Antiviral agent

• US 20040229909A1
• Filed: 01/30/2004
• Published: 11/18/2004
• Est. Priority Date: 08/10/2001
• Status: Abandoned Application

• Current Assignee: Shionogi & Co., Ltd.
• Original Assignee: Shionogi & Co., Ltd.
• Inventors: Kanda, Yasuhiko, Takechi, Shozo, Kawasuji, Takashi, Tada, Yukio, Fujishita, Toshio, Kiyama, Ryuichi, Fuji, Masahiro
• Application Number:
  US10/485,394
• Publication Number:
  US 20040229909A1
• Time in Patent Office: Days
• US Class Current: 514/317
• CPC Class Codes: A61K 31/351 not condensed with another ring
• CPC Class Codes: A61K 31/4025 not condensed and containing further heterocyclic rings, e.g. cromakalim
• CPC Class Codes: A61K 31/4155 non condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4178 not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
• CPC Class Codes: A61K 31/4196 1,2,4-Triazoles
• CPC Class Codes: A61K 31/422 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/4245 Oxadiazoles
• CPC Class Codes: A61K 31/427 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/433 Thidiazoles
• CPC Class Codes: A61K 31/4427 containing further heterocyclic ring systems
• CPC Class Codes: A61K 31/4433 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4439 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole nicotine A61K31/465
• CPC Class Codes: A61K 31/4709 Non-condensed quinolines and containing further heterocyclic rings
• CPC Class Codes: A61K 31/497 containing further heterocyclic rings
• CPC Class Codes: A61K 31/501 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/506 not condensed and containing further heterocyclic rings
• CPC Class Codes: A61K 31/513 having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
• CPC Class Codes: A61K 31/53 having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine melarsoprol A61K31/555 ; with four nitrogen atoms A61K31/495
• CPC Class Codes: A61K 31/5377 not condensed and containing further heterocyclic rings, e.g. timolol
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 207/38 : 2-Pyrrolones
• CPC Class Codes: C07D 307/46 : Doubly bound oxygen atoms, or two oxygen atoms singly bound to the same carbon atom
• CPC Class Codes: C07D 311/24 : with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 401/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 403/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 405/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 409/14 : containing three or more hetero rings
• CPC Class Codes: C07D 413/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 413/06 : linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/04 : directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/06 : linked by a carbon chain containing only aliphatic carbon atoms

Abstract

The present invention provides an integrase inhibitor. The inventors have have found the following compound of formula (I) possessing an integrase inhibitory activity.

(wherein, R^C and R^D taken together with the neighboring carbon atoms form a ring which may be a condensed ring, Y is hydroxy, mercapto or amino; Z is O, S or NH; R^A is a group shown by

(wherein, C ring is N-containing aromatic heterocycle) or the like)

Claims

1. A method for preventing or treating a viral infectious disease in a patient, which comprises administering to the patent a therapeutically effective amount of a compound of formula (I)

2. A method of claim 1 wherein the ring formed by R^C and R^D is a 5- to 6-membered ring which may contain a hetero atom(s) and be condensed with.

3. A method of claim 2 wherein the ring formed by R^C and R^D is a 5- to 6-membered ring which may contain a hetero atom(s) of O and/or N and be condensed with a benzene ring.

4. A method of claim 3 wherein the ring formed by R^C and R^D is a 5-membered ring which contains a hetero atom(s) of N.

5. A method of claim 3 wherein the ring formed by R^C and R^D is a 6-membered ring which contains a hetero atom(s) of O and is condensed with a benzene ring.

6. A method of claim 3 wherein the ring formed by R^C and R^D is a 6-membered ring which contains a hetero atom(s) of N and is condensed with a benzene ring.

