Agent for inducing apoptosis

A method for preventive and/or therapeutic treatment of a disease resulting from increased expression of a Bcl-2 family protein, comprising administering a preventively and/or therapeutically effective amount of a tetrocarcin derivative or a physiologically acceptable salt thereof to a mammal, the tetrocarcin derivative or physiologically acceptable salt thereof represented by the following general formula (I) or a physiologically acceptable salt thereof:

• wherein ---- represents a single bond or a double bond provided that two adjacent bonds are not simultaneously double bonds;
• j and k represent 0 or 1;
• R1, R2, R3, R7, R8, R9, R10, and R14 independently represent a hydrogen atom, a substituted or unsubstituted lower alkyl group, a formyl group or a carboxyl group;
• R4, R12, R13, and R15 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by —[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m and p independently represent an integer of from 0 to 8, and R20, R21, and R22 independently represent a lower alkyl group or a substituted or unsubstituted aryl group);
• R16, R17, and R18 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, a group represented by —[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20, R21, and R22 have the same meanings as those defined above), a substituted or unsubstituted lower alkoxyalkyl group, a formyl group, a carboxyl group, a substituted or unsubstituted lower alkoxycarbonyl group, a substituted or unsubstituted lower alkanoyloxyalkyl group, a group represented by —(CH2)rOSi(R23)(R24)(R25) (in the formula, r represents an integer of from 1 to 8, R23, R24, and R25 independently represent a lower alkyl group or a substituted or unsubstituted aryl group), a group represented by —CH═CHR26 (in the formula, R26 represents a substituted or unsubstituted lower alkoxycarbonyl group), a group represented by —CH═NOR27 (in the formula, R27 represents a hydrogen atom or a substituted or unsubstituted lower alkyl group), or —CH(X1R28)2 (in the formula, X1 represents an oxygen atom or a sulfur atom, and R28 represents a lower alkyl group or two of R28 are combined together to represent —(CH2)2— or —(CH2)3—), or R16 and R17 are combined together to represent an oxygen atom;
• R11 represents a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by —[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20, R21, and R22 have the same meanings as those defined above), or a group represented by the following formula (A):
• (in the formula, R29 represents a hydrogen atom or a lower alkyl group, R30 represents a hydrogen atom, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyl group, or a substituted or unsubstituted lower alkoxycarbonyl group, and R31 represents a nitro group, a nitroso group, a hydroxyl group, or an amino group);
• R19 represents a hydroxyl group, a substituted or unsubstituted lower alkoxyl group, or a substituted or unsubstituted lower alkanoyloxy group;
• R5 and R6 are combined together to represent an oxygen atom or R5 and R6 independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkoxycarbonyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted arylsulfonyloxy group, a substituted or unsubstituted aroyloxyalkyl group, or a group represented by —[O(CH2)m]pSi(R20)(R21)(R22) (in the formula, m, p, R20, R21, and R22 have the same meanings as those defined above), or when R5 represents a hydrogen atom, R6 may be a group selected from the group consisting of the groups represented by the following formulas (B), (B-2), (C-1), (C-2), (D), and (E):
• (in the formula, ---- represents a single bond or a double bond, R32 represents a hydrogen atom, a formyl group, or a group represented by —CH2R32a, and R33, R34, R35, and R32a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20a)(R21a)(R22a) (in the formula, R20a, R21a, and R22a have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, or a substituted or unsubstituted aralkylamino group);
• (in the formula, R35b represents a substituted or unsubstituted lower alkyl group, R32b represents a hydrogen atom, a formyl group, or a group represented by —CH2R32c, and R33b, R34b, and R32c independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20a1)(R21a1)(R22a1) (in the formula, R20a1, R21a1, and R22a1 have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group or a substituted or unsubstituted aralkylamino group);
• (in the formula, ---- represents a single bond or a double bond, R36 represents a hydrogen atom, a formyl group, or a group represented by —CH2R36a, R41 represents a hydrogen atom or a group represented by —CH2R41a, and R37, R38, R39, R40, R41a, R42, and R36a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20b)(R21b)(R22b) (in the formula, R20b, R21b, and R22b have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group or a substituted or unsubstituted aralkylamino group);
• (in the formula, ---- represents a single bond or a double bond, R43 represents a hydrogen atom, a formyl group or a group represented by —CH2R43a, R44 represents a hydrogen atom or a group represented by —CH2R44a, and R44a, R45, R46, R47, R48, R49, and R43a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20c)(R21c)(R22c) (in the formula, R20c, R21c, and R22c have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, or a substituted or unsubstituted aralkylamino group);
• (in the formula, ---- represents a single bond or a double bond, R50 represents a hydrogen atom, a formyl group or a group represented by —CH2R50a, R58 represents a hydrogen atom or a group represented by —CH2R58a, R54 represents a hydrogen atom or a group represented by —CH2R54a, and R51, R52, R53, R54a, R55, R56, R57, R58a, R59, and R50a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20d)(R21d)(R22d) (in the formula, R20d, R21d, and R22d have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, a substituted or unsubstituted aralkylamino group, or a group represented by the aforementioned formula (B));
• and
• (in the formula, ---- represents a single bond or a double bond, R60 represents a hydrogen atom, a formyl group or a group represented by —CH2R60a, R61 represents a hydrogen atom or a group represented by —CH2R61a, R65 represents a hydrogen atom or a group represented by —CH2R65a, and R61a, R62, R63, R64, R65a, R66, R67, R68, R69, and R60a independently represent a hydrogen atom, a hydroxyl group, a substituted or unsubstituted lower alkyl group, a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aroyloxy group, a substituted or unsubstituted lower alkenoyloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted aryloxy group, —OSi(R20e)(R21e)(R22e) (in the formula, R20e, R21e, and R22e have the same meanings as the above defined R20, R21, and R22, respectively), a substituted or unsubstituted heteroaroylamino group, a substituted or unsubstituted lower alkylamino group, a substituted or unsubstituted lower alkanoylamino group, a substituted or unsubstituted arylamino group, a substituted or unsubstituted aroylamino group, a substituted or unsubstituted aralkylamino group, or a group represented by the aforementioned formula (B)).

