulator. It is expected to be used widely, as an immunostimulant or an immunosuppressant, and development of it as a pharmaceutical is desired.
Further, aminopeptidase N (APN) is distributed mainly in epithelial cells of kidney and small intestine, monocytes and granulocytes, cancer cells and on cell surface membrane of placenta, liver and pancreas, and its various physiological functions such as digestion and absorption of amino acids, biosyntheses and degradation of bioactive substances such as peptide hormones, growth factors and autacoid and degradation of extracellular matrix, have been studied. And a pharmaceutical which inhibits the activity of APN is expected as a preventive drug or a therapeutic drug for cancer, cancer metastasis, inflammatory diseases, autoimmune diseases and allergic diseases, and development of a pharmaceutical drug which is an aminopeptidase N inhibitor is desired.
Excessive activation of angiogenesis is known to relate to onset or progression steps of various diseases, and development of a pharmaceutical which is an angiogenesis inhibitor which is useful as a preventive drug or a therapeutic drug of such diseases is desired.
Further, it is meaningful to find out an excellent pharmaceutical composition with respect to a certain novel and characteristic isoindole derivative or its salt.
In order to find out an excellent pharmaceutical a composition with respect to a certain isoindole derivative or its salt, the present inventors have paid attention to modulate production of tumor necrosis factor (TNF-xcex1) which is considered to be one of factors which cause various diseases. Further, they have found that by using an optically active substance of the isoindole derivative or its salt, the control of TNF-xcex1 production can be divided into enhancing effect and suppressive effect, whereby a compound which has only one of these effects can be obtained, and as a result, they have accomplished the present invention.
Further, they have found that a cyclic imide derivative having a certain chemical structure or its salt has amino peptidase N inhibitory effect or anti-angiogenetic effect, and have accomplished the present invention.
Namely, the present invention relates to:
(1) An aminopeptidase N inhibitor which comprises a cyclic imide derivative represented by the general formula (I): 
xe2x80x83wherein Q1 is a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, each of Q2 and Q3 which are independent of each other, is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, provided that at least one of Q2 and Q3 is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94, Z is a single bond or a lower alkanediyl group, R is an aryl group which may be substituted or a cycloalkyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt, and a pharmaceutically acceptable carrier;
(2) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q1 is a single bond or xe2x80x94CH2xe2x80x94, and Z is a single bond;
(3) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q1 is a single bond or xe2x80x94CH2xe2x80x94, Z is a single bond, and R is a phenyl group which may be substituted;
(4) The aminopeptidase N inhibitor according to (1), wherein in the cyclic imide derivative, Q1 is xe2x80x94CH2xe2x80x94, Z is a single bond, and R is a phenyl group which may be substituted;
(5) An angiogenesis inhibitor which comprises a cyclic imide derivative represented by the general formula (I): 
xe2x80x83wherein Q1 is a single bond, xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94, each of Q2 and Q3 which are independent of each other, is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94, or xe2x80x94CH2xe2x80x94, provided that at least one of Q2 and Q3 is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94, Z is a single bond or a lower alkanediyl group, R is an aryl group which may be substituted or a cycloalkyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, and provided that when Z is a single bond, R is an aryl group which may be substituted, or its salt, and a pharmaceutically acceptable carrier;
(6) The angiogenesis inhibitor according to (5), wherein Q1 in the cyclic imide derivative is a single bond or xe2x80x94CH2xe2x80x94;
(7) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q1 is a single bond or xe2x80x94CH2xe2x80x94, and R is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted;
(8) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q1 is a single bond or xe2x80x94CH2xe2x80x94, Z is a single bond or a 1,1-ethanediyl group, R is a phenyl group which may be substituted, a inaphthyl group which may be substituted or a cyclohexyl group which may be substituted;
(9) The angiogenesis inhibitor according to (5), wherein in the cyclic imide derivative, Q1 is a single bond or xe2x80x94CH2xe2x80x94, Z is a single bond or a 1,1-ethanediyl group, R is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a fluorine atom and m is 4;
(10) A cyclic imide derivative represented by the general formula (Ixe2x80x2): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x2 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, Y is an oxygen atom or a sulfur atom, and Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, or its salt;
(11) The cyclic imide derivative according to (10), wherein the compound of the formula (Ixe2x80x2) is an optically active substance of S-form or R-form, or its salt;
(12) The cyclic imide derivative according to (10) or (11), wherein Zxe2x80x2 is a methyl group, or its salt;
(13) The cyclic imide derivative according to (10) or (11), wherein Zxe2x80x2 is a methyl group, X is a fluorine atom and m is 4, or its salt;
(14) A pharmaceutical composition, which comprises the cyclic imide derivative as defined in (10), or its salt and a pharmaceutically acceptable carrier;
(15) A TNF-xcex1 production modulator which comprises the cyclic imide derivative as defined in (10), or its salt and a pharmaceutically acceptable carrier;
(16) The cyclic imide derivative according to (10), which is an isoindole derivative represented by the general formula (Ixe2x80x3): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x3 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, the substituent is a nitro group, an amino group, a lower acylamino group, an alkoxy group, an alkylthio group or an alkyl group, Xxe2x80x2 is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom or an alkyl group, each of Y and A which are independent of each other, is an oxygen atom or a sulfur atom, m is an integer of from 0 to 4, when m is 2 or above, Xxe2x80x2 may be the same or different, and n is 0 or 1, or its salt;
