Novel physiologically active substances

Abstract

The present invention relates to a compound represented by the formula (I): (wherein, R 3 , R 6 , R 7 and R 21 are the same as or different from one another and each represents a hydroxyl group etc.), a pharmacologically acceptable salt thereof or a hydrate of them. The compound (I) of the present invention suppresses angiogenesis, in particular, suppresses VEGF production in a hypoxic condition and is useful as a therapeutic agent for treating solid cancer.

1 . A compound represented by the formula (I):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 3 , R 6 , R 7  and R 21  are the same as or different from one another and each represents 
 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3 , R 6 , R 7  and R 21  is bound, provided that R 6  is limited to hydroxyl group,  
 2) an optionally substituted C 1-22  alkoxy group,  
 3) an optionally substituted unsaturated C 2-22  alkoxy group,  
 4) an optionally substituted C 7-22  aralkyloxy group,  
 5) an optionally substituted 5 to 14-membered heteroaralkyloxy group,  
 6) RCO—O— (wherein R represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted 5 to 14-membered heteroaryl group,  
 f) an optionally substituted C 7-22  aralkyl group,  
 g) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 h) an optionally substituted C 1-22  alkoxy group,  
 i) an optionally substituted unsaturated C 2-22  alkoxy group,  
 j) an optionally substituted C 6-14  aryloxy group or  
 k) an optionally substituted 5 to 14-membered heteroaryloxy group),  
 
 7) R S1 R S2 R S3 SiO— (wherein R S1 , R S2  and R S3  are the same as or different from one another and each represents 
 a) a C 1-6  alkyl group or  
 b) a C 6-14  aryl group),  
 
 8) a halogen atom,  
 9) R N1 R N2 N—R M — (wherein R M  represents 
 a) a single bond,  
 b) —CO—O—,  
 c) —SO 2 —O—,  
 d) —CS—O— or  
 e) —CO—NR N3 — (wherein R N3  represents a hydrogen atom or an optionally substituted C 1-6  alkyl group), provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom; and  
 
  R N1  and R 12  are the same as or different from each other and each represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted aliphatic C 2-22  acyl group,  
 e) an optionally substituted aromatic C 7-15  acyl group,  
 f) an optionally substituted C 6-14  aryl group,  
 g) an optionally substituted 5 to 14-membered heteroaryl group,  
 h) an optionally substituted C 7-22  aralkyl group,  
 i) an optionally substituted C 1-22  alkylsulfonyl group,  
 j) an optionally substituted C 6-14  arylsulfonyl group,  
 k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by  
 
  R N1  and R N2  together with the nitrogen atom to which R N1  and R N2  are bound, and the non-aromatic heterocyclic group may have substituents, 
 l) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 m) an optionally substituted C 3-14  cycloalkyl group or  
 n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group),  
 
 10) R N4  SO 2 —O— (wherein R N4  represents 
 a) an optionally substituted C 1-22  alkyl group,  
 b) an optionally substituted C 6-14  aryl group,  
 c) an optionally substituted C 1-22  alkoxy group,  
 d) an optionally substituted unsaturated C 2-22  alkoxy group,  
 e) an optionally substituted C 6-14  aryloxy group,  
 f) an optionally substituted 5 to 14-membered heteroaryloxy group,  
 g) an optionally substituted C 7-22  aralkyloxy group or  
 h) an optionally substituted 5 to 14-membered heteroaralkyloxy group),  
 
 11) (R N5 O) 2 PO—(wherein R N5  represents 
 a) an optionally substituted C 1-22  alkyl group,  
 b) an optionally substituted unsaturated C 2-22  alkyl group,  
 c) an optionally substituted C 6-14  aryl group,  
 d) an optionally substituted 5 to 14-membered heteroaryl group,  
 e) an optionally substituted C 7-22  aralkyl group or  
 f) an optionally substituted 5 to 14-membered heteroaralkyl group),  
 
