IP Library › Granted Patent US 7,342,006

Granted Patent B2

US 7,342,006 · App. 10/923,592 · Granted Mar 11, 2008

Substituted 8-heteroaryl xanthines

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Quick Facts

Patent No.: US 7,342,006
App. No.: 10/923,592
Granted: Mar 11, 2008
Kind: B2

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Abstract

Selective antagonists of A 2B adenosine receptors like those of formula I are provide. The compounds and compositions are useful as pharmaceutical agents.

Claims (282)

1. A compound of formula I:

wherein:

R is hydrogen, (C 1 -C 5 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 5 )alkenyl, or (C 3 -C 5 )alkynyl;

R 1 and R 2 are independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heterocycle, (C 4 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, or (C 5 C 10 )heteroaryl(C 1 -C 8 )alkyl-;

X is

Z is —OR 3 , —SR 3 , —S(O) m —NR 4 R 5 , —NR 4 R 5 , or (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 1 -C 8 )alkyl, (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

provide that X-(Z′) n -Z is other than 6-(pyrid-2-yl)-pyrid-2yl;

each Z 1 is independently (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, —OR 6 , —SR 6 , halo, R 6 O(C 1 -C 8 )alkyl, R 7 R 8 N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR 7 R 8 , R 7 R 8 N(C 1 -C 8 )alkyl, —C(O)R 6 , —COOR 6 , and —C(O)NR 7 R 8 ;

R 3 is (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —C(O)R 6 , or —C(O)NR 7 R 8 ;

R 4 and R 5 are independently hydrogen, (C 1 -C 8 )alkyl, (C 3 -C 8 )alkenyl, (C 3 -C 8 )alkynyl, (C 1 -C 8 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyl(C 1 -C 8 )alkyl-, (C 6 -C 18 )polycycloalkyl, (C 6 -C 18 )polycycloalkyl(C 1 -C 8 )alkyl-, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, —NR 7 R 8 , (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 5 -C 10 )heteroaryl, (C 5 -C 10 )heteroaryl(C 1 -C 8 )alkyl-, —C(O)R 6 , —CO 2 R 6 , —C(O)NR 7 R 8 , or —S(O) 2 —NR 7 R 8 ; or R 4 and R 5 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )— in the ring, and wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 , or —NR 7 R 8 ; and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )—;

wherein the alkyl, alkenyl, cycloalkyl, alkynyl, aryl, heterocycle or heteroaryl groups of R 1 , R 2 , R 3 , R 4 and R 5 groups are optionally substituted with one or more substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

wherein R 6 is hydrogen, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl, (C 4 -C 10 )heteroaryl(C 1 -C 8 )alkyl-; wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and C(O)NR b R c ;

wherein R 7 , R 8 and R 9 are independently hydrogen, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl; —COOR a , —C(O)R a , or —C(O)NR b R c wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ; or R 7 and R 8 together with the atoms to which they are attached form a saturated or partially unsaturated, mono-, bicyclic- or aromatic ring having 3, 4, 5, 6, 7, or 8, ring atoms optionally ring having from 4 to eight ring atoms and optionally comprising 1, 2, 3, or 4 heteroatoms selected from non-peroxide oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) or amine —N(R b )— in the ring;

R a is hydrogen, or (C 1 -C 6 )alkyl; R b and R c are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, (C 3 -C 8 )cycloalkyl, (C 1 -C 6 )alkylthio, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 6 )alkyl-, heteroaryl, or heteroaryl(C 1 -C 6 )alkyl-; or R b and R c together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring; and

where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, or 2; and q is 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl.

3. The compound of claim 1 , wherein R is hydrogen, methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br, or —CH 2 —CH 2 —CH 2 —F.

4. The compound of claim 1 , wherein R is hydrogen.

5. The compound of claim 1 , wherein R 1 is hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, or phenyl(C 1 -C 4 )alkyl.

6. The compound of claim 1 , wherein R 1 is (C 3 -C 6 )cycloalkyl and (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-.

7. The compound of claim 1 , wherein R 1 is cyclopropyl or cyclopropylmethyl.

8. The compound of claim 1 , wherein R 1 is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, benzyl, or (methoxyphenyl)ethyl.

9. The compound of claim 1 , wherein R 1 is ethyl, n-propyl or allyl.

10. The compound of claim 1 , wherein R 2 is hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, phenyl(C 1 -C 4 )alkyl, or (methoxyphenyl)ethyl.

