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Novel physiologically active substancesRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms DoaiNovel physiologically active substances description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060009439, Novel physiologically active substances. Brief Patent Description - Full Patent Description - Patent Application Claims
TECHNICAL FIELD [0001] The present invention relates to a 12-membered ring macrolide compound useful as a medicament, preparation thereof and use thereof. BACKGROUND OF THE INVENTION [0002] Compounds having cytotoxicity have been used as antitumor agents, and many screenings have been carried out using cytotoxicity as an index. As a result, most of pre-existing antitumor agents give affection to cancer cells and simultaneously to normal tissues in which a proliferation of cell is active, for example, to bone marrow, intestine epithelium and the like. Thus, the improvement of QOL of patients has not been sufficiently accomplished yet. [0003] Further, although it can be expected that treatments by the antitumor agents are rather effective for leukemia, it cannot be always said that they are effective for solid cancer. Therefore strong demands have been made to provide antitumor agents that are effective for solid cancer and are highly safe. [0004] Screenings for fermentation products of microorganism have been carried out using the cytotoxicity in vitro as an index, expecting that they might also be used as antitumor agents. Many compounds having cytotoxicity have been found, however, most of them show cytotoxic activities only in vitro, and few compounds of them show antitumor activities in vivo, and very few compounds exhibit effectiveness for solid cancer. DISCLOSURE OF THE INVENTION [0005] It is the object of the present invention to find out compounds which show antitumor activity not only in vitro but also in vivo and have antitumor activities for solid cancer from fermentation products of microorganism or derivatives thereof. [0006] It is considered that tumorgenesis of a normal cell is caused by mutation of a gene in the cell occurs and an abnormal gene is expressed. Accordingly, the present inventors have made intensive investigations based on the inference that the growth of a tumor cell can be suppressed by changing the gene expression of the tumor cell, namely, the growth of the tumor cell can be controlled by changing the gene expression of oncogene or tumor suppressor gene, or by changing the gene expression involved in cell cycle. The present inventors have considered that a compound changing of the gene expression, in particular, a compound suppressing VEGF (vascular endothelial growth factor) production at a hypoxic condition could suppress angiogenesis by a tumor and has an antitumor activities for solid cancer. Then, they carried out screening for fermentation products of microorganism and derivatives thereof using the VEGF production by U251 cell under hypoxic stimulation as an index. As the results, the inventors have found out novel physiologically active compounds, 12-membered ring macrolide compounds, named 11107 and analogues thereof which suppress the VEGF production at a hypoxic condition in vitro, and further suppress the growth of solid tumor cells in vivo. [0007] The present inventors have further found that 11107D among the 11107 analogues is stable even in an aqueous solution, and that compounds obtained by chemical modifications of 11107D (hereinafter, these are referred to as 11107D derivatives) inherit the property of stability in an aqueous solution from 11107D and inhibit the growth of solid tumor cells in vivo experiments in much more degree. The present invention has been accomplished based on these findings. [0008] As a related art of a 12-membered ring macrolide compound which is most structurally similar to the compounds of the present invention, a 12-membered ring macrolide compound FD-895 (JP-A 4-352783) represented by the formula (XIV): is mentioned. The publication discloses that FD-895 has in vitro cell growth inhibitory activities against P388 mouse leukemia cell, L-1210 mouse leukemia cell and HL-60 human leukemia cell in RPM-1640 medium (column 6, Table 2). However, it has been reported that FD-895 did not show antitumor activities in an in vivo experiment using P388 mouse leukemia cell (Seki-Asano M. et al, J. Antibiotics, 47, 1395-1401, 1994). [0009] In addition, FD-895 is unstable in an aqueous solution as described later and is expected to be inappropriate to mix with an infusion solution upon administration. Thus, it cannot be said that FD-895 has sufficient qualities as an antitumor agent. [0010] That is, the present invention relates to: [0011] (1) a compound represented by the formula (I): (in the formula, R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are the same as or different from one another and each represents [0012] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.3, R.sup.6, R.sup.7 and R.sup.21 is bound, provided that R.sup.6 is limited to a hydroxyl group, [0013] 2) an optionally substituted C.sub.1-22 alkoxy group, [0014] 3) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0015] 4) an optionally substituted C.sub.7-22 aralkyloxy group, [0016] 5) an optionally substituted 5 to 14-membered heteroaralkyloxy group, [0017] 6) RCO--O-- (wherein R represents [0018] a) a hydrogen atom, [0019] b) an optionally substituted C.sub.1-22 alkyl group, [0020] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0021] d) an optionally substituted C.sub.6-14 aryl group, [0022] e) an optionally substituted 5 to 14-membered heteroaryl group, [0023] f) an optionally substituted C.sub.7-22 aralkyl group, [0024] g) an optionally substituted 5 to 14-membered heteroaralkyl group, [0025] h) an optionally substituted C.sub.1-22 alkoxy group, [0026] i) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0027] j) an optionally substituted C.sub.6-14 aryloxy group or [0028] k) an optionally substituted 5 to 14-membered heteroaryloxy group), [0029] 7) R.sup.S1R.sup.S2R.sup.S3SiO-- (wherein R.sup.S1, R.sup.S2 and R.sup.S3 are the same as or different from one another and each represents [0030] a) a C.sub.1-6 alkyl group or [0031] b) a C.sub.6-14 aryl group), [0032] 8) a halogen atom, [0033] 9) R.sup.N1R.sup.N2N--R.sup.M-- (wherein R.sup.M represents [0034] a) a single bond, [0035] b) --CO--O--, [0036] c) --SO.sub.2--O--, [0037] d) --CS--O-- or [0038] e) --CO--NR.sup.N3-- (wherein R.sup.N3 represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group), provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom; and [0039] R.sup.N1 and R.sup.N2 are the same as or different from each other and each represents [0040] a) a hydrogen atom, [0041] b) an optionally substituted C.sub.2-22 alkyl group, [0042] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0043] d) an optionally substituted aliphatic C.sub.2-22 acyl group, [0044] e) an optionally substituted aromatic C.sub.7-15 