A tetrocarcin derivative represented by the following formula (Ia) or a salt thereof:

• wherein R15a represents a hydroxyl group, —OSi(R70)(R71)(R72) (in the formula, R70, R71, and R72 independently represent a lower alkyl group or a substituted or unsubstituted aryl group), a substituted or unsubstituted lower alkoxyl group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, a substituted or unsubstituted lower alkanoyloxy group, a substituted or unsubstituted lower alkenoyloxy group or a substituted or unsubstituted aroyloxy group;
• R11a represents any one of the substituents defined for the aforementioned R15a, or a group represented by the following formula (F):
• R5a represents any one of the substituents defined for the aforementioned R15a, or a group selected from the group consisting of a group represented by the following formula (G):
• (in the formula, ---- represents a single bond or a double bond, R93 represents a hydrogen atom or a group represented by —CH2R93a, and R73, R74, R94, and R93a independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (G-2):
• (in the formula, R94b represents a substituted or unsubstituted lower alkyl group, R93b represents a hydrogen atom or a group represented by —CH2R93c, and R73b, R74b and R93c independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (H):
• (in the formula, ---- represents a single bond or a double bond, R95 represents a hydrogen atom or a group represented by —CH2R95a, R99 represents a hydrogen atom or a group represented by —CH2R99a, and R95a, R75, R96, R97, R98, R76 and R99a independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), a group represented by the following formula (J):
• (in the formula, ---- represents a single bond or a double bond, R100 represents a hydrogen atom or a group represented by —CH2R100a, R104 represents a hydrogen atom or a group represented by —CH2R104a, R105 represents a hydrogen atom or a group represented by —CH2R105a, and R100a, R77, R101, R102, R103, R104a, R105a, R79, R78, and R106 independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a), and a group represented by the following formula (K):
• (in the formula, ---- represents a single bond or a double bond, R107 represents a hydrogen atom or a group represented by —CH2R107a, R111 represents a hydrogen atom or a group represented by —CH2R111a, R113 represents a hydrogen atom or a group represented by —CH2R113a, R114 represents a hydrogen atom or a group represented by —CH2R114a, and R107a, R80, R108, R109, R110, R111a, R113a, R81, R112, R114a, R82, R115, and R116 independently represent a hydrogen atom or any one of the substituents defined for the aforementioned R15a);
• R18a represents a formyl group, a group represented by —CH═CHR83 (in the formula, R83 represents any one of the substituents defined for the above R26), a group represented by —CH═NOR84 (in the formula, R84 represents any one of the substituents defined for the above R27), or a group represented by —CH(X2R85)2 (in the formula, X2 represents any one of the substituents defined for the above X1, and R85 represents any one of the substituents defined for the above R28);
• and
• R19a represents a hydroxyl group or a substituted or unsubstituted lower alkoxyl group:
• provided that:
• the aforementioned derivative wherein R15a, R11a, and R5a represent a hydroxyl group, R18a represents a formyl group, and R19a represents a methoxy group is excluded;
• the aforementioned derivative wherein R15a and R5a independently represent a hydroxyl group or a lower alkanoyloxy group, R11a represents a hydroxyl group, a lower alkanoyloxy group, or a group represented by formula (F), R18a represents a formyl group, and R19a represents a hydroxyl group is excluded;
• a compound represented by the following formula (Ib):
• α β γ ε A B C
• (in the formula,
• R5b represents a group represented by Aα-Bα-Bβ-Cα (Aα substitutes for R5b at •, Aα-Bα means that {circle around (1)} of Aα and {circle around (2)} of Bα are bound to each other, and in the other definitions, {circle around (1)} and {circle around (2)} are bound to each other in the same manner) and R18b represents a formyl group;
• R5b represents a group represented by Aα-Bα-Cβ and R18b represents a formyl group;
• R5b represents a group represented by Cγ (Cγ substitutes for R5b at •) and R18b represents a formyl group;
• R5b represents a group represented by Cε (Cε substitutes for R5b at •) and R18b represents a formyl group;
• R5b represents a group represented by Aα-Cα and R18b represents a formyl group;
• R5b represents a group represented by Aα-Bβ-Cβ and R18b represents a formyl group;
• or
• R5b represents a group represented by Aα-Bβ-Bβ-Cα and R18b represents a formyl group) is excluded;
• and
• a compound represented by the following formula (Ic):
• (in the formula, R15c, R81c, and R82c represents an acetoxy group and R19c represents a hydroxyl group, or R15c, R19c, R81c, and R82c represent a methoxy group) is excluded.