Oligomer-calcium channel blocker conjugates
View Patent ↗The invention provides small molecule drugs that are chemically modified by covalent attachment of a water soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the characteristics of the small molecule drug not attached to the water soluble oligomer.
1. A compound comprising a calcium channel blocker residue covalently attached via a stable linkage to a water-soluble, non-peptidic oligomer, wherein the calcium channel blocker residue is a residue of a calcium channel blocker having the formula:
wherein:
R 1 is a member selected from the group consisting of lower alkyl, cyclohexyl, and phenyl;
each R is independently selected from the group consisting of hydrogen, chlorine, lower alkoxy and lower alkyl, wherein at least one R is selected from chlorine, lower alkoxy and lower alkyl; and
(n) is an integer from 2 to 3, inclusive; and
wherein the water soluble, non-peptidic oligomer is made of 2 to 30 monomers.
2. The compound of claim 1 , wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide).
3. The compound of claim 2 , wherein the poly(alkylene oxide) is a poly(ethylene oxide).
4. The compound of claim 3 , wherein the water-soluble, non-peptidic oligomer is made of between 2 and 10 monomers.
5. The compound of claim 2 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
6. The compound of claim 1 , wherein a single water-soluble, non-peptidic oligomer is attached to the calcium channel blocker residue.
7. The compound of claim 1 , wherein more than one water-soluble, non-peptidic oligomer is attached to the calcium channel blocker residue.
8. The compound of claim 1 , wherein the linkage is an ether linkage.
9. A composition comprising a compound of claim 1 , and optionally, a pharmaceutically acceptable excipient.
10. A composition of matter comprising a compound of claim 1 , wherein the compound is present in a dosage form.
11. A compound, having a structure selected from
wherein X is a stable linker and POLY is a poly(alkylene oxide) oligomer made of 2 to 30 monomers.
12. The compound of claim 11 , wherein X is O and the poly(alkylene oxide) oligomer is a poly(ethylene oxide) oligomer.
13. The compound of claim 11 , wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.
14. The compound of claim 11 , having the structure
wherein n is 2 to 30.
15. The compound of claim 14 , wherein n is 2 to 10.
16. The compound of claim 11 , having the structure:
wherein n is 2 to 30.
17. The compound of claim 16 , wherein n is 2 to 11.
18. A compound of claim 11 , having the structure:
wherein each n is independently an integer from 2 to 30.
19. A compound of claim 18 , wherein each n is independently an integer from 2 to 10.