acyl group, [0045] f) an optionally substituted C.sub.6-14 aryl group, [0046] g) an optionally substituted 5 to 14-membered heteroaryl group, [0047] h) an optionally substituted C.sub.7-22 aralkyl group, [0048] i) an optionally substituted C.sub.1-22 alkylsulfonyl group, [0049] j) an optionally substituted C.sub.6-14 arylsulfonyl group, [0050] k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R.sup.N1 and R.sup.N2 together with the nitrogen atom to which R.sup.N1 and R.sup.N2 are bound, and the non-aromatic heterocyclic group may have substituents, [0051] l) an optionally substituted 5 to 14-membered heteroaralkyl group, [0052] m) an optionally substituted C.sub.3-14 cycloalkyl group or [0053] n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group), [0054] 10) R.sup.N4 SO.sub.2--O-- (wherein R.sup.N4 represents [0055] a) an optionally substituted C.sub.1-22 alkyl group, [0056] b) an optionally substituted C.sub.6-14 aryl group, [0057] c) an optionally substituted C.sub.1-22 alkoxy group, [0058] d) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0059] e) an optionally substituted C.sub.6-14 aryloxy group, [0060] f) an optionally substituted 5 to 14-membered heteroaryloxy group, [0061] g) an optionally substituted C.sub.7-22 aralkyloxy group or [0062] h) an optionally substituted 5 to 14-membered heteroaralkyloxy group), [0063] 11) (R.sup.N5O).sub.2PO--O-- (wherein R.sup.N5 represents [0064] a) an optionally substituted C.sub.1-22 alkyl group, [0065] b) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0066] c) an optionally substituted C.sub.6-14 aryl group, [0067] d) an optionally substituted 5 to 14-membered heteroaryl group, [0068] e) an optionally substituted C.sub.7-22 aralkyl group or [0069] f) an optionally substituted 5 to 14-membered heteroaralkyl group), [0070] 12) (R.sup.N1R.sup.N2N).sub.2- PO--O-- (wherein R.sup.N1 and R.sup.N2 have the same meanings as defined above) or [0071] 13) (R.sup.N1R.sup.N2 N)(R.sup.N5O)PO--O-- (wherein R.sup.N1, R.sup.N2 and R.sup.N5 have the same meanings as defined above), provided that a compound in which R.sup.3, R.sup.6, R.sup.7 and R.sup.21 are all hydroxyl groups, and a compound in which R.sup.3, R.sup.6 and R.sup.21 are all hydroxyl groups and R.sup.7 is an acetoxy group are excluded), a pharmacologically acceptable salt thereof or a hydrate of them; [0072] (2) the compound described in (1) represented by the formula (I-a): (in the formula, R.sup.3a, R.sup.6a, R.sup.7a and R.sup.2a are the same as or different from one another and each represents [0073] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.3a, R.sup.6a, R.sup.7a and R.sup.21a is bound, provided that R.sup.6a is limited to a hydroxyl group, [0074] 2) an optionally substituted C.sub.1-22 alkoxy group, [0075] 3) R.sup.aCO--O-- (wherein R.sup.a represents [0076] a) a hydrogen atom, [0077] b) an optionally substituted C.sub.1-22 alkyl group, [0078] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0079] d) an optionally substituted C.sub.6-14 aryl group, [0080] e) an optionally substituted 5 to 14-membered heteroaryl group, [0081] f) an optionally substituted C.sub.7-22 aralkyl group, [0082] g) an optionally substituted 5 to 14-membered heteroaralkyl group, [0083] h) an optionally substituted C.sub.1-22 alkoxy group, [0084] i) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0085] j) an optionally substituted C.sub.6-14 aryloxy group or [0086] k) an optionally substituted 5 to 14-membered heteroaryloxy group), [0087] 4) R.sup.aS1R.sup.aS2R.sup.aS3SiO-- (wherein R.sup.aS1, R.sup.aS2 and R.sup.aS3 are the same as or different from one another and each represents [0088] a) a C.sub.1-6 alkyl group or [0089] b) a C.sub.6-14 aryl group), [0090] 5) a halogen atom or [0091] 6) R.sup.aN1R.sup.aN2N--R.sup.aM-- (wherein R.sup.aM represents [0092] a) a single bond, [0093] b) --CO--O--, [0094] c)--SO.sub.2--O--, [0095] d) --CS--O-- or [0096] e) --CO--NR.sup.aN3-- (wherein R.sup.aN3 represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group, provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom); and [0097] R.sup.aN1 and R.sup.aN2 are the same as or different from each other and each represents [0098] a) a hydrogen atom, [0099] b) an optionally substituted C.sub.1-22 alkyl group, [0100] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0101] d) an optionally substituted aliphatic C.sub.2-22 acyl group, [0102] e) an optionally substituted aromatic C.sub.7-15 acyl group, [0103] f) an optionally substituted C.sub.6-14 aryl group, [0104] g) an optionally substituted 5 to 14-membered heteroaryl group, [0105] h) an optionally substituted C.sub.7-22 aralkyl group, [0106] i) an optionally substituted C.sub.1-22 alkylsulfonyl group, [0107] j) an optionally substituted C.sub.6-14 arylsulfonyl group, [0108] k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R.sup.aN1 and R.sup.aN2 together with the nitrogen atom to which R.sup.aN1 and R.sup.aN2 are bound, and the non-aromatic heterocyclic group may have substituents, [0109] l) an optionally substituted 5 to 14-membered heteroaralkyl group, [0110] m) an optionally substituted C.sub.3-14 cycloalkyl group or [0111] n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them; [0112] (3) the compound described in (1) represented by the formula (I-b): (in the formula, R.sup.3b, R.sup.6b, R.sup.7b and R.sup.21b are the same as or different from one another and each represents [0113] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.3b, R.sup.6b, R.sup.7b and R.sup.21b is bound, provided that R.sup.6b is limited to a hydroxyl group, [0114] 2) an optionally substituted C.sub.1-22 alkoxy group, [0115] 3) R.sup.bCO--O-- (wherein R.sup.b represents [0116] a) a hydrogen atom, [0117] b) an optionally substituted C.sub.1-22 alkyl group, [0118] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0119] d) an optionally substituted C.sub.6-14 aryl group, [0120] e) an optionally substituted 5 to 14-membered heteroaryl group, [0121] f) an optionally substituted C.sub.7-22 aralkyl group, [0122] g) an optionally substituted 5 to 14-membered heteroaralkyl group, [0123] h) an optionally substituted C.sub.1-22 alkoxy group, [0124] i) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0125] j) an optionally substituted C.sub.6-14 aryloxy group or [0126] k) an optionally substituted 5 to 14-membered heteroaryloxy group), [0127] 4) R.sup.bS1R.sup.bS2R.sup.bS3SiO-- (wherein R.sup.bS1, R.sup.bS2 and R.sup.bS3 are the same as or different from one another and each represents [0128] a) a C.sub.1-6 alkyl group or [0129] b) a C.sub.6-14 aryl group) or [0130] 5) R.sup.bN1R.sup.bN2N--R.sup.bM-- (wherein R.sup.bM represents [0131] a) --CO--O-- or [0132] b) --CS--O--, provided that each of the leftmost bond in a) and b) is bound to the nitrogen atom; and [0133] R.sup.bN1 and R.sup.bN2 are the same as or different from each other and each represents [0134] a) a hydrogen atom, [0135] b) an optionally substituted C.sub.1-22 alkyl