(17) The cyclic imide derivative according to (16), wherein Zxe2x80x2 is a methyl group, Rxe2x80x3 is a phenyl group, a naphthyl group or a cyclohexyl group, Xxe2x80x2 is a fluorine atom, each of Y and A is an oxygen atom, m is 0 or 4, and n is 1, or its salt;
(18) The pharmaceutical composition according to (14), which comprises, as an active ingredient, an isoindole derivative represented by the general formula (Ixe2x80x3): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x3 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, provided that the substituent is a nitro group, an amino group, a lower acyl amino group, an alkoxy group, an alkylthio group or an alkyl group, Xxe2x80x2 is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom or an alkyl group, each of Y and A which are independent of each other, is an oxygen atom or a sulfur atom, m is an integer of from 0 to 4, when m is 2 or above, Xxe2x80x2 may be the same or different, and n is 0 or 1, or its salt;
(19) A TNF-xcex1 production modulator which comprises, as an active ingredient, the isoindole derivative or its salt, as the pharmaceutical composition as defined in (18);
(20) The TNF-xcex1 production modulator according to (19), wherein the isoindole derivative or its salt is an optically active substance of S-form or R-form;
(21) The TNF-xcex1 production suppressant according to (20), wherein the isoindole derivative or its salt is an optically active substance of R-form;
(22) The TNF-xcex1 production suppressant according to (21), wherein the isoindole derivative or its salt is an optically active substance of R-form, wherein Zxe2x80x2 is a methyl group, Rxe2x80x3 is a phenyl group, a naphthyl group or a cyclohexyl group, Xxe2x80x2 is a fluorine atom, each of Y and A is an oxygen atom, m is 0 or 4, and n is 1;
(23) A method for producing a cyclic imide derivative represented by the general formula (Ixe2x80x2-1): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x2 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt; which comprises reacting a phthalaldehyde corresponding to the cyclic imide derivative represented by the general formula (Ixe2x80x2-1), with a compound of the general formula (III): 
xe2x80x83wherein Zxe2x80x2 and Rxe2x80x2 are as defined above; and conducting a salt-forming reaction, as the case requires;
(24) A method for producing a cyclic imide derivative represented by the general formula (Ixe2x80x2-2): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x2 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt; which comprises reacting a compound of the general formula (II): 
xe2x80x83wherein X and m are as defined above, with a compound of the general formula (III): 
xe2x80x83wherein Zxe2x80x2 and Rxe2x80x2 are as defined above; and conducting a salt-forming reaction, as the case requires; and
(25) A method for producing a cyclic imide derivative represented by the general formula (Ixe2x80x2-3): 
xe2x80x83wherein Zxe2x80x2 is an alkyl group, Rxe2x80x2 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, and Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, or its salt; which comprises reacting a compound of the general formula (Ixe2x80x2-4): 
xe2x80x83wherein Zxe2x80x2, Rxe2x80x2, X and m are as defined above, and Q4 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, with di-phosphorus pentasulfide; and conducting a salt-forming reaction as the case requires.
In another mode, the present invention provides:
(26) An aminopeptidase N inhibitor according to (1), which comprises an N-phenylimide derivative represented by the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2): 
xe2x80x83wherein each of R1 and R2 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, each of X1 and X2 is a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxyl group, an amino group which may be acylated, an alkyl group, an alkoxy group or an alkylthio group, m is 0 or an integer of from 1 to 4, when m is 2 or above, X1 may be the same or different, p is 0 or an integer of from 1 to 6, when p is 2 or above, X2 may be the same or different, and Q5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, or its salt and a pharmaceutically acceptable carrier;
(27) The aminopeptidase N inhibitor according to (26), wherein both R1 and R2 are isopropyl groups, Y is an oxygen atom, m or p is 0, and Q5 is xe2x80x94C(O)xe2x80x94;
(28) The angiogenesis inhibitor according to (5), which comprises an N-phenylimide compound represented by the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2): 
xe2x80x83wherein each of R1 and R2 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, each of X1 and X2 is a halogen atom, a nitro group, a cyano group, a trifluoromethyl group, a hydroxyl group, an amino group which may be acylated, an alkyl group, an alkoxy group or an alkylthio group, m is 0 or an integer of from 1 to 4, when m is 2 or above, X1 may be the same or different, p is 0 or an integer of from 1 to 6, when p is 2 or above, X2 may be the same or different, and Q5 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, or its salt and a pharmaceutically acceptable carrier;
(29) The angiogenesis inhibitor according to (28), wherein both R1 and R2 are isopropyl groups, Y is an oxygen atom, m or p is 0, and Q5 is xe2x80x94C(O)xe2x80x94;
(30) The aminopeptidase N inhibitor according to (1), which comprises a phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3): 
xe2x80x83wherein Rxe2x80x3xe2x80x3 is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower-alkylthiophenyl group, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt and a pharmaceutically acceptable carrier;
(31) The angiogenesis inhibitor according to (5), which comprises a phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3): 
xe2x80x83wherein Rxe2x80x3xe2x80x3 is an adamantyl group, a 2,6-diisopropylphenyl group or a 2-lower-alkylthiophenyl group, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, Y is an oxygen atom or a sulfur atom, Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, m is an integer of from 0 to 4, and when m is 2 or above, X may be the same or different, or its salt and a pharmaceutically acceptable carrier;
(32) The angiogenesis inhibitor according to (5), which comprises at least one N-phenylphthalimide derivative selected from the group consisting of N-phenylphthalimide, N-phenylthiophthalimide, N-(2,6-diisopropylphenyl)-phthalimide, N-(2,6-diisopropylphenyl)-4,5,6,7-tetrafluoro-phthalimide, N-(2,6-diisopropylphenyl)-4-nitrophthalimide and N-(2,6-diisopropylphenyl)-5-nitrophthalimide, or its salt and a pharmaceutically acceptable carrier;
(33) The pharmaceutical composition according to (18), which has an enhancing effect of production of tumor necrosis factor (TNF-xcex1);
