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1. (WO2010011537) INHIBITORS OF THE PLASMODIAL SURFACE ANION CHANNEL AS ANTIMALARIALS
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters Machine translation

CLAIM(S):

1. A method of preventing malaria or treating an animal afflicted with malaria comprising administering to the animal:

(i) an effective amount of a compound of formula I:


wherein R1 is hydrogen or alkyl and R2 is arylalkyl, optionally substituted on the aryl with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; or R2 is a group of formula (II):


wherein n=0 to 6;

or R1 and R2 together with the N to which they are attached form a heterocycle of formula III:


wherein X is N or CH; and

Y is aryl, alkylaryl, dialkylaryl, arylalkyl, alkoxyaryl, or heterocyclic, optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

R3- R10 are hydrogen or alkyl; or a pharmaceutically acceptable salt thereof;

(ii) an effective amount of a compound of formula IV:


wherein

Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, the rings may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

Ra is hydrogen, alkyl, or alkoxy;

P is a bond, alkyl, alkoxy, (CH2)r, or (CH2O)8, wherein r and s are independently 1 to 6;

Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

when P is alkyl or alkoxy, Q is absent;

or a pharmaceutically acceptable salt thereof;

(iii) an effective amount of a compound of formula V:

wherein R1 ' and R12 are independently hydrogen, alkyl, cycloalkyl, or aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

R13- R15 are independently selected from the group consisting of alkyl, halo, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

or a pharmaceutically acceptable salt thereof; or

(iv) an effective amount of any combination of the compounds of formulas I, IV, and V, or pharmaceutically acceptable salts thereof.

2. The method of claim 1, wherein R3 in formula I is hydrogen.

3. The method of claim 1 or 2, wherein R4- R7 in formula I are hydrogen.

4. The method of any one of claims 1 to 3, wherein R1 in formula I is hydrogen or alkyl and R2 is a group of formula II, wherein n = 1 to 6.

5. The method of claim 4, wherein n = 2 to 4.

6. The method of any one of claims 1 to 3, wherein R1 and R2 together with the N to which they are attached form a heterocycle of formula III.

7. The method of any one of claims 1 to 3 or 6, wherein X in formula III is N.

8. The method of claim 7, wherein in formula III, Y is aryl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

9. The method of claim 7 or 8, wherein in formula III, Y is phenyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

10. The method of claim 9, wherein Y is phenyl or phenyl substituted with one or more substituents selected from the group consisting of methyl, chloro, fluoro, and methoxy.

11. The method of any one of claims 1 to 10, wherein the compound of formula

I is:


12. The method of any one of claims 1 to 3 or 6, wherein X in formula III is

CH.

13. The method of claim 12, wherein Y is arylalkyl or heterocyclic, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

14. The method of claim 12 or 13, Y is benzyl or piperidinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

15. The method of any one of claims 12 to 14, wherein the compound of formula I is:


16. The method of any one of claims 1 to 3, wherein R1 in formula I is hydrogen and R2 is arylalkyl, optionally substituted on the aryl with a substituent selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, and formyl.

17. The method of claim 16, wherein R2 is arylalkyl.

18. The method of claim 16 or 17, wherein R2 is phenylalkyl.

19. The method of claim 18, wherein the phenylalkyl is phenylbutyl.

20. The method of any one of claims 16 to 19, wherein the compound of formula I is:


21. The method of claim 5, wherein the compound of formula II is:


22. The method of any one of claims 1 to 21 , wherein, in the compound of formula IV, P is a bond or (CH2O)5, and Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

23. The method of claim 22, wherein Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, they may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

24. The method of claim 23, wherein Z is a group having one or two 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two 4-7 membered rings are present, they may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

25. The method of any one of claims 22 to 24, wherein Q is an aryl group, optionally substituted with an alkoxy group or Q is a heterocyclic group which is saturated or unsaturated.

26. The method of claim 25, wherein the aryl group is phenyl or naphthyl.

27. The method of claim 25 or 26, wherein the compound of formula FV is:


28. The method of any one of claims 22 to 24, wherein Q is a heteroaromatic group.

29. The method of claim 28, wherein Q is pyridyl.

30. The method of claim 29, wherein the compound of formula IV is:


31. The method of any one of claims 1-21, wherein P is an alkyl group and Q is absent.

32. The method of claim 31 , wherein the compound of formula IV is:

33. The method of any one of claims 1 to 32, wherein, in the compound of formula V, R . 13 is alkyl or alkoxy and R 14 and R » 15 are hydrogen.

34. The method of claim 33, wherein R13 is methyl or methoxy.

35. The method of claim 33 or 34, wherein R11 is alkyl and R12 is alkyl, cycloalkyl, or aryl, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

36. The method of claim 35, wherein R12 is alkyl, cycloalkyl, or aryl, wherein said aryl is optionally substituted with one or more alkyl and/or alkoxy substituents.

37. The method of claim 36, wherein the compound of formula V is:


38. The method of claim 33 or 34, wherein R11 is hydrogen and R12 is cycloalkyl or aryl, which is optionally substituted with one or more alkyl and/or alkoxy substituents.