 12) (R N1 R N2 N) 2 PO—O— (wherein R N1  and R N2  have the same meanings as defined above) or  
 13) (R N1 R N2 N)(R N5 O)PO—O— (wherein R N1 , R N2  and R N5  have the same meanings as defined above), provided that a compound in which R 3 , R 6 , R 7  and R 21  are all hydroxyl groups, and a compound in which R 3 , R 6  and R 21  are all hydroxyl groups and R 7  is an acetoxy group are excluded), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         2 . The compound according to  claim 1  represented by the formula (I-a):  
       
         
           
           
               
               
           
         
         (in the formula, R 3a , R 6a , R 7a  and R 21a  are the same as or different from one another and each represents  
         1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3a , R 6a , R 7a  and R 21a  is bound, provided that R 6a  is limited to a hydroxyl group,  
         2) an optionally substituted C 1-22  alkoxy group,  
         3) R a CO—O— (wherein R a  represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted 5 to 14-membered heteroaryl group,  
 f) an optionally substituted C 7-22  aralkyl group,  
 g) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 h) an optionally substituted C 1-22  alkoxy group,  
 i) an optionally substituted unsaturated C 2-22  alkoxy group,  
 j) an optionally substituted C 6-14  aryloxy group or  
 k) an optionally substituted 5 to 14-membered heteroaryloxy group),  
 
         4) R aS1 R aS2 R aS3 SiO— (wherein R aS1 , R aS2  and R aS3  are the same as or different from one another and each represents 
 a) a C 1-6  alkyl group or  
 b) a C 6-14  aryl group),  
 
         5) a halogen atom or  
         6) R aN1 R aN2 N—R aM — (wherein R aM  represents 
 a) a single bond,  
 b) —CO—O—,  
 c) —SO 2 —O—,  
 d) —CS—O— or  
 e) —CO—NR aN3 — (wherein R aN3  represents a hydrogen atom or an optionally substituted C 1-6  alkyl group, provided that each of the leftmost bond in b) to e) is bound to the nitrogen atom); and  
 
         R aN1  and R aN2  are the same as or different from each other and each represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted aliphatic C 2-22  acyl group,  
 e) an optionally substituted aromatic C 7-15  acyl group,  
 f) an optionally substituted C 6-14  aryl group,  
 g) an optionally substituted 5 to 14-membered heteroaryl group,  
 h) an optionally substituted C 7-22  aralkyl group,  
 i) an optionally substituted C 1-22  alkylsulfonyl group,  
 j) an optionally substituted C 6-14  arylsulfonyl group,  
 k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R aN1  and R aN2  together with the nitrogen atom to which R aN1  and R aN2  are bound, and the non-aromatic heterocyclic group may have substituents,  
 l) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 m) an optionally substituted C 3-1   4  cycloalkyl group or  
 n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
       
     
     
         3 . The compound according to  claim 1  represented by the formula (I-b):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 3b , R 6b , R 7b  and R 21b  are the same as or different from one another and each represents 
 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3b , R 6b , R 7b  and R 21b  is bound, provided that R 6b  is limited to a hydroxyl group,  
 2) an optionally substituted C 1-22  alkoxy group,  
 3) R b CO—O— (wherein R b  represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted 5 to 14-membered heteroaryl group,  
 f) an optionally substituted C 7-22  aralkyl group,  
 g) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 h) an optionally substituted C 1-22  alkoxy group,  
 i) an optionally substituted unsaturated C 2-22  alkoxy group,  
 j) an optionally substituted C 6-14  aryloxy group or  
 k) an optionally substituted 5 to 14-membered heteroaryloxy group),  
 
 4) R bS1 R bS2 R bS3 SiO— (wherein R bS1 , R bS2  and R bS3  are the same as or different from one another and each represents 
 a) a C 1-6  alkyl group or  
 b) a C 6-14  aryl group) or  
 
 5) R bN1 R bN2 N—R bM — (wherein R bM  represents 
 a) —CO—O— or  
 b) —CS—O—, provided that each of the leftmost bond in a) and b) is bound to the nitrogen atom; and  
 
