Benzothiepines having activity as inhibitors of ileal bile acid transport and taurocholate uptake

An oral pharmaceutical composition comprising an ileal bile acid transport (IBAT) inhibitor in a dosage range from about 0.3 mg/kg bodyweight/day to about 100 mg/kg bodyweight/day and a pharmaceutically acceptable carrier, wherein said oral pharmaceutical composition provides delayed release or sustained release of said IBAT inhibitor to the gastrointestinal tract of a subject to whom said composition is administered, and wherein said IBAT inhibitor is represented by a compound of formula (I):

• wherein:
• q is an integer from 1 to 4;
• n is an integer from 0 to 2;
• R1 and R2 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl,
• wherein alkyl, alkenyl, alkynyl, haloalkyl, alkylaryl, arylalkyl, alkoxy, alkoxyalkyl, dialkylamino, alkylthio, (polyalkyl)aryl, and cycloalkyl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R10RwA−, SR9, S+R9R10A−, P+R9R10R11A−, S(O)R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10,
• wherein alkyl, alkenyl, alkynyl, alkylaryl, alkoxy, alkoxyalkyl, (polyalkyl)aryl, and cycloalkyl optionally have one or more carbons replaced by O, NR9, N+R9R10A−, S, SO, SO2, S+R9A−, P+R9R10A−, or phenylene,
• wherein R9, R10, and Rw are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;
• or
• R1 and R2 taken together with the carbon to which they are attached form C3-C10 cycloalkyl;
• R3 and R4 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, acyloxy, aryl, heterocycle, OR9, NR9R10, SR9, S(O)R9, SO2R9, and SO3R9, wherein R9 and R10 are as defined above;
• or
• R3 and R4 together form ═O, ═NOR11, ═S, ═NNR11R12, ═NR9, or ═CR11R12, wherein R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyallcyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(O)R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH, or
• R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• R5 and R6 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, OR30, SR9, S(O)R9, SO2R9, and SO3R9,
• wherein alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, quaternary heterocycle, and quaternary heteroaryl can be substituted with one or more substituent groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A−, P(OR13)OR14, S+R13R14A−, and N+R9R11R12A−,
• wherein:
• A− is a pharmaceutically acceptable anion and M is a pharmaceutically acceptable cation,
• said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can be further substituted with one or more substituent groups selected from the group consisting of OR7, NR7R8, SR7, S(O)R7, SO2R7, SO3R7, CO2R7, CN, oxo, CONR7R8, N+R7R8R9A−, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocycle, arylalkyl, quaternary heterocycle, quaternary heteroaryl, P(O)R7R8, P+R7R8R9A−, and P(O)(OR7)OR8 and
• wherein said alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, and heterocycle can optionally have one or more carbons replaced by O, NR7, N+R7R8A−, S, SO, SO2, S+R7A−, PR7, P(O)R7, P+R7R8A−, or phenylene, and R13, R14, and R15 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary beteroarylalkyl,
• wherein alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl optionally have one or more carbons replaced by O, NR9, N+R9R10A−, S, SO, SO2, S+R9A−, PR9, P+R9R10A−, P(O)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide, and
• R13, R14 and R15 are optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9R11R12A−, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16)OR17, P+R9R10R11A−, S+R9R10A−, and C(O)OM,
• wherein R16 and R17 are independently selected from the substituents constituting R9 and M;
• or
• R14 and R15, together with the nitrogen atom to which they are attached, form a cyclic ring;
• and
• R30 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, alkylammoniumalkyl, and arylalkyl;
• and
• R7 and R8 are independently selected from the group consisting of hydrogen and alkyl;
• and
• one or more Rx are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, polyalkyl, acyloxy, aryl, arylalkyl, halogen, haloalkyl, cycloalkyl, heterocycle, heteroaryl, polyether, quaternary heterocycle, quaternary heteroaryl, OR13, NR13R14, SR13, S(O)R13, S(O)2R13, SO3R13, S+R13R14A−, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, NR14C(O)R13, C(O)NR13R14, NR14C(O)R13, C(O)OM, COR13, OR18, S(O)nNR18, NR13R18, NR18OR14, N+R9R11R12A−, P+R9R11R12A−, amino acid, peptide, polypeptide, and carbohydrate,
• wherein alkyl, alkenyl, alkynyl, cycloalkyl, aryl, polyalkyl, heterocycle, acyloxy, arylalkyl, haloalkyl, polyether, quaternary heterocycle, and quaternary heteroaryl can be further substituted with OR9, NR9R10, N+R9R11R12A−, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR16)OR17, P+R9R11R12A−, S+R9R10A−, or C(O)M, and
• wherein R18 is selected from the group consisting of acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl,
• wherein acyl, arylalkoxycarbonyl, arylalkyl, heterocycle, heteroaryl, alkyl, quaternary heterocycle, and quaternary heteroaryl optionally are substituted with one or more substituents selected from the group consisting of OR9, NR9R10, N+R9R11R12A−, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO3R9, SO2OM, SO2NR9R10, PO(OR16)OR17, and C(O)OM,
• wherein in Rx, one or more carbons are optionally replaced by O, NR13, N+R13R14A−, S, SO, SO2, S+R13A−, PR13, P(O)R13, P+R13R14A−, phenylene, amino acid, peptide, polypeptide, carbohydrate, polyether, or polyalkyl,
• wherein in said polyalkyl, phenylene, amino acid, peptide, polypeptide, and carbohydrate, one or more carbons are optionally replaced by O, NR9, N+R9R10A−, S, SO, SO2, S+R9A−, PR9, P+R9R10A−, or P(O)R9;
• wherein quaternary heterocycle and quaternary heteroaryl are optionally substituted with one or more groups selected from the group consisting of alkyl, alkenyl, alkynyl, polyalkyl, polyether, aryl, haloalkyl, cycloalkyl, heterocycle, arylalkyl, halogen, oxo, OR13, NR13R14, SR13, S(O)R13, SO2R13, SO3R13, NR13OR14, NR13NR14R15, NO2, CO2R13, CN, OM, SO2OM, SO2NR13R14, C(O)NR13R14, C(O)OM, COR13, P(O)R13R14, P+R13R14R15A−, P(OR13)OR14, S+R13R14A−, and N+R9R11R12A−,
• provided that both R5 and R6 cannot be hydrogen or SH;
• provided that when R5 or R6 is phenyl, only one of R1 or R2 is H;
• provided that when q=1 and Rx is styryl, anilido, or anilinocarbonyl, only one of R5 or R6 is alkyl;
• or
• a pharmaceutically acceptable salt, solvate, or prodrug thereof.

