Bile-acid derived compounds for enhancing oral absorption and systemic bioavailability of drugs

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is CHOH;
• R2 is CHOH;
• R3 and R4 together with the carbon atoms to which they are attached form a cycloalkyl-R9, substituted cycloalkyl-R9, cycloalkenyl-R9, substituted cycloalkenyl-R9, heterocycloalkyl-R9, substituted heterocycloalkyl-R9, heterocycloalkenyl-R9, substituted heterocycloalkenyl-R9, aryl-R9, substituted aryl-R9, heteroaryl-R9 or substituted heteroaryl-R9 ring;
• R5 is H, OH, alkylene-R10, substituted alkylene-R10, cycloalkylene-R10, substituted cycloalkylene-R10, alkenylene-R10, substituted alkenylene-R10, cycloalkenylene-R10, substituted cycloalkenylene-R10, alkynylene-R10, substituted alkynylene-R10, arylene-R10, substituted arylene-R10, heteroarylene-R10, substituted heteroarylene-R10, heterocyclene-R10, or substituted heterocyclene-R10
• R6 is H, OH, alkylene-R11, substituted alkylene-R11, cycloalkylene-R11, substituted cycloalkylene-R11, alkenylene-R11, substituted alkenylene-R11, cycloalkenylene-R11, substituted cycloalkenylene-R11, alkynylene-R11, substituted alkynylene-R11, arylene-R11, substituted arylene-R11, heteroarylene-R11, substituted heteroarylene-R11, heterocyclene-R11 or substituted heterocyclene-R11;
• R7 is OH, an alkylamino group substituted with a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, a di-substituted alkylamino group substituted with L-D and a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, or pharmaceutically acceptable salts thereof;
• R9 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R10 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R11 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R13 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• dashed lines represent possible sites of unsaturation;
• L is a covalent bond or a linking group;
• and
• D is a drug;
• provided that
• not more than one of the substituents R3, R4, R5, R6, and R7 includes moiety L-D;
• and
• when R1 and R2 are CHOH, R5 and R6 are H, and R7 is OH, then R3 and R4 together with the carbon atoms to which they are attached do not form

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein:
• R1 is CR12OH;
• R2 is CR12OH;
• R3 and R4 together with the carbon atoms to which they are attached form a cycloalkyl-R9, substituted cycloalkyl-R9, cycloalkenyl-R9, substituted cycloalkenyl-R9, heterocycloalkyl-R9, substituted heterocycloalkyl-R9, heterocycloalkenyl-R9, substituted heterocycloalkenyl-R9, aryl-R9, substituted aryl-R9, heteroaryl-R9 or substituted heteroaryl-R9 ring;
• R5 is H, OH, alkylene-R10, substituted alkylene-R10, cycloalkylene-R10, substituted cycloalkylene-R10, alkenylene-R10, substituted alkenylene-R10, cycloalkenylene-R10, substituted cycloalkenylene-R10, alkynylene-R10, substituted alkynylene-R10, arylene-R10, substituted arylene-R10, heteroarylene-R10, substituted heteroarylene-R10, heterocyclene-R10, or substituted heterocyclene-R10
• R6 is H, OH, alkylene-R11, substituted alkylene-R11, cycloalkylene-R11, substituted cycloalkylene-R11, alkenylene-R11, substituted alkenylene-R11, cycloalkenylene-R11, substituted cycloalkenylene-R11, alkynylene-R11, substituted alkynylene-R11, arylene-R11, substituted arylene-R11, heteroarylene-R11, substituted heteroarylene-R11, heterocyclene-R11 or substituted heterocyclene-R11;
• R7 is OH, an alkylamino group substituted with a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, a di-substituted alkylamino group substituted with L-D and a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, or pharmaceutically acceptable salts thereof;
• R9 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R10 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R11 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R12 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• R13 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• dashed lines represent possible sites of unsaturation;
• L is a covalent bond or a linking group;
• and
• D is a drug;
• provided that not more than one of the substituents R3, R4, R5, R6, and R7 includes moiety L-D.

A compound of formula (I):

• or a pharmaceutically acceptable salt thereof;
• wherein
• R1 is CH2, CHOH or CR12OH;
• R2 is CH2, CHOH or CR12OH;
• R3 and R4 together with the carbon atoms to which they are attached form a 5-membered ring selected from the group consisting of the following 5-membered rings:
• wherein
• R9 is L-D;
• R14 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13 or CON(R13)2;
• and
• R15 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13 or CON(R13)2;
• R5 is H, OH, alkylene-R10, substituted alkylene-R10, cycloalkylene-R10, substituted cycloalkylene-R10, alkenylene-R10, substituted alkenylene-R10, cycloalkenylene-R10, substituted cycloalkenylene-R10, alkynylene-R10, substituted alkynylene-R10, arylene-R10, substituted arylene-R10, heteroarylene-R10, substituted heteroarylene-R10, heterocyclene-R10, or substituted heterocyclene-R10;
• R6 is H, OH, alkylene-R11, substituted alkylene-R11, cycloalkylene-R11, substituted cycloalkylene-R11, alkenylene-R11, substituted alkenylene-R11, cycloalkenylene-R11, substituted cycloalkenylene-R11, alkynylene-R11, substituted alkynylene-R11, arylene-R11, substituted arylene-R11, heteroarylene-R11, substituted heteroarylene-R11, heterocyclene-R11 or substituted heterocyclene-R11;
• R7 is OH, an alkylamino group substituted with a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, a di-substituted alkylamino group substituted with L-D and a moiety that is negatively charged at physiological pH and located 5 to 15 atoms from C-22 of the bile acid nucleus, or pharmaceutically acceptable salts thereof;
• R10 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R11 is H, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroalkyl, substituted heteroalkyl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, substituted heteroaryl, OH, OR13, SH, SR13, NH2, NHR13, N(R13)2, CO2H, CO2R13, CONH2, CONHR13, CON(R13)2 or L-D;
• R12 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• R13 is alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl;
• dashed lines represent possible sites of unsaturation;
• L is a covalent bond or a linking group;
• and
• D is a drug;
• provided that not more than one of the substituents R3, R4, R5, R6, and R7 includes moiety L-D.