  R bN1  and R bN2  are the same as or different from each other and each represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted aliphatic C 2-22  acyl group,  
 e) an optionally substituted aromatic C 7-15  acyl group,  
 f) an optionally substituted C 6-14  aryl group,  
 g) an optionally substituted 5 to 14-membered heteroaryl group,  
 h) an optionally substituted C 7-22  aralkyl group,  
 i) an optionally substituted C 1-22  alkylsulfonyl group,  
 j) an optionally substituted C 6-14  arylsulfonyl group,  
 k) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R bN1  and R bN2  together with the nitrogen atom to which R bN1  and R bN2  are bound, and the non-aromatic heterocyclic group may have substituents,  
 l) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 m) an optionally substituted C 3-14  cycloalkyl group or  
 n) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
 
     
     
         4 . The compound according to  claim 1  represented by the formula (I-c):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 3c , R 6c , R 7c  and R 21c  are the same as or different from one another and each represents 
 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3c , R 6c , R 7c  and R 21c  is bound, provided that R 6c  is limited to a hydroxyl group,  
 2) an optionally substituted C 1-22  alkoxy group,  
 3) R c CO—O— (wherein R c  represents 
 a) an optionally substituted C 1-22  alkyl group,  
 b) an optionally substituted C 6-14  aryl group,  
 c) an optionally substituted C 7-22  aralkyl group or  
 d) an optionally substituted C 6-14  aryloxy group),  
 
 4) R cS1 R cS2 R cS3 SiO— (wherein R cS1 , R cS2  and R cS3  are the same as or different from one another and each represents 
 a) a C 1-6  alkyl group or  
 b) a C 6-14  aryl group) or  
 
 5) R cN1 R cN2 N—R cM — (wherein R cM  represents 
 a) —CO—O— or  
 b) —CS—O—, provided that each of the leftmost bond in a) and b) is bound to the nitrogen atom; and  
 
  R cN  and R cN2  are the same as or different from each other and each represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R cN1  and R cN2  together with the nitrogen atom to which R cN1  and R cN2  are bound, and the non-aromatic heterocyclic group may have substituents,  
 d) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 e) an optionally substituted C 3-14  cycloalkyl group or  
 f) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
 
     
     
         5 . The compound according to  claim 1  represented by the formula (I-d):  
       
         
           
           
               
               
           
         
         (in the formula, R 3d  represents  
         1) a hydroxyl group or an oxo group formed together with the carbon atom to which R 3d  is bound,  
         2) an optionally substituted C 1-22  alkoxy group,  
         3) an optionally substituted unsaturated C 2-22  alkoxy group,  
         4) an optionally substituted C 7-22  aralkyloxy group,  
         5) R d CO—O— (wherein R d  represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted 5 to 14-membered heteroaryl group,  
 f) an optionally substituted C 7-22  aralkyl group,  
 g) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 h) an optionally substituted C 1-22  alkoxy group,  
 i) an optionally substituted unsaturated C 2-22  alkoxy group,  
 j) an optionally substituted C 6-14  aryloxy group or  
 k) an optionally substituted 5 to 14-membered heteroaryloxy group) or  
 
         6) R dN1 R dN2 N—CO—O— (wherein R dN1  and R dN2  are the same as or different from each other and each represents 
 a) a hydrogen atom,  
 b) an optionally substituted C 1-22  alkyl group,  
 c) an optionally substituted unsaturated C 2-22  alkyl group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted 5 to 14-membered heteroaryl group,  
 f) an optionally substituted C 7-22  aralkyl group,  
 g) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 h) an optionally substituted C 3-14  cycloalkyl group,  
 i) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group or  
 j) an optionally substituted 3 to 14-membered non-aromatic heterocyclic group formed by R dN1  and R dN2  together with the nitrogen atom to which R dN1  and R dN2  are bound, and the non-aromatic heterocyclic group may have substituents); and  
 