39. The method of claim 38, wherein the compound of formula V is:


40. The method of any one of claims 1 to 39, wherein an effective amount of a combination of compounds of formulas I and IV, or pharmaceutically acceptable salts thereof, is administered.

41. The method of any one of claims 1 to 39, wherein an effective amount of a combination of compounds of formulas I and V, or pharmaceutically acceptable salts thereof, is administered.

42. The method of any one of claims 1 to 39, wherein an effective amount of a combination of compounds of formulas IV and V, or pharmaceutically acceptable salts thereof, is administered.

43. The method of any one of claims 1 to 39, wherein an effective amount of a combination of compounds of formulas I, IV, and V, or pharmaceutically acceptable salts thereof, is administered.

44. The method of any one of claims 1 to 43, wherein said animal is a human.

45. The method of any one of claims 1 to 44, wherein a compound selected from the group consisting of:

or a pharmaceutically acceptable salt thereof is administered in combination with


or a pharmaceutically acceptable salt thereof.

46. The method of any one of claims 1 to 44, wherein a compound selected from the group consisting of:


pharmaceutically acceptable salt thereof is administered in combination with

or a pharmaceutically acceptable salt thereof.

47. The method of any one of claims 1 to 44, wherein


or a pharmaceutically acceptable salt thereof is administered in combination with


or a pharmaceutically acceptable salt thereof.

48. The method of any one of claims 1 to 44, wherein


or a pharmaceutically acceptable salt thereof is administered in combination with


, or a pharmaceutically acceptable salt thereof.

49. The method of any one of claims 1 to 44, which involves a further administration of a compound of the formula:



acceptable salt thereof.

50. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and

(i) a compound of formula I:


wherein R1 is hydrogen or alkyl and R2 is arylalkyl, optionally substituted on the aryl with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; or R2 is a group of formula (II):


wherein n=0 to 6;

or R 1 1 a ,-,„nd j τ R> 2 . together with the N to which they are attached form a heterocycle of formula III:

wherein X is N or CH; and

Y is aryl, alkylaryl, dialkylaryl, arylalkyl, alkoxyaryl, or heterocyclic, optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

R3- R10 are hydrogen or alkyl; or a pharmaceutically acceptable salt thereof;

(ii) a compound of formula IV:


wherein

Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, the rings may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

Ra is hydrogen, alkyl, or alkoxy;

P is a bond, alkyl, alkoxy, (CH2)r, or (CH2O)5, wherein r and s are independently 1 to 6;

Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

when P is alkyl or alkoxy, Q is absent;

or a pharmaceutically acceptable salt thereof;

(iii) a compound of formula V:


wherein R1 ' and R12 are independently hydrogen, alkyl, cycloalkyl, or aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

R13- R15 are independently selected from the group consisting of alkyl, halo, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

or a pharmaceutically acceptable salt thereof; or

(iv) any combination of the compounds of formulas I, IV, and V, or pharmaceutically acceptable salts thereof.

51. Use of (i) a compound of formula I:


wherein R1 is hydrogen or alkyl and R2 is arylalkyl, optionally substituted on the aryl with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; or R2 is a group of formula (II):


wherein n=0 to 6;

or R and R together with the N to which they are attached form a heterocycle of formula III:


wherein X is N or CH; and

Y is aryl, alkylaryl, dialkylaryl, arylalkyl, alkoxyaryl, or heterocyclic, optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

R3- R10 are hydrogen or alkyl; or a pharmaceutically acceptable salt thereof;

(ii) a compound of formula IV:


wherein

Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, the rings may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

Ra is hydrogen, alkyl, or alkoxy;

P is a bond, alkyl, alkoxy, (CH2),-, or (CH2O)5, wherein r and s are independently 1 to 6;

Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl; and

when P is alkyl or alkoxy, Q is absent;

or a pharmaceutically acceptable salt thereof;

(iii) a compound of formula V:


wherein Rn and R12 are independently hydrogen, alkyl, cycloalkyl, or aryl which is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

R13- R15 are independently selected from the group consisting of alkyl, halo, alkoxy, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl;

or a pharmaceutically acceptable salt thereof; or (iv) any combination of the compounds of formulas I, IV, and V, or pharmaceutically acceptable salts thereof;

in the preparation of a medicament for preventing malaria or treating an animal afflicted with malaria.

52. The use of claim 51 , wherein R3 in formula I is hydrogen.

53. The use of claim 51 or 52, wherein R4- R7 in formula I are hydrogen.

54. The use of any one of claims 51 to 53, wherein R1 in formula I is hydrogen or alkyl and R2 is a group of formula II, wherein n = 1 to 6.

55. The use of claim 54, wherein n = 2 to 4.

56. The use of any one of claims 51 to 53, wherein R1 and R2 together with the N to which they are attached form a heterocycle of formula III.

57. The use of any one of claims 51 to 53 or 56, wherein X in formula III is N.

58. The use of claim 57, wherein in formula III, Y is aryl which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

59. The use of claim 57 or 58, wherein in formula III, Y is phenyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, alkoxy, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

60. The use of claim 59, wherein Y is phenyl or phenyl substituted with one or more substituents selected from the group consisting of methyl, chloro, fluoro, and methoxy.