group, [0136] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0137] d) an optionally substituted aliphatic C.sub.2-22 acyl group, [0138] e) an optionally substituted aromatic C.sub.7-15 acyl group, [0139] f) an optionally substituted C.sub.6-14 aryl group, [0140] g) an optionally substituted 5 to 14-membered heteroaryl group, [0141] h) an optionally substituted C.sub.7-22 aralkyl group, [0142] i) an optionally substituted C.sub.1-22 alkylsulfonyl group, [0143] j) an optionally substituted C.sub.6-14 arylsulfonyl group, [0144] k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R.sup.bN1 and R.sup.bN2 together with the nitrogen atom to which R.sup.bN1 and R.sup.bN2 are bound, and the non-aromatic heterocyclic group may have substituents, [0145] l) an optionally substituted 5 to 14-membered heteroaralkyl group, [0146] m) an optionally substituted C.sub.3-14 cycloalkyl group or [0147] n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them; [0148] (4) the compound described in (1) represented by the formula (I-c): (in the formula, R.sup.3c, R.sup.6c, R.sup.7c and R.sup.21c are the same as or different from one another and each represents [0149] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.3c, R.sup.6c, R.sup.7c and R.sup.21c is bound, provided that R.sup.6c is limited to a hydroxyl group, [0150] 2) an optionally substituted C.sub.1-22 alkoxy group, [0151] 3) R.sup.cCO--O-- (wherein R.sup.c represents [0152] a) an optionally substituted C.sub.1-22 alkyl group, [0153] b) an optionally substituted C.sub.6-14 aryl group, [0154] c) an optionally substituted C.sub.7-22 aralkyl group or [0155] d) an optionally substituted C.sub.6-14 aryloxy group), [0156] 4) R.sup.cS1R.sup.cS2R.sup.cS3SiO-- (wherein R.sup.cS1, R.sup.cS2 and R.sup.cS3 are the same as or different from one another and each represents [0157] a) a C.sub.1-6 alkyl group or [0158] b) a C.sub.6-14 aryl group) or [0159] 5) R.sup.cN1R.sup.cN2N--R.sup.cM-- (wherein R.sup.cM represents [0160] a) --CO--O-- or [0161] b) --CS--O--, provided that each of the leftmost bond in a) and b) is bound to the nitrogen atom; and [0162] R.sup.cN1 and R.sup.cN2 are the same as or different from each other and each represents [0163] a) a hydrogen atom, [0164] b) an optionally substituted C.sub.1-22 alkyl group, [0165] c) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R.sup.cN1 and R.sup.cN2 together with the nitrogen atom to which R.sup.cN1 and R.sup.cN2 are bound, and the non-aromatic heterocyclic group may have substituents, [0166] d) an optionally substituted 5 to 14-membered heteroaralkyl group, [0167] e) an optionally substituted C.sub.3-14 cycloalkyl group or [0168] f) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group, and the non-aromatic heterocyclic group may have substituents)), a pharmacologically acceptable salt thereof or a hydrate of them; [0169] (5) the compound described in (1) represented by the formula (I-d): (in the formula, R.sup.3d represents [0170] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which R.sup.3d is bound, [0171] 2) an optionally substituted C.sub.1-22 alkoxy group, [0172] 3) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0173] 4) an optionally substituted C.sub.7-22 aralkyloxy group, [0174] 5) R.sup.dCO--O-- (wherein R.sup.d represents [0175] a) a hydrogen atom, [0176] b) an optionally substituted C.sub.1-22 alkyl group, [0177] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0178] d) an optionally substituted C.sub.6-14 aryl group, [0179] e) an optionally substituted 5 to 14-membered heteroaryl group, [0180] f) an optionally substituted C.sub.7-22 aralkyl group, [0181] g) an optionally substituted 5 to 14-membered heteroaralkyl group, [0182] h) an optionally substituted C.sub.1-22 alkoxy group, [0183] i) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0184] j) an optionally substituted C.sub.6-14 aryloxy group or [0185] k) an optionally substituted 5 to 14-membered heteroaryloxy group) or [0186] 6) R.sup.dN1R.sup.dN2N--CO--C-- (wherein R.sup.dN1 and R.sup.dN2 are the same as or different from each other and each represents [0187] a) a hydrogen atom, [0188] b) an optionally substituted C.sub.1-22 alkyl group, [0189] c) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0190] d) an optionally substituted C.sub.6-14 aryl group, [0191] e) an optionally substituted 5 to 14-membered heteroaryl group, [0192] f) an optionally substituted C.sub.7-22 aralkyl group, [0193] g) an optionally substituted 5 to 14-membered heteroaralkyl group, [0194] h) an optionally substituted C.sub.3-14 cycloalkyl group, [0195] i) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group or [0196] j) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R.sup.dN1 and R.sup.dN2 together with the nitrogen atom to which R.sup.dN1 and R.sup.dN2 are bound, and the non-aromatic heterocyclic group may have substituents); and [0197] R.sup.6d, R.sup.7d and R.sup.21d are the same as or different from one another and each represents [0198] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.6d, R.sup.7d and R.sup.21d is bound, provided that R.sup.6d is limited to a hydroxyl group, [0199] 2) an optionally substituted C.sub.1-22 alkoxy group, [0200] 3) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0201] 4) an optionally substituted C.sub.7-22 aralkyloxy group, [0202] 5) R.sup.dCO--O-- (wherein R.sup.d has the same meaning as defined above), [0203] 6) R.sup.dN1R.sup.dN2N--CO--O-- (wherein R.sup.dN1 and R.sup.dN2 have the same meanings as defined above), [0204] 7) R.sup.dN1R.sup.dN2N--SO.sub.2--O-- (wherein R.sup.dN1 and R.sup.dN2 have the same meanings as defined above), [0205] 8) R.sup.dN1R.sup.dN2N--CS--- C-- (wherein R.sup.dN1 and R.sup.dN2 have the same meanings as defined above), [0206] 9) R.sup.dN3SO.sub.2--O-- (wherein R.sup.dN3 represents [0207] a) an optionally substituted C.sub.1-22 alkyl group, [0208] b) an optionally substituted C.sub.1-22 alkoxy group, [0209] c) an optionally substituted unsaturated C.sub.2-22 alkoxy group, [0210] d) an optionally substituted C.sub.6-14 aryl group, [0211] e) an optionally substituted C.sub.6-14 aryloxy group, [0212] f) an optionally substituted 5 to 14-membered heteroaryloxy group, [0213] g) an optionally substituted C.sub.7-22 aralkyloxy group or [0214] h) an optionally substituted 5 to 14-membered heteroaralkyloxy group), [0215] 10) (R.sup.dN5O).sub.2PO-- (wherein R.sup.dN5 represents [0216] a) an optionally substituted C.sub.1-22 alkyl group, [0217] b) an optionally substituted unsaturated C.sub.2-22 alkyl group, [0218] c) an optionally substituted C.sub.6-14 aryl group, [0219] d) an optionally substituted 5 to 14-membered heteroaryl group, [0220] e) an optionally substituted C.sub.7-22 aralkyl group or [0221] f) an optionally substituted 5 to 14-membered heteroaralkyl group), [0222] 11) (R.sup.dN1R.sup.dN2N).sub.2PO-- (wherein R.sup.dN1 and R.sup.dN2 have the same meanings as defined above) or [0223] 12) (R.sup.dN1R.sup.dN2N)(R.sup.dN5O)PO-- (wherein R.sup.dN1, R.sup.dN2 and R.sup.dN5 have the same meanings