Triterpene derivatives and remedies for liver diseases

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

• 24
• wherein
• R1 represents a hydroxyl group, lower alkoxy, or lower alkanoyloxy;
• R2 represents hydroxymethyl, lower alkoxymethyl, lower alkanoyloxymethyl, or carboxyl;
• or R1 and R may combine with each other to form —O—C(R14)R15—O—CH2— wherein R14 and R15, which may be the same or different, represent a hydrogen atom or lower alkyl;
• R3 and R4, which may be the same or different, represent
• a hydrogen atom,
• a hydroxyl group,
• lower alkyl,
• lower alkenyl,
• aryl,
• hydroxymethyl,
• —N(R11)R12 wherein R11 and R12, which may be the same or different, represent a hydrogen atom, lower alkyl, or lower alkanoyl,
• formyl,
• —COOR6 wherein R6 is as defined above,
• —OR13 wherein R13 represents lower alkyl, cyclo-lower alkyl, aralkyl, lower alkanoyl, arylcarbonyl, aralkylcarbonyl, lower alkenyl, lower alkenylcarbonyl, or aryl-lower alkenylcarbonyl;
• or R3 and R4 may combine with each other to form oxo, hydroxyimino, or alkylidene;
• and
• X represents O, CH2, or NH,
• provided that compounds wherein R1 represents a hydroxyl group, R2 represents hydroxymethyl, R3 represents a hydrogen atom, R4 represents a hydroxyl group and X represents O are excluded.

A pharmaceutical composition for treating a hepatic disorder, comprising as an active ingredient a triterpene derivative represented by the following formula (II) or a salt thereof:

• 25
• wherein
• R16 represents
• a hydroxyl group,
• arylmethyloxy,
• lower alkoxy, or
• lower alkanoyloxy;
• R17 represents
• lower alkyl,
• lower alkenyl
• —CH2OR5 wherein R5 is as defined above,
• formyl,
• —COOR6 wherein R6 is as defined above,
• —CH2OCON(R9)R10 wherein R9 and R10 are as defined above,
• —CON(R29)R30 wherein R29 and R30, which may be the same or different, represent a hydrogen atom, lower alkyl, lower alkanoyl, aryl, or aralkyl;
• —CH2N(R7)R8 wherein R7 and R8 are as defined above;
• —C(R6)2OH wherein R6 is as defined above;
• —COR6a wherein R6a represents lower alkyl;
• —CH═CHR6 wherein R6 is as defined above;
• or R16 and R17 may combine with each other to form —O—C(R9)R10—O—CH2— wherein R9 and R10 are as defined above;
• R18 and R19, which may be the same or different, represent
• a hydrogen atom,
• a hydroxyl group,
• arylmethyloxy,
• lower alkyl,
• —N(R11)R12 wherein R11 and R12 are as defined above,
• —COOR6 wherein R6 is as defined above,
• —OR13 wherein R13 is as defined above,
• —O—(CH2)m—R22
• wherein
• R22 represents
• amino,
• —NH—COOR23 wherein R23 represents arylmethyl or lower alkyl,
• a hydroxyl group,
• arylmethyloxy, or
• —COOR24 wherein R24 represents a hydrogen atom, lower alkyl, or arylmethyl, and
• m is an integer of 1 to 4,
• —OCOCH(R25)(CH2)n—R22 wherein R22 is as defined above, R25 represents a hydrogen atom, lower alkyl, aralkyl, or aryl, and n is an integer of 0 to 3,
• —OCOCH═CH—COOR6 wherein R6 is as defined above, or —OCON(R29)R30 wherein R29 and R30 are as defined above;
• or R18 and R19 may combine with each other to form oxo,
• R20 and R21 respectively represent the same meanings as R18 and R19, provided that R20 and R21 do not represent a hydrogen atom;
• or R18 and R20 may combine with each other to form —O—[C(R9)R10]p—O— wherein R9 and R10 are as defined above and p is an integer of 1 to 3, or —OCO—[C(R9)R10]q—OCO— wherein R9 and R10 are as defined above and q is an integer of 0 to 2;
• and
• Y represents O, CH2, NH, or a single bond to form a double bond in the ring with Y bonded thereto.