11. The compound of claim 1 , wherein R 2 is (C 3 -C 6 )cycloalkyl or (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-.

12. The compound of claim 1 , wherein R 2 is cyclopropyl or cyclopropylmethyl.

13. The compound of claim 1 , wherein R 2 is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl, phenyl, phenethyl, or benzyl.

14. The compound of claim 1 , wherein R 2 is ethyl, n-propyl or allyl.

15. The compound of claim 1 , wherein Z is —O(C 1 -C 4 )alkyl, —O(C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl(C 1 -C 4 )alkyl, —NR 4 R 5 , F, Cl, Br, or I.

16. The compound of claim 1 , wherein R 4 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl-, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 6 R 7 .

17. The compound of claim 1 , wherein R 4 is hydrogen, (C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 -O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

18. The compound of claim 1 , wherein R 4 is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

19. The compound of claim 1 , wherein R 4 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

20. The compound of claim 1 , wherein R 5 is hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalkyl(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl (C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl-, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 6 R 7 .

21. The compound of claim 1 , wherein R 5 is hydrogen, (C 6 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

22. The compound of claim 1 , wherein R 5 is hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

23. The compound of claim 1 , wherein R 5 is methyl, ethyl, cyclopropyl, cyclopropylmethyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

24. The compound of claim 1 , wherein R 4 and R 5 taken together with the nitrogen to which they are attached, is a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, each optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

25. The compound of claim 1 , wherein R 6 is (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )cycloalky(C 1 -C 4 )alkyl-, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 4 )alkyl-, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )-alkyl-, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, nitro, (C 1 -C 8 )alkyl, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

26. The compound of claim 1 , wherein R 6 is (C 6 -C 10 )aryl, (C 5 -C 6 )heteroaryl, each optionally substituted with 1, 2, or 3 substituents independently selected from halo, cyano, nitro, (C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —COOR a , and —C(O)NR b R c .

27. The compound of claim 1 , wherein R 6 is pyridyl, optionally substituted with F, Cl, Br, I, CF 3 , cyano, nitro, —COOR a , or —CONHR a .

28. The compound of claim 1 , wherein:

R is hydrogen, methyl, or ethyl;

R 1 and R 2 are independently methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, or n-butyl; and

X is 3-pyridyl substituted in the 6 position with Z, wherein Z is (C 4 -C 10 )heterocycle or —NR 4 R 5 , wherein R 4 is methyl, ethyl, cyclopropyl, cyclopropylmethyl and R 5 is —C(O)R 6 , wherein R 6 is heteroaryl optionally substituted with 1, 2 or 3 substituents independently selected from halo, cyano, nitro, halo(C 1 -C 8 )alkyl, —C(O)R a , —COOR a , and —C(O)NR b R c , and wherein R a , R b and R c are independently hydrogen, methyl, ethyl, propyl, isopropyl, or cyclopropyl.

29. The compound of claim 1 , wherein R 1 and R 2 are independently hydrogen, (C 1 -C 4 )alkyl, (C 3 -C 4 )alkenyl, (C 3 -C 4 )alkynyl, phenyl, or phenyl(C 1 -C 4 )alkyl.

30. The compound of claim 1 , wherein R is hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, n-butyl, i-butyl or halo(C 1 -C 4 )alkyl; and R 1 and R 2 are independently hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl, phenyl, phenethyl, or benzyl.

31. The compound of claim 1 , wherein R is hydrogen, methyl, ethyl, —CH 2 —CH 2 —Cl, —CH 2 —CH 2 —Br, or —CH 2 —CH 2 —CH 2 —F; and R 1 and R 2 are independently hydrogen, methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, or (methoxyphenyl)ethyl.

32. The compound of claim 1 , wherein —X(Z 1 ) n -Z has the formula

33. The compound of claim 1 , wherein Z is —O(C 1 -C 4 )alkyl, —OC(O)NR 7 R 8 , (C 1 -C 4 )alkyl, —NR 4 R 5 , F, Cl, Br, or I, wherein R 4 and R 5 are independently hydrogen, (C 1 -C 6 )alkyl, (C 3 -C 6 )cycloalkyl, (C 3 -C 6 )heterocycle, (C 6 -C 10 )aryl, (C 7 -C 12 )aralkyl, (C 5 -C 6 )heteroaryl, or (C 5 -C 6 )heteroaryl(C 1 -C 4 )alkyl, —S(O 2 )NH 2 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 6 R 7 .