as defined above), provided that a compound in which R.sup.3d, R.sup.6d, R.sup.7d and R.sup.21d are all hydroxyl groups, and a compound in which R.sup.3d, R.sup.6d and R.sup.21d are hydroxyl groups and R.sup.7d is an acetoxy group are excluded), a pharmacologically acceptable salt thereof or a hydrate of them; [0224] (6) the compound described in (1), wherein R.sup.6 and/or R.sup.7 represents R.sup.N1R.sup.N2N--R.sup.M-- (wherein R.sup.M represents [0225] a) --CO--O-- or [0226] b) --CS--O--; and [0227] R.sup.N1 and R.sup.N2 have the same meanings as defined above, provided that each of the leftmost bond in a) and b) is bound to the nitrogen atom), a pharmacologically acceptable salt thereof or a hydrate of them; [0228] (7) the compound described in (1), a pharmacologically acceptable salt thereof or a hydrate of them, wherein R.sup.21 is an oxo group formed together with the carbon atom to which R.sup.21 is bound; [0229] (8) the compound described in (5) represented by the formula (I-e): (in the formula, R.sup.3e and R.sup.21e are the same as or different from each other and each represents [0230] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.3e and R.sup.21e is bound, [0231] 2) an optionally substituted C.sub.1-6 alkoxy group, [0232] 3) an optionally substituted unsaturated C.sub.2-10 alkoxy group, [0233] 4) an optionally substituted C.sub.7-10 aralkyloxy group, [0234] 5) an optionally substituted aliphatic C.sub.2-6 acyloxy group or [0235] 6) R.sup.eN1R.sup.eN2N--CO--O-- (wherein R.sup.eN1 and R.sup.eN2 are the same as or different from each other and each represents [0236] A) a hydrogen atom or [0237] B) an optionally substituted C.sub.1-6 alkyl group); and [0238] R.sup.6e and R.sup.7e are the same as or different from each other and each represents [0239] 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R.sup.6e and R.sup.7e is bound, provided that R.sup.6e is limited to a hydroxyl group, [0240] 2) an optionally substituted C.sub.1-6 alkoxy group, [0241] 3) an optionally substituted unsaturated C.sub.2-10 alkoxy group, [0242] 4) an optionally substituted C.sub.7-10 aralkyloxy group, [0243] 5) an optionally substituted aliphatic C.sub.2-6 acyloxy group or [0244] 6) R.sup.eC(.dbd.Y.sup.e)--O-- (wherein Y.sup.e represents an oxygen atom or a sulfur atom; and R.sup.e represents [0245] a) a hydrogen atom, [0246] b) an optionally substituted C.sub.1-6 alkyl group, [0247] c) an optionally substituted C.sub.7-10 aralkyl group, [0248] d) an optionally substituted 5 to 14-membered heteroaralkyl group, [0249] e) the formula (III): [0250] (in the formula, [0251] A) n represents an integer of 0 to 4; [0252] X.sub.e represents [0253] i) --CHR.sup.eN4, [0254] ii) --NR.sup.eN5--, [0255] iii) --O--, [0256] iv) --S--, [0257] v) --SO-- or [0258] vi) --SO.sub.2--; [0259] R.sup.eN1 represents [0260] i) a hydrogen atom or [0261] ii) a C.sub.1-6 alkyl group; [0262] R.sup.eN2 represents [0263] i) hydrogen atom or [0264] ii) a C.sub.1-6 alkyl group; [0265] R.sup.eN3 and R.sup.eN4 are the same as or different from each other and each represents [0266] i) a hydrogen atom, [0267] ii) an optionally substituted C.sub.1-6 alkyl group, [0268] iii) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0269] iv) an optionally substituted C.sub.6-14 aryl group, [0270] v) an optionally substituted 5 to 14-membered heteroaryl group, [0271] vi) an optionally substituted C.sub.7-10 aralkyl group, [0272] vii) an optionally substituted C.sub.3-8 cycloalkyl group, [0273] viii) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0274] ix) an optionally substituted 5 to 14-membered heteroaralkyl group, [0275] x) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group, [0276] xi) --NR.sup.eN6R.sup.eN7 (wherein R.sup.eN6 and R.sup.eN7 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group) or [0277] xii) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R.sup.eN3 and R.sup.eN4 together with the carbon atom to which R.sup.eN3 and R.sup.eN4 are bound, and the non-aromatic heterocyclic group may have substituents; and [0278] R.sup.eN5 represents [0279] i) a hydrogen atom, [0280] ii) an optionally substituted C.sub.1-6 alkyl group, [0281] iii) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0282] iv) an optionally substituted C.sub.6-14 aryl group, [0283] v) an optionally substituted 5 to 14-membered heteroaryl group, [0284] vi) an optionally substituted C.sub.7-10 aralkyl group, [0285] vii) an optionally substituted C.sub.3-8 cycloalkyl group, [0286] viii) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0287] ix) an optionally substituted 5 to 14-membered heteroaralkyl group, [0288] x) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group or [0289] xi) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R.sup.eN3 and R.sup.eN5 together with the nitrogen atom to which R.sup.eN3 and R.sup.eN5 are bound, and the non-aromatic heterocyclic group may have substituents, [0290] B) X.sub.e, n, R.sup.eN3, R.sup.eN4 and R.sup.eN5 each represents the group as defined above; and R.sup.eN1 and R.sup.eN2 together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group, [0291] C) X.sub.e, n, R.sup.eN2, R.sup.eN4 and R.sup.eNn5 each represents the group as defined above; and R.sup.eN1 and R.sup.eN3 together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group or [0292] D) X.sub.e, n, R.sup.eN1, R.sup.eN4 and R.sup.eN5 each represents the group as defined above; and R.sup.eN2 and R.sup.eN3 together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group) or [0293] f) the formula (IV): [0294] (in the formula, R.sup.eN8 and R.sup.eN9 are the same as or different from each other and each represents [0295] i) a hydrogen atom, [0296] ii) an optionally substituted C.sub.1-6 alkyl group, [0297] iii) an optionally substituted C.sub.6-14 aryl group, [0298] iv) an optionally substituted 5 to 14-membered heteroaryl group, [0299] v) an optionally substituted C.sub.7-10 aralkyl group or [0300] vi) an optionally substituted 5 to 14-membered heteroaralkyl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0301] (9) the compound described in (5), wherein R.sup.6d and/or R.sup.7d represents R.sup.d1C(.dbd.Y.sup.d1)- --O-- (wherein Y.sup.d1 represents an oxygen atom or a sulfur atom; and R.sup.d1 represents [0302] 1) a hydrogen atom, [0303] 2) an optionally substituted C.sub.1-6 alkyl group, [0304] 3) an optionally substituted C.sub.7-10 aralkyl group or [0305] 4) an optionally substituted 5 to 14-membered heteroaralkyl group), a pharmacologically acceptable salt thereof or a hydrate of them; [0306] (10) the compound described in (5), wherein R.sup.6d and/or R.sup.7d represents R.sup.d2C(.dbd.Y.sup.d2)- --O-- (wherein Y.sup.d2 represents an oxygen atom or a sulfur atom; and R.sup.d2 represents the formula (III'): (in the formula, n represents an integer of 0 to 4; X.sub.1 represents [0307] 1) CHR.sup.dN7--, [0308] 2) --NR.sup.dN8--, [0309] 3) --O--, [0310] 4) --S--, [0311] 5) --SO-- or [0312] 6) --SO.sub.2--; [0313] R.sup.dN4 and R.sup.dN5 