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1. (WO2018213933) METHODS OF PREVENTING OR TREATING ATHEROSCLEROSIS WITH INHIBITORS OF SPECIFIC ISOENZYMES OF HUMAN NEURAMINIDASE
Note: Text based on automatic Optical Character Recognition processes. Please use the PDF version for legal matters

CLAIMS:

1. A method of preventing or treating atherosclerosis or a symptom thereof comprising administering to a subject in need thereof a therapeutically effective amount of a specific inhibitor of neuraminidase 1 (neul); neuraminidase 3 (neu3); or a bispecific inhibitor of neul or neu3.

2. The method of claim' 1, wherein the inhibitor is a compound of formula I


wherein Ri is H; a C1-C10 alkyl; C1-C10 heteroalkyi; C3-C7 cycloalkyi; C3-C7 heterocycloalkyi; C3-C8 aryl; or C3-C8 heteroaryl; wherein the alkyl, heteroalkyi, cycloalkyi, heterocycloalkyi, aryl and heteroaryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyi, a C3-C7 aryl, an halogen, an amide or an hydroxyl;

R2 is H; -OH, -NHC(=NH)NH2; or azide;

R3 is -NHC(0)(CH2)nR5,

wherein R5 is H; -OH; C1-C10 alkyl; C1-C10 heteroalkyi; C3-C7 cycloalkyi; C3-C7 heterocycloalkyi; or C3-C8 aryl; wherein the alkyl, heteroalkyi, cycloalkyi, heterocycloalkyi, and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyi, a C3-C7 aryl, an halogen, an amide or an hydroxyl; and

n is 0 or 1;

R4 is H; -OH; -O-alkyl; -C(0)-alkyl-NHC(0)-aryl; -NHC(0)R6; or

wherein the alkyl and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyi, a C3-C7 aryl, an halogen, an amine, an amide or an hydroxyl,

wherein:R6 is H, C1-C10 alkyi; or C3-C7 aryl.wherein the C1-C10 alkyi and C3-C7 aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyi, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amide, an amine or an hydroxyl;

R7 is H; halogen; -0-alkyl; -C(0)OH; amine; acetamide; -C1-C10 alkyi; -0-C3-C7 aryl; or -(CH2)qNH(CO)aryl,

wherein the C1-C10 alkyi and C3-C7 aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyi, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amide, an amine or an hydroxyl, wherein q is 0 or 1 ; and

p is O, 1 , 2 or 3; and

X is 0, CH2 or S,

with the proviso that when R2 and R4 are OH, R3 is not -NHC(0)CH3,

or is an ester, solvate, hydrate or pharmaceutical salt of the compound of formula I.

3. The method of claim' 2, wherein R3 is -NHC(0)(CH2)nR5.

4. The method of claim' 2, wheiren n is 0.

5. The method of claim' 4, wheiren R5 is cycloalkyl.

6. The method of claim' 4, wheiren R5 is aryl.

7. The method of claim' 4, wheiren R5 is C1-C10 alkyi.

8. The method of claim' 4, wheiren R5 is C1-C10 alkyi substituted with a C1-C10 alkyi.

9. The method of claim' 2, wherein n is 1.

10. The method of claim' 9, wheiren R5 is H.

11. The method of claim' 9, wheiren R5 is C1 -C5 alkyi.

12. The method of claim' 11 , wherein the C1-C5 alkyi is branched.

13. The method of any one of claims 2-12, wherein R2 is OH.

14. The method of any one of claims 2-11 , wherein R2 is -NHC(=NH)NH2.

15. The method of any one of claims 2-11, wherein R2 is azido.

The method of any one of claims 2-15, wherein F¾ is -OH.

The method of any one of claims 2-15, wherein f¾ is -ΝΗ0(0)Γ¾.

The method of claim' 17, wherein f¾ is C1-C10 alkyl.

The method of claim' 18, wherein the C1-C10 alkyl is branched.

20. The method of claim' 17, wherein l¾ is C3-C7 aryl.

21. The method of claim' 20, wherein the C3-C7 aryl is substituted with an amine or an amide.

22. The method of any one of claims 2-15, wherein F¾ is

wherein R7 and p are as defined in claim' 2.