          R 6d , R 7d  and R 21d  are the same as or different from one another and each represents  
         1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 6d , R 7d  and R 21d  is bound, provided that R 6d  is limited to a hydroxyl group,  
         2) an optionally substituted C 1-22  alkoxy group,  
         3) an optionally substituted unsaturated C 2-22  alkoxy group,  
         4) an optionally substituted C 7-22  aralkyloxy group,  
         5) R d CO—O— (wherein Rd has the same meaning as defined above),  
         6) R dN1 R dN2 N—CO—O— (wherein R dN1  and R dN2  have the same meanings as defined above),  
         7) R dN1 R dN2 N—SO 2 —O— (wherein R dN1  and R dN2  have the same meanings as defined above),  
         8) R dN1 R dN2 N—CS—O— (wherein R dN1  and R dN2  have the same meanings as defined above),  
         9) R dN3 SO 2 —O— (wherein R dN3  represents 
 a) an optionally substituted C 1-22  alkyl group,  
 b) an optionally substituted C 1-22  alkoxy group,  
 c) an optionally substituted unsaturated C 2-22  alkoxy group,  
 d) an optionally substituted C 6-14  aryl group,  
 e) an optionally substituted C 6-14  aryloxy group,  
 f) an optionally substituted 5 to 14-membered heteroaryloxy group,  
 g) an optionally substituted C 7-22  aralkyloxy group or  
 h) an optionally substituted 5 to 14-membered heteroaralkyloxy group),  
 
         10) (R dN5 O) 2 PO— (wherein R dN5  represents 
 a) an optionally substituted C 1-22  alkyl group,  
 b) an optionally substituted unsaturated C 2-22  alkyl group,  
 c) an optionally substituted C 6-14  aryl group,  
 d) an optionally substituted 5 to 14-membered heteroaryl group,  
 e) an optionally substituted C 7-22  aralkyl group or  
 f) an optionally substituted 5 to 14-membered heteroaralkyl group),  
 
         11) (R dN1 R dN2 N) 2 PO— (wherein R dN1  and R dN2  have the same meanings as defined above) or  
         12) (R dN1 R dN2 N)(R dN5 O)PO— (wherein R dN1 , R dN2  and R dN1  have the same meanings as defined above), provided that a compound in which R 3d , R 6d , R 7d  and R 21d  are all hydroxyl groups, and a compound in which R 3d , R 6d  and R 21d  are hydroxyl groups and R 7d  is an acetoxy group are excluded), a pharmacologically acceptable salt thereof or a hydrate of them.  
       
     
     
         6 . The compound according to  claim 1 , wherein R 6  and/or R 7  represents R N1 R N2 N—R M — (wherein R M  represents 
 a) —CO—O— or    b) —CS—O—; and    R N1  and R 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.    
     
     
         7 . The compound according to  claim 1 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein R 21  is an oxo group formed together with the carbon atom to which R 21  is bound.  
     
     
         8 . The compound according to  claim 5  represented by the formula (I-e):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 3e  and R 21e  are the same as or different from each other and each represents 
 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 3e  and R 21e  is bound,  
 2) an optionally substituted C 1-6  alkoxy group,  
 3) an optionally substituted unsaturated C 2-10  alkoxy group,  
 4) an optionally substituted C 7-10  aralkyloxy group,  
 5) an optionally substituted aliphatic C 2-6  acyloxy group or  
 6) R eN1 R eN2 N—CO—O— (wherein R eN1  and R eN2  are the same as or different from each other and each represents  
 A) a hydrogen atom or  
 B) an optionally substituted C 1-6  alkyl group); and  
 R 6e  and R 7e  are the same as or different from each other and each represents  
 1) a hydroxyl group or an oxo group formed together with the carbon atom to which each of R 6e  and R 7e  is bound, provided that R 6e  is limited to a hydroxyl group,  
 2) an optionally substituted C 1-6  alkoxy group,  
 3) an optionally substituted unsaturated C 2-10  alkoxy group,  
 4) an optionally substituted C 7-10  aralkyloxy group,  
 5) an optionally substituted aliphatic C 2-6  acyloxy group or  
 6) R e C(═Y e )—O— (wherein Y e  represents an oxygen atom or a sulfur atom; and R e  represents  
 a) a hydrogen atom,  
 b) an optionally substituted C 1-6  alkyl group,  
 c) an optionally substituted C 7-10  aralkyl group,  
 d) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 e) the formula (III):  
                     