A triterpene derivative represented by the following formula (IIa) or a salt thereof:

• 26
• wherein
• R16 represents
• a hydroxyl group,
• arylmethyloxy,
• lower alkoxy, excluding methoxy, or
• lower alkanoyloxy, excluding acetoxy;
• R17 represents
• lower alkyl,
• lower alkenyl
• —CH2OR5 wherein R5 is as defined above,
• formyl,
• —COOR6 wherein R6 is as defined above,
• —CH2OCON(R9)R10 wherein R9 and R10 are as defined above,
• —CON(R7)R8 wherein R7 and R8 are as defined above,
• —CH2N(R7)R8 wherein R7 and R8 are as defined above,
• —C(R6)2OH wherein R6 is as defined above,
• —COR6a wherein R6a represents lower alkyl,
• —CH═CHR6 wherein R6 is as defined above;
• R16 and R17 may combine with each other to form —O—C(R9)R10—O—CH2— wherein R9 and R10 are as defined above;
• R18 and R19, which may be the same or different, represent
• a hydrogen atom,
• a hydroxyl group,
• arylmethyloxy,
• lower alkyl,
• —N(R11)R12 wherein R11 and R12 are as defined above,
• —COOR6 wherein R6 is as defined above,
• —OR13 wherein R is as defined above,
• —O—(CH2)m—R22
• wherein
• R22 represents
• amino,
• —NH—COOR23 wherein R23 represents arylmethyl or lower alkyl,
• a hydroxyl group,
• arylmethyloxy, or
• —COOR24 wherein R24 represents a hydrogen atom, lower alkyl, or arylmethyl, and
• m is an integer of 1 to 4,
• —OCOCH(R25)(CH2)n—R22 wherein R22 is as defined above, R25 represents a hydrogen atom, lower alkyl;
• aralkyl, or aryl, and n is an integer of 0 to 3,
• —OCOCH═CH—COOR6 wherein R6 is as defined above,
• or —OCON(R29)R30 wherein R29 and R30 are as defined above;
• or R18 and R19 may combine with each other to form oxo, R20 and R21 respectively represent the same meanings as R18 and R19, provided that R20 and R21 do not represent a hydrogen atom;
• or R18 and R20 may combine with each other to form —O—[C(R9)R10]p—O— wherein R9 and R10 are as defined above and p is an integer of 1 to 3, or —OCO—[C(R9)R10]q—OCO— wherein R9 and R10 are as defined above and q is an integer of 0 to 2;
• and
• Y represents O, CH2, NH, or a single bond to form a double bond in the ring with Y bonded thereto;
• provided that compounds wherein R16 represents a hydroxyl group, R17 represents —CH2OCH3, R20 represents a hydroxyl group or methoxy, both R18 and R21 represent a hydrogen atom, R19 represents a hydroxyl group or methoxy and Y represents a single bond, and compounds wherein R16 represents a hydroxyl group, R17 represents —CH2OH, R20 represents a hydroxyl group, R18, R19, and R21 represent a hydrogen atom and Y represents a single bond are excluded.

A triterpene derivative represented by the following formula (III) or a salt thereof:

• 27
• wherein
• R1, R2, and Y are as defined above;
• and
• R27 represents
• —O—(CH2)m—R22 wherein R22 and m are as defined above,
• OCOCH(R254)(CH2)n—R22 wherein R22, R25, and n are as defined above,
• —OCON(R29)R30 wherein R29 and R30 are as defined above,
• —OCO—(CH2)n—R16 wherein R16 is as defined above, or
• —OCOCH═CH—COOR6 wherein R6 is as defined above.

A triterpene derivative represented by the following formula (IV) or a salt thereof:

• 28
• wherein
• R1, R18, R19, and Y are as defined above,
• R28 represents
• —CON(R29)R30 wherein R29 and R30 are as defined above,
• —C(R6)2OH wherein R6 is as defined above,
• —COR6a wherein R6a represents lower alkyl, or
• —CH═CHR6 wherein R6 is as defined above.