IP Library › Granted Patent US 7,576,207

Granted Patent B2

US 7,576,207 · App. 11/696,585 · Granted Aug 18, 2009

Spirocyclic heterocyclic derivatives and methods of their use

Assignee: Adolor Corporation

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Quick Facts

Patent No.: US 7,576,207
App. No.: 11/696,585
Granted: Aug 18, 2009
Kind: B2

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Abstract

Spirocyclic heterocyclic derivatives, pharmaceutical compositions containing these compounds, and methods for their pharmaceutical use are disclosed. In certain embodiments, the spirocyclic heterocyclic derivatives are ligands of the δ-opioid receptor and may be useful, inter alia, for treating and/or preventing pain, anxiety, gastrointestinal disorders, and other δ-opioid receptor-mediated diseases, disorders, and/or conditions.

Claims (153)

1. A compound of formula I:

wherein:

W is alkylene;

Z is alkoxy, —C(═O)—R 2 , —NR 3 —C(═O)—R 4 , or —NR 3 S(═O) m alkyl;

each R 1 is independently carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialkylaminocarbonyl;

R 2 is —NR 5 R 6 or alkoxy;

R 3 and R a are each independently H or alkyl;

R 4 is alkyl or —NR 5 R 6 ;

R 5 and R 6 are each independently H or alkyl, or R 5 and R 6 taken together with the nitrogen atom to which they are connected form a 3- to 8-membered heterocycloalkyl ring in which 1 or 2 of the heterocycloalkyl ring carbon atoms independently may each be optionally replaced by —O—, —S—, —N(R 7 )—, —N(R 8 )—C(═O)—, or —C(═O)—N(R 9 )—;

R 7 , R 8 , and R 9 are each independently H or alkyl;

X is —CH 2 — or —O—;

A and B are each H, or taken together with the carbon atoms through which they are connected form a double bond; and

t is 0, 1 or 2;

or a pharmaceutically acceptable salt thereof.

2. A compound according to claim 1 , wherein A and B are each H.

3. A compound according to claim 1 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.

4. A compound according to claim 1 , wherein X is —O—.

5. A compound according to claim 1 , wherein X is —CH 2 —.

6. A compound according to claim 1 , wherein R a is H.

7. A compound according to claim 1 , wherein Z is —C(═O)—R 2 .

8. A compound according to claim 7 , wherein R 2 is —NR 5 R 6 .

9. A compound according to claim 8 , wherein R 5 and R 6 are each independently H or alkyl.

10. A compound according to claim 9 , wherein R 5 and R 6 are each independently H or C 1-4 alkyl.

11. A compound according to claim 10 , wherein R 5 and R 6 are each independently C 1-4 alkyl.

12. A compound according to claim 11 , wherein R 5 and R 6 are each independently C 2-3 alkyl.

13. A compound according to claim 6 , having the formula II:

14. A compound according to claim 13 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.

15. A compound according to claim 14 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 , or —NR 3 S(═O) 2 alkyl.

16. A compound according to claim 15 , wherein Z is —C(═O)—R 2 .

17. A compound according to claim 16 , wherein R 2 is —NR 5 R 6 .

18. A compound according to claim 17 , wherein R 5 and R 6 are each independently C 2-3 alkyl.

19. A compound according to claim 18 , wherein t is 0.

20. A compound according to claim 13 , wherein A and B are each H.

21. A compound according to claim 20 , having the formula III:

wherein:

Q 1 and Q 2 are each independently H, carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialkylaminocarbonyl.

22. A compound according to claim 21 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 , or —NR 3 S(═O) 2 alkyl.

23. A compound according to claim 22 , wherein Z is —C(═O)—R 2 .

24. A compound according to claim 23 , wherein R 2 is —NR 5 R 6 .

25. A compound according to claim 24 , wherein R 5 and R 6 are each independently C 2-3 alkyl.

26. A compound according to claim 25 , wherein at least one of Q 1 and Q 2 is H.

27. A compound according to claim 26 , wherein Q 1 and Q 2 are each H.

28. A compound according to claim 26 , wherein one of Q 1 and Q 2 is carboxy, hydroxy, alkoxy, halo, aminocarbonyl, or N-alkylaminocarbonyl.

29. A compound according to claim 28 , wherein the halo is fluoro and the N-alkylaminocarbonyl is N-C 1-3 alkylaminocarbonyl.

30. A compound according to claim 29 , wherein Q 2 is carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl, or N-C 1-3 alkylaminocarbonyl.

31. A compound according to claim 28 , wherein Q 1 is hydroxy or alkoxy.

32. A compound according to claim 6 , having the formula IV:

33. A compound according to claim 32 , wherein A and B are taken together with the carbon atoms through which they are connected to form a double bond.