 (in the formula,  
 A) n represents an integer of 0 to 4;  
 X e  represents  
 i) —CHR eN4 —,  
 ii) —NR eN5 —,  
 iii) —O—,  
 iv) —S—,  
 v) —SO— or  
 vi) —SO 2 —;  
 R eN1  represents  
 i) a hydrogen atom or  
 ii) a C 1-6  alkyl group;  
 R eN2  represents  
 i) a hydrogen atom or  
 ii) a C 1-6  alkyl group;  
 R eN3  and R eN4  are the same as or different from each other and each represents  
 i) a hydrogen atom,  
 ii) an optionally substituted C 1-6  alkyl group,  
 iii) an optionally substituted unsaturated C 2-10  alkyl group,  
 iv) an optionally substituted C 6-14  aryl group,  
 v) an optionally substituted 5 to 14-membered heteroaryl group,  
 vi) an optionally substituted C 7-10  aralkyl group,  
 vii) an optionally substituted C 3-8  cycloalkyl group,  
 viii) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 ix) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 x) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group,  
 xi) —NR eN6 R eN7  (wherein R eN6  and R eN7  are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C 1-6  alkyl group) or  
 xii) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R eN3  and R eN4  together with the carbon atom to which R eN3  and R eN4  are bound, and the non-aromatic heterocyclic group may have substituents; and  
 R eN5  represents  
 i) a hydrogen atom,  
 ii) an optionally substituted C 1-6  alkyl group,  
 iii) an optionally substituted unsaturated C 2-10  alkyl group,  
 iv) an optionally substituted C 6-14  aryl group,  
 v) an optionally substituted 5 to 14-membered heteroaryl group,  
 vi) an optionally substituted C 7-10  aralkyl group,  
 vii) an optionally substituted C 3-8  cycloalkyl group,  
 viii) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 ix) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 x) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group or  
 xi) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R eN3  and R eN5  together with the nitrogen atom to which R eN3  and R eN5  are bound, and the non-aromatic heterocyclic group may have substituents,  
 B) X e , n, R eN3 , R eN4  and R eN5  each represents the group as defined above; and R eN1  and R eN2  together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group,  
 C) X e , n, R eN2 , R eN4  and R eNn5  each represents the group as defined above; and R eN1  and R eN3  together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group or  
 D) X e , n, R eN1 , R eN4  and R eN5  each represents the group as defined above; and R eN2  and R eN3  together form an optionally substituted 5 to 14-membered non-aromatic heterocyclic group) or  
 f) the formula (IV):  
                     
 (in the formula, R eN8  and R eN9  are the same as or different from each other and each represents  
 i) a hydrogen atom,  
 ii) an optionally substituted C 1-6  alkyl group,  
 iii) an optionally substituted C 6-14  aryl group,  
 iv) an optionally substituted 5 to 14-membered heteroaryl group,  
 v) an optionally substituted C 7-10  aralkyl group or  
 vi) an optionally substituted 5 to 14-membered heteroaralkyl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         9 . The compound according to  claim 5 , wherein R 6d  and/or R 7d  represents R d1 C(═Y d1 )—O— (wherein Y d1  represents an oxygen atom or a sulfur atom; and R d1  represents 
 1) a hydrogen atom,    2) an optionally substituted C 1-6  alkyl group,    3) an optionally substituted C 7-10  aralkyl group or    4) an optionally substituted 5 to 14-membered heteroaralkyl group), a pharmacologically acceptable salt thereof or a hydrate of them.    
     
     
         10 . The compound according to  claim 5 , wherein R 6d  and/or R 7d  represents R d2 C(═Y d2 )—O— (wherein Y d2  represents an oxygen atom or sulfur atom; and R d2  represents the formula (III′):  
       
         
           
           
               
               
           
         
       
       (in the formula, n represents an integer of 0 to 4; X 1  represents 
 1) —CHR dN7 —,  
 2) NR dN8 —,  
 3) —O—,  
 4) —S—,  
 5) —SO— or  
 6) —SO 2 —;  
 R dN4  and R dN5  are the same as or different from each other and each represents  
 1) a hydrogen atom or  
 2) a C 1-6  alkyl group;  
 R dN6  and R dN7  are the same as or different from each other and each represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group,  
 11) —NR dN9 R dN10  (wherein R dN9  and R dN10  are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C 1-6  alkyl group) or  
 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed together by R dN6  and R dN7 , and the non-aromatic heterocyclic group may have substituents; and  
 R dN8  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group,  
 11) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by R dN4 , d dN5  or R dN6  together with the nitrogen atom to which each of R dN4 , R dN5  and R dN5  is bound, and the non-aromatic heterocyclic group may have substituents or  
 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group formed by two substituents selected from the group consisting of R dN4 , R dN5  and R 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.  
 