34. The compound of claim 1 , wherein Z is —NR 4 R 5 .

35. The compound of claim 1 , wherein R 4 and R 5 together with the nitrogen to which they are attached, form a pyrrolidyl, piperidyl, piperazinyl, azepinyl, diazepinyl, morpholinyl, or thiomorpholinyl ring, wherein the ring is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

36. The compound of claim 1 , wherein R 4 and R 5 are independently hydrogen, (C 1 -C 4 )alkyl, hydroxy(C 2 -C 4 )alkyl, (C 3 -C 6 )cycloalkyl, (C 6 -C 10 )aryl, (C 7 -C 10 )aralkyl, (C 5 -C 6 )heteroaryl, —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—OR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—COOR a , —(CH 2 —CH 2 —O) q —(CH 2 —CH 2 )—NR a R b , —NR 7 R 8 , —C(O)R 6 , —CO 2 R 6 , or —C(O)NR 7 R 8 .

37. The compound of claim 1 , wherein R 4 and R 5 are independently hydrogen, methyl, ethyl, propyl, pentyl, hydroxyethyl, hydroxypropyl, ethoxyethyl, diethoxyethyl, methylbenzyl, aminomethylbenzyl, methoxybenzyl, methoxyphenethyl, furylmethyl, cyclopentyl, cyclohexyl, thiophenyl, —C(O)R 6 , —CO 2 R 6 , or —C(O)NHR 7 .

38. The compound of claim 1 , wherein R 6 is methyl, methoxy, or pyridyl, and R 7 is phenyl, fluorophenyl, or methoxyphenyl.

39. The compound of claim 1 , wherein:

R is hydrogen, methyl, or ethyl;

R 1 and R 2 are independently methyl, ethyl, allyl, propargyl, i-propyl, n-propyl, cyclopropyl, cyclopropylmethyl, n-butyl, i-butyl; and

Z is (C 4 -C 10 )heterocycle wherein the heterocycle is optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c .

40. The compound of claim 1 , wherein Z is selected from the group consisting of:

41. The compound of claim 1 , wherein —X(Z 1 ) n -Z is selected from the group consisting of:

wherein Me is methyl.

42. The compound of claim 1 , wherein R 1 and R 2 are n-propyl; R is hydrogen and n is zero.

43. The compound of claim 1 , wherein —X(Z 1 ) n -Z is selected from the group consisting of:

44. The compound of claim 1 that is:

1,3-Dipropyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-ethylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-(2-hydroxyethyl)amino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(4-acetylpiperazinyl)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-pyrrolidinylpyrid-3-yl)xanthine;

1,3-Dipropyl-8-(6-methylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(2-hydroxypropyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2,2-dimethoxyethyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

or a pharmaceutically acceptable salt thereof.

45. The compound of claim 1 that is:

1,3-Diethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

8-[6-(2,5-diaza-bicyclo[2.2.2]oct-2-yl)-pyridin-3-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;

1,3-Dipropyl-8-(6-(2-acetylaminoethyl)amino-3-pyridyl)xanthine;

1-(5-(1,3-Diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)pyridin-2-yl)-1-(2-methoxyethyl)-3-(pyridine-4-yl)urea;

1,3-Dimethyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Propargyl, 3-methyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-(isoxazole-5-carbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(2-pyrazinecarbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(isoxazole-5-carbonyl)methylamino]-3-pyridyl)xanthine;

1-Cyclopropyl-3-propyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine; and

1,3-Diethyl-8-[6-[N-nicotinoylcyclopropylmethylamino]-3-pyridyl)xanthine;

or a pharmaceutically acceptable salt thereof.

46. A compound of claim 1 selected from the group consisting of:

1,3-Dipropyl-8-{6-[4-methyl(perhydro-1,4-diazaepin-1-yl)]-3 pyridyl}xanthine;

1,3-Dipropyl-8-[6-(1-hydroxy-2-propyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-morpholino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-dimethylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-piperazino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(4-aminomethylbenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-cyclopropylamino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[N-isonicotinoylmethylamino]-3-pyridyl)xanthine; and

1,3-Dipropyl-8-[6-(hexahydro-1,4-diazaepin-1-yl)-3-pyridyl]xanthine;

or a pharmaceutically acceptable salt thereof.