(34) The pharmaceutical composition according to (18), which has a suppressive effect of production of tumor necrosis factor (TNF-xcex1);
(35) The pharmaceutical composition according to (18), which has a favorable influence upon at least one bioactivity selected from the group consisting of cytotoxicity against tumor cells, activation of T cells, activation of anti-tumor macrophages, activation of neutrophils, induction of interferon-xcex22 by fibroblasts, and stimulation of immuno systems;
(36) The pharmaceutical composition according to (18), which suppresses at least one bioactivity selected from the group consisting of enhancement of cancer metastasis and angiogenesis, induction of endotoxin shock, induction of inflammation of organs and tissues, inhibition of lipoprotein lipase of adipocytes, and induction of replication of human immunodeficiency viruses;
(37) The pharmaceutical composition according to (18), which has inflammation suppressive effect or immune modulation effect;
(38) The pharmaceutical composition according to (18), which is a preventive drug or a therapeutic drug for autoimmune diseases such as rheumatic fever or rheumatoid arthritis, erythema nodosum leprosum, Behchet""s disease, lupus erythematosus or aphthous ulcer;
(39) The pharmaceutical composition according to (18), which is a preventive drug or a therapeutic drug for a cachexia in cancer or infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, inflammatory enteropathy, multiple organ failure, malaria, meningitidis, hepatitis, diabetes or acquired immunodeficiency syndrome;
(40) The pharmaceutical composition according to (18), which suppresses side effects caused by TNF-xcex1;
(41) A controlling agent of biological response which comprises, as an active ingredient, the isoindole derivative or its salt, as the pharmaceutical composition as defined in (18);
(42) A biological response modulator which comprises, as an active ingredient, the isoindole derivative or its salt, as the pharmaceutical composition as defined (18);
(43) An immunostimulant which comprises, as an active ingredient, the isoindole derivative or its salt, as the pharmaceutical composition as defined in (18);
(44) The immunostimulant according to (43), which is a therapeutic drug for cancer;
(45) An immunosuppressant which comprises, as an active ingredient, the isoindole derivative or its salt, as the pharmaceutical composition as defined in (18);
(46) The immunosuppressant according to (45), which is a therapeutic drug for transplant graft rejection, graft versus host diseases or immune diseases;
(47) The angiogenesis inhibitor according to (5), which is a preventive drug or a therapeutic drug for at least one disease selected from the group consisting of cancer; cancer metastasis; benign tumors including angioma, auditory neuroma, neurofibroma, trachoma, purulent granuloma and granulation; chronic inflammatory diseases including rheumatoid arthritis; psoriasis; eye diseases relating to angiogenesis including diabetic retinopathy, retinopathy of prematurity, macular degeneration, glaucoma, retrolental fibroplasia and central retinal vein atresia; angiogenesis resulting from corneal transplantation; hypertrophic scar; atherosclerosis; scleredema and nephropathy;
(48) The aminopeptidase N inhibitor according to (1), which has a favorable influence upon at least one bioactivity selected from the group consisting of digestion and absorption of amino acids; biosyntheses and degradation of bioactive substances including peptide hormones, growth factors and autacoids; and degradation of extracellular matrix;
(49) The aminopeptidase N inhibitor according to (1), which has immune function modulation effect;
(50) The aminopeptidase N inhibitor according to (1), which suppresses metastasis of cancer cells;
(51) The aminopeptidase N inhibitor according to (1), which is a preventive drug or a therapeutic drug for at least one disease selected from the group consisting of cancer, cancer metastasis, inflammatory diseases, autoimmune diseases and allergic diseases;
(52) The aminopeptidase N inhibitor according to (1), wherein the substituent for the aryl group which may be substituted or the cycloalkyl group which may be substituted in the definition of R, is selected from the group consisting of a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group and an alkylthio group;
(53) The angiogenesis inhibitor according to (5), wherein the substituent for the aryl group which may be substituted or the cycloalkyl group which may be substituted in the definition of R, is selected from the group consisting of a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group and an alkylthio group;
(54) The cyclic imide derivative according to (10), wherein the substituent for the phenyl group which may be substituted, the naphthyl group which may be substituted or the cyclohexyl group which may be substituted in the definition of Rxe2x80x2, is selected from the group consisting of a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group and an alkylthio group, or its salt;
(55) The aminopeptidase N inhibitor according to (30), which comprises the phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3) of (30), except the compound wherein (1) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 0, (2) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, X is a halogen atom, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 4, (3) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, X is a nitro group, an amino group or a hydroxyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 1, and (4) Rxe2x80x3xe2x80x3 is an adamantyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 0, or its salt; and
(56) The angiogenesis inhibitor according to (31), which comprises the phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3) of (31), except the compound wherein (1) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 0, (2) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, X is a halogen atom, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 4, (3) Rxe2x80x3xe2x80x3 is a 2,6-diisopropylphenyl group, X is a nitro group, an amino group or a hydroxyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 1, and (4) Rxe2x80x3xe2x80x3 is an adamantyl group, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 and m is 0, or its salt.
In one of the preferred modes, the present invention provides a cyclic imide derivative represented by the general formula (Ixe2x80x2): 
wherein Zxe2x80x2 is an alkyl group, Rxe2x80x2 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, Y is an oxygen atom or a sulfur atom, and Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, or its salt, a method for producing it and a pharmaceutical composition comprising it.