are the same as or different from each other and each represents [0314] 1) a hydrogen atom or [0315] 2) a C.sub.1-6 alkyl group; [0316] R.sup.dN6 and R.sup.dN7 are the same as or different from each other and each represents [0317] 1) a hydrogen atom, [0318] 2) an optionally substituted C.sub.1-6 alkyl group, [0319] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0320] 4) an optionally substituted C.sub.6-14 aryl group, [0321] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0322] 6) an optionally substituted C.sub.7-10 aralkyl group, [0323] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0324] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0325] 9) an optionally substituted 5 to 14-membered heteroaralkyl group, [0326] 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group, [0327] 11) --NR.sup.dN9R.sup.dN10 (wherein R.sup.dN9 and R.sup.dN10 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group) or [0328] 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed together by R.sup.dN6 and R.sup.dN7, and the non-aromatic heterocyclic group may have substituents; and [0329] R.sup.dN8 represents [0330] 1) a hydrogen atom, [0331] 2) an optionally substituted C.sub.1-6 alkyl group, [0332] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0333] 4) an optionally substituted C.sub.6-14 aryl group, [0334] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0335] 6) an optionally substituted C.sub.7-10 aralkyl group, [0336] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0337] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0338] 9) an optionally substituted 5 to 14-membered heteroaralkyl group, [0339] 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group, [0340] 11) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R.sup.dN4, R.sup.dN5 or R.sup.dN6 together with the nitrogen atom to which each of R.sup.dN4, R.sup.dN5 and R.sup.dN6 is bound, and the non-aromatic heterocyclic group may have substituents or [0341] 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by two substituents selected from the group consisting of R.sup.dN4, R.sup.dN5 and R.sup.dN6 together with the nitrogen atom to which it is bound, and the non-aromatic heterocyclic group may have substituents)), a pharmacologically acceptable salt thereof or a hydrate of them; [0342] (11) the compound described in (10), a pharmacologically acceptable salt thereof or a hydrate of them, wherein X.sub.1 represents --NR.sup.dN8-- (wherein NR.sup.dN8 has the same meanings as defined above); [0343] (12) the compound described in (5) represented by the formula (I-f): (in the formula, R.sup.7f represents R.sup.fC(.dbd.Y.sup.f)--O-- (wherein Y.sup.f represents an oxygen atom or a sulfur atom; and R.sup.f represents the formula (V): (wherein n represents an integer of 0 to 4; [0344] R.sup.fN1 represents [0345] 1) a hydrogen atom, [0346] 2) a methyl group or [0347] 3) an ethyl group; and [0348] R.sup.fN2 represents [0349] 1) a hydrogen atom, [0350] 2) a methylamino group, [0351] 3) a dimethylamino group, [0352] 4) an ethylamino group, [0353] 5) a diethylamino group, [0354] 6) an ethylmethylamino group, [0355] 7) a pyridinyl group, [0356] 8) a pyrrolidin-1-yl group, [0357] 9) a piperidin-1-yl group, [0358] 10) a morpholin-4-yl group or [0359] 11) a 4-methylpiperazin-1-yl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0360] (13) the compound described in (5), wherein R.sup.6d and/or R.sup.7d represents R.sup.d3CO--O-- (wherein R.sup.d3 represents the formula (VI): (wherein n.sub.1 and n.sub.2 are the same as or different from each other and each represents an integer of 0 to 4; [0361] X.sub.2 represents [0362] 1) --CHR.sup.dN13--, [0363] 2) --NR.sup.dN14--, [0364] 3) --O--, [0365] 4) --S--, [0366] 5) --SO-- or [0367] 6) --SO.sub.2--; [0368] R.sup.dN11 represents [0369] 1) a hydrogen atom or [0370] 2) an optionally substituted C.sub.1-6 alkyl group; [0371] R.sup.dN12 represents [0372] 1) a hydrogen atom, [0373] 2) an optionally substituted C.sub.1-6 alkyl group, [0374] 3) an optionally substituted C.sub.6-14 aryl group or [0375] 4) an optionally substituted C.sub.7-10 aralkyl group; [0376] R.sup.dN13 represents [0377] 1) a hydrogen atom, [0378] 2) an optionally substituted C.sub.1-6 alkyl group, [0379] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0380] 4) an optionally substituted C.sub.6-14 aryl group, [0381] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0382] 6) an optionally substituted C.sub.7-10 aralkyl group, [0383] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0384] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0385] 9) an optionally substituted 5 to 14-membered heteroaralkyl group, [0386] 10) --NR.sup.dN15R.sup.dN16 (wherein R.sup.dN15 and R.sup.dN16 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group) or [0387] 11) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and [0388] R.sup.dN14 represents [0389] 1) a hydrogen atom, [0390] 2) an optionally substituted C.sub.1-6 alkyl group, [0391] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0392] 4) an optionally substituted C.sub.6-14 aryl group, [0393] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0394] 6) an optionally substituted C.sub.7-10 aralkyl group, [0395] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0396] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0397] 9) an optionally substituted 5 to 14-membered heteroaralkyl group or [0398] 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them; [0399] (14) the compound described in (5) represented by the formula (I-g): (in the formula, R.sup.7g represents R.sup.gCO--O-- (wherein R.sup.g represents the formula (VII): (wherein n.sub.3 represents 1 or 2; [0400] R.sup.dN17 represents [0401] 1) a hydrogen atom, [0402] 2) a methyl group or [0403] 3) an ethyl group; and [0404] R.sup.dN18 represents [0405] 1) a hydrogen atom, [0406] 2) a methyl group or [0407] 3) an ethyl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0408] (15) the compound described in (5), wherein R.sup.6d and/or R.sup.7d represents R.sup.d4CO--O-- (wherein R.sup.d4 represents the formula (VIII): (wherein n.sub.1 and n.sub.2 are the same as or different from each other and each represents an integer of 0 to 4; [0409] X.sub.3 represents [0410] 1) --CHR.sup.dN21--, [0411] 2) --NR.sup.dN222--, [0412] 3) --O--, [0413] 4) --S--, [0414] 5) --SO-- or [0415] 6) --SO.sub.2--; [0416] R.sup.dN19 represents [0417] 1) a hydrogen atom or [0418] 2) a C.sub.1-6 alkyl group; [0419] R.sup.dN20 represents [0420] 1) a hydrogen atom, [0421] 2) an optionally substituted C.sub.1-6 alkyl group, [0422] 3) an optionally substituted C.sub.6-14 aryl group or [0423] 4) an optionally substituted C.sub.7-10 aralkyl group; [0424] R.sup.dN21 represents [0425] 1) a hydrogen atom, [0426] 2) an optionally substituted C.sub.1-6 alkyl group, [0427] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0428] 4) an optionally substituted C.sub.1-6 alkoxy group, [0429] 5) an optionally substituted C.sub.6-14 aryl group, [0430] 6) an