Oligomer-opioid agonist conjugates
The invention provides compounds that are chemically modified by covalent attachment of a water—soluble oligomer. A compound of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from those of the compound not attached to the water—soluble oligomer.
1. An opioid agonist compound according to Formula I-Ca:
wherein:
R 2 is OH;
R 3 is methyl;
R 4 is H;
R 5 is —C(O)—;
Y 1 is —O—;
the dotted line (“- - -”) is absent;
X is a single bond, —C(O)O—, —OC(O)—, —CH 2 C(O)O—, —CH 2 OC(O)—, —C(O)OCH 2 —, —OC(O)CH 2 —, —O—, —NH—, —S—, —C(O)—, —C(O)NH—, —NHC(O)NH—, —OC(O)NH—, —C(S)—, —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 —, —OCH 2 —, —CH 2 O—, —OCH 2 CH 2 —, —CH 2 OCH 2 —, —CH 2 CH 2 O—, —OCH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 —, —CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 O—, —OCH 2 CH 2 CH 2 CH 2 —, —CH 2 OCH 2 CH 2 CH 2 —, —CH 2 CH 2 OCH 2 CH 2 —, —CH 2 CH 2 CH 2 OCH 2 —, —CH 2 CH 2 CH 2 CH 2 O—, —C(O)NHCH 2 —, —C(O)NHCH 2 CH 2 —, —CH 2 C(O)NHCH 2 —, —CH 2 CH 2 C(O)NH—, —C(O)NHCH 2 CH 2 CH 2 —, —CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 —, —CH 2 CH 2 CH 2 C(O)NH—, —C(O)NHCH 2 CH 2 CH 2 CH 2 —, —CH 2 C(O)NHCH 2 CH 2 CH 2 —, —CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 CH 2 C(O)NHCH 2 —, —CH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 —, —CH 2 CH 2 CH 2 CH 2 C(O)NH—, —NHC(O)CH 2 —, —CH 2 NHC(O)CH 2 —, —CH 2 CH 2 NHC(O)CH 2 —, —NHC(O)CH 2 CH 2 —, —CH 2 NHC(O)CH 2 CH 2 —, —CH 2 CH 2 NHC(O)CH 2 CH 2 —, —C(O)NHCH 2 —, —C(O)NHCH 2 CH 2 —, —OC(O)NHCH 2 —, —OC(O)NHCH 2 CH 2 —, —NHCH 2 —, —NHCH 2 CH 2 —, —CH 2 NHCH 2 —, —CH 2 CH 2 NHCH 2 —, —C(O)CH 2 —, —C(O)CH 2 CH 2 —, —CH 2 C(O)CH 2 —, —CH 2 CH 2 C(O)CH 2 —, —CH 2 CH 2 C(O)CH 2 CH 2 —, —CH 2 CH 2 C(O)—, —CH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 NH—, —CH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)—, —CH 2 CH 2 CH 2 C(O)NHCH 2 CH 2 NHC(O)CH 2 —, a bivalent cycloalkyl group, or —N(R 6 )—;
R 6 is H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, or substituted aryl; and
POLY is a poly(ethylene oxide) having from about 1 to about 30 monomers.
2. The compound of claim 1 , wherein POLY possess from about 1 to about 10 monomers.
3. The compound of claim 1 , wherein POLY possess 1 monomer.
4. The compound of claim 1 , wherein POLY possess 2 monomers.
5. The compound of claim 1 , wherein POLY possess 3 monomers.
6. The compound of claim 1 , wherein POLY possess 4 monomers.
7. The compound of claim 1 , wherein POLY possess 5 monomers.
8. The compound of claim 1 , wherein POLY possess 6 monomers.
9. The compound of claim 1 , wherein POLY possess 7 monomers.
10. The compound of claim 1 , wherein POLY possess 8 monomers.
11. The compound of claim 1 , wherein POLY possess 9 monomers.
12. The compound of claim 1 , wherein POLY possess 10 monomers.
13. The compound of claim 1 , wherein POLY is a methoxy end-capped poly(ethylene oxide).
14. A composition comprising:
(i) a compound of claim 1 ; and
(ii) optionally, a pharmaceutically acceptable excipient.
15. A dosage form comprising a compound of claim 1 .
16. A method of treating pain comprising administering a compound of claim 1 to a patient in need thereof.
17. The compound of claim 1 , wherein X is a single bond, —O—, or —OC(O)CH 2 O—.
18. The compound of claim 1 according to either of the following formulas:
wherein n is an integer from 1-30.