Oligomer-Opioid Agonist Conjugates

• US 20100048602A1
• Filed: 09/11/2009
• Published: 02/25/2010
• Est. Priority Date: 03/12/2007
• Status: Active Grant

• Current Assignee: Nektar Therapeutics Incorporated
• Original Assignee: Nektar Therapeutics Incorporated
• Inventors: Riggs-Sauthier, Jennifer, Riley, Timothy A., Deng, Bo-Liang
• Granted Patent: US 8,173,666 B2
• Time in Patent Office: Days
• US Class Current: 514/282
• CPC Class Codes: A61K 31/402 1-aryl substituted, e.g. piretanide
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/4468 having a nitrogen directly attached in position 4, e.g. clebopride, fentanyl
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 47/10 Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: C07D 489/02 with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone

Abstract

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.

Claims

1. A compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer.

2. The compound of claim 1, wherein the opioid agonist is a kappa opioid agonist.

3. The compound of claim 1, wherein the opioid agonist is a mu opioid agonist.

4. The compound of claim 1, having the following structure:

wherein;

R² is H or OH;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

the dotted line (“

---”

) represents an optional double bond;

Y¹ is O or S;

R⁵ is selected from the group consisting of

wherein R⁶ is an organic radical;

X is a spacer moiety;

POLY is a water-soluble non-peptidic oligomer.

5. The compound of claim 1, having the following structure:

wherein;

R¹ is H or an organic radical;

R² is H or OH;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

the dotted line (“

---”

) represents an optional double bond;

Y¹ is O or S;

X is a spacer moiety; and

POLY is a water-soluble, non-peptidic oligomer.

6. The compound of claim 1, having the following structure:

wherein;

R¹ is H or an organic radical;

R² is H or OH;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

Y¹ is O or S; and

R⁵ is selected from the group consisting of

wherein R⁶ is an organic radical;

X is a spacer moiety; and

POLY is a water-soluble, non-peptidic oligomer.

7. The compound of claim 1, having the following structure:

wherein;

R¹ is H or an organic radical;

R² is H or OH;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

the dotted line (“

---”

) represents an optional double bond;

Y¹ is O or S;

R⁵ is selected from the group consisting of

wherein R⁶ is an organic radical;

X is a spacer moiety; and

POLY is a water-soluble, non-peptidic oligomer.

8. The compound of claim 1, having the following structure:

wherein;

R¹ is H or an organic radical;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

the dotted line (“

---”

) represents an optional double bond;

Y¹ is O or S; and

R⁵ is selected from the group consisting of

wherein R⁶ is an organic radical;

X is a spacer moiety; and

POLY is a water-soluble, non-peptidic oligomer.

9. The compound of claim 1, wherein the opioid agonist is selected from the group consisting of asimadoline, bremazocine, enadoline, ethylketocyclazocine, GR89,696, ICI204448, ICI197067, PD117,302, nalbuphine, pentazocine, quadazocine (WIN 44, 441-3), salvinorin A, spiradoline, TRK-820, U50488, and U69593.

19. The compound of claim 1, wherein the water-soluble, non-peptidic oligomer is a poly(alkylene oxide).

20. The compound of claim 19, wherein the poly(alkylene oxide) is a poly(ethylene oxide).

21. The compound of claim 1, wherein the water-soluble, non-peptidic oligomer is made of between 1 and 30 monomers.

22. The compound of claim 21, wherein the water-soluble, non-peptidic oligomer is made of between 1 and 10 monomers.

23. The compound of claim 19, wherein the poly(alkylene oxide) includes an alkoxy or hydroxy end-capping moiety.

24. The compound of claim 1, wherein a single water-soluble, non-peptidic oligomer is attached to the residue of the opioid agonist.

25. The compound of claim 1, wherein the residue of the opioid agonist is covalently attached via a stable linkage.

26. The compound of claim 1, wherein the residue of the opioid agonist is covalently attached via a degradable linkage.

27. The compound of claim 1, wherein the linkage is an ether linkage.

10. A compound corresponding to a structure selected from the group consisting of Formula I-Cb, Formula I-Cc, Formula I-Cd, and Formula I-Ce, wherein

R¹ is H

R² is H or OH;

R³ is H or an organic radical;

R⁴ is H or an organic radical;

R⁵ is selected from the group consisting of

wherein R⁶ is an organic radical;

the dotted line (“

---”

) represents an optional double bond;

Y¹ is O or S;

X is a spacer moiety; and

POLY is a water-soluble, non-peptidic oligomer.

11. A compound of claim 10, wherein Y is O.

12. A compound of claim 10, wherein R² is OH.

13. A compound of claim 10, wherein R² is OH.

14. A compound of claim 10, wherein R³ is selected from the group consisting of H, unsubstituted alkyl, cycloalkyl-substituted alkyl, and allyl.

15. A compound of claim 10, wherein R⁴ is H.

16. A compound of claim 10, wherein R⁵ is selected from the group consisting of

17. A compound of claim 10, wherein the optional double bond is present.

18. A compound of claim 10, wherein the optional double bond is not present.

28. A composition comprising a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, and optionally, a pharmaceutically acceptable excipient.

29. A composition of matter comprising a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer, wherein the compound is present in a dosage form.

30. A method comprising covalently attaching a water-soluble, non-peptidic oligomer to an opioid agonist.

31. A method comprising administering a compound comprising a residue of an opioid agonist covalently attached via a stable or degradable linkage to a water-soluble, non-peptidic oligomer.

32. A method comprising binding mu opioid receptors, wherein said binding is achieved by administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer.

33. A method comprising binding kappa opioid receptors, wherein said binding is achieved by administering a compound comprising a residue of an opioid agonist covalently attached to a water-soluble, non-peptidic oligomer.