optionally substituted 5 to 14-membered heteroaryl group, [0431] 7) an optionally substituted C.sub.7-10 aralkyl group, [0432] 8) an optionally substituted C.sub.3-8 cycloalkyl group, [0433] 9) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0434] 10) an optionally substituted 5 to 14-membered heteroaralkyl group, [0435] 11) --NR.sup.dN23R.sup.dN24 (wherein R.sup.dN23 and R.sup.dN24 are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C.sub.1-6 alkyl group) or [0436] 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and [0437] R.sup.dN22 represents [0438] 1) a hydrogen atom, [0439] 2) an optionally substituted C.sub.1-6 alkyl group, [0440] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0441] 4) an optionally substituted C.sub.6-14 aryl group, [0442] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0443] 6) an optionally substituted C.sub.7-10 aralkyl group, [0444] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0445] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0446] 9) an optionally substituted 5 to 14-membered heteroaralkyl group or [0447] 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them; [0448] (16) the compound described in (5) represented by the formula (I-h): (in the formula, R.sub.7h represents R.sup.hCO--O-- (wherein R.sup.h represents the formula (IX): (wherein n.sub.4 represents an integer of 1 to 3; and [0449] R.sup.dN25 represents [0450] 1) an amino group, [0451] 2) a methylamino group, [0452] 3) a dimethylamino group, [0453] 4) a pyrrolidin-1-yl group, [0454] 5) a piperidin-1-yl group or [0455] 6) a morpholin-4-yl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0456] (17) the compound described in (5) represented by the formula (I-i): (in the formula, R.sup.7i represents R.sup.iCO--O-- (wherein R.sup.i represents the formula (X): (wherein n.sub.4 represents an integer of 1 to 3; [0457] R.sup.dN26 represents [0458] 1) a hydrogen atom, [0459] 2) an optionally substituted C.sub.1-6 alkyl group, [0460] 3) an optionally substituted C.sub.6-14 aryl group or [0461] 4) an optionally substituted C.sub.7-10 aralkyl group; and [0462] R.sup.dN27 represents [0463] 1) a hydrogen atom, [0464] 2) an optionally substituted C.sub.1-6 alkyl group, [0465] 3) an optionally substituted C.sub.3-8 cycloalkyl group, [0466] 4) an optionally substituted 3 to 8-membered non-aromatic heterocyclic group, [0467] 5) an optionally substituted C.sub.6-14 aryl group, [0468] 6) an optionally substituted 5 to 14-membered heteroaryl group, [0469] 7) an optionally substituted C.sub.7-10 aralkyl group, [0470] 8) an optionally substituted 5 to 14-membered heteroaralkyl group or [0471] 9) an optionally substituted C.sub.4-9 cycloalkyl alkyl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0472] (18) the compound described in (5) represented by the formula (I-j): (in the formula, R.sup.7j represents R.sup.jCO--O-- (wherein R.sup.j represents the formula (XI): (wherein n.sub.4 represents an integer of 1 to 3; and [0473] R.sup.dN28 represents [0474] 1) a hydrogen atom, [0475] 2) an optionally substituted C.sub.1-6 alkyl group, [0476] 3) a C.sub.3-8 cycloalkyl group, [0477] 4) a C.sub.4-9 cycloalkyl alkyl group, [0478] 5) a C.sub.7-10 aralkyl group, [0479] 6) a pyridinyl group or [0480] 7) a tetrahydropyranyl group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0481] (19) the compound described in (5) represented by the formula (I-k): (in the formula, R.sup.7k represents R.sup.kCO--O-- (wherein R.sup.k represents the formula (XII): (wherein m.sub.1, m.sub.2, m.sub.3 and m.sub.4 are the same as or different from one another and each represents 0 or 1; [0482] n.sub.4 represents an integer of 1 to 3; and [0483] R.sup.dN29 represents [0484] 1) a hydrogen atom, [0485] 2) an optionally substituted C.sub.1-6 alkyl group, [0486] 3) an optionally substituted unsaturated C.sub.2-10 alkyl group, [0487] 4) an optionally substituted C.sub.6-14 aryl group, [0488] 5) an optionally substituted 5 to 14-membered heteroaryl group, [0489] 6) an optionally substituted C.sub.7-10 aralkyl group, [0490] 7) an optionally substituted C.sub.3-8 cycloalkyl group, [0491] 8) an optionally substituted C.sub.4-9 cycloalkyl alkyl group, [0492] 9) an optionally substituted 5 to 14-membered heteroaralkyl group or [0493] 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group))), a pharmacologically acceptable salt thereof or a hydrate of them; [0494] (20) the compound described in (5) represented by the formula (I-m): (in the formula, R.sup.7m represents R.sup.mCO--O-- (wherein R.sup.m represents the formula (XIII): (wherein m.sub.5 represents an integer of 1 to 3; and n.sub.5 represents 2 or 3))), a pharmacologically acceptable salt thereof or a hydrate of them; [0495] (21) the compound described in (5) represented by the formula (I-n) (in the formula, R.sup.7n represents R.sup.nCO--O-- (wherein R.sup.n is a group represented by the formula (XIV): a pharmacologically acceptable salt thereof or a hydrate of them; [0496] (22) the compound described in (1), which is selected from: (8E,12E,14E)-7-(N-(2-(N',N'-Dimethylamino)et- hyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethy- l-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 6); (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy- lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 9); (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentameth- yl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trie- n-11-olide (Compound 12); (8E,12E,14E)-7-((4-Butylpiperazin-1-yl)carbonyl)- oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,- 12,14-trien-11-olide (Compound 16); (8E,12E,14E)-7-((4-Ethylpiperazin-1-yl- )carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxy- tricosa-8,12,14-trien-11-olide (Compound 21); (8E,12E,14E)-3,6,16,21-Tetra- hydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-- 18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 25); (8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrah- ydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 26); (8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbo- nyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricos- a-8,12,14-trien-11-olide (Compound 27); (8E,12E,14E)-3,6,16,21-Tetrahydrox- y-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18- ,19-epoxytricosa-8,12,14-trien-11-olide (Compound 31); (8E,12E,14E)-7-((4-(Cyclopropylmethyl)homopiperazin-1-yl)carbonyl)oxy-3,6- ,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-t- rien-11-olide (Compound 36); (8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)- carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxyt- ricosa-8,12,14-trien-11-olide (Compound 38); (8E,12E,14E)-3,6,16,21-Tetrah- ydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethy- l-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 44); (8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra- hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid- e (Compound 