Polymers with rigid spacing groups comprising biologically active compounds
Compounds useful as biologically active compounds are disclosed. The compounds have the following structure (I): or a stereoisomer, tautomer or salt thereof, wherein A, R 1 , R 2 , R 3 , R 4 , R 5 , L, L 1 , L 2 , L 3 , L 4 , M, m and n are as defined herein. Methods associated with preparation and use of such compounds is also provided.
1. A composition comprising a pharmaceutically acceptable carrier and 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 selected from the group consisting of an NSAID, a kinase inhibitor, an anthracycline, an EGFR inhibitor, an alkylating agent and an anti-cancer drug or a fluorescent dye, provided at least one occurrence of M is not a fluorescent dye;
A is, at each occurrence, independently
or a moiety comprising a fused aryl or heteroaryl ring system;
L is a physiologically cleavable linker cleavable at a pH ranging from 6 to 8, cleavable at a temperature ranging from 20° C. to 40° C., or cleavable by an enzyme;
L 1 , L 2 , L 3 and L 4 are, at each occurrence, independently absent or an alkylene, alkenylene, alkynylene, heteroalkylene, heteroalkenylene, heteroalkynylene or heteroatomic linker;
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, —OP(═R a )(R b )R c , Q or L′, wherein: 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 , SR d , OL′, alkyl, alkoxy, alkylether, alkoxyalkylether, phosphate, thiophosphate, phosphoalkyl, thiophosphoalkyl, phosphoalkylether or thiophosphoalkylether; and R d is a counter ion;
R 4 is, at each occurrence, independently OH, SH, O − , S − , OR d or SR d ;
R 5 is, at each occurrence, independently oxo, thioxo or absent;
Q is, at each occurrence, independently a moiety comprising a reactive group capable of forming a covalent bond with an analyte molecule, a solid support or a complementary reactive group Q′;
L′ is, at each occurrence, independently a linker covalently bonded to Q, a targeting moiety, a linker covalently bonded to a targeting moiety, a solid support or solid support residue, a linker covalently bonded to a solid support or solid support residue or a linker covalently bonded to a further compound of structure (I);
m is, at each occurrence, independently an integer of zero or greater, provided that at least one occurrence of m is an integer of one or greater; and
n is an integer of one or greater,
wherein the compound is present in the composition at a therapeutically effective amount for treating a disease or condition.
2. The composition of claim 1 , wherein A, at each occurrence, independently has one of the following structures:
3. The composition 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 heterocyclic or a heteroaryl group.
4. The composition of claim 1 , wherein L 1 , L 2 , L 3 and L 4 are, at each occurrence, independently C 1 -C 6 alkylene, C 2 -C 6 alkenylene or C 2 -C 6 alkynylene.
5. The composition of claim 1 , wherein the compound has the following structure (IA):
wherein:
x 1 , x 2 , x 3 , x 4 , x 5 and x 6 are, at each occurrence, independently an integer from 0 to 6.
6. The composition of claim 1 , wherein R 4 is, at each occurrence, independently OH, O − or OR d .
7. The composition of claim 1 , wherein R 5 is, at each occurrence, oxo.
8. The composition of claim 1 , wherein R 1 is H.
9. The composition 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 covalently bonded to Q.
10. The composition of claim 1 , wherein R 2 and R 3 are each independently OH or —OP(═R a )(R b )R c .
11. The composition of claim 1 , wherein Q is a moiety having one of the following structures:
wherein:
X is halo; and
EWG is an electron withdrawing group.
12. The composition of claim 1 , wherein the targeting moiety is an antibody or cell surface receptor antagonist.
13. The composition of claim 12 , wherein the antibody or cell surface receptor antagonist is an epidermal growth factor receptor (EGFR) inhibitor, a hepatocyte growth factor receptor (HGFR) inhibitor, an insulin-like growth factor receptor (IGFR) inhibitor, a folate, or a MET inhibitor.
14. The composition of claim 1 , wherein M is, at each occurrence, independently an anti-cancer drug, and the targeting moiety is an antibody specific for a tumor cell antigen.
15. The composition of claim 14 , wherein the tumor cell antigen is an EGFR, a HER 2, a folate receptor, CD 20 or CD 33.
16. The composition of claim 1 , wherein the compound has one of the following structures:
wherein:
N′ is
I′ is
and
dT is
wherein R is H or direct bond.
17. The composition of claim 1 , wherein the composition comprises a plurality of conjugates, the conjugates comprising a compound of claim 1 covalently bound to an antibody via a single linkage, wherein the plurality of conjugates has at least 90% structural homogeneity.
18. A method of treating a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a composition of claim 1 , wherein each M is independently a biologically active moiety effective for treating the disease.