7. A method of claim 3 wherein the ring formed by R^C and R^D is a 6-membered ring which contains a hetero atom(s) of O.

8. A method of claim 3 wherein the ring formed by R^C and R^D is a 6-membered ring which contains a hetero atom(s) of N.

9. A method of claim 1 wherein the ring formed by R^C and R^D is a 6-membered carbocycle.

10. A method of claim 4 which contains as an active ingredient a compound of formula (II-1)

11. A method of claim 4 which contains as an active ingredient a compound of formula (III-1)

14. A method of claim 3 which contains as an active ingredient a compound of formula (IV-1):

15. A method of claim 5 which contains as an active ingredient a compound of formula(IV-2):

16. A method of claim 3 which contains as an active ingredient a compound of formula (V-1)

17. A method of claim 5 which contains as an active ingredient a compound of formula (V-2):

20. A method of claim 3 which contains as an active ingredient a compound of formula(VII-1):

21. A method of claim 3 which contains as an active ingredient a compound of formula(VII-2):

22. A method of claim 3 which aontains as an active ingredient a compound of formula (VII-3):

25. A method of claim 8 which contains as an active ingredient a compound of formula (IX-1):

26. A method of claim 8 which contains as an active ingredient a compound of formula (IX-2):

35. A method of claim 1, wherein the non-interfering substituents are independently selected from hydrogen, halogen, alkoxycarbonyl carboxy, alkyl, alkoxy, alkoxyalkyl, nitro, hydroxy, hydroxyalkyl, alkenyl, alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio, alkylthioalkyl haloalkyl, haloalkoxy, haloalkoxyalkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl optionally substituted heterocycle, oxo, thioxo, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkylcarbonyl alkylcarbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl, optionally substituted heteroarylalkyl, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted arylthio, optionally substituted heteroarylthio, optionally substituted aralkyloxy, optionally substituted heteroarylalkyloxy, optionally substituted aralkylthio, optionally substituted heteroarylalkylthio, optionally substituted aryloxyalkyl optionally substituted heteroaryloxyalkyl optionally substituted arylthioalkyl, optionally substituted heteroarylthioalkyl optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroarylalkylsulfonyl.

38. A compound of formula(I-Q):

Q—

Z¹—

Z²—

Z³—

R¹, its prodrug or pharmaceutically acceptable salt or solvate thereof, wherein, Z¹, Z², Z³ and R¹ are the same as claim 1;

Q is shown by any one of the following formulae;

39. A compound of claim 38, shown by formula (H-1):

40. A compound of claim 39, wherein Z¹ and Z³ are each independently a bond or alkylene;

Z² is a bond or —

O—

;

R¹ is optionally substituted aryl or optionally substituted heteroaryl its prodrug or pharmaceutically acceptable salt or solvate thereof.

41. A compound of claim 39, wherein C ring is pyrimidine-4yl or 1,3,4-oxadiazole-2yl;

Z¹ is a bond;

Z² is −

0 or alkylene;

Z³ is a bond or alkylene;

R¹ is aryl optionally substituted with halogen;

R³, R⁴ and R¹⁹ are hydrogens;

R⁵ is alkyl, aralkyl, cycloalkyl, aryl or alkoxy, its prodrug or pharmaceutically acceptable salt or solvate thereof.

42. A compound of claim 38, shown by formula (III-1):

43. A compound of claim 39 or 42, wherein, R⁵ is hydrogen, alkyl, aralkyl, cycloalkyl, optionally substituted aryl, alkoxy, alkoxyalkyl optionally substituted ammo, hydroxyalkyl, alkenyl alkoxycarbonylalkyl or heteroarylalkyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

52. A compound of claim 38, shown by formula (IV-2):

53. A compound of claim 52, wherein C ring is pyridine-2-yl, 1,2,4-triazole-3-yl or imidazole-2-yl optionally substituted with alkyl;

Z¹ is a bond;

Z² is —

O—

;

Z³ is alkylene;

R¹ is aryl optionally substituted with halogen;

R⁸ to R¹³ are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.

54. A compound of claim 38, shown by formula (V-2):

55. A compound of claim 52 or 54, wherein Z¹ and Z³ are each independently a bond or alkylene;

Z² is a bond or —

O—

;

R¹ is optionally substituted aryl or optionally substituted heteroaryl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

56. A compound of claim 54, wherein C ring is 1,3,4-oxadiazole-2y1;

Z¹ and Z³ are bonds;

Z² is alkylene;

R¹ is aryl optionally substituted with halogen;

R⁹ to R¹⁴ are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.

60. A compound of claim 38, shown by formula (VI-4):

61. A compound of claim 60, wherein R^B is fran-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

62. A compound of claim 60, wherein R^B is fran-2-yl;

Z¹ and Z³ are bonds;

Z² is alkylene;

R¹ is aryl optionally substituted with halogen;

R⁶,R⁷,R¹¹ to R¹⁴ are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.

63. A compound of claim 38, shown by formula (VII-5):

64. A compound of claim 63, wherein, R^B is fran-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

65. A compound of claim 63, wherein, R^B is fran-2yl;

Z¹ and Z³ are bonds;

Z² is alkylene;

R¹ is aryl optionally substituted with halogen;

R⁶,R⁷, R^E and R^F are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.