Particularly, in one of the more preferred modes, the present invention relates to an isoindole derivative represented by the general formula (Ixe2x80x3): 
wherein Zxe2x80x2 is an alkyl group, Rxe2x80x3 is a phenyl group which may be substituted, a naphthyl group which may be substituted or a cyclohexyl group which may be substituted, provided that the substituent is a nitro group, an amino group, a lower acylamino group, an alkoxy group, an alkylthio group or an alkyl group, Xxe2x80x2 is a nitro group, an amino group, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom or an alkyl group, each of Y and A which may be the same or different, is an oxygen atom or a sulfur atom, m is an integer of from 0 to 4, when m is 2 or above, X may be the same or different, and n is 0 or 1, or its salt, a method for producing it and a pharmaceutical composition comprising it.
The present invention provides a pharmaceutical composition having aminopeptidase N inhibitory effect, which comprises, as an active ingredient, a cyclic imide derivative represented by the general formula (I) or its salt (a pharmaceutically acceptable salt); a pharmaceutical composition having angiogenesis inhibitory effect, which comprises, as an active ingredient, a cyclic imide derivative represented by the general formula (I) or its salt (a pharmaceutically acceptable salt); and further, a pharmaceutical composition, which comprises a novel cyclic imide derivative represented by the general formula (Ixe2x80x2) or its salt (a pharmaceutically acceptable salt), which, however, is included in the cyclic imide derivative represented by the general formula (I) or its salt. Further, the present invention provides a cyclic imide derivative represented by the general formula (Ixe2x80x2) or its salt, a method for producing it, and a pharmaceutical composition having tumor necrosis factor production modulating effect, which comprises, as an active ingredient, the cyclic imide derivative or its salt.
In the above-mentioned general formulae (I), (Ixe2x80x2) and (Ixe2x80x3xe2x80x3), and the following general formula (Ixe2x80x2xe2x80x3xe2x80x3), the halogen atom for X may be a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. As the alkyl group for X, a lower alkyl group, which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, may be mentioned, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group or a hexyl group. As the alkoxy group for X, a lower alkoxy group, which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, may be mentioned, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a tert-butoxy group, a pentyloxy group or a hexyloxy group. As the alkylthio group, a lower alkylthio group, which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, may be mentioned, such as a methylthio group, an ethylthio group a propylthio group, an isopropylthio group, a butylthio group, a tert-butylthio group, a pentylthio group or a hexylthio group. The amino group for X may be substituted by an acyl group. As the acyl group, one having an alkyl group residue may be mentioned, and the alkyl group portion may be as mentioned above. The alkyl group portion in the above group may be substituted by the above-mentioned halogen atom.
In the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2), the halogen atom, the alkyl group, the alkoxy group or the alkylthio group for X1 or X2, is as defined above for X. The amino group which may be acylated for X1 or X2 is as defined for X. As the halogen atom for X1 or X2, fluorine is preferred.
In the general formula (I), as the lower alkanediyl group for Z, a linear or branched one which has a carbon number of from 1 to 6, preferably from 1 to 4, may be mentioned, such as a methylene group, an ethylene group, a propylene group, a xe2x80x94CH(CH3)xe2x80x94 group, a xe2x80x94C(CH3)2xe2x80x94 group, a xe2x80x94CH(CH3)xe2x80x94CH2xe2x80x94 group, a xe2x80x94C(CH3)2CH2xe2x80x94 group, a xe2x80x94CH(CH3)xe2x80x94CH(CH3)xe2x80x94 group or a xe2x80x94C(CH3)2xe2x80x94CH2xe2x80x94CH2xe2x80x94 group. In the general formula (Ixe2x80x2), as the alkyl group for Zxe2x80x2, the alkyl group as defined above for X may be mentioned.
In the general formula (I) or (Ixe2x80x2), as the aryl portion of the aryl group which may be substituted in the definition of R or Rxe2x80x2, monocyclic or bicyclic one, or heterocyclic one which has one or more of hetero atoms including a nitrogen atom, a sulfur atom, and an oxygen atom, such as a phenyl group, a naphthyl group, a pyridyl group, a thenyl group, a furanyl group, a pyrimidyl group, an oxazole group or an imidazole group. The substituent for the aryl group which may be substituted, may be the same as mentioned above for X. It is preferably an alkyl group, particularly a lower alkyl group, which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group or a hexyl group. As the more preferred substituent, a nitro group, an amino group which may be acylated such as an amino group, an alkanoylamino group, preferably an alkanoylamino group, which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, an alkylthio group, preferably an alkylthio group which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, may be mentioned. As the cycloalkyl portion of the cycloalkyl group which may be substituted in the definition of R or Rxe2x80x2, monocyclic one, bicyclic one or tricyclic one, such as a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclohexyl group or an adamantyl group may be mentioned. The substituent for the cycloalkyl group which may be substituted, may be the same as mentioned above for X. It is preferably an alkyl group, particularly a lower alkyl group which is linear or branched, and has a carbon number of from 1 to 6, preferably from 1 to 4, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a tert-butyl group, a pentyl group or a hexyl group. In the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2), the lower alkyl group, the lower alkoxy group or the lower alkylthio group for R1 or R2 is as defined above for X.
In the general formula (I), (Ixe2x80x2), (Ixe2x80x3), (Ixe2x80x2xe2x80x3-1) and (Ixe2x80x3xe2x80x3), when m is 2 or above, X may be the same or different, Xxe2x80x2 and X1 may also be the same or different. Further, in the general formula (Ixe2x80x2xe2x80x3-2), when p is 2 or above, X2 may be the same or different. In the general formula (Ixe2x80x3), the substituent for the phenyl group which may be substituted, the naphthyl group which may be substituted or the hexyl group which may be substituted in the definition of Rxe2x80x3, is as defined above for R and Rxe2x80x2. The lower acylamino group may, for example, be a linear or branched lower alkanoylamino group which has a carbon number of from 1 to 6, preferably from 1 to 4.
