IONIC POLYMERS COMPRISING BIOLOGICALLY ACTIVE COMPOUNDS
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): structure (I) or a stereoisomer, tautomer or salt thereof, wherein R 1 , R 2 , R 3 , L, L 1 , L 2 , L 3 , L 4 , 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 is a physiologically cleavable linker;
L 1 , L 2 and L 3 are, at each occurrence, independently an optional alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
L 4 is, at each occurrence, independently an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene or heteroalkynylene linker comprising one or more charged moieties, provided at least one charged moiety is not a phosphate ester;
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, alkylaminyl, alkylcarbonyl, alkoxycarbonyl, —OP(═R a )(R b )R c , Q or a protected form thereof, or L′;
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 1 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 solid support or solid support residue, a linker comprising a covalent bond to a solid support or solid support residue or a linker comprising a covalent bond to a further compound of structure (I); and
n is an integer of one or greater.
2 . The compound of claim 1 , wherein the charged moieties are positively charged.
3 . (canceled)
4 . The compound of claim 1 , wherein the charged moieties are negatively charged.
5 . (canceled)
6 . The compound of claim 1 , wherein L 4 comprises one of the following structures:
wherein:
R is, at each occurrence, independently H or C 1 -C 6 alkyl;
x is an integer from 0 to 6; and
m is an integer of 1 or greater.
7 . The compound of claim 1 , wherein L is at each occurrence a linker comprising a functional group capable of formation by reaction of two complementary reactive groups.
8 . The compound of claim 1 , wherein L is, at each occurrence, independently a linker comprising an amide bond, an ester bond, a disulfide bond, a double bond, a triple bond, an ether bond, a ketone, a diol, a cyano, a nitro, a heterocycle, a heteroaryl or combinations thereof.
9 . (canceled)
10 . The compound of claim 1 , wherein R 2 and R 3 are each independently —OH or —OP(═R a )(R b )R c .
11 . The compound of claim 1 , wherein one of R 2 or R 3 is —OH or —OP(═R a )(R b )R c , and the other of R 2 or R 3 is Q or a linker comprising a covalent bond to Q.
12 . (canceled)
13 . The compound of claim 1 , wherein Q comprises a sulfhydryl, disulfide, N-succinimide ester, imidoester, polyflourophenyl ester, isothiocyanate, azide, alkyne, alkene, diene, dienophile, acid halide, sulfonyl halide, phosphine, α-haloamide, biotin, amino or maleimide functional group.
14 - 15 . (canceled)
16 . The compound of claim 1 , wherein Q is a moiety selected from Table 1.
17 - 18 . (canceled)
19 . The compound of claim 1 , wherein one of R 2 or R 3 is L′, and L′ is a targeting moiety or a linker to a targeting moiety.
20 . The compound of claim 19 , wherein L′ is a linker to a targeting moiety, the linker comprising a heteroalkylene linker.
21 - 22 . (canceled)
23 . The compound of claim 1 , wherein n is an integer from 1 to 100.
24 . (canceled)
25 . The compound of claim 1 , wherein M comprises at each occurrence, independently an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor or an alkylating agent.
26 . The compound of claim 1 , wherein M comprises, at each occurrence, independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen.
27 . (canceled)
28 . The compound of claim 1 , wherein the compound is selected from a compound in Table 2.
29 . A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
30 . A composition comprising a plurality of conjugates, the conjugates comprising a compound of claim 1 comprising a covalent bond to an antibody via a single linkage, wherein the plurality of conjugates has at least 90% structural homogeneity.
31 - 32 . (canceled)
33 . The composition of claim 29 , wherein one of R 2 and R 3 is —OP(═R a )(R b ) OL′ or L′, and L′ is the antibody or a linker comprising a covalent bond to the antibody.
34 . A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1 , wherein each M is independently a biologically active moiety effective for treating the disease.
35 . (canceled)