23. The method of claim' 22, wherein p is 0.

24. The method of claim' 23, wherein R7 is -(CH2)qNH(CO)aryl.

25. The method of claim' 23, wherein R7 is -hydroxy C1-C10 alkyl.

26. The method of claim' 20, wherein R7 is C1-C10 alkyl.

27. The method of claim' 22, wherein p is 1.

28. The method of claim' 27, wherein R7 is halogen.

29. The method of claim' 27, wherein R7 is O-alkyl.

30. The method of claim' 27, wherein R7 is -C(0)OH.

31. The method of claim' 27, wherein R7 is amine.

32. The method of claim' 27, wherein R7 is acetamide.

33. The method of claim' 27, wherein R7 is -C1-C10 alkyl.

34. The method of claim' 27, wherein R7 is -CH2NH(CO)aryl.

35. The method of claim' 27, wherein R7 is -0-C3-C7 aryl.

36. The method of claim' 22, wherein p is 2.

37. The method of claim' 36, wherein R7 is H.

38. The method of any one of claims 2-15, wherein R4 is -C(0)-alkyl-NHC(0)-aryl.

39. The method of claim' 38, wherein the alkyl is C1-C10 alkyl.

40. The method of claim' 38 or 39, wherein the aryl is C3-C7 aryl.

41. The method of claim' 38, wherein the C3-C7 aryl is substituted with an amide.

42. The method of claim' 2, wherein :

(iv) R3 is -NHC(0)(CH2)nR5, wherein n is 0 to 7 and wherein R5 is C1-C10 alkyl, C3-C7 cycloalkyi, or C3-C8 aryl, wherein the alkyl, cycloalkyi, and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyi, a C3-C7 aryl, an halogen, an amide or an hydroxy I;

(v) R2 is -OH, -NHC(=NH)NH2 or azide; and

(vi) R4 is -OH; -NHC(0)R6, wherein R6 is C1-C10 alkyl or C1-C5 aryl; -(CH2)qNH(CO)aryl, wherein q is

0 or 1 ; or
, wherein p is 0, 1 , 2 or 3, and R7 is H, -C(=0)OH, phenyl, or phenyloxy,

with the proviso that when R2 and R4 are OH, R3 is not -NHC(0)CH3.

43. The method of claim' 2, wherein :

(iv) R3 is -NHC(0)(CH2)nCH3, wherein n is 0 to 7;

(v) R2 is -OH or -NHC(=NH)NH2; and

(vi) R4 is -OH; -NHC(0)R6, wherein R6 is C3-C7 aryl or C1-C10 alkyl;

or
, wherein p is 1, 2 or 3, and R7 is H, -C(=0)OH, phenyl, or phenyloxy,

with the proviso that when R2 and R4 are OH, R3 is not -NHC(0)CH3.

44. The method of any one of claims 2 to 43, wherein X is 0.

45. The method of any one of claims 2 to 44, wherein Ri is H or alkyl.

46. The method of claim' 2, wherein the compound is of formula I, wherein X is 0, Ri is H, and R3, R2 and R4 are as set forth below:



or an ester, solvate, hydrate or pharmaceutical salt of the compound of formula I.

47. The method of claim' 2, wherein the compound is of formula I, wherein X is 0, Ri is H, and R3, R2 and R are as set forth below:


or an ester, solvate, hydrate or pharmaceutical salt of the compound of formula I.

48. The method of any one of claims 2 to 47, wherein the compound of formula I is of formula la:


(la),

wherein Ri, R2, R3, 4 and X are as defined in any one of claims 2 to 47.

49. The method of any one of claims 2 to 47, wherein the compound of formula I is of formula lb:


wherein Ri, R2, R3, R4 and X are as defined in any one of claims 2 to 47.

50. The method of any one of claims 1 to 49, wherein the inhibitor is a specific or bispecific inhibitor of neul .

51. The method of any one of claims 1 to 49, wherein the inhibitor is a specific or bispecific inhibitor of neu3.

52. The method of claim' 51 , wherein the inhibitor reduces the total plasma cholesterol and/or plasma LDL.

53. A method of reducing inflammation comprising administering to a subject in need thereof a specific bispecific inhibitor of neuraminidase 1 or neuraminidase 3.

