PROGRAMMABLE POLYMERIC DRUGS
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , L a , L b , L 1 , L 2 , L 3 , M, m, and n are as defined herein. Methods associated with preparation and use of such compounds are also provided.
1 . A compound having the following structure (I):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M is, at each occurrence, independently a biologically active moiety, or fragment thereof, a prodrug of a biologically active moiety, or fragment thereof, a fluorescent dye, an imaging agent, or a radioisotope binding site, provided at least one occurrence of M is not a fluorescent dye;
L a is, at each occurrence, independently an optional physiologically cleavable linker and L b is, at each occurrence, independently an optional physiologically non-cleavable linker, provided that at least one occurrence of L a and L b together comprise more than 4 carbons;
L 1 and L 2 are, at each occurrence, independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
L 3 is, at each occurrence, independently a heteroalkylene, heteroalkenylene or heteroalkynylene linker of greater than three atoms in length, wherein the heteroatoms in the heteroalkylene, heteroalkenylene and heteroalkynylene linker are selected from O, N and S;
R 1 is, at each occurrence, independently H, alkyl or alkoxy;
R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkylether, heteroalkyl, —OP(═R a )(R b )R c , Q, or a protected form thereof, or L′;
R 4 is, at each occurrence, independently O, S, OZ, SZ or N(R 6 ) 2 , where Z is a cation and each R 6 is independently H or alkyl;
R 5 is, at each occurrence, independently oxo, thioxo or absent;
R a is O or S;
R b is OH, SH, O − , S − , OR d or SR d ;
R c is OH, SH, O − , S − , OR d , OL′, SR d , alkyl, alkoxy, heteroalkyl, heteroalkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether;
R d is a counter ion;
Q is, at each occurrence, independently a moiety comprising a reactive group, or protected form thereof, capable of forming a covalent bond with a complementary reactive group Q′ on a targeting moiety;
L′ is, at each occurrence, independently a linker comprising a covalent bond to Q, a targeting moiety, a linker comprising a covalent bond to a targeting moiety, a linker comprising a covalent bond to a solid support, a linker comprising a covalent bond to a solid support residue, a linker comprising a covalent bond to a nucleoside or a linker comprising a covalent bond to a further compound of structure (I);
m is, at each occurrence, independently an integer of zero or greater; and
n is an integer of one or greater.
2 .- 4 . (canceled)
5 . The compound of claim 1 , L 3 is polyethylene oxide, and the compound has the following structure (IA):
wherein z is an integer from 2 to 100.
6 . (canceled)
7 . (canceled)
8 . The compound of claim 1 , L 3 is polyethylene oxide, and the compound has the following structure (IB):
wherein:
z is an integer from 2 to 30;
x 1 and x 2 are each independently an integer from 0 to 6; and
x 3 and x 4 are, at each occurrence, independently an integer from 0 to 6.
9 . (canceled)
10 . The compound of claim 8 wherein z is an integer from 3 to 6 and m is 3 for at least one occurrence of n.
11 . (canceled)
12 . The compound of claim 8 , wherein z is an integer from 44 to 54 for at least one occurrence of m.
13 .- 15 . (canceled)
16 . The compound of claim 1 , wherein at least one occurrence of L a comprises an amide bond, an ester bond, a phosphodiester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a hydrazone, an amino acid sequence, a ketone, a diol, a cyano, a nitro or combinations thereof.
17 . The compound of claim 16 , wherein L a comprises an amino acid sequence recognized by a sortase enzyme.
18 . The compound of claim 17 , wherein the amino acid sequence is Leu-Pro-X-Thr-Gly, wherein X is any amino acid residue.
19 . (canceled)
20 . (canceled)
21 . The compound of claim 1 , wherein at least one occurrence of L a comprises one of the following structures:
22 .- 28 . (canceled)
29 . The compound of claim 1 , wherein at least one occurrence of L a comprises one of the following structures:
30 .- 35 . (canceled)
36 . The compound of claim 1 , wherein at least one occurrence of L b comprises a thioether bond.
37 . (canceled)
38 . The compound of claim 1 , wherein at least one occurrence of L b comprises one of the following structures:
39 .- 51 . (canceled)
52 . The compound of claim 1 , wherein L′ has the following structure:
wherein:
m″ and n″ are independently an integer from 1 to 10;
R e is H, an electron pair or a counter ion;
L″ is the targeting moiety or a linkage to the targeting moiety.
53 .- 57 . (canceled)
58 . The compound of claim 1 , wherein R 2 or R 3 has one of the following structures:
59 . The compound of claim 1 , wherein R 3 has the following structure:
60 . The compound of claim 1 , wherein R 2 or R 3 comprises one of the following structures:
61 .- 69 . (canceled)
70 . The compound of claim 1 , wherein:
A) at least one occurrence of M is an antineoplastic agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, a kinase inhibitor, an anthracycline, and EGFR inhibitor or an alkylating agent;
B) at least one occurrence of M is an antineoplastic agent, an enediyne antitumor antibiotic, a maytansinoid, a topoisomerase inhibitor, or an alkylating agent;
C) at least one occurrence of M is selected from the group consisting of auristatin F, monomethyl auristatin F, monomethyl auristatin E, paciltaxol, SN-38, calicheamicin, anthramycin, abbeymycin, chicamycin, DC-81, mazethramycin, neothramycin A, neothramycin B, porothramycin prothracarcin, sibanomicin, sibiromycin, tomamycin, mertansine, emtansine, irinotecan, camptothecin, topotecan, silatecan, cositecan, Exatecan, Lurtotecan, gimatecan, Belotecan, and Rubitecan; or
D) at least one occurrence of M has one of the following structures:
71 .- 76 . (canceled)
77 . The compound of claim 1 , wherein the compound has one of the following structures:
wherein:
F has the following structure:
dT has the following structure:
wherein:
R is H or a direct bond.
78 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
79 . A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of the compound of claim 1 , wherein at least one M is a biologically active moiety effective for treating the disease.
80 .- 92 . (canceled)