Among the cyclic imide derivatives represented by the general formula (I), a compound wherein X is an amino group or a hydroxyl group (and/or a compound wherein R has an amino group or a hydroxyl group as a substituent) may form a salt. The salt may be any salt so long as it is pharmaceutically acceptable. For example, it includes an inorganic acid salt such as hydrochloride, sulfate and nitrate; an organic acid salt such as acetate and methane sulfonate; an alkali metal salt such as sodium salt and potassium salt; an alkaline earth metal salt such as magnesium salt and calcium salt; and an organic amine salt such as triethanolamine salt and tris(hydroxymethyl)aminomethane salt. Among the isoindole derivatives represented by the general formula (Ixe2x80x2) or (Ixe2x80x3), a compound wherein X or Xxe2x80x2 is an amino group or a hydroxyl group (and/or a compound wherein Rxe2x80x2 or Rxe2x80x3 has an amino group or a hydroxyl group as a substituent), may also form a salt. The salt may be any salt so long as it is pharmaceutically acceptable. For example, it includes salts as mentioned above.
In the constituting component 
of the general formula (Ixe2x80x2) and (Ixe2x80x3), one asymmetric carbon atom exists, and thus an optically active substance of S-form or R-form exists. In the present invention, the isoindole derivative represented by the general formula (Ixe2x80x2) and (Ixe2x80x3), or its salt, includes a racemic modification, the S-form or the R-form, unless otherwise specified.
In the general formula (Ixe2x80x2), the racemic modifications, the optically active substances of S-form or R-form of the following compounds are preferred.
(1) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x2 is a phenyl group, a naphthyl group or a cyclohexyl group, X is a nitro group or a halogen atom, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94, and m is 0, 1 or 4.
(2) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x2 is a phenyl group, a naphthyl group or a cyclohexyl group, X is a fluorine atom, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94 or xe2x80x94C(S)xe2x80x94, and m is 0 or 4.
(3) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x2 is a phenyl group, a naphthyl group or a cyclohexyl group, X is a fluorine atom, Y is an oxygen atom, Q3 is xe2x80x94C(O)xe2x80x94, and m is 0 or 4.
In the general formula (Ixe2x80x3), the racemic modifications, the optically active substances of S-form or R-form of the following compounds are more preferred.
(1) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x3 is a phenyl group, a naphthyl group or a cyclohexyl group, Xxe2x80x2 is a nitro group or 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) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x3 is a phenyl group, a naphthyl group or a cyclohexyl group, Xxe2x80x2 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) A compound wherein Zxe2x80x2 is a methyl group, Rxe2x80x3 is a phenyl group, a naphthyl group or a cyclohexyl group, Xxe2x80x2 is a fluorine atom, Y and A are oxygen atoms, m is 0 or 4, and n is 1.
Further, in the general formula (Ixe2x80x2), the following compounds are more preferred.
(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)-1H-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-1H-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, in the general formula (I), the following compounds are most preferred.
(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.
As the N-phenylimide compound of the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2) or its salt, the preferred is as follows:
(1) Both R1 and R2 are isopropyl groups.
(2) X1 or X2 is a fluorine atom or a nitro group.
(3) Each of m and p is 0 or 1.
(4) Q5 is xe2x80x94C(O)xe2x80x94.
The cyclic imide derivative of the general formula (I) or its salt of the present invention (hereinafter referred to as the compound of the present invention for short) can be produced by various methods. For example, the compound of the present invention can be produced by methods [A] to [C] as shown hereinafter or by conventional salt-forming reactions. Further, as the case requires, by modifying the substituent of the compound thus obtained or converting the substituent to another substituent, the compound can be converted to a compound having the corresponding substituent. As such a treatment, acylation of an amino acid or reduction of a nitro group, may, for example, be mentioned.
[A] In a case where Q2 is xe2x80x94C(O)xe2x80x94 and Q3 is xe2x80x94CH2xe2x80x94, or Q2 is xe2x80x94CH2xe2x80x94 and Q3 is xe2x80x94C(O)xe2x80x94: 
xe2x80x83wherein Q1, Z, R, X and m are as defined above.
[B] In a case where Q2 is xe2x80x94C(O)xe2x80x94 and Q3 is xe2x80x94C(O)xe2x80x94: 
xe2x80x83wherein Q1, Z, R, X and m are as defined above.
[C] In a case where Q2 is xe2x80x94C(S)xe2x80x94: 
xe2x80x83wherein Q3, Z, R, X and m are as defined above, and Q6 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94.
The reaction [A] will be described below.
The reaction [A] is usually conducted in the presence of an acid substance. As the acid substance, one or more are suitably selected from the group consisting of organic acids such as acetic acid and toluene sulfonic acid, and inorganic acids such as sulfuric acid and hydrochloric acid.
The reaction [A] is conducted in the presence of a solvent, as the case requires. The solvent may be any solvent so long as it is inert to the reaction. It may, for example, be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; a cyclic or non-cyclic aliphatic hydrocarbon such as carbon tetrachloride, methylene chloride, chloroform, dichloromethane, dichloroethane, trichloroethane, hexane or cyclohexane; an ether such as dioxane; a polar aprotic solvent such as dimethylsulfoxide, dimethylacetamide, dimethylformamide or N-methylpyrrolidone; or an organic acid such as acetic acid. One or more of them are suitably selected.
The reaction temperature of the reaction [A] varies depending upon the reaction condition, and can not be absolutely defined. It is usually from 0 to 80xc2x0 C., preferably from 20 to 40xc2x0 C. The reaction time is usually from 0.1 to 4 hours, preferably from 0.2 to 2 hours.
The reaction [B] will be described below.
