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 , L, L 1 , L 2 , L 3 , M and n are as defined herein. Methods associated with preparation and use of such compounds is also provided.
1. A compound having the following structure (IB):
or a stereoisomer, pharmaceutically acceptable salt or tautomer thereof, wherein:
M at each occurrence, independently has one of the following structures:
provided that at least one occurrence of M does not have the following structure:
L is, at each occurrence, independently —NH—, —NH(CH 2 ) 4 —, or —NH(CH 2 ) 3 OCH 2 ;
L 2 and L 3 are, at each occurrence, independently an optional alkylene, heteroalkylene, or heteroatomic linker;
R 1 is, at each occurrence, independently H;
R 2 and R 3 are each independently H, OH, SH, alkyl, alkoxy, alkylether, heteroalkyl, —OP(═R a )(R b )R c , or L′;
R 4 is, at each occurrence, independently OH, O − or OR d ;
R 5 is, at each occurrence oxo;
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 has one of the following structures:
wherein x is halo;
L′ is, at each occurrence, independently an alkylene or heteroalkylene linker comprising a covalent bond to Q, an antibody or a cell surface receptor antagonist an alkylene or heteroalkylene linker comprising a covalent bond to an antibody or a cell surface receptor antagonist, an alkylene or heteroalkylene linker comprising a covalent bond to a solid support, or an alkylene or heteroalkylene linker comprising a covalent bond to a solid support residue;
z is, at each occurrence, independently an integer from 3 to 26;
m is, at each occurrence, independently an integer from 1 to 10; and
n is an integer from 1 to 10.
2. The compound of claim 1 , wherein each occurrence of z is an integer from 3 to 6.
3. The compound of claim 1 , wherein L 2 and L 3 are, at each occurrence, independently C 1 -C 6 alkylene.
4. The compound of claim 1 , wherein the compound has the following structure (IC):
wherein:
x 1 , x 2 , x 3 and x 4 are, at each occurrence, independently an integer from 0 to 6.
5. The compound of claim 4 , wherein at least one occurrence of x 1 , x 2 , x 3 or x 4 is 1.
6. The compound of claim 4 , wherein x 1 , x 2 , x 3 and x 4 are each 1 at each occurrence.
7. The compound of claim 1 , wherein R 2 and R 3 are each independently OH or —OP(═R a )(R b )R c .
8. The compound of claim 1 , wherein one of R 2 and R 3 is OH or —OP(═R a )(R b )R c , and the other of R 2 and R 3 is Q or a linker comprising a covalent bond to Q.
9. The compound of claim 1 , wherein one of R 2 and R 3 is —OP(═R a )(R b )R c or L′.
10. The compound of claim 9 , wherein R c is OL′.
11. The compound of claim 9 , wherein L′ is an antibody or a cell surface receptor antagonist or a linker to an antibody or a cell surface receptor antagonist.
12. The compound of claim 11 , wherein L′ is a linker to an antibody or a cell surface receptor antagonist, the linker comprising an alkylene oxide or phosphodiester moiety, or combinations thereof.
13. The compound of claim 12 , 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 antibody or cell surface receptor antagonist or a linkage to the antibody or cell surface receptor antagonist.
14. The compound of claim 1 , 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.
15. The compound of claim 1 , wherein R 2 or R 3 has one of the following structures:
16. The compound of claim 1 , wherein R 2 or R 3 has the following structure:
17. The compound of claim 1 , wherein m is, at each occurrence, independently an integer from 1 to 5.
18. The compound of claim 1 , wherein M is, at each occurrence, independently an anti-cancer drug, and the antibody or cell surface receptor antagonist is an antibody specific for a tumor cell antigen.
19. The compound of claim 18 , wherein the tumor cell antigen is an EGFR, a HER 2, a folate receptor, CD20, or CD 33.
20. The compound of claim 1 , wherein at least one occurrence of M has one of the following structures:
21. The compound of claim 1 , wherein each occurrence of M has one of the following structures:
22. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
23. 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.
24. The method of claim 23 , wherein the disease is cancer, and each M is an anti-cancer drug.
25. The method of claim 23 , wherein each occurrence of M has the following structure:
26. The method of claim 23 , wherein at least one occurrence of M has one of the following structures:
27. The method of claim 23 , wherein each occurrence of M has one of the following structure:
28. 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 22 , wherein each M is independently a biologically active moiety effective for treating the disease.