     
     
         11 . The compound according to  claim 10 , a pharmacologically acceptable salt thereof or a hydrate of them, wherein X 1  represents —NR dN8 — (wherein NR dN8  has the same meanings as defined above).  
     
     
         12 . The compound according to  claim 5  represented by the formula (I-f):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 7f  represents R f C(═Y f )—O— (wherein Y f  represents an oxygen atom or a sulfur atom; and R f  represents the formula (V):  
       
         
           
           
               
               
           
         
       
       (wherein n represents an integer of 0 to 4;  
       R fN1  represents 
 1) a hydrogen atom,  
 2) a methyl group or  
 3) an ethyl group; and  
 R fN2  represents  
 1) a hydrogen atom,  
 2) a methylamino group,  
 3) a dimethylamino group,  
 4) an ethylamino group,  
 5) a diethylamino group,  
 6) an ethylmethylamino group,  
 7) a pyridinyl group,  
 8) a pyrrolidin-1-yl group,  
 9) a piperidin-1-yl group,  
 10) a morpholin-4-yl group or  
 11) a 4-methylpiperazin-1-yl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         13 . The compound according to  claim 5 , wherein R 6d  and/or R 7d  represents R d3 CO—O— (wherein R d3  represents the formula (VI):  
       
         
           
           
               
               
           
         
       
       (wherein n 1  and n 2  are the same as or different from each other and each represents an integer of 0 to 4;  
       X 2  represents 
 1) —CHR dN13 —,  
 2) —NR dN14 —,  
 3) —O—,  
 4) —S—,  
 5) —SO— or  
 6) —SO 2 —;  
 R dN11  represents  
 1) a hydrogen atom or  
 2) an optionally substituted C 1-6  alkyl group;  
 R dN12  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted C 6-14  aryl group or  
 4) an optionally substituted C 7-10  aralkyl group;  
 R dN13  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 10) —NR dN15 R dN16  (wherein R dN15  and R dN16  are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C 1-6  alkyl group) or  
 11) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and  
 R dN14  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group or  
 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         14 . The compound according to  claim 5  represented by the formula (I-g):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 7g  represents R g CO—O— (wherein R g  represents the formula (VII):  
       
         
           
           
               
               
           
         
       
       (wherein n 3  represents 1 or 2;  
       R dN17  represents 
 1) a hydrogen atom,  
 2) a methyl group or  
 3) an ethyl group; and  
 R dN18  represents  
 1) a hydrogen atom,  
 2) a methyl group or  
 3) an ethyl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         15 . The compound according to  claim 5 , wherein R 6d  and/or R 7d  represents R d4 CO—O— (wherein R d4  represents the formula (VIII):  
       
         
           
           
               
               
           
         
       
       (wherein n 1  and n 2  are the same as or different from each other and each represents an integer of 0 to 4;  
       X 3  represents 
 1) —CHR dN21 ,  
 2) NR dN22 —,  
 3) —O—,  
 4) —S—,  
 5) —SO— or  
 6) —SO 2 —;  
 R dN19  represents  
 1) a hydrogen atom or  
 2) a C 1-6  alkyl group;  
 R dN20  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted C 6-14  aryl group or  
 4) an optionally substituted C 7-10  aralkyl group;  
 R dN21  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 1-6  alkoxy group,  
 5) an optionally substituted C 6-14  aryl group,  
 6) an optionally substituted 5 to 14-membered heteroaryl group,  
 7) an optionally substituted C 7-10  aralkyl group,  
 8) an optionally substituted C 3-8  cycloalkyl group,  
 9) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 10) an optionally substituted 5 to 14-membered heteroaralkyl group,  
 11) —NR dN23 R dN24  (wherein R dN23  and R dN24  are the same as or different from each other and each represents a hydrogen atom or an optionally substituted C 1-6  alkyl group) or  
 12) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group; and  
 R dN22  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group or  
 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group)), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         16 . The compound according to  claim 5  represented by the formula (I-h):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 7h  represents R h CO—O— (wherein R h  represents the formula (IX):  
       