The reaction [B] is conducted in the presence of a solvent, as the case requires. The solvent may be any solvent so long as it is inert to the reaction. It may, for example, be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an ether such as dioxane; a polar aprotic solvent such as dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or more of them are suitably selected.
The reaction temperature of the reaction [B] varies depending upon the reaction condition, and can not be absolutely defined. It is usually from 100 to 200xc2x0 C., preferably from 140 to 200xc2x0 C. The reaction time is usually from 1 to 4 hours, preferably from 1 to 2 hours.
The reaction [C] will be described below.
The reaction [C] is conducted in the presence of a solvent, as the case requires. The solvent may be any solvent so long as it is inert to the reaction. It may, for example, be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an ether such as dioxane; or a polar aprotic solvent such as dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or more of them are suitably selected.
The reaction temperature of the reaction [C] varies depending upon the reaction condition, and can not be absolutely defined. It is usually from 100 to 200xc2x0 C., preferably from 120 to 180xc2x0 C. The reaction time is usually from 0.5 to 40 hours, preferably from 1 to 40 hours.
In the reaction [C], as di-phosphorus pentasulfide, di-phosphorus pentasulfide itself or its dimer may be used. Further, in the reaction [C], by employing an optional reaction condition, it is possible to selectively produce monothio type, or to produce a mixture of monothio type and dithio type. In the case where the mixture of monothio type and dithio type is obtained, it is possible to separate them by purification means such as column separation.
The isoindole derivative represented by the general formula (Ixe2x80x2) or its salt can be produced by the methods [Axe2x80x2] to [Cxe2x80x2] as shown hereinafter or by conventional salt-forming reactions.
[Axe2x80x2] In a case where Y is an oxygen atom and Q3 is xe2x80x94CH2xe2x80x94: 
[Bxe2x80x2] In a case where Y is an oxygen atom and Q3 is xe2x80x94C(O) xe2x80x94: 
[Cxe2x80x2] In a case where Y is a sulfur atom: 
In an amine represented by the general formula (III): 
one asymmetric carbon atom exists, and thus an optically active substance of S-form or R-form exists. The amine includes a racemic modification, the S-form or R-form, unless otherwise specified.
The reaction [Axe2x80x2] can be conducted in the same manner as the reaction [A]. In the reaction [Axe2x80x2], Zxe2x80x2, Rxe2x80x2, X and m are as defined above.
The reaction [Bxe2x80x2] can be conducted in the same manner as the reaction [B]. In the reaction [Bxe2x80x2], Zxe2x80x2, Rxe2x80x2, X and m are as defined above.
The reaction [Cxe2x80x2] can be conducted in the same manner as the reaction [C]. In the reaction [Cxe2x80x2], Zxe2x80x2, Rxe2x80x2, X and m are as defined above, Q3 is xe2x80x94C(O)xe2x80x94, xe2x80x94C(S)xe2x80x94 or xe2x80x94CH2xe2x80x94, and Q4 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94.
The N-phenylimide compound of the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2) or its salt of the present invention, can be produced by various methods. For example, the N-phenylimide compound or its salt of the present invention can be produced by the following reaction. 
wherein R1, R2, X1, X2, m and p are as defined above, Q7 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94, and Q8 is xe2x80x94C(O)xe2x80x94 or xe2x80x94CH2xe2x80x94.
With regard to the N-phenylimide compound represented by the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2), one having an oxygen atom as Y, is produced by the former step of the reaction, and one having a sulfur atom as Y, is produced by the latter step of the reaction. In the latter step of the reaction, it is possible to produce compounds represented by the following general formulae as well as the general formula (Ixe2x80x2xe2x80x3-3) or (Ixe2x80x2xe2x80x3-4). By employing optional reaction conditions, these compounds may be produced selectively or as a mixture. In the case where they are produced as a mixture, it is possible to separate them by purification means such as column separation. 
The reaction of the compound represented by the general formula (IX) or (XI) with the aniline compound represented by the general formula (XIII) is conducted in the same manner as the reaction [A].
The reaction of the compound represented by the general formula (IX), (X), (XI) or (XII) with an aniline compound represented by the general formula (XIII), can be conducted in the presence of an inert solvent, or may be conducted in a molten state without using a solvent. The inert solvent may, for example, be an aromatic hydrocarbon such as benzene, toluene, xylene or chlorobenzene; an ether such as dioxane; a polar aprotic solvent such as dimethylsulfoxide, dimethylacetamide or N-methylpyrrolidone. One or more of them are suitably selected. The reaction of the imide compound represented by the general formula (XIV) or (XV) with phosphorus pentasulfide or its dimer, is usually conducted in the presence of an inert solvent, and the inert solvent is as defined above.
The compound of the general formula (Ixe2x80x2xe2x80x3-2) may form a salt as well as the compound of the general formula (Ixe2x80x2xe2x80x3-1) of the present invention. Further, it is also useful as an active ingredient of a pharmaceutical composition. It has bioactivities as explained with regard to the compound of the general formula (Ixe2x80x2xe2x80x3-1), which will be explained hereinafter.
The phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3) or its salt can be produced by methods [A] to [C], by using e.g. Rxe2x80x3xe2x80x3xe2x80x94NH2 as Rxe2x80x94Zxe2x80x94NH2.
The N-phenylphthalimide derivative can be made by various methods. Among these, N-phenylphthalimide can be produced by reacting phthalic anhydride with aniline as shown by the reaction [A]. Further, N-phenylthiophthalimide can be produced by reacting N-phenylphthalimide with di-phosphorus pentasulfide or one having the same function as its dimer, as shown by the reaction [C].