61. The use of any one of claims 51 to 60, wherein the compound of formula I is:


62. The use of any one of claims 51 to 53 or 56, wherein X in formula III is

CH.

63. The use of claim 62, wherein Y is arylalkyl or heterocyclic, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

64. The use of claim 62 or 63, Y is benzyl or piperidinyl, which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

65. The use of any one of claims 62 to 64, wherein the compound of formula I is:


66. The use of any one of claims 51 to 53, wherein R1 in formula I is hydrogen and R2 is arylalkyl, optionally substituted on the aryl with a substituent selected from the group consisting of halo, hydroxyl, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, and formyl.

67. The use of claim 66, wherein R2 is arylalkyl.

68. The use of claim 66 or 67, wherein R2 is phenylalkyl.

69. The use of claim 68, wherein the phenylalkyl is phenylbutyl.

70. The use of any one of claims 66 to 69, wherein the compound of formula I is:


71. The use of claim 55 , wherein the compound of formula H is:

72. The use of any one of claims 51 to 71 , wherein, in the compound of formula IV, P is a bond or (CH2O)8, and Q is a heterocyclic group, an aryl group, or an heterocyclyl aryl group, each of which is optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

73. The use of claim 72, wherein Z is a group having one or more 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two or more 4-7 membered rings are present, they may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

74. The use of claim 73, wherein Z is a group having one or two 4-7 membered rings, wherein at least one of the rings has at least one heteroatom selected from the group consisting of O, S, and N; and when two 4-7 membered rings are present, they may be fused or unfused; wherein the rings are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkoxy, nitro, cyano, amino, alkyl, aminoalkyl, alkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

75. The use of any one of claims 72 to 74, wherein Q is an aryl group, optionally substituted with an alkoxy group or Q is a heterocyclic group which is saturated or unsaturated.

76. The use of claim 75, wherein the aryl group is phenyl or naphthyl.

77. The use of claim 75 or 76, wherein the compound of formula IV is:


78. The use of any one of claims 72 to 74, wherein Q is a heteroaromatic group.

79. The use of claim 78, wherein Q is pyridyl.

80. The use of claim 79, wherein the compound of formula IV is:

81. The use of any one of claims 51 to 71 , wherein P is an alkyl group and Q is absent.

82. The use of claim 81 , wherein the compound of formula IV is:


83. The use of any one of claims 51 to 82, wherein, in the compound of formula V, R13 is alkyl or alkoxy and R14 and R15 are hydrogen.

84. The use of claim 83, wherein R13 is methyl or methoxy.

85. The use of claim 83 or 84, wherein R11 is alkyl and R12 is alkyl, cycloalkyl, or aryl, wherein said aryl is optionally substituted with one or more substituents selected from the group consisting of alkyl, alkoxy, halo, hydroxy, nitro, cyano, amino, alkylamino, aminoalkyl, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, and formyl.

86. The use of claim 85, wherein R12 is alkyl, cycloalkyl, or aryl, wherein said aryl is optionally substituted with one or more alkyl and/or alkoxy substituents.

87. The use of claim 86, wherein the compound of formula V is:

88. The use of claim 83 or 84, wherein R11 is hydrogen and R12 is cycloalkyl or aryl, which is optionally substituted with one or more alkyl and/or alkoxy substituents.

89. The use of claim 88, wherein the compound of formula V is:


90. The use of any one of claims 51 to 89, wherein the medicament includes a combination of compounds of formulas I and IV, or pharmaceutically acceptable salts thereof.

91. The use of any one of claims 51 to 89, wherein the medicament includes a combination of compounds of formulas I and V, or pharmaceutically acceptable salts thereof.

92. The use of any one of claims 51 to 89, wherein the medicament includes a combination of compounds of formulas IV and V, or pharmaceutically acceptable salts thereof.

93. The use of any one of claims 51 to 89, wherein the medicament includes a combination of compounds of formulas I, IV, and V, or pharmaceutically acceptable salts thereof.

94. The use of any one of claims 51 to 93, wherein said animal is a human.

95. The use of any one of claims 51 to 94, wherein the medicament includes a compound selected from the group consisting of:


or a pharmaceutically acceptable salt thereof, for combined use with


or a pharmaceutically acceptable salt thereof.

96. The use of any one of claims 51 to 94, wherein the medicament includes a compound selected from the group consisting of:


pharmaceutically acceptable salt thereof, for combined use with


or a pharmaceutically acceptable salt thereof.

97. The use of any one of claims 51 to 94, wherein the medicament

includes
or a pharmaceutically acceptable salt thereof, for combined use with


or a pharmaceutically acceptable salt thereof.

98. The use of any one of claims 51 to 94, wherein the medicament


or a pharmaceutically acceptable salt thereof, for combined use with


, or a pharmaceutically acceptable salt thereof.

99. The use of any one of claims 51 to 94, wherein the medicament further includes a compound of the formula:


salt thereof.