47. A compound of claim 1 selected from the group consisting of:

1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-(2-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(3-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(3-methoxybenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(2-pyridyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-[2-(1-pyrrolidinyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[N-(5-methylisoxazol-3-yl-3-carbonyl)methylamino]-3-pyridyl)xanthine; and

1,3-Diethyl-8-[6 (N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;

or a pharmaceutically acceptable salt thereof.

48. A compound of claim 1 selected from the group consisting of:

1-Propyl-3-propargyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-ethylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-(2-hydroxyethyl)amino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(4-acetylpiperazinyl)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(benzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(1-piperidinyl)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-pyrrolidinylpyrid-3-yl)xanthine;

1,3-Dipropyl-8-{6-[4-methyl(perhydro-1,4-diazaepin-1-yl)]-3 pyridyl}xanthine;

1,3-Dipropyl-8-(6-methylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(4-methoxybenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(3-methylpiperidino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2-hydroxypropyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2,2-dimethoxyethyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(1-hydroxy-2-propyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-morpholino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-dimethylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-piperazino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(2-hydroxy-2-phenylethyl)amino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(4-aminomethylbenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-phenylamino-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-cyclopropylamino-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(6-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-(4-methylpiperazino)-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(3-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2-methylbenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(3,4-dimethoxyphenyl)ethylamino]-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[(N-propylcarbamoyl), methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(3-pentylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2,2-diphenylethylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(1-ethylpyrrolidin-2-yl)methylamino)]-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(3-methoxybenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(furfurylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(4-methoxyphenyl)ethylamino]-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(2-methoxybenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(propylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(cyclopentylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-(cyclohexylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-7-ethyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-7-(3-fluoropropyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-7-methyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-7(2-bromoethyl)-8-(6-chloro-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(2-thiophenemethylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[(N-(4-methoxyphenylcarbamoyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[(N-(4-fluorophenylcarbamoyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-isonicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-methoxycarbonylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-phenylcarbamoyl, N-(2 phenylcarbamoyloxyethyl)amino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-{6-[4-(N-phenylcarbamoyl)]piperazino-3-pyridyl}xanthine;

1,3-Dipropyl-8-{6-[4-(N-isonicotinoyl)]piperazino-3-pyridyl}xanthine;

1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-chloro-3-pyridyl)xanthine;

1-Propyl-3-(methoxyphenylethyl)-8-(6-piperazino-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-(4-pyridylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-{6-[4-(N-nicotinoyl)]piperazino-3-pyridyl}xanthine;

1,3-Dipropyl-8-[6-(hexahydro-1,4-diazaepin-1-yl)-3-pyridyl]xanthine;

1,3-Diethyl-8-(6-chloro-3-pyridyl)xanthine;

1,3-Diethyl-8-(6-piperazino-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[(N-phenylcarbamoyl)methylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-(6-methylamino-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-nicotinoylcyclopropylamino]-3-pyridyl)xanthine;

1,3-Dicyclopropylmethyl-8-(6-methylaminopyridin-3-yl)xanthine;

1-Propargyl-3-methyl-8-(6-methylamino-3-pyridyl)xanthine;

8-[6-(2,5-diaza-bicyclo[2.2.2]oct-2-yl)-pyridin-3-yl}-1,3-dipropyl-3,7-dihydro-purine-2,6-dione;

1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dicylopropylmethyl-8-[6-[N-nicotinoylethylamino]-3-pyridyl)xanthine;

1,3-Diallyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Clopropylmethyl-3-ethyl-8-(6-methylaminopyridin-3-yl)xanthine;

1,3-Diethyl-8-[6-(2-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(3-pyridylmethylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(3-methoxybenzylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(3-pyridyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-[2-(3-pyridyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Dipropyl-8-[6-[2-(2-pyridyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-[2-(2-pyridyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Diethyl-8-(6-pyrrolidinylpyrid-3-yl)xanthine;

1,3-Diethyl-8-[6-[2-(1-pyrrolidinyl)-ethylamino]-3-pyridyl]xanthine;

1,3-Dipropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(6-(2-acetylaminoethyl)amino-3-pyridyl)xanthine;

1,3-Diethyl-8-(6-bromo-3-pyridyl)xanthine;

1,3-Dipropyl-8-{6-[4-(2-pyridyl)-piperazino]-3-pyridyl}xanthine;

1,3-Dithyl-8-{6-[4-(2-pyridyl)-piperazino]-3-pyridyl}xanthine;