45); (8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-methylc- arbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxyt- ricosa-8,12,14-trien-11-olide (Compound 75); (8E,12E,14E)-3,6,16,21-Tetrah- ydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentame- thyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 54); (8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahy- droxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 63); (8E,12E,14E)-7-((4-Butylhomopiperazin-1-yl)carbonyl)oxy-3,- 6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-- trien-11-olide (Compound 64); (8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,- 10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epox- ytricosa-8,12,14-trien-11-olide (Compound 85); (8E,12E,14E)-3,16,21-Trihyd- roxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-(piperidin-1-yl)piperidin-1- -yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 109); (8E,12E,14E)-7-((4-(2,2-Dimethylpropyl)homopiperazin-1-yl)carbonyl)oxy-3,- 6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-- trien-11-olide (Compound 69); and (8E,12E,14E)-3,6,16-Trihydroxy-21-methox- y-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-- epoxytricosa-8,12,14-trien-11-olide (Compound 131); [0497] (23) the compound described in (1), which is selected from: (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methy- lhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide (Compound 9); (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentameth- yl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trie- n-11-olide (Compound 12); (8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carb- onyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytrico- sa-8,12,14-trien-11-olide (Compound 26); (8E,12E,14E)-3,6,16,21-Tetrahydro- xy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18- ,19-epoxytricosa-8,12,14-trien-11-olide (Compound 44); (8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetra- hydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olid- e (Compound 45); and (8E,12E,14E)-7-(N-(2-(N',N'-Diethylamino)ethyl)-N-met- hylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-ep- oxytricosa-8,12,14-trien-11-olide (Compound 75); [0498] (24) a medicament comprising the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them as an active ingredient; [0499] (25) a pharmaceutical composition comprising the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them as an active ingredient; [0500] (26) the medicament described in (24), which is an agent for preventing or treating a disease against which a regulation of gene expression is efficacious; [0501] (27) the medicament described in (22), which is an agent for preventing or treating a diseases against which suppression of VEGF production is efficacious; [0502] (28) the medicament described in (22), which is an agent for preventing or treating a disease against which an antiangiogenic effect is efficacious; [0503] (29) the medicament described in (24), which is an angiogenesis inhibitor; [0504] (30) the medicament described in (24), which is an antitumor agent; [0505] (31) the medicament described in (24), as a therapeutic agent for treating angioma; [0506] (32) the medicament described in (24), which is a cancer metastasis inhibitor; [0507] (33) the medicament described in (22), which is a therapeutic agent for treating retinal neovascularization or diabetic retinopathy; [0508] (34) the medicament described in (24), which is a therapeutic agent for treating inflammatory disease; [0509] (35) the medicament described in (24), which is a therapeutic agent for treating inflammatory diseases consisting of deformans arthritis, rheumatoid arthritis, psoriasis and delayed hypersensitivity reaction; [0510] (36) the medicament described in (24), which is a therapeutic agent for treating atherosclerosis; [0511] (37) the medicament described in (24), which is a therapeutic agent for treating solid cancer; [0512] (38) the medicament described in (37), wherein the solid cancer is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, colon cancer or melanoma; [0513] (39) the medicament described in (24), which is a therapeutic agent for treating leukemia; [0514] (40) the medicament described in (24), which is an antitumor agent based on a regulation of gene expression; [0515] (41) the medicament described in (24), which is an antitumor agent based on suppression of VEGF production; [0516] (42) the medicament described in (24), which is an antitumor agent based on an effect of angiogenesis inhibition; [0517] (43) a method for preventing or treating a disease against which a regulation of gene expression is efficacious, which comprises administering a pharmacologically effective dose of the medicament described in (24) to a patient; [0518] (44) a method for preventing or treating a disease against which suppression of VEGF production is efficacious, which comprises administering a pharmacologically effective dose of the medicament described in (24) to a patient; [0519] (45) a method for preventing or treating a disease against which an angiogenesis inhibition is efficacious, which comprises administering a pharmacologically effective dose of the medicament described in (24) to a patient; [0520] (46) use of the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them, for manufacturing an agent for preventing or treating a disease against which a regulation of gene expression is efficacious; [0521] (47) use of the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them, for manufacturing an agent for preventing or treating a disease against which suppression of VEGF production is efficacious; [0522] (48) use of the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them, for manufacturing an agent for preventing or treating a disease against which an angiogenesis inhibition is efficacious; and [0523] (49) use of the compound described in any one of (1) to (23), a pharmacologically acceptable salt thereof or a hydrate of them, for producing an agent for preventing or treating solid cancers. [0524] The terms, symbols and the like used in the present specification will be illustrated below. [0525] In the present specification, the chemical formula of the compound according to the present invention is illustrated as a planimetric chemical formula for convenience but the compound can include certain isomers drawn from the chemical formula. The present invention can include all isomers and mixtures of the isomers such as a geometric isomer which is generated from the configuration of the compound, an optical isomer based on an asymmetric carbon, a rotamer, a stereoisomer and a tautomer. The present invention is not limited to the expediential description of the chemical formula, and can include either of isomers or a mixture thereof. Accordingly, when the compound of the present invention has an asymmetric carbon in the molecule, and its optically active substance and racemate exist, any one is included. Further, when polymorphic crystals exist, the crystal