An oral pharmaceutical composition comprising an ileal bile acid transport (IBAT) inhibiting compound of formula (I):

• wherein:
• q is 1 or 2;
• n is 2;
• R1 and R2 are each alkyl;
• R3 is hydroxy;
• R4 and R6 are hydrogen;
• R5 has the formula (II)
• wherein t is an integer from 0 to 5;
• one or more Ry are OR13;
• R13 is selected from the group consisting of hydrogen, alkyl, ailcenyl, alkynyl, polyalkyl, aryl, arylalkyl, cycloalkyl, heterocycle, heteroaryl, quaternary heterocycle, quaternary heteroaryl, and quaternary heteroarylalkyl;
• said R13 alkyl, alkenyl, alkynyl, arylalkyl, heterocycle, and polyalkyl groups optionally have one or more carbons replaced by O, NR9, N+R9R10A−, S, SO, SO2, S+R9A−, PR9, P+R9R10A−;
• P(O)R9, phenylene, carbohydrate, amino acid, peptide, or polypeptide;
• R13 is optionally substituted with one or more groups selected from the group consisting of sulfoalkyl, quaternary heterocycle, quaternary heteroaryl, OR9, NR9R10, N+R9R11R12A−, SR9, S(O)R9, SO2R9, SO3R9, oxo, CO2R9, CN, halogen, CONR9R10, SO2OM, SO2NR9R10, PO(OR61)OR17, P+R9R10R11A−, S+R9R10A−, and C(O)OM,
• wherein A is a pharmaceutically acceptable anion, and M is a pharmaceutically acceptable cation,
• R9 and R10 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl, aryl, acyl, heterocycle, ammoniumalkyl, arylalkyl, and alkylammoniumalkyl;
• R11 and R12 are independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkenylalkyl, alkynylalkyl, heterocycle, carboxyalkyl, carboalkoxyalkyl, cycloalkyl, cyanoalkyl, OR9, NR9R10, SR9, S(O)R9, SO2R9, SO3R9, CO2R9, CN, halogen, oxo, and CONR9R10, wherein R9 and R10 are as defined above, provided that both R3 and R4 cannot be OH, NH2, and SH;
• or
• R11 and R12 together with the nitrogen or carbon atom to which they are attached form a cyclic ring;
• and
• R16 and R17 are independently selected from the substituents constituting R9 and M;
• R7 and R8 are hydrogen;
• and
• one or more Rx are independently selected from the group consisting of alkoxy, alkylamino and dialkylamino;
• or
• a pharmaceutically acceptable salt, solvate, or prodrug thereof, and
• a pharmaceutically acceptable carrier suitable for delivery of said compound of formula (I) to the small intestine by oral administration.