Controlled release from solid supports
The invention relates to solid supports useful in medical applications that provide controlled release of drugs, such as peptides, nucleic acids and small molecules. The drugs are covalently coupled to the solid support through a linkage that releases the drug or a prodrug through controlled beta elimination.
1. A composition of the formula
wherein m=0 or 1;
at least one or both R 1 and R 2 is independently CN; NO 2 ; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; COR 3 or SOR 3 or SO 2 R 3 wherein R 3 is H or optionally substituted alkyl; aryl or arylalkyl, each optionally substituted; heteroaryl or heteroarylalkyl, each optionally substituted; or OR 9 or N(R 9 ) 2 wherein each R 9 is independently H or optionally substituted alkyl, or both R 9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring; or SR 4 wherein R 4 is optionally substituted alkyl; aryl or arylalkyl, each optionally substituted; or heteroaryl or heteroarylalkyl, each optionally substituted; wherein R 1 and R 2 are joined to form a 3-8 membered ring; and wherein one and only one of R 1 and R 2 is H or is alkyl, arylalkyl or heteroarylalkyl, each optionally substituted; each R 5 is independently H or is alkyl, alkenylalkyl, alkynylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted; D is a residue of a drug or prodrug coupled through O, S, or N; Y is absent and X is O or S; or Y is NBCH 2 and X is O; wherein B is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted; and wherein one of R 1 , R 2 , R 5 or B is coupled to a solid support.
2. The composition of claim 1 wherein the solid support is a stent, a hydrogel, a catheter, a wound dressing, an implant, a plaster, an orthopedic device, or a dental prosthesis.
3. The composition of claim 1 wherein said solid support is further coupled to a protective inert polymer.
4. A composition of the formula
wherein m=0 or 1;
at least one or both R 1 and R 2 is independently CN; NO 2 ; optionally substituted aryl; optionally substituted heteroaryl; optionally substituted alkenyl; optionally substituted alkynyl; COR 3 or SOR 3 or SO 2 R 3 wherein R 3 is H or optionally substituted alkyl; aryl or arylalkyl, each optionally substituted; heteroaryl or heteroarylalkyl, each optionally substituted; or OR 9 or N(R 9 ) 2 wherein each R 9 is independently H or optionally substituted alkyl, or both R 9 groups taken together with the nitrogen to which they are attached form a heterocyclic ring; or SR 4 wherein R 4 is optionally substituted alkyl; aryl or arylalkyl, each optionally substituted; or heteroaryl or heteroarylalkyl, each optionally substituted; wherein R 1 and R 2 are joined to form a 3-8 membered ring; and wherein one and only one of R 1 and R 2 is H or is alkyl, arylalkyl or heteroarylalkyl, each optionally substituted; each R 5 is independently H or is alkyl, alkenylalkyl, alkynylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted; D is a residue of a drug or prodrug coupled through O, S, or N; Y is absent and X is O or S; or Y is NBCH 2 and X is O; wherein B is alkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl, each optionally substituted; and wherein said coupling is through any of R 1 , R 2 , R 5 or B.
5. The solid support of claim 4 which is a stent, a hydrogel, a catheter, a wound dressing, an implant, a plaster, an orthopedic device, or a dental prosthesis.
6. The solid support of claim 4 which further comprises a multiplicity of coupled inert protective polymers.
7. The solid support of claim 6 wherein the protective polymer is polyethylene glycol (PEG).
8. The solid support of claim 4 wherein the drug is a peptide, a nucleic acid or a small molecule.
9. The solid support of claim 4 wherein one of R 1 and R 2 is CN.
10. The solid support of claim 4 wherein at least of one R 1 and R 2 comprises phenyl or phenylene.
11. The solid support of claim 4 wherein one of R 1 and R 2 is SO 2 R 3 and the other is H, alkyl or phenyl.
12. The solid support of claim 4 wherein m is 0.
13. A method to prepare a solid support of claim 4 which method comprises providing a compound of formula (3)
wherein m, R 1 , R 2 , R 5 , X, Y, m and D are as defined in formula (1) or (2); and wherein one of R 1 , R 2 , R 5 and B comprises a functional group that couples formula (3) to a solid support, to react with the solid support under conditions whereby said solid support is coupled to said compound.
14. The solid support of claim 4 wherein R 1 is phenylsulfonyl, substituted phenylsulfonyl, methanesulfonyl, (R 9 ) 2 N—SO 2 , or CN; and R 2 is H; or R 1 and R 2 taken together with the CH to which they are attached form 9-fluorenyl.
15. The solid support of claim 4 wherein m is 0; R 1 is phenylsulfonyl, substituted phenylsulfonyl, methanesulfonyl, (R 9 ) 2 N—SO 2 , or CN; R 2 is H; one R 5 is optionally substituted alkyl and the other R 5 is H; and B is phenyl or substituted phenyl; and wherein one of R 1 , R 5 , and B further comprises a connection to the solid support.
16. A drug-solid support conjugate, wherein the drug is connected to the solid support via a linker; the drug molecule is attached to the linker through O, S, or N of formula (1), (2), or (3); and the drug is released from the conjugate under physiological conditions through a beta-elimination reaction.