IP Library › Granted Patent US 7,598,261

Granted Patent B2

US 7,598,261 · App. 11/393,133 · Granted Oct 6, 2009

Spirocyclic heterocyclic derivatives and methods of their use

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Quick Facts

Patent No.: US 7,598,261
App. No.: 11/393,133
Granted: Oct 6, 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 conditions.

Claims (254)

1. A compound of formula XIV:

wherein:

W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from hydroxy, aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C═O)—N(alkyl)(alkyl));

R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

2. A compound according to claim 1 , wherein W 2 is:

3. A compound according to claim 2 , wherein W 2 is:

4. A compound according to claim 1 , wherein X 2 is —O—.

5. A compound according to claim 1 , wherein A 2 and B 2 together form a double bond.

6. A compound according to claim 1 , of formula XV:

7. A compound according to claim 1 , of formula XVI:

8. A compound according to claim 1 , wherein the compound is:

9. A compound according to claim 1 , wherein the compound is:

10. A compound of formula XXII:

wherein:

W 2 is aryl or heteroaryl, wherein the aryl or heteroaryl is substituted with 0-3 groups selected independently from heteroaryl, hydroxy, carboxy (—COOH), —C(═O)-alkyl, —C(═O)-aryl, —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl); aminocarbonyl (—C(═O)—NH 2 ), N-alkylaminocarbonyl (—C(═O)—NH(alkyl)), and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl) (alkyl));

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from halo, heterocycloalkyl, hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), carboxy (—COOH), —C(═O)—O-alkyl, and N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl));

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that:

when W 2 is para-diethylaminocarbonylphenyl, para-prop-2-ylaminocarbonylphenyl, orpara-pent-3-ylaminocarbonylphenyl, R 23 and R 24 are each H, and A and B are each H or together form a double bond, then J 2 is other than unsubstituted phenyl or anisyl; and

when W 2 is:

R 23 and R 24 are each H, and A and B together form a double bond; then J 2 is other than unsubstituted phenyl.

11. A compound according to claim 10 , wherein W 2 is:

12. A compound according to claim 10 , wherein R 23 and R 24 are each H.

13. A compound according to claim 10 , of formula XXIII:

wherein:

Q 1 and Q 2 are each independently H, halo, heterocycloalkyl, hydroxy, alkoxy, —S(═O) 2 -alky, —S(═O) 2 —NH 2, —S(═O) 2 —N(alkyl)(alkyl), carboxy (—COOH), —C(═O)—O-alkyl, or N,N-dialkylaminocarbonyl (—C(═O)—N(alkyl)(alkyl)).

14. A compound according to claim 13 , wherein W 2 is:

15. A compound according to claim 14 , wherein R 23 and R 24 are each H.

16. A compound according to claim 10 , of formula XXIV:

17. A compound according to claim 10 , wherein the compound is:

18. A compound according to claim 17 , wherein the compound is:

19. A compound of formula XXV:

wherein:

W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

X 2 is —CH 2 — or —O—; and

J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 0-3 groups selected independently from hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), and —C(═O)—O-alkyl;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that the compound of formula XXV is other than 4-phenyl-spiro[2H,1-benzopyran-2,4′-piperidine].

20. A compound according to claim 19 , wherein R 23 and R 24 are each H.

21. A compound according to claim 19 of formula XXVI:

wherein:

Q 1 and Q 2 are each independently H, hydroxy, alkoxy, —S(═O) 2 -alkyl, —S(═O) 2 —NH 2 , —S(═O) 2 —NH(alkyl), —S(═O) 2 —N(alkyl)(alkyl), —C(═O)—N(alkyl)(alkyl), carboxy (—COOH), or —C(═O)—O-alkyl.

22. A compound according to claim 19 , wherein A 2 and B 2 taken together form a double bond.

23. A compound according to claim 22 , wherein X 2 is —O—.

24. A compound of formula XXVII:

wherein:

W 2 is para-dialkylaminocarbonylphenyl, the phenyl group of which is further optionally substituted with 1-2 groups independently selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH 2 );

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

Q 1 and Q 2 are each independently H, hydroxy, alkoxy, haloalkoxy, halo, or heterocycloalkyl;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof; provided that:

when one of Q 1 and Q 2 is hydroxy and the other is H, or both Q 1 and Q 2 are hydroxy, then the phenyl group of W 2 is further substituted with 1-2 groups selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH 2 );

when Q 1 , Q 2 , R 23 , and R 24 are each H and the phenyl group of W 2 is further substituted with one hydroxy, then A 2 and B 2 are each H;

when W 2 is para-dialkylaminocarbonylphenyl, then at least one of Q 1 , Q 2 , R 23 , and R 24 is other than H;

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, and Q 2 is halo, then Q 1 is other than H or hydroxy;

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, Q 1 is methoxy, or cyclopropylmethoxy, and Q 2 is H, then A 2 and B 2 are each H; and

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, and Q 1 is H or OH, then Q 2 is other than methoxy, cyclopropylmethoxy.