         
           
           
               
               
           
         
       
       (wherein n 4  represents an integer of 1 to 3; and  
       R dN25  represents 
 1) an amino group,  
 2) a methylamino group,  
 3) a dimethylamino group,  
 4) a pyrrolidin-1-yl group,  
 5) a piperidin-1-yl group or  
 6) a morpholin-4-yl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         17 . The compound according to  claim 5  represented by the formula (I-i):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 7i  represents R i CO—O— (wherein R i  represents the formula (X):  
       
         
           
           
               
               
           
         
       
       (wherein n 4  represents an integer of 1 to 3;  
       R dN26  represents 
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted C 6-14  aryl group or  
 4) an optionally substituted C 7-10  aralkyl group; and  
 R dN27  represents  
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted C 3-8  cycloalkyl group,  
 4) an optionally substituted 3 to 8-membered non-aromatic heterocyclic group,  
 5) an optionally substituted C 6-14  aryl group,  
 6) an optionally substituted 5 to 14-membered heteroaryl group,  
 7) an optionally substituted C 7-10  aralkyl group,  
 8) an optionally substituted 5 to 14-membered heteroaralkyl group or  
 9) an optionally substituted C 4-9  cycloalkyl alkyl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         18 . The compound according to  claim 5  represented by the formula (I-j):  
       
         
           
           
               
               
           
         
       
       (in the formula, R 7j  represents R j CO—O— (wherein R j  represents the formula (XI):  
       
         
           
           
               
               
           
         
       
       (wherein n 4  represents an integer of 1 to 3; and  
       R dN28  represents 
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) a C 3-8  cycloalkyl group,  
 4) a C 4-9  cycloalkyl alkyl group,  
 5) a C 7-10  aralkyl group,  
 6) a pyridinyl group or  
 7) a tetrahydropyranyl group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
     
     
         19 . The compound according to  claim 5  represented by the formula (I-k):  
       
         
           
           
               
               
           
         
         (in the formula, R 7k  represents R k CO—O— (wherein R k  represents the formula (XII):  
         
           
             
             
                 
                 
             
           
         
         (wherein m 1 , m 2 , m 3  and m 4  are the same as or different from one another and each represents 0 or 1;  
         n 4  represents an integer of 1 to 3; and  
         R dN29  represents 
 1) a hydrogen atom,  
 2) an optionally substituted C 1-6  alkyl group,  
 3) an optionally substituted unsaturated C 2-10  alkyl group,  
 4) an optionally substituted C 6-14  aryl group,  
 5) an optionally substituted 5 to 14-membered heteroaryl group,  
 6) an optionally substituted C 7-10  aralkyl group,  
 7) an optionally substituted C 3-8  cycloalkyl group,  
 8) an optionally substituted C 4-9  cycloalkyl alkyl group,  
 9) an optionally substituted 5 to 14-membered heteroaralkyl group or  
 10) an optionally substituted 5 to 14-membered non-aromatic heterocyclic group))), a pharmacologically acceptable salt thereof or a hydrate of them.  
 
       
     
     
         20 . The compound according to  claim 5  represented by the formula (I-m):  
       
         
           
           
               
               
           
         
         (in the formula, R 7m  represents R m CO—O— (wherein R m  represents the formula (XIII):  
         
           
             
             
                 
                 
             
           
         
         (wherein m 5  represents an integer of 1 to 3; and n 5  represents 2 or 3))), a pharmacologically acceptable salt thereof or a hydrate of them.  
       
     
     
         21 . The compound according to  claim 5  represented by the formula (I-n):  
       
         
           
           
               
               
           
         
         (in the formula, R 7n  represents R n CO—O— (wherein R n  is a group represented by the formula (XIV):  
         
           
             
             
                 
                 
             
           
         
         a pharmacologically acceptable salt thereof or a hydrate of them.  
       
