Sustained release delivery systems comprising traceless linkers
Described herein are drug delivery systems for delivering biologically active agents comprising primary or secondary amines, or a ring nitrogen atom of an azaheteroaryl ring, pharmaceutically acceptable salts thereof, drug delivery reagents related thereto, pharmaceutical compositions comprising the drug delivery systems, and the use of the drug delivery systems as sustained release therapeutics.
1. A drug delivery system or pharmaceutically acceptable salt thereof characterized in that is represented by Formula (XXX), where Drug is a biologically active moiety comprising at least one primary or secondary amine or a ring nitrogen atom of an azaheteroaryl ring; w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; q is independently at each occurrence 1, 2, or 3; m is 1 or 0; p is a weighted average length of between 2 and 50; and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-cyclopropyl, or methoxymethyl:
2. A drug delivery system or pharmaceutically acceptable salt thereof characterized in that is represented by Formula (XXXII), where Drug is a biologically active moiety comprising at least one primary or secondary amine or a ring nitrogen atom of an azaheteroaryl ring; w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; q is independently at each occurrence 1, 2, or 3; m is 1 or 0; p is a weighted average length of between 2 and 50; and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-cyclopropyl, or methoxymethyl:
3. A drug delivery system or pharmaceutically acceptable salt thereof characterized in that is represented by Formula (XXXIV), where Drug is a biologically active moiety comprising at least one primary or secondary amine or a ring nitrogen atom of an azaheteroaryl ring; w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; q is independently at each occurrence 1, 2, or 3; m is 1 or 0; p is a weighted average length of between 2 and 50; and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-cyclopropyl, or methoxymethyl:
4. A drug delivery system or pharmaceutically acceptable salt thereof characterized in that is represented by Formula (XXXVI), where Drug is a biologically active moiety comprising at least one primary or secondary amine or a ring nitrogen atom of an azaheteroaryl ring; w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; q is independently at each occurrence 1, 2, or 3; m is 1 or 0; p is a weighted average length of between 2 and 50; and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-cyclopropyl, or methoxymethyl:
5. A drug delivery system or pharmaceutically acceptable salt thereof characterized in that is represented by Formula (XXXVIII), where Drug is a biologically active moiety comprising at least one primary or secondary amine or a ring nitrogen atom of an azaheteroaryl ring; w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; q is independently at each occurrence 1, 2, or 3; m is 1 or 0; p is a weighted average length of between 2 and 50; and R 4 is methyl, ethyl, propyl, isopropyl, 1-methyl-cyclopropyl, or methoxymethyl:
6. A carrier composition or pharmaceutically acceptable salt thereof, characterized in that is represented by formula:
wherein
L is an optionally substituted bivalent linker Q-[Sp-Q] h -Q;
Q is independently selected at each occurrence from a bond, O, C(O), N(H), N(C 1 -C 4 alkyl), C(O)NH, C(O)N(C 1 -C 4 alkyl), N(H)C(O), N(C 1 -C 4 alkyl)C(O), N(H)C(O)O, N(C 1 -C 4 alkyl)C(O)O, OC(O)N(H), OC(O)N(C1-C4alkyl), N(H)C(O)N(H), N(C 1 -C 4 alkyl)C(O)N(H), N(H)C(O)N(C 1 -C 4 alkyl), N(C 1 -C 4 alkyl)C(O)N(C 1 -C 4 alkyl), C(O)O, OC(O), OC(O)O, S, S(O) 2 , N(H)S(O) 2 , N(C 1 -C 4 alkyl)S(O) 2 , S(O) 2 N(H), S(O) 2 N(C 1 -C 4 alkyl), C 1 -C 2 alkyl-C(O)N(H), N(H)C(O)C 1 -C 2 alkyl, C 1 -C 2 alkyl-C(O)O, OC(O)C 1 -C 2 alkyl, 1,2,3-triazole, OP(O) 2 , P(O) 2 O, C 1 -C 4 alkyl-P(O) 2 —O, or O—P(O) 2 —C 1-4 alkyl;
Sp is independently selected at each occurrence from an optionally substituted C 1 -C 20 alkyl, C 2 -C 20 alkenyl, C 2 -C 20 alkynyl, [W—O] g , C 1 -C 8 alkyl-[O—W] g , [O—W] g -O-C 1 -C 8 alkyl, C 1 -C 8 Calkyl-[O-W] g -O-C 1 -C 8 alkyl, or oligopeptide;
h is an integer of between 1 and 20;
g is a weighted average number of between about 2 and about 50;
W is C 2 -C 4 alkyl-1,2-diyl in which a hydrogen, methyl, or ethyl side chain may be present on either backbone carbon atom;
q is independently at each occurrence 1, 2, or 3;
m is 1 or 0;
p is a weighted average length of between 2 and 50;
w is the number of repeating PEG monomer units having a nominal average molecular weight of 2 kDa; and
R 4 is C 1 -C 8 alkyl or C 3 -C 7 cycloalkyl, wherein cycloalkyl is optionally substituted with 0, 1, or 2 independently selected C 1 -C 4 alkyl groups and wherein alkyl is optionally substituted by C 1 -C 4 alkoxy.
7. The carrier composition of claim 6 , characterized by having one of the following formula:
or