70. A compound of claim 38, shown by formula (IX-1):

73. A compound of claim 38, shown by formula (IX-2):

90. A compound of claim 38, 39, 46, 52, 54, 57, 69, 73, 77, 81, 85 or 89, wherein C ring is optionally substituted pyridine-2-yl, optionally substituted pyrimidine-4-yl, optionally substituted 1,3,4-oxadiazole-2yl, optionally substituted 1,2,4-triazole-3yl or optionally substituted imidazole-2-yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

91. A compound of claim 38,(39),(46),(52),(54),(57),(69),(73),(77),(81),(85) or (89), wherein Z¹ and Z³ are each independently a bond or alkylene;

Z² is a bond or —

O—

;

R¹ is optionally substituted aryl or optionally substituted heteroaryl its prodrug or pharmaceutically acceptable salt or solvate thereof.

92. A compound of claim 38,(39),(46),(52),(54),(57),(69),(73),(77),(81),(85) or (89), wherein C ring is pyrimidine-4-yl or 1,3,4-oxadiazole-2-yl;

Z¹ is a bond;

Z² is —

O or allylene;

Z³ is a bond or alkylene;

R¹ is aryl optionally substituted with halogen R³,R⁴ and R¹⁹ are hydrogens, its prodrug or pharmaceutically acceptable salt or solvate thereof.

93. A compound of claim 38,(39),(42),(46),(49),(52),(54),(57),(60).(63),(66),(69),(70),(73),(74,(77),(78),(81),(82),(85),(86) or (89), wherein each non-interfering substituent is independently selected from hydrogen, halogen, alkoxycarbonyl, carboxy, alkyl, alkoxy, alkoxy alkyl, nitro, hydroxy, alkenyl, alkynyl, alkylsulfonyl, optionally substituted amino, alkylthio, alkylthio alkyl, haloalkyl, haloalkoxy, haloalkoxy alkyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycle, oxo, thioxo, nitroso, azide, amidino, guanidino, cyano, isocyano, mercapto, optionally substituted carbamoyl, sulfamoyl, sulfoamino, formyl, alkyl carbonyl, alkyl carbonyloxy, hydrazino, morpholino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted aralkyl optionally substituted heteroaryl alkyl, optionally substituted aryl oxy, optionally substituted heteroaryl oxy, optionally substituted aryl thio, optionally substituted heteroaryl thio, optionally substituted aralkyloxy, optionally substituted heteroaryl alkyl oxy, optionally substituted aralkylthio, optionally substituted heteroaryl alkylthio, optionally substituted aryl oxyalkyl, optionally substituted heteroaryl oxyalkyl, optionally substituted aryl thioalkyl, optionally substituted heteroaryl thioalkyl, optionally substituted arylsulfonyl, optionally substituted heteroarylsulfonyl, optionally substituted aralkylsulfonyl and optionally substituted heteroaryl alkylsulfonyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

94. A compound of claim 38, (39), (42), (46), (49), (52), (54), (57), (60). (63), (66), (69), (70), (73), (74), (77), (78), (81), (82), (85), (86) or (89), wherein Z¹, Z² and Z³ are not bonds at the same, its prodrug or pharmaceutically acceptable salt or solvate thereof.

95. A compound of claim 94, wherein R¹ is phenyl optionally substituted with halogen, Z¹ is a bond, Z² is alkylene or —

O—

, Z³ is a bond or alkylene, its prodrug or pharmaceutically acceptable salt or solvate thereof.

96. A compound of claim 95, wherein R¹ is 4-fluorophenyl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

100. A pharmaceutical composition comprising a compound of any one of claims 38 to 99, its prodrug or pharmaceutically acceptable salt or solvate thereof.

12-13. -13. (Cancelled)

18-19. -19. (Cancelled)

23-24. -24. (Cancelled)

27-34. -34. (Cancelled)

36-37. -37. (Cancelled)

44. A compound of above 42, wherein R^B is fran-2yl, its prodrug or pharmaceutically acceptable salt or solvate thereof.

45. A compound of above 42, wherein R^B is aryl or fran-2yl;

Z¹ and Z³ are bonds;

Z² is alkylene;

R¹ is aryl optionally substituted with halogen;

R⁶,R⁷ and R¹⁹ are hydrogens;

R⁵ is alkyl, cycloalkyl, alkoxy, aryl optionally substituted with alkoxy, hydroxyalkyl, alkenyl aralkyl, alkoxycarbonylalkyl, or pyridine-2ylmethyl its prodrug or pharmaceutically acceptable salt or solvate thereof.

46-51. -51. (Cancelled)

57-59. -59. (Cancelled)

66-69. -69. (Cancelled)

71-72. -72. (Cancelled)

74-89. -89. (Cancelled)

97-99. -99. (Cancelled)

101-120. -120. (Cancelled)

121. A method for preventing or treating an integrase-mediated disease in a patient, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I):