     
     
         22 . The compound according to  claim 1 , which is selected from: 
 (8E,12E,14E)-7-(N-(2-(N′,N′-Dimethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (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; (8E,12E,14E)-7-((4-Ethylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-Cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-(Cyclopropylmethyl)piperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-propylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (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-trien-11-olide; (8E,12E,14E)-7-((4-Cyclopentylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-Tetrahydroxy-7-((4-isobutylhomopiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-Ethylhomopiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (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; (8E,12E,14E)-3,16,21-Trihydroxy-6-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,16,21-Trihydroxy-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; (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; and (8E,12E,14E)-3,6,16-Trihydroxy-21-methoxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide.    
     
     
         23 . The compound according to  claim 1 , which is selected from: 
 (8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-(4-methylhomopiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-7-((4-methylpiperazin-1-yl)carbonyl)oxy-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-cyclohexylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-3,6,16,21-tetrahydroxy-7-((4-isopropylpiperazin-1-yl)carbonyl)oxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; (8E,12E,14E)-7-((4-Cycloheptylpiperazin-1-yl)carbonyl)oxy-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide; and (8E,12E,14E)-7-(N-(2-(N′,N′-Diethylamino)ethyl)-N-methylcarbamoyloxy)-3,6,16,21-tetrahydroxy-6,10,12,16,20-pentamethyl-18,19-epoxytricosa-8,12,14-trien-11-olide.    
     
     
         24 . A medicament comprising the compound according to  claim 1 , a pharmacologically acceptable salt thereof or a hydrate of them as an active ingredient.  
     
     
         25 . A pharmaceutical composition comprising the compound according to  claim 1 , a pharmacologically acceptable salt thereof or a hydrate of them as an active ingredient.  
     
     
         26 . The medicament according to  claim 24 , which is an agent for preventing or treating a disease against which a regulation of gene expression is efficacious.  
     
     
         27 . The medicament according to  claim 24 , which is an agent for preventing or treating a diseases against which suppression of VEGF production is efficacious.  
     
     
         28 . The medicament according to  claim 24 , which is an agent for preventing or treating a disease against which an antiangiogenic effect is efficacious.  
     
     
         29 . The medicament according to  claim 24 , which is an angiogenesis inhibitor.  
     
     
         30 . The medicament according to  claim 24 , which is an antitumor agent.  
     
     
         31 . The medicament according to  claim 24 , as a therapeutic agent for treating angioma.  
     
     
         32 . The medicament according to  claim 24 , which is cancer metastasis inhibitor.  
     
     
         33 . The medicament according to  claim 24 , which is a therapeutic agent for treating retinal neovascularization or diabetic retinopathy.  
     
     
         34 . The medicament according to  claim 24 , which is a therapeutic agent for treating inflammatory disease.  
     
     
         35 . The medicament according to  claim 24 , which is a therapeutic agent for treating inflammatory diseases consisting of deformans arthritis, rheumatoid arthritis, psoriasis and delayed hypersensitivity reaction.  
     
     
         36 . The medicament according to  claim 24 , which is a therapeutic agent for treating atherosclerosis.  
     
     
         37 . The medicament according to  claim 24 , which is a therapeutic agent for treating solid cancer.  
     
     
         38 . The medicament according to  claim 37 , wherein the solid cancer is lung cancer, brain tumor, breast cancer, prostate cancer, ovarian cancer, colon cancer or melanoma.  
     
     
         39 . The medicament according to  claim 24 , which is a therapeutic agent for treating leukemia.  
     
     
         40 . The medicament according to  claim 24 , which is an antitumor agent based on a regulation of gene expression.  
     
     
         41 . The medicament according to  claim 24 , which is an antitumor agent based on suppression of VEGF production.  
     
     
         42 . The medicament according to  claim 24 , which is an antitumor agent based on an effect of angiogenesis inhibition.  
     
     
         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 according to  claim 24  to a patient.  
     
     
         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 according to  claim 24  to a patient.  
     
     
         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 according to  claim 24  to a patient.  
     
     
         46 . Use of the compound according to  claim 1 , 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.  
     
     
         47 . Use of the compound according to  claim 1 , 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.  
     
     
         48 . Use of the compound according to  claim 1 , 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.  
     
     
         49 . Use of the compound according to  claim 1 , a pharmacologically acceptable salt thereof or a hydrate of them, for manufacturing an agent for preventing or treating solid cancers.