Degradable hyaluronic acid hydrogels

A conjugate comprising crosslinked hyaluronic acid strands to which a plurality of drug moieties are covalently and reversibly conjugated, wherein the conjugate comprises a plurality of connected units selected from the group consisting of

• wherein
• an unmarked dashed line indicates a point of attachment to an adjacent unit at a dashed line marked with #or to a hydrogen;
• a dashed line marked with #indicates a point of attachment to an adjacent unit at an unmarked dashed line or to a hydroxyl;
• a dashed line marked with § indicates a point of connection between at least two units Z3 via a moiety -CL-;
• each -D is independently a drug moiety;
• each -L1- is independently a linker moiety to which -D is covalently and reversibly conjugated;
• wherein the bond between -L1- and -D is cleaved in aqueous buffer at pH 7.4 and 37° C. with a half-life ranging from 12 hours to three months and -D is released non-enzymatically in its unmodified, pharmacologically active form;
• each -L2-, -L3- and -L4- is independently either absent or a spacer moiety;
• each —CL- is independently a moiety connecting at least two units Z3 and wherein there is at least one degradable bond in the direct connection between any two carbon atoms marked with the * connected by a moiety —CL-;
• each —SP— is independently absent or a spacer moiety;
• each —Ra1 is independently selected from the group consisting of —H, C1-4 alkyl, an ammonium ion, a tetrabutylammonium ion, a cetyl methylammonium ion, an alkali metal ion and an alkaline earth metal ion;
• each —Ra2 is independently selected from the group consisting of —H and C1-10 alkyl;
• each —X0A—, —X0B—, —X0C and —X0D is independently either absent or a linkage;
• each —X0E— is
• wherein the unmarked dashed line indicate attachment to —SP— and the dashed line marked with an asterisk indicate attachment to the carbonyl of the hyaluronic acid, wherein R01 is independently selected from the group consisting of halogen, —H, —CN, -T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl:
• wherein -T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more —R02, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of -T0, —C(O)O—, —O—, C(O)—, —C(O)N(R03)—, —S(O)2N(R03)—, —S(O)N(R03)—, —S(O)2—, —S(O)—, N(R03)S(O)2N(R03a)—, —S—, —N(R03)—, —OC(OR03)(R03a), —N(R03)C(O)N(R03a)—, and —OC(O)N(R03) wherein each T0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl;
• wherein each T0 is independently optionally substituted with one or more R02, which are the same or different;
• and wherein each —R02, —R03 and —R03a is independently selected from the group consisting of H and C1-6 alkyl:
• wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
• each —X0F- is
• wherein R04 is independently selected from the group consisting of halogen, —H, CN, T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl:
• wherein T0, C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally substituted with one or more R06, which are the same or different, and wherein C1-50 alkyl, C2-50 alkenyl, and C2-50 alkynyl are optionally interrupted by one or more groups selected from the group consisting of T0, —C(O)O—, —O—, —C(O)—, —C(O)N(R07)—, —S(O)2N(R07)—, —S(O)N(R07)—, —S(O)2—, —S(O)—, —N(R07)S(O)2N(R07a)—, —S—, N(R07)—, —OC(OR07)(R07a), —N(R07)C(O)N(R07a)—, and —OC(O)N(R07);
• wherein each T0 is independently selected from the group consisting of phenyl, naphthyl, indenyl, indanyl, tetralinyl, C3-10 cycloalkyl, 3- to 10-membered heterocyclyl, and 8- to 11-membered heterobicyclyl;
• wherein each T0 is independently optionally substituted with one or more R06, which are the same or different;
• and wherein each R06, R07 and R07a is independently selected from the group consisting of H and C1-6 alkyl;
• wherein C1-6 alkyl is optionally substituted with one or more halogen, which are the same or different;
• optionally —X0A— and/or —X0B- form together with -L4- or parts of -L4- one or more ring structure selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclyl and adamantyl;
• optionally —X0B— and/or —X0C— form together with -L3- or parts of -L3- one or more ring structure selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclyl and adamantyl;
• optionally, —X0C— and/or —X0D— form together with -L2- or parts of -L2- one or more ring structure selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclyl and adamantyl;
• optionally —X0E— and/or —X0F— form together with —SP— or parts of —SP— one or more ring structure selected from the group consisting of 4- to 7-membered heterocyclyl, 8- to 11-membered heterobicyclyl and adamantyl;
• wherein
• all units Z1 present in the conjugate may be the same or different;
• all units Z2 present in the conjugate may be the same or different;
• all units Z3 present in the conjugate may be the same or different;
• at least one unit Z3 is present per hyaluronic acid strand which is connected to at least one unit Z3 on a different hyaluronic acid strand;
• and
• the conjugate comprises at least one unit Z2;
• wherein —CL- is a moiety of formula (D)
• wherein
• the dashed lines indicate attachment to a moiety —X0F—;
• and
• m2, m3 and m4 are independently an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 and 25;
• and
• wherein -L1- is of formula (I):
• wherein
• the dashed line indicates the attachment to a nitrogen, hydroxyl or thiol of -D;
• —X— is selected from the group consisting of —C(R4R4a)—, —N(R4)—, —O—, —C(R4R4a)—C(R5R5a)—, —C(R5R5a)—C(R4R4a)—, —C(R4R4a)—N(R6)—, —N(R6)—C(R4R4a)—, —C(R4R4a)—O—, —O—C(R4R4a)—, and —C(R7R7a)—,
• X1 is selected from the group consisting of C and S(O);
• —X2— is selected from the group consisting of —C(R8R8a)— and —C(R8R8a)—C(R9R9a)—;
• ═X3 is selected from the group consisting of ═O, ═S, and ═N—CN;
• —R1, —R1a, —R2, —R2a, —R4, —R4a, —R5, —R5a, —R6, —R8, —R8a, —R9 and —R9a are independently selected from the group consisting of —H and C1-6 alkyl;
• —R3 and —R3a are independently selected from the group consisting of —H and C1-6 alkyl, provided that in case one of —R3 and —R3a or both are other than —H they are connected to N to which they are attached through an sp3-hybridized carbon atom;
• —R7 is selected from the group consisting of —N(R10R10a) and —NR10—(C═O)—R11;
• —R7a, —R10, —R10a and —R11 are independently selected from the group consisting of —H and C1-6 alkyl;
• alternatively, one or more of the pairs —R1a/—R4a, —R1a/—R5a, —R1a/—R7a, —R4a/—R5a and —R8a/—R9a form a chemical bond;
• alternatively, one or more of the
• pairs —R1/—R1a, —R2/—R2a, —R4/—R4a, —R5/—R5a, —R8/—R8a and —R9/—R9a are joined together with the atom to which they are attached to form a C3-10 cycloalkyl or 3- to 10-membered heterocyclyl;
• alternatively, one or more of the pairs —R1/—R4, —R1/—R5, —R1/—R6, —R1/—R7a, —R4/—R5, —R4/—R6, —R8/—R9 and —R2/—R3 are joined together with the atoms to which they are attached to form a ring A;
• alternatively, —R3/—R3a are joined together with the nitrogen atom to which they are attached to form a 3- to 10-membered heterocycle;
• A is selected from the group consisting of phenyl;
• naphthyl;
• indenyl;
• indanyl;
• tetralinyl;
• C3-10 cycloalkyl;
• 3- to 10-membered heterocyclyl;
• and 8- to 11-membered heterobicyclyl;
• and
• wherein -L1- is substituted with —X0D-L2- and wherein -L1- is optionally further substituted, provided that the hydrogen marked with the asterisk in formula (I) is not replaced by —X0D-L2- or a substituent.