In this case, it is possible to conduct the reaction [A] in the presence of an acid substance as mentioned above, and it is also possible to use an excess amount of phthalic anhydride. In the case where a solvent is used in the reaction, an aromatic hydrocarbon, an ether or a polar aprotic solvent as mentioned above, is preferably used. The reaction temperature of the reaction [A] varies depending upon the reaction condition, and can not be absolutely defined. It is usually from 100 to 200xc2x0 C., preferably from 140 to 200xc2x0 C. The reaction time is usually from 1 to 4 hours, preferably from 1 to 2 hours.
In a case where the solvent is used in the reaction [C], the same solvent as mentioned in the reaction [A] is preferably used. The reaction temperature of the reaction [C] varies depending upon the reaction condition, and can not be absolutely defined. It is usually from 100 to 200xc2x0 C., preferably from 120 to 180xc2x0 C. The reaction time is usually from 0.5 to 40 hours, preferably from 1 to 40 hours.
In one of other modes, the present invention provides an N-phenylphthalimide derivative represented by the general formula (Ixe2x80x2xe2x80x3xe2x80x3): 
wherein R is an aryl group which may be substituted, such as a phenyl group which may be substituted, provided that the substituent may, for example, be a nitro group or an amino group which may be acylated such as an amino group or a lower acylamino group, an alkoxy group, an alkylthio group or an alkyl group, X is a nitro group, an amino group which may be acylated, a cyano group, a trifluoromethyl group, a hydroxyl group, a halogen atom, an alkyl group, an alkoxy group or an alkylthio group, and m is an integer of from 0 to 4, provided that when m is 2 or above, X may be the same or different, or its salt, a method for producing it, and a pharmaceutical composition comprising it. According to the present invention, an aminopeptidase N inhibitor and an angiogenesis inhibitor, and further, a TNF-xcex1 production modulator such as a TNF- a production inhibitor or a TNF-xcex1production enhancer, which comprises an N-phenylphthalimide derivative represented by the general formula (Ixe2x80x2xe2x80x3xe2x80x3) or its salt, and a pharmaceutically acceptable carrier, can be provided.
The compound of the present invention is useful as an active ingredient of a pharmaceutical composition. Particularly, it has effect to modulate (enhance or suppress) production of tumor necrosis factor (TNF-xcex1), anti-angiogenetic activity and/or aminopeptidase N inhibitory activity. Therefore, it can be effectively used to treat or prevent various diseases. Among these, an optically active substance of R-form of the compound represented by the general formula (Ixe2x80x2) or its salt suppresses production of tumor necrosis factor well, and thus it can be effectively used to treat or prevent various diseases.
(Effect of Modulating TNF-xcex1Production)
TNF-xcex1 has been known as a cytokine which widely relates to control of biological responses by means of inflammation and immuno reactions, with various activities such that it has desirable effects such as cytotoxicity against tumor cells, activation of T cells which is one of immuno cells, activation of anti-tumor macrophages, activation of neutrophils, induction of interferon-xcex22 by fibroblasts and stimulation of immuno systems, while excessive production of TNF-xcex1 causes undesirable effects such as acceleration of cancer metastasis and angiogenesis, induction of endotoxin shock, induction of inflammation of organs and tissues, inhibition of lipoprotein lipase of adipocytes, and induction of replication of human immuno deficiency viruses. The pharmaceutical composition which comprises the compound of the present invention is a biological response modulator which makes it possible to modulate the amount of TNF-xcex1 in the body. It can be used as an immunostimulant which is effective for treatment of diseases such as cancer, and as an immunosuppressant which has therapeutic effect against transplant graft rejection, graft versus host diseases or immune diseases. It also has therapeutic effect against other diseases which relate to TNF-xcex1. As the immune diseases, autoimmune diseases such as rheumatic fever and rheumatoid arthritis, erythema nodosum leprosum, Behchet""s diseases, lupus erythematosus and aphthous ulcer may, for example, be mentioned. As the other diseases which relate to TNF-xcex1, cachexia in cancer or infectious diseases, septic shock, adult respiratory distress syndrome, osteoarthritis, multiple sclerosis, inflammatory enteropathy, multiple organ failure, malaria, meningitidis, hepatitis, diabetes and acquired immunodeficiency syndrome may, for example, be mentioned. Further, in the case where the amount of TNF-xcex1 increases excessively by e.g. cancer treatment, by using the pharmaceutical composition which comprises the compound of the present invention together, it is possible to suppress side effects by excessive TNF-xcex1 induced.
(Inhibition of Angiogenesis)
It has been known that excessive activation of angiogenesis relates to onset or progression step of various diseases. As the diseases, specifically, cancer and cancer metastasis; benign tumors such as angioma, auditory neuroma, neurofibroma, trachoma, purulent granuloma and granulation; chronic inflammatory diseases such as rheumatoid arthritis; psoriasis; eye diseases relating to angiogenesis, such as diabetic retinopathy, retinopathy of prematurity, macular degeneration, glaucoma, retrolental fibroplasia and central retinal vein atresia; angiogenesis resulting from corneal transplantation; hypertrophic scar; atherosclerosis; scleredema; and nephropathy may, for example, be mentioned. The pharmaceutical composition which comprises the compound of the present invention can be used as an angiogenesis inhibitor, and it is useful as a preventive drug or a therapeutic drug for such diseases.
