Carrier-Linked Prostanoid Prodrugs

A carrier-linked prostanoid prodrug of formula (I) or a pharmaceutically acceptable salt thereof, where formula (I) is:

• Z1—(X0-L0-PG0)y (I);
• wherein:
• each PG0 is independently a prostanoid moiety except treprostinil which is attached to L0 through a hydroxyl or carboxyl group of PG0;
• each L0 is independently —(C═O)— or —O—(C═O)—, if PG0 is attached to L0 through a hydroxyl group;
• and —O—, if PG0 is attached to L0 through a carboxyl group;
• y is an integer ranging of from 1 to 64;
• each X0 is independently (X0B)m1—(X0A)m2;
• m1 and m2 are independently 0, or 1;
• each X0A is independently T0;
• each X0B is independently a linear or branched C1-50 alkyl, C2-50 alkenyl, or C2-50 alkinyl which is optionally one or more times interrupted by at least one group selected from the group consisting of:
• R1;
• phenyl, naphthyl, azulenyl, indenyl, indanyl, C3-7 cycloalkyl, 3-membered to 7-membered heterocyclyl, and 8-membered to 11-membered heterobicyclyl;
• and
• the following bivalent groups:
• wherein:
• dashed lines indicate attachment points;
• and
• R0 and R0a are independently of each other selected from the group consisting of H and C1-6 alkyl;
• wherein:
• R1 is halogen, C1-6 alkyl, CN, C(O)R2, C(O)OR2, oxo (═O), OR2, C(O)R2, C(O)N(R2R2a), S(O)2N(R2R2a), S(O)N(R2R2a), S(O)2R2, S(O)R2, N(R2)S(O)2N(R2aR2b), SR2, N(R2R2a), NO2, OC(O)R2, N(R2)C(O)R2a, N(R2)SO2R2a, N(R2)S(O)R2a, N(R2)C(O)N(R2aR2b), N(R2)C(O)OR2a, OC(O)N(R2R2a), or T0;
• R2, R2a, and R2b are independently H, T0, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R3, which are the same or different;
• R3 is halogen, CN, C(O)R4, C(O)OR4, OR4, C(O)R4, C(O)N(R4R4a), S(O)2N(R4R4a), S(O)N(R4R4a), S(O)2R4, S(O)R4, N(R4)S(O)2N(R4R4b), SR4, N(R4R4a), NO2, OC(O)R4, N(R4)C(O)R4a, N(R4)SO2R4a, N(R4)S(O)R4a, N(R4)C(O)N(R4aR4b), N(R4)C(O)OR4a, or OC(O)N(R4R4a);
• R4, R4a, and R4b are independently H, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same or different;
• T0 is phenyl, naphthyl, azulenyl, indenyl, indanyl, C3-10 cycloalkyl, 3-membered to 7-membered heterocyclyl, or 8-membered to 11-membered heterobicyclyl, wherein T0 is optionally substituted with one or more R5, which are the same or different;
• R5 is halogen, CN, COOR6, OR6, C(O)R6, C(O)N(R6R6a), S(O)2N(R6R6a), S(O)N(R6R6a), S(O)2R6, S(O)R6, N(R6)S(O)2N(R6aR6b), SR6, N(R6R6a), NO2, OC(O)R6, N(R6)C(O)R6a, N(R6)S(O)2R6a, N(R6)S(O)R6a, N(R6)C(O)OR6a, N(R6)C(O)N(R6aR6b), OC(O)N(R6R6a), oxo (═O) where the ring is at least partially saturated, C1-6 alkyl, C2-6 alkenyl, or C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R7, which are the same or different;
• R6, R6a, and R6b are independently H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl;
• wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more R8, which are the same of different;
• R7 and R8 are independently halogen, CN, C(O)R9, C(O)OR9, OR9, C(O)R9, C(O)N(R9R9a), S(O)2N(R9R9a), S(O)N(R9R9a), S(O)2R9, S(O)R9, N(R9)S(O)2N(R9aR9b), SR9, N(R9R9a), NO2, OC(O)R9, N(R9)C(O)R9a, N(R9)SO2R9a, N(R9)S(O)R9a, N(R9)C(O)N(R9aR9b), N(R9)C(O)OR9a, or OC(O)N(R9R9a);
• R9, R9a, and R9b are independently H, C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl, wherein said C1-6 alkyl, C2-6 alkenyl, and C2-6 alkynyl are optionally substituted with one or more halogen, which are the same of different;
• Z1 is a carrier comprising;
• a covalently bound polymer;
• or
• a covalently bound C10-24 fatty acid;
• wherein the carrier is covalently attached to a moiety X0, when at least one of m1 and m2 is 1;
• and
• wherein the carrier is covalently attached to L0 when m1 and m2 are 0.