IP Library › Granted Patent US 8,263,762

Granted Patent B2

US 8,263,762 · App. 12/827,932 · Granted Sep 11, 2012

Alkoxy-carbonyl-amino-alkynyl-adenosine compounds and derivatives thereof as A

View Patent ↗

Loading inventors, assignments & file history…

Monitor This Case

Get email alerts when status or documents change.

Order Certified Copies

Most orders are placed with the USPTO same day — all within 24 business hours.

Order via The Patent Place →

Pre-filled with this patent's details

Quick Facts

Patent No.: US 8,263,762
App. No.: 12/827,932
Granted: Sep 11, 2012
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

Provided herein are alkoxy-carbonyl-amino-alkynyl-adenosine compounds and derivatives thereof and pharmaceutical compositions containing the same that are selective agonists of A 2A adenosine receptors (ARs). These compounds and compositions are useful as pharmaceutical agents.

Claims (104)

1. A compound of formula Ia:

wherein:

R 1 and R 2 independently are selected from: H, C 1-8 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R 3 is —C 1-8 alkyl-;

R 4 is independently selected from: H, —C 2-6 alkyl-OR a , —C 2-6 alkyl-NR a R b , C 1-10 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R 5 is selected from: C 1-8 alkyl, —C 2-6 alkyl-NR a R b , C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, —C 2-6 alkyl-OR a and (C 5-10 heteroaryl)C 1-8 alkyl-;

X is selected from: —CH 2 OR c , —OCO 2 R c , —OCH 2 OC(O)R c , —C(O)NR c R d , —CH 2 SR c , —C(S)OR c , —CH 2 OC(S)R c , C(S)NR c R d and —CH 2 NR c R d ; or X is a C 5-6 heteroaryl;

R a and R b are each independently selected from H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; or R a and R b , together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;

R c is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and

R d is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; and stereoisomers or pharmaceutically acceptable salts thereof.

2. The compound of claim 1 , wherein R 1 and R 2 are each hydrogen.

3. The compound of claim 2 , wherein R 3 is C 1 alkyl.

4. The compound of claim 3 , wherein X is —C(O)NR c R d .

5. The compound of claim 4 , wherein R c is hydrogen.

6. The compound of claim 4 , wherein R d is C 1-8 alkyl, R 4 is C 1-10 alkyl and R 5 is C 1-8 alkyl.

7. The compound of claim 5 , wherein R d is C 3-8 cycloalkyl.

8. The compound of claim 7 , wherein said cycloalkyl is C 3 cycloalkyl.

9. The compound of claim 7 , wherein R 5 is C 1-8 alkyl.

10. The compound of claim 9 , wherein said alkyl is C 1 alkyl.

11. The compound of claim 9 , wherein R 4 is selected from C 3-8 cycloalkyl, C 1-10 alkyl and (C 6-10 aryl)C 1-8 alkyl-.

12. The compound of claim 11 , wherein said C 1-10 alkyl is a C 1 , C 2 , C 3 or C 4 alkyl.

13. The compound of claim 12 , wherein said C 1-10 alkyl is methyl.

14. The compound of claim 13 , wherein said methyl is unsubstituted or substituted with aryl or cycloalkyl.

15. The compound of claim 7 , wherein R 4 is C 1-10 alkyl.

16. The compound of claim 15 , wherein said alkyl is C 1 alkyl.

17. The compound of claim 15 , wherein R 5 is selected from C 6-10 aryl and —C 2-6 alkyl-OR a .

18. The compound of claim 1 , wherein said compound is selected from:

and pharmaceutically acceptable salts thereof.

19. The compound of claim 1 , wherein said compound of formula Ia is a compound of formula I:

wherein

R 6 is hydrogen, C 1-8 alkyl, or C 3-6 cycloalkyl;

R 7 is hydrogen atom or C 1-10 alkyl;

R 8 is C 1-8 alkyl, C 3-8 cycloalkyl, unsubstituted phenyl, or a phenyl substituted with at least a halogen atom or -G-O—R 9 ;

R 9 is alkyl, cycloalkyl, phenyl, (cycloalkyl)alkyl, or (phenyl)alkyl; and G is alkylene;

or a pharmaceutically acceptable salt thereof.

20. The compound of claim 19 , wherein R 6 is a cycloalkyl.

21. The compound of claim 20 , wherein R 7 is alkyl.

22. The compound of claim 21 , wherein R 8 is alkyl.

23. A compound of formula Ib:

wherein:

R 1′ and R 2′ independently are selected from: H, C 1-8 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R 3′ is —C 1-8 alkyl-;

R 4′ and R 4″ are independently selected from: H, —C 2-6 alkyl-OR a′ , —C 2-6 alkyl-NR a′ R b′ , C 1-10 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R 5′ is selected from: C 1-8 alkyl, —C 2-6 alkyl-NR a′ R b′ , C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 4-10 heterocycle, (C 4-10 heterocycle)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, —C 2-6 alkyl-OR a′ and (C 5-10 heteroaryl)C 1-8 alkyl-;

X′ is selected from: —CH 2 OR c′ , —OCO 2 R c′ , —OCH 2 OC(O)R c′ , —C(O)NR c′ R d′ , —CH 2 SR c′ , —C(S)OR c′ , —CH 2 OC(S)R c′ , C(S)NR c′ R d′ and —CH 2 NR c′ R d′ ; or X′ is a C 5-6 heteroaryl;

R a′ and R b′ are each independently selected from H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; or R a′ and R b′ , together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;

R c′ is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and

R d′ is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; and stereoisomers or pharmaceutically acceptable salts thereof.