(Inhibition of Aminopeptidase N)
Aminopeptidase N is an enzyme which hydrolyzes peptides, as substrates, having e.g. alanine, leucine, phenylalanine, tyrosine, arginine, methionine, lysine, tryptophan, glycine, serine or histidine, at the amino terminal. Aminopeptidase N is distributed mainly in epithelial cells of kidney and small intestine, monocytes or granulocytes, cancer cells and on cell surface membrane of placenta, liver and pancreas. Its various physiological functions such as digestion and absorption of amino acids, biosyntheses and degradation of peptide hormones, growth factors and autacoids and degradation of extracellular matrix, have been studied (Ketsueki, Shuyo-ka, vol. 29, 288-296, 1994). Further, relation of the enzyme to immune functions has been indicated (Japanese Journal of Cancer and Chemotherapy, vol. 9, 1019-1024, 1982). Further, it was reported that inhibition of aminopeptidase N suppresses metastasis of cancer cells (Cancer Research, vol. 46, 4505-4510, 1986). The pharmaceutical composition which comprises the compound of the present invention can be used as an aminopeptidase N inhibitor, and it is useful as a preventive drug or a therapeutic drug for cancer, cancer metastasis, inflammatory diseases, autoimmune diseases or allergic diseases.
Particularly preferred modes are as follows:.
(1) An angiogenesis inhibitor which comprises, as an active ingredient, the cyclic imide derivative represented by the general formula (I).
(2) An aminopeptidase N inhibitor which comprises, as an active ingredient, the cyclic imide derivative represented by the general formula (I).
(3) An biological response modulator which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(4) An immunostimulant which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(5) An immunosuppressant which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(6) A TNF-xcex1 production enhancer which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(7) A TNF-xcex1 production suppressor which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(8) An anticancer agent which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(9) An anti-inflammatory agent which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(10) An anti-diabetic agent which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(11) An angiogenesis inhibitor which comprises, as an active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(12) An anti-rheumatic agent which comprises, as an 15 active ingredient, the isoindole derivative represented by the general formula (Ixe2x80x2).
(13) An angiogenesis inhibitor which comprises, as an active ingredient, the N-phenyl imide compound represented by the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2).
(14) An aminopeptidase N inhibitor which comprises, as an active ingredient, the N-phenyl imide compound represented by the general formula (Ixe2x80x2xe2x80x3-1) or (Ixe2x80x2xe2x80x3-2).
(15) An angiogenesis inhibitor which comprises, as an active ingredient, the phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3).
(16) An aminopeptidase N inhibitor which comprises, as an active ingredient, the phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3).
(17) An angiogenesis inhibitor which comprises, as an active ingredient, the N-phenyl phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3).
(18) An aminopeptidase N inhibitor which comprises, as an active ingredient, the N-phenyl phthalimide derivative represented by the general formula (Ixe2x80x3xe2x80x3).
When the compound of the present invention is administered as the pharmaceutical composition, it is administered usually alone or in admixture with various pharmaceutically acceptable formulation adjuvants, in the form of a drug formulation suitable for peroral, parenteral, topical or per rectal use, such as a tablet, a capsule, a powder, a granule, an injection drug, a liquid formulation, a syrup, a suspension, an ophthalmic solution, an inhalant, an ointment or a suppository.
As the formulation suitable for peroral use, a solid composition such as a tablet, a capsule, a powder, a granule or a troach, or a liquid composition such as a liquid formulation, a syrup or a suspension may, for example, be mentioned. To formulate the solid composition, as the formulation adjuvant, a binder such as carboxymethyl cellulose, gum arabic, tragacanth gum, calcium carbonate, gelatin, polyvinylpyrrolidone, water, ethanol, glucose solution or starch solution; an excipient such as starch, lactose, sucrose, glucose, sodium chloride, calcium carbonate, carboxymethyl cellulose or silicic acid; a disintegrator such as alginic acid, starch, carboxymethyl cellulose, sodium carboxymethyl cellulose; a lubricant such as magnesium stearate, light silicic anhydride or urea; a surface active agent such as a polyoxyethylene sorbitan fatty acid ester or an alkylsulfate; a capsule base such as gelatin; or a sweetener, a flavoring agent, a disintegration inhibitor, an absorption accelerator, a stabilizer, a preservative or a thickener can be used. To formulate the liquid composition, as the formulation adjuvant, sorbitol, gelatin, methyl cellulose, carboxymethyl cellulose or a vegetable oil, and further emulsifying agent, a sweetener, a favoring agent, an absorption accelerator, a stabilizer or a preservative can be used. It is formulated so that the compound of the present invention is contained usually in an amount of from 0.1 to 95 wt %.
As the formulation suitable for parenteral use, an injecting drug may, for example, be mentioned. To formulate an injecting drug, by using a carrier such as distilled water or isotonic sodium chloride solution, the compound is formulated into a form to be injected, such as a suspension or an emulsion. In this case, a pharmaceutically acceptable buffer or a reagent to modulate osmotic pressure, such as benzyl alcohol as a preservative or ascorbic acid as an antioxidant, may be contained. The injection drug is formulated so that the compound of the present invention is contained usually in an amount of from 0.1 to 10 wt %.
As the formulation suitable for topical or per rectal use, an ophthalmic solution, an inhalant, an ointment or a suppository may, for example, be mentioned. The ophthalmic solution is formulated by the conventional method by using a pharmaceutically acceptable carrier. When the compound of the present invention is administered as an inhalant, it is administered to respiratory organs in a form such that the compound of the present invention itself or with a pharmaceutically acceptable inert carrier is dissolved in a solution for an aerosol or a nebulizer, or in a form of a fine powder for inhalation. An ointment is formulated by the conventional method by adding e.g. a base which is usually used. It is formulated so that the compound of the present invention is contained usually in an amount of from about 0.1 to about 30 wt %. A suppository is formulated by the conventional method by using a carrier which is known in the filed, such as polyethyleneglycol, lanolin, cacao butter or fatty acid triglyceride. It is formulated so that the compound of the present invention is contained usually in an amount of from about 0.1 to about 95 wt %.