1,3-Diethyl-8-[6-(trans-2,5-dimethylpiperazino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-{6-[4-(2-pyrimidinyl)-piperazino]-3-pyridyl}xanthine;

1,3-Diethyl-8-{6-[4-(2-pyrimidinyl)-piperazino]-3-pyridyl}xanthine;

1,3-Diethyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;

1-Propargyl, 3-methyl-8-(6-Bromo-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-nicotinoyl, N-(2-methoxyethyl)amino]-3-pyridyl)xanthine;

1-Propargyl, 3-methyl-8-(6-(2-methoxyethyl)-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-isonicotinoyl, N-(2-methoxyethyl)amino]-3-pyridyl)xanthine;

1-(5-(1,3-Diethyl-2,3,6,7-tetrahydro-2,6-dioxo-1H-purin-8-yl)pyridin-2-yl)-1-(2-methoxyethyl)-3-(pyridine-4-yl)urea;

1,3-Dimethyl-8-(6-bromo-3-pyridyl)xanthine;

1,3-Dimethyl-8-(6-methylamino-3-pyridyl)xanthine;

1,3-Dimethyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-nicotinoyl, N-(2-methoxyethyl)amino]-3-pyridyl)xanthine;

1-Propargyl, 3-methyl-8-[6-[N-nicotinoyl, N-(2-methoxyethyl)amino]-3-pyridyl)xanthine;

1-Propargyl, 3-methyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-(2,6-dichloro-3-pyridyl)xanthine;

1,3-Dipropyl-8-(2,6-dimethylamino-3-pyridyl)xanthine;

1,3-Dipropyl-8-(2,6-di(2-methoxyethyl)-3-pyridyl)xanthine;

1,3-Dipropyl-8-[2,6-di[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[2,6-di[N-nicotinoyl, N-methoxyethyl]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-(2-pyrazinecarbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-(isoxazole-5-carbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(2-pyrazinecarbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(isoxazole-5-carbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(5-methylisoxazol-3-yl-3-carbonyl)methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(2-chloro-6-methoxypyridinyl-4-carbonyl), N-methylamino]-3-pyridyl)xanthine;

1,3-Dipropyl-8-[6-[N-(Isonicotinoyl N-oxide), N-methylamino]-3-pyridyl)xanthine;

1-propyl-3-(4-methoxyphenyl)ethyl-8-(6-methylamino-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-[N-(Isonicotinoyl N-oxide), N-methylamino]-3-pyridyl)xanthine;

1,3-Diallyl-8-(6-chloro-3-pyridyl)xanthine;

1-propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-nicotinoylmethylamino)-3-pyridyl]xanthine;

1-propyl-3-(4-methoxyphenyl)ethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;

1,3-diallyl-8-[6-(N-nicotinoylmethylamino)-3-pyridyl]xanthine;

1,3-diallyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;

1,3-dipropyll-8-[6-(N-[6-(trifluoromethyl)nicotinoyl]methylamino)-3-pyridyl]xanthine;

1,3-diethyl-8-[6-(2-hydroxy-5-methyl)benzaldehydehydrazono]-3-pyridyl]xanthine;

1,3-diethyl-8-[6-(bromopyridine-3-carbaldehydehydrazono]-3-pyridyl]xanthine;

1-Cyclopropyl-3-ethyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Cyclopropyl-3-propyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Propyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Cyclopropyl-3-propyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;

1-Cyclopropyl-3-propyl-8-[6-[N-nicotinoylmethylamino]-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-(N-(6-chloronicotinoyl)methylamino)-3-pyridyl]xanthine;

1,3-Dipropyl-8-(2-chloro-6-methoxyethylamino-4-pyridyl)xanthine;

1,3-Dipropyl-8-(2-chloro-6-methylamino-4-pyridyl)xanthine;

1,3-Dipropyl-8-[2-[N-nicotinoyl, N-(2-methoxyethyl)amino]-6-chloro-4-pyridyl)xanthine;

1,3-Dipropyl-8-[2-[N-nicotinoyl, N-methylamino]-6-chloro-4-pyridyl)xanthine;

1-Cyclopropyl-3-propyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl)xanthine;

1-Ethyl-3-cyclopropyl-8-(6-methylamino-3-pyridyl)xanthine;

1-Ethyl-3-cyclopropyl-8-(6-(2-methoxyethyl)amino-3-pyridyl)xanthine;

1,3-Diethyl-8-[6-hydrazino-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(cyclopropylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(cyclopropylmethyl)amino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-(ethylamino)-3-pyridyl]xanthine;

1,3-Diethyl-8-[6-[N-nicotinoyl-N-(cyclopropylmethyl)amino]-3-pyridyl)xanthine; and

1-Cyclopropylmethyl-3-ethyl-8-[6-[N-(6-chloronicotinoyl)methylamino]-3-pyridyl)xanthine;

or a pharmaceutical acceptable salt thereof, optionally in the form of a single stereoisomer or mixture of stereoisomers thereof.

49. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 1 ; and

(b) a pharmaceutically acceptable excipient.

50. A pharmaceutical composition comprising:

(a) a therapeutically effective amount of a compound of claim 48 ; and

(b) a pharmaceutically acceptable excipient.

51. A method for treating asthma comprising administering an effective amount of a compound of claim 1 to a mammal in need of such treatment.

52. A method for improving insulin sensitivity, comprising administering an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment.

53. A compound of formula I:

wherein:

R is hydrogen, (C 1 -C 5 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 5 )alkenyl, or (C 3 -C 5 )alkynyl;

X is 2-pyridinyl, 3-pyridinyl, or 4-pyridinyl, each optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halo, cyano, nitro, (C 1 -C 8 )alkyl, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and —C(O)NR b R c ;

provide that X-(Z′) n -Z is other than 6-(pyrid-2-yl)-pyrid-2yl;

X 1 is —OR 6 , —C(O)R 6 , —CO 2 R 6 , or —NR 7 R 8 ; and Y is oxy (—O—), thio (—S—), sulfinyl (—SO—), sulfonyl (—S(O) 2 —) and amine —N(R 9 )—;

wherein R 6 is hydrogen, (C 1 -C 8 )alkyl, R a O(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, (C 3 -C 10 )heterocycle, (C 3 -C 10 )heterocycle(C 1 -C 8 )alkyl-, (C 6 -C 10 )aryl, (C 6 -C 10 )aryl(C 1 -C 8 )alkyl-, (C 4 -C 10 )heteroaryl, (C 4 -C 10 )heteroaryl(C 1 -C 9 )alkyl-; wherein the heterocycle, heteroaryl or aryl are optionally substituted with 1, 2, 3, or 4 substituents independently selected from halo, cyano, nitro, —OR a , —SR a , (C 6 -C 10 )aryl, —O(C 6 -C 10 )aryl, hydroxy(C 1 -C 8 )alkyl, R b R c N(C 1 -C 8 )alkyl, halo(C 1 -C 8 )alkyl, —NR b R c , —C(O)R a , —COOR a , and C(O)NR b R c ;

where n is 0, 1, 2, 3, 4, 5, 6, 7, or 8; m is 1, or 2; and q is 1, 2, 3, or 4; or

a pharmaceutically acceptable salt thereof.

54. The compound of claim 53 , wherein wherein —X(Z 1 ) n -Z is:

55. The compound of claim 54 , wherein X wherein —X(Z 1 ) n -Z has the formula

Assignments (10)

MERGER Recorded Jun 26, 2018

From: DOGWOOD PHARMACEUTICALS, INC.

To: ALLERGAN SALES, LLC

Reel/Frame 046208/0691 →

CORRECTIVE ASSIGNMENT TO CORRECT THE EXECUTION DATE OF THE PREVIOUSLY RECORDED ASSIGNMENT FROM DECEMBER 31, 2011 TO MARCH 15, 2013 PREVIOUSLY RECORDED ON REEL 029737 FRAME 0130. ASSIGNOR(S) HEREBY CONFIRMS THE THE EXECUTION DATE OF THE ORIGINAL ASSIGNMENT WAS INCORRECTLY DATED DECEMBER 31, 2011. Recorded Mar 19, 2013

From: FOREST LABORATORIES HOLDINGS LIMITED

To: DOGWOOD PHARMACEUTICALS, INC.

Reel/Frame 030045/0915 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2013

From: DOGWOOD PHARMACEUTICALS, INC.

To: FOREST LABORATORIES HOLDINGS LIMITED

Reel/Frame 029737/0043 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2013

From: FOREST LABORATORIES HOLDINGS LIMITED

To: DOGWOOD PHARMACEUTICALS, INC.

Reel/Frame 029737/0130 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Feb 1, 2013