24. A pharmaceutical composition comprising an effective amount of a compound of claim 1 or claim 23 and a pharmaceutically acceptable excipient.

25. The pharmaceutical composition of claim 24 , wherein said effective amount is effective to treat an adenosine A 2A receptor associated state in a subject.

26. The composition of claim 24 , wherein said pharmaceutically composition is formulated for delivery to the eyes.

27. A method for achieving an effect in a subject comprising administering to the subject an effective amount of a compound of formula Ia:

wherein:

R 3 is —C 1-8 alkyl-;

X is selected from: —CH 2 OR c , —OCO 2 R c , —OCH 2 OC(O)R c , —C(O)NR c R d , —CH 2 SR c , —C(S)OR c , —CH 2 OC(S)R c , C(S)NR c R d and —CH 2 NR c R d ; or X is a C 5-6 heteroaryl;

R c is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and

R d is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; and

stereoisomers or pharmaceutically acceptable salts thereof, wherein the effect is A 2A receptor agonism.

28. A method for achieving an effect in a subject comprising administering to the subject an effective amount of a compound of formula Ib

wherein:

R 3′ is —C 1-8 alkyl-;

R 4′ and R 4″ are independently selected from: H, —C 2-6 -alkyl-OR a″ , C 2-6 alkyl-NR a′ R b′ , C 1-10 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R a′ and R b′ are each independently selected from H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; or R a′ and R″, together with the nitrogen to which they are attached, form a ring selected from pyrrolidino, piperidino, morpholino, and thiomorpholino ring;

R c′ is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and R d′ is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; and stereoisomers or pharmaceutically acceptable salts thereof, wherein the effect is A 2A receptor agonism.

29. The method of claim 27 or 28 , wherein said subject has a condition selected from an autoimmune stimulation, inflammation, allergic diseases, skin diseases, infectious diseases, wasting diseases, organ transplantation, tissue or cell transplantation, open wounds, adverse effects from drug therapy, a cardiovascular condition, ischemia-reperfusion injury, gout, chemical trauma, thermal trauma, diabetic nephropathy, sickle cell disease, laminitis, founder's disease, glaucoma, and ocular hypertension.

30. The method of claim 29 , wherein said condition is glaucoma or ocular hypertension.

31. A method of reducing intraocular pressure in a subject comprising administering to the subject an effective amount of a compound of formula Ia

wherein:

R 3 is —C 1-8 alkyl-;

X is selected from: —CH 2 OR c , —OCO 2 R c , —OCH 2 OC(O)R c , —C(O)NR c R d , —CH 2 SR c , —C(S)OR c , —CH 2 OC(S)R c , C(S)NR c R d and —CH 2 NR c R d ; or X is a C 5-6 heteroaryl;

R c is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and

R d is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; or stereoisomers or pharmaceutically acceptable salts thereof,

formula Ib

wherein:

R 3′ is —C 1-8 alkyl-;

R 4′ and R 4″ are independently selected from: H, —C 2-6 -alkyl-OR a′ , —C 2-6 alkyl-NR a′ R b′ , C 1-10 alkyl, C 3-8 cycloalkyl, (C 3-8 cycloalkyl)C 1-8 alkyl-, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-;

R c′ is selected from: H, C 1-8 alkyl, C 3-6 cycloalkyl, and (C 3-6 cycloalkyl)C 1-8 alkyl-; and R d′ is selected from: H, C 1-8 alkyl, (C 1-8 alkoxy) 1-3 C 1-8 alkyl-, C 3-8 cycloalkyl, C 6-10 aryl, (C 6-10 aryl)C 1-8 alkyl-, C 5-10 heteroaryl, and (C 5-10 heteroaryl)C 1-8 alkyl-; or stereoisomers or pharmaceutically acceptable salts thereof,

or formula I

wherein

R 6 is hydrogen, C 1-8 alkyl, or C 3-6 cycloalkyl,

R 7 is hydrogen atom or C 1-10 alkyl;

R 8 is C 1-8 alkyl, C 3-8 cycloalkyl, unsubstituted phenyl, or a phenyl substituted with at least a halogen atom or -G-O—R 9 ;

R 9 is alkyl, cycloalkyl, phenyl, (cycloalkyl)alkyl, or (phenyl)alkyl; and G is alkylene;

or stereoisomers or pharmaceutically acceptable salts thereof,

such that the intraocular pressure is reduced.

32. A method of reducing intraocular pressure in a subject according to claim 31 wherein the compound is selected from one or more of the following:

and pharmaceutically acceptable salts thereof.

33. A compound according to claim 23 wherein said compound is selected from:

and a pharmaceutically acceptable salt thereof.

Assignments (3)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 9, 2013

From: DOGWOOD PHARMACEUTICALS, INC.

To: ADENOSINE THERAPEUTICS, LLC

Reel/Frame 029785/0460 →

CHANGE OF NAME Recorded Jan 28, 2011

From: PGXHEALTH, LLC

To: TROVIS PHARMACEUTICALS, LLC

Reel/Frame 025709/0994 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Sep 20, 2010

From: BEAUGLEHOLE, ANTHONY R.; SCHMIDTMANN, FRANK W.; RIEGER, JAYSON M.; THOMPSON, ROBERT

To: PGXHEALTH, LLC

Reel/Frame 025011/0350 →