25. A compound according to claim 24 , wherein W 2 is:

26. A compound according to claim 24 , wherein R 23 and R 24 are each H.

27. A compound according to claim 25 , wherein R 23 and R 24 are each H.

28. A compound according to claim 24 , wherein the compound is:

29. A compound of formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

30. A compound according to claim 29 , wherein R 23 and R 24 are each H.

31. A compound according to claim 29 , wherein R 26 is H.

32. A compound according to claim 29 , wherein the compound is:

33. A compound of formula XXIX:

wherein:

W 2 is para-N(alkyl),N(alkyl-Z)aminocarbonylaryl or para-N(alkyl),N(alkyl-Z)aminocarbonylheteroaryl, wherein the aryl or heteroaryl ring of W 2 is substituted with 0-2 groups selected independently from hydroxy and alkoxy;

Z is alkoxy, alkylamino, or dialkylamino;

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

34. A compound according to claim 33 , wherein W 2 is:

35. A compound according to claim 34 , wherein W 2 is:

36. A compound according to claim 33 , wherein A 2 and B 2 together form a double bond.

37. A compound according to claim 33 , wherein X 2 is —O—.

38. A compound according to claim 33 , wherein R 23 and R 24 are each H.

39. A compound according to claim 33 , wherein the compound is:

40. A compound of formula XXX:

wherein:

W 2 is:

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

X 2 is —CH 2 — or —O—; and

J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo and haloalkoxy;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that when W 2 is:

then the aryl ring of J 2 is substituted with at least one haloalkoxy.

41. A compound according to claim 40 , wherein R 23 and R 24 are each H.

42. A compound according to claim 40 , of formula XXXI:

wherein:

Q 1 and Q 2 are each independently H, halo, or haloalkoxy, provided that at least one of Q 1 and Q 2 is other than H.

43. A compound according to claim 42 , wherein R 23 and R 24 are each H.

44. A compound according to claim 40 , wherein the compound is:

45. A compound of formula XXXII:

wherein:

D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;

R 23 , R 24 , and R 26 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that when D is:

and X 2 is —O—, then A 2 and B 2 are each H.

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

47. A compound according to claim 45 , wherein X 2 is —O—.

48. A compound according to claim 45 , wherein the heteroaryl ring of D is thienyl or pyridyl.

49. A compound according to claim 45 , wherein the compound is:

50. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XIV:

wherein:

R 23 and R 24 are each independently H or alkyl, provided that at least one of R 23 and R 24 is alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

51. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXII:

wherein:

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that:

when W 2 is para-diethylaminocarbonylphenyl, para-prop-2-ylaminocarbonylphenyl, or para-pent-3-ylaminocarbonylphenyl, R 23 and R 24 are each H, and A and B are each H or together form a double bond, then J 2 is other than unsubstituted phenyl or anisyl; and

when W 2 is:

R 23 and R 24 are each H, and A and B together form a double bond; then J 2 is other than unsubstituted phenyl.

52. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXV:

wherein:

W 2 is aryl optionally substituted with —C(═O)-alkyl or —C(═O)-aryl;

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

X 2 is —CH 2 — or —O—; and

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that the compound of formula XXV is other than 4-phenyl-spiro[2H,1-benzopyran-2,4′-piperidine].

53. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXVIIA:

wherein:

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

Q 1 and Q 2 are each independently H, hydroxy, alkoxy, haloalkoxy, halo, or heterocycloalkyl;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that:

when one of Q 1 and Q 2 is hydroxy and the other is H, then the phenyl group of W 2 is further substituted with 1-2 groups selected from tetrazolyl, N-alkyltetrazolyl, hydroxy, carboxy (—COOH), and aminocarbonyl (—C(═O)—NH 2 );

when Q 1 , Q 2 , R 23 , and R 24 are each H and the phenyl group of W 2 is further substituted with one hydroxy, then A 2 and B 2 are each H;

when W 2 is para-dialkylaminocarbonylphenyl, then at least one of Q 1 , Q 2 , R 23 , and R 24 is other than H;

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, and Q 2 is halo, then Q 1 is other than H;

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, Q 1 is methoxy, cyclopropylmethoxy, and Q 2 is H, then A 2 and B 2 are each H; and

when W 2 is para-dialkylaminocarbonylphenyl, R 23 and R 24 are each H, and Q 1 is H, or OH, then Q 2 is other than methoxy, cyclopropylmethoxy.

54. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXVIII:

wherein:

D is:

K is carboxy (—COOH), —C(═O)—O-alkyl, —S(═O) 2 —N(alkyl)(alkyl), heteroaryl, alkylheteroaryl, aminocarbonyl (—C(═O)—NH 2 ), or N-alkylaminocarbonyl (—C(═O)—NH(alkyl));

R 23 , R 24 , and R 26 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

55. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXIX:

wherein:

Z is alkoxy, alkylamino, or dialkylamino;

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

56. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXX:

wherein:

W 2 is:

R 23 and R 24 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond;

X 2 is —CH 2 — or —O—; and

J 2 when taken together with the carbon atoms to which it is attached forms a 6-membered aryl ring substituted with 1-3 groups selected independently from halo or haloalkoxy;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that when W 2 is:

then the aryl ring of J 2 is substituted with at least one haloalkoxy.

57. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of formula XXXII:

wherein:

D is N(alkyl),N(alkyl)aminocarbonylheteroaryl;

R 23 , R 24 , and R 26 are each independently H or alkyl;

A 2 and B 2 are each H, or together form a double bond; and

X 2 is —CH 2 — or —O—;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof;

provided that when D is:

and X 2 is —O—, then A 2 and B 2 are each H.

58. A compound according to claim 10 , wherein the compound is:

59. A compound according to claim 19 , wherein the compound is:

60. A compound according to claim 24 , wherein the compound is:

61. A compound according to claim 29 , wherein the compound is:

62. A compound according to claim 33 , wherein the compound is:

63. A compound according to claim 40 , wherein the compound is:

64. A compound according to claim 45 , wherein the compound is:

65. A compound of formula XXXIII:

wherein:

F 1 is heteroaryl; and

G is C 1-6 alkylene substituted with NH 2 , NHC(═O)alkyl, NH(C(O)N(H)alkyl, or NHS(═O) 2 alkyl;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

66. A compound according to claim 65 , wherein the heteroaryl is a 5- or 6-membered heteroaryl having 1 to 4 heteroatoms.

67. A compound according to claim 66 , wherein the heteroaryl is a 5- or 6-membered heteroaryl having 2 to 4 heteroatoms.

68. A compound according to claim 67 , wherein the heteroaryl is a 5-membered heteroaryl.

69. A compound according to claim 68 , wherein the heteroaryl is a tetrazole.

70. A compound according to claim 69 , wherein F 1 -G is:

71. A compound according to claim 65 , wherein G is C 4-6 alkylene substituted with NH 2 , NHC(═O)alkyl, or NHS(═O) 2 alkyl.

72. A compound according to claim 71 , wherein the alkyl is C 1-6 alkyl.

73. A compound according to claim 72 , wherein the alkyl is C 1 alkyl.

74. A compound according to claim 71 , wherein G is C 4-6 alkylene substituted with NH 2 .

75. A compound according to claim 70 , wherein G is C 4-6 alkylene substituted with NH 2 , NHC(═O)alkyl, or NHS(═O) 2 alkyl.

76. A compound according to claim 75 , wherein G is C 4-6 alkylene substituted with NH 2 .

77. A compound according to claim 65 , selected from the group consisting of:

78. A compound according to claim 14 , selected from the group consisting of:

79. A compound according to claim 14 , wherein Q 2 is hydroxy and W 2 is:

80. A compound according to claim 79 , wherein R 23 and R 24 are H and W 2 is:

81. A compound according to claim 80 , wherein Q 1 is H.

82. A compound of formula XXXIV:

wherein:

F 2 is aryl or heteroaryl; and

Q 3 is hydroxy or alkoxy;

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

83. A compound according to claim 82 , wherein F 2 is phenyl.

84. A compound according to claim 82 , wherein F 2 is pyridyl or benzothiophenyl.

85. A compound according to claim 82 , wherein Q 3 is hydroxy, methoxy, or cyclopropylmethoxy.

86. A compound according to claim 83 , wherein Q 3 is methoxy or cyclopropylmethoxy.

87. A compound according to claim 84 , wherein Q 3 is hydroxy.

88. A compound according to claim 27 , which is:

89. A compound according to claim 88 , wherein the compound is substantially enantiomerically pure.

90. A compound selected from the group consisting of:

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

91. A compound according to claim 90 , selected from the group consisting of:

or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof.

92. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of claim 65 .

93. A pharmaceutical composition, comprising:

a pharmaceutically acceptable carrier; and a compound of claim 82 .

Assignments (3)

RELEASE OF SECURITY INTEREST Recorded Jul 24, 2015

From: ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT

To: CALIXA THERAPEUTICS, INC.; ADOLOR CORPORATION; CUBIST PHARMACEUTICALS, INC.

Reel/Frame 036180/0070 →

SECURITY AGREEMENT Recorded Nov 20, 2012

From: CUBIST PHARMACEUTICALS, INC.; ADOLOR CORPORATION; CALIXA THERAPEUTICS, INC.; CUBIST PHARMACEUTICALS HOLDINGS, INC.; CUBIST PHARMACEUTICALS U.S.

To: ROYAL BANK OF CANADA, AS ADMINISTRATIVE AGENT

Reel/Frame 029339/0669 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 8, 2006

From: DOLLE, ROLAND E.; LE BOURDONNEC, BERTRAND; CHU, GUO-HUA

To: ADOLOR CORPORATION

Reel/Frame 017747/0395 →