34. A compound according to claim 33 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 , or —NR 3 S(═O) 2 alkyl.

35. A compound according to claim 34 , wherein Z is —C(═O)—R 2 .

36. A compound according to claim 35 , wherein R 2 is —NR 5 R 6 .

37. A compound according to claim 36 , wherein R 5 and R 6 are each independently C 2-3 alkyl.

38. A compound according to claim 37 , wherein t is 0.

39. A compound according to claim 32 , wherein A and B are each H.

40. A compound according to claim 39 , having the formula V:

wherein:

Q 1 and Q 2 are each independently H, carboxy, hydroxy, alkoxy, halo, aminocarbonyl, N-alkylaminocarbonyl, or N,N-dialkylaminocarbonyl.

41. A compound according to claim 40 , wherein Z is —C(═O)—R 2 , —NR 3 —C(═O)—R 4 , or —NR 3 S(═O) 2 alkyl.

42. A compound according to claim 41 , wherein Z is —C(═O)—R 2 .

43. A compound according to claim 42 , wherein R 2 is —NR 5 R 6 .

44. A compound according to claim 43 , wherein R 5 and R 6 are each independently C 2-3 alkyl.

45. A compound according to claim 44 , wherein at least one of Q 1 and Q 2 is H.

46. A compound according to claim 45 , wherein Q 1 and Q 2 are each H.

47. A compound according to claim 45 , wherein one of Q 1 and Q 2 is carboxy, hydroxy, alkoxy, halo, aminocarbonyl, or N-alkylaminocarbonyl.

48. A compound according to claim 46 , wherein the halo is fluoro and the N-alkylaminocarbonyl is N—C 1-3 alkylaminocarbonyl.

49. A compound according to claim 47 , wherein Q 2 is carboxy, hydroxy, alkoxy, fluoro, aminocarbonyl, or N—C 1-3 alkylaminocarbonyl.

50. A compound according to claim 47 , wherein Q 1 is hydroxy or alkoxy.

51. A compound according to claim 1 , selected from the group consisting of:

4-[2-(N,N-diethylaminocarbonyl)ethyl]-spiro[2H,1-benzopyran-2,4′-piperidine];

4-[3-(N,N-diethylaminocarbonyl)propyl]-spiro[2H,1-benzopyran-2,4′-piperidine];

4-[2-(N,N-diethylaminocarbonyl)ethyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N,N-diethylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(ethoxycarbonyl)propyl]-spiro[2H,1-benzopyran-2,4′-piperidine];

4-[3-(N,N-diisopropylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(1-(isoindolin-2-yl)carbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N-ethylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N-butylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1 -benzopyran-2,4′-piperidine];

4-[4-(N,N-diethylaminocarbonyl)butyl]-spiro[3,4-dihydro-2H,1 -benzopyran-2,4′-piperidine];

4-[5-(N,N-diethylaminocarbonyl)pentyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[5-(N,N-diisopropylaminocarbonyl)pentyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[4-(N,N-diethylaminocarbonyl)butyl]-spiro[6-fluoro-3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[4-(N,N-diethylaminocarbonyl)butyl]-spiro[5-methoxy-3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[4-(N,N-diethylaminocarbonyl)butyl]-spiro[5-hydroxy-3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N,N-diethylaminocarbonylamino)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N-(2-ethylbutanoyl)amino)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(3-(N-methyl-N-(2-ethylbutanoyl)amino)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(3-(ethylsulfonylamino)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(3-(N-methyl-N-(ethylsulfonyl)amino)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(N,N-diethylaminocarbonyl)methyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(N,N-diethylaminocarbonylmethylaminocarbonyl)methyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(2-(N,N-diethylaminocarbonylmethyloxy)ethyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[(4-(methoxycarbonyl)butyl]-spiro[6-fluoro-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-fluoro-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-methoxy-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-hydroxy-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-carboxy-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-aminocarbonyl-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-N-methylaminocarbonyl-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine]; and

4-[(4-N,N-diethylaminocarbonyl)butyl]-spiro[6-N-ethylcarbonyl-1,2,3,4-tetrahydronaphthalene-2,4′-piperidine];

or a pharmaceutically acceptable salt thereof.

52. A compound according to claim 51 , selected from the group consisting of:

4-[3-(N,N-diethylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[3-(N,N-diisopropylaminocarbonyl)propyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];

4-[4-(N,N-diethylaminocarbonyl)butyl]-spiro[3,4-dihydro-2H,1-benzopyran-2,4′-piperidine];