form of the present invention is not specifically limited to one form, and any one of the crystal forms may be single or a mixture of the crystal forms. The compound represented by the formula (I) according to the present invention or a salt thereof may be an anhydrate or a hydrate, and both are included in the present invention. The metabolite which is generated in vivo by decomposition of the compound of the formula (I) according to the present invention and the prodrug of the compound of the formula (I) according to the present invention or a salt thereof are also included in the present invention. [0526] The "halogen atom" used in the specification of the present application means a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Among them, for example, a fluorine atom, a chlorine atom or a bromine atom is preferred, of which a fluorine atom or a chlorine atom is typically preferred. [0527] The "C.sub.1-22 alkyl group" used in the specification of the present application indicates a linear or branched alkyl group having 1 to 22 carbon atoms, such as methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group, n-pentyl group, 1,1-dimethylpropyl group, 1,2-dimethylpropyl group, 2,2-dimethylpropyl group, 1-ethylpropyl group, n-hexyl group, 1-ethyl-2-methylpropyl group, 1,1,2-trimethylpropyl group, 1-propylpropyl group, 1-methylbutyl group, 2-methylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2-ethylbutyl group, 2-methylpentyl group, 3-methylpentyl group, n-heptyl group, n-octyl group, n-nonyl group or n-decyl group; preferably a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl group, ethyl group, n-propyl group, iso-propyl group, n-butyl group, iso-butyl group, sec-butyl group, tert-butyl group or n-pentyl group; and more preferably, for example, methyl group, ethyl group, propyl group, iso-propyl group, n-butyl group, iso-butyl group or tert-butyl group. [0528] The "unsaturated C.sub.2-22 alkyl group" used in the specification of the present application indicates a linear or branched alkenyl group having 2 to 22 carbon atoms or a linear or branched alkynyl group having 2 to 22 carbon atoms, such as vinyl group, allyl group, 1-propenyl group, isopropenyl group, 2-methyl-1-propenyl group, 2-methyl-2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-pentenyl group, 1-hexenyl group, 1,3-hexadienyl group, 1,5-hexadienyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group, 1-ethynyl-2-propynyl group, 2-methyl-3-butynyl group, 1-pentynyl group, 1-hexynyl group, 1,3-hexanediynyl group or 1,5-hexanediynyl group. It preferably indicates a linear or branched alkenyl group having 2 to 10 carbon atoms or a linear or branched alkynyl group having 2 to 10 carbon atoms, such as vinyl group, allyl group, 1-propenyl group, 2-propenyl group, isopropenyl group, 3-methyl-2-butenyl group, 3,7-dimethyl-2,6-octadienyl group, ethynyl group, 1-propynyl group, 2-propynyl group, 1-butynyl group, 2-butynyl group, 3-butynyl group or 3-methyl-1-propynyl group. [0529] The "C.sub.6-14 aryl group" used in the specification of the present application means an aromatic cyclic hydrocarbon group having 6 to 14 carbon atoms, and a monocyclic group and condensed rings such as a bicyclic group and a tricyclic group are included. Examples thereof are phenyl group, indenyl group, 1-naphthyl group, 2-naphthyl group, azulenyl group, heptalenyl group, indacenyl group, acenaphthyl group, fluorenyl group, phenalenyl group, phenanthrenyl group and anthracenyl group; of which a preferred example is phenyl group, 1-naphthyl group or 2-naphthyl group. [0530] The "5 to 14-membered heteroaryl group" used in the specification of the present application means a monocyclic, bicyclic or tricyclic 5 to 14-membered aromatic heterocyclic group which contains one or more of hetero atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Preferred examples thereof are a nitrogen-containing aromatic heterocyclic group such as pyrrolyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group, pyrazinyl group, triazolyl group, tetrazolyl group, benzotriazolyl group, pyrazolyl group, imidazolyl group, benzimidazolyl group, indolyl group, isoindolyl group, indolizinyl group, purinyl group, indazolyl group, quinolinyl group, isoquinolinyl group, quinolizinyl group, phthalazinyl group, naphthyridinyl group, quinoxalinyl group, quinazolinyl group, cinnolinyl group, pteridinyl group, imidazotriazinyl group, pyrazinopyridazinyl group, acridinyl group, phenanthridinyl group, carbazolyl group, carbazolinyl group, perimidinyl group, phenanthrolinyl group, phenazinyl group, imidazopyridinyl group, imidazopyrimidinyl group, pyrazolopyridinyl group or pyrazolopyridinyl group; a sulfur-containing aromatic heterocyclic group such as thienyl group or benzothienyl group; and an oxygen-containing aromatic heterocyclic group such as furyl group, pyranyl group, cyclopentapyranyl group, benzofuryl group or isobenzofuryl group; an aromatic heterocyclic group containing two or more different hetero atoms, such as thiazolyl group, isothiazolyl group, benzothiazolyl group, benzthiadiazolyl group, phenothiazinyl group, isoxazolyl group, furazanyl group, phenoxazinyl group, oxazolyl group, isoxazoyl group, benzoxazolyl group, oxadiazolyl group, pyrazolooxazolyl group, imidazothiazolyl group, thienofuranyl group, furopyrrolyl group or pyridoxazinyl group, of which a preferred example is thienyl group, furyl group, pyridinyl group, pyridazinyl group, pyrimidinyl group or pyrazinyl group. [0531] The "3 to 14-membered non-aromatic heterocyclic group" used in the specification of the present application indicates a monocyclic, bicyclic or tricyclic 3 to 14-membered non-aromatic heterocyclic group which may contain one or more hetero atoms selected from the group consisting of nitrogen atom, sulfur atom and oxygen atom. Preferred examples thereof are aziridinyl group, azetidinyl group, pyrrolidinyl group, pyrrolyl group, piperidinyl group, piperazinyl group, homopiperidinyl group, homopiperazinyl group, imidazolyl group, pyrazolidinyl group, imidazolidinyl group, morpholinyl group, thiomorpholinyl group, imidazolinyl group, oxazolinyl group, 2,5-diazabicyclo[2.2.1]heptyl group, 2,5-diazabicyclo[2.2.2]octyl group, 3,8-diazabicyclo[3.2.1]octyl group, 1,4-diazabicyclo[4.3.0]nonyl group, quinuclidinyl group, tetrahydrofuranyl group and tetrahydrothiophenyl group. The non-aromatic heterocyclic group also includes a group derived from a pyridone ring, and a non-aromatic fused ring (e.g., a group derived from, for example, phthalimide ring or succinimide ring). Continue reading about Novel physiologically active substances... Full patent description for Novel physiologically active substances Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Novel physiologically active substances patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. Each week you receive an email with patent applications related to your keywords. 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