54. The method of claims 53, wherein the specific inhibitor is as defined in any one of claims 2 to 53.

55. A compound of formula I


wherein Ri is H, a C1-C10 alkyl, C1-C10 heteroalkyi; C3-C7 cycloalkyl; C3-C7 heterocycloalkyi; C3-C8 aryl; or C3-C8 heteroaryl; wherein the alkyl, heteroalkyi, cycloalkyl, heterocycloalkyi, aryl and heteroaryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amide or an hydroxyl;

R2 is H; -OH; -NHC(=NH)NH2; azide; or -NHC(0)R;

wherein R is -NH(CH2)mCOOH, wherein m is 1 , 2 or 3;

R3 is -NHC(0)(CH2)nR5,

wherein R5 is H; -OH; C1-C10 alkyl; C1-C10 heteroalkyi; C3-C7 cycloalkyl; C3-C7 heterocycloalkyi; C3-C8 aryl;


C3-C8 heteroaryl; or

wherein the alkyl, heteroalkyi, cycloalkyl, heterocycloalkyi, aryl and heteroaryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl; a C3-C8 cycloalkyl; a C3- halogen; a -C(0)OH; an amide; or an hydroxyl;

R8 is a trifluoromethyl, a C1-C10 alkyl, a -C(0)0H, a -O-C1-C10 alkyl, an halogen, an amine, or -NH- acetamido; and

r is O, 1 , 2 or 3; and

n is 0 or 1 ;

R4 is H; -OH; -0-alkyl; -C(0)-alkyl-NHC(0)-aryl; -NHC(0)R6; or

wherein the alkyl and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amine, an amide or an hydroxyl,

and wherein:

Re is H. C1-C10 alkyl; or C3-C7 aryl,

wherein the C1-C10 alkyl and C3-C7 aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amide, an amine or an hydroxyl;

R7 is H; halogen; -0-alkyl; -C(0)0H; amine; amide; -C1-C10 alkyl; -0-C3-C7 aryl; or -(CH2)qNH(CO)aryl,

wherein q is 0 or 1; and

p is O, 1 , 2 or 3; and

X is 0, CH2 or S,

or an ester, solvate, hydrate or pharmaceutical salt thereof,

with the proviso that:

when R2 and R4 is -OH, R3 is not -NHC(=0)CH3, -NHC(=0)CH2CH3, -NHC(=0)(CH2)2CH3, - NHC(=0)CH(CH3)2, -NHC(=0)CH2CH(CH3)2, -NHC(=0)cyclopropyl, -NHC(=0)cyclobutyl, or -NHC(=0)phenyl; when R2 is -OH and R3 is -NHC(=0)CH3, R4 is not -1 ,2,3-triazolyl-CH2OH, -NHC(=0)(CH2)2CH3, - NHC(=0)(CH2)3CH3 , -NHC(=0)CH(CH3)2l -NHC(=0)CH2CH(CH3)2, or -NHC(=0)phenyl; and

when R3 is -NHC(=0)CH3 and R4 is OH, R2 is not -NHC(=NH)NH2.

The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 55, with the further proviso

when R3 is -NHC(=0)CH3, R2 is -OH, and R4 is

R7 is not -N(CH3)2, -NHC(=0)CH3, -NH¾ -CH3, -OCH3, F, -CF3, or -C(=0)OH.

57. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 55 or 56, wherein R3 is -NHC(0)(CH2)nR5.

58. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 57, wheiren n is 0.

59. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 58, wheiren R5 is cycloalkyl.

60. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 58, wheiren R5 is aryl.

61. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 58, wheiren R5 is C1-C10

62. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 58, wheiren R5 is C1-C10 alkyl substituted with a C1-C10 alkyl.

63. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 57, wherein n is 1.

64. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 63, wheiren R5 is H.

65. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 63, wheiren R5 is C1-C5 alkyl.

66. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 65, wherein the C1-C5 alkyl is branched.

67. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 63, wherein R5 is heteroaryl.

68. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 63, wherein R5 is


wherein R8 is -CF3, -CH3, -C(=0)OH, -OCH3, F, -NH2, -N(CH3)2, or - NHC(=0)CH3.

69. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 68, wherein r is 1.

70. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-69, wherein R2 is OH.

71. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-69, wherein R2 is -NHC(=NH)NH2.

72. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-69, wherein R2 is azido.

73. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-69, wherein R2 is -NHC(0)R.

74. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-69, wherein R2 is -NH(CH2)mC(0)OH, wherein m is 1 , 2 or 3.

75. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-74, wherein R4 is -OH.

76. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-74, wherein R4 is -NHC(0)R6.

77. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 76, wherein R6 is C1-C10 alkyl.

78. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 77, wherein the C1C10 alkyl is branched.

79. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 76, wherein R6 is C3-C7 aryl.

80. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 79, wherein the C3-C7 aryl is substituted with an amine or an amide.

81. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-75, wherein

R4 IS
, wherein R7 and p are as defined in claim' 55.

82. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 81 , wherein p is 0.

83. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 82, wherein R7 is -(CH2)qNH(CO)aryl.

84. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 82, wherein R7 is C1-C10 alkyl.

85. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 81 , wherein p is 1.

86. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is halogen.

87. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is O-alkyl.

88. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is -C(0)OH.

89. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is amine.

90. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is acetamide.

91. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is C1-C10 alkyl.

92. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is -CH2NH(CO)aryl.

93. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 85, wherein R7 is -0-C3-C7 aryl.

94. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 81 , wherein p is 2.

95. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 94, wherein R is H.

96. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55-74, wherein R4 is -C(0)-alkyl-NHC(0)-aryl.

97. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 96, wherein the alkyl is C1-C10 alkyl.

98. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 96 or 97, wherein the aryl is C3-C7 aryl.

99. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 99, wherein the C3-C7 aryl is substituted with an amide.

100. The compound of claim' 55 or 56, wherein :

(iv) R3 is -NHC(0)(CH2)nR5, wherein n is 0 to 7 and wherein R5 is C1-C10 alkyl, C3-C7 cycloalkyl, or C3-C8 aryl, wherein the alkyl, cycloalkyl, and aryl are optionally substituted by at least one substituent, each substituent being independently a C1-C10 alkyl, a C3-C8 cycloalkyl, a C3-C7 aryl, an halogen, an amide or an hydroxyl;

(v) R2 is -OH, -NHC(=NH)NH2 or azide; and

(vi) R4 is -OH; -NHC(0)R6, wherein R6 is C1-C10 alkyl or C1-C5 aryl; -(CH2)qNH(CO)aryl, wherein q is 0 or

1 ; or
, wherein p is 0, 1 , 2 or 3, and R7 is H, -C(=0)OH, phenyl, or phenyloxy,

with the proviso that:

when R2 and R4 is -OH, R3 is not -NHC(=0)CH3, -NHC(=0)CH2CH3, -NHC(=0)(CH2)2CH3, - NHC(=0)CH(CH3)2, -NHC(=0)CH2CH(CH3)2, -NHC(=0)cyclopropyl, -NHC(=0)cyclobutyl, or - NHC(=0)phenyl;

when R2 is -OH and R3 is -NHC(=0)CH3, R4 is not -NHC(=0)(CH2)2CH3, -NHC(=0)(CH2)3CH3, - NHC(=0)CH(CH3)2l -NHC(=0)CH2CH(CH3)2, or -NHC(=0)phenyl; and

when R3 is -NHC(=0)CH3 and R4 is OH, R2 is not -NHC(=NH)NH2.

101. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of claim' 55 or 56, wherein :

(iv) R3 is -NHC(0)(CH2)nCH3, wherein n is 0 to 7;

(v) R2 is -OH or -NHC(=NH)NH2; and

(vi) R is -OH; -NHC(0)R6, wherein R6 is C3-C7 aryl or C1-C10 alkyl;

or
wherein p is 1 , 2 or 3, and R7 is H, -C(=0)OH, phenyl, or phenyloxy,

with the proviso that:

when R2 and R4 is -OH, R3 is not -NHC(=0)CH3, -NHC(=0)CH2CH3, or -NHC(=0)(CH2)2CH3;

when R2 is -OH and R3 is -NHC(=0)CH3, R4 is not -NHC(=0)(CH2)2CH3, -NHC(=0)(CH2)3CH3, - NHC(=0)CH(CH3)2, -NHC(=0)CH2CH(CH3)2, or -NHC(=0)phenyl; and

when R3 is -NHC(=0)CH3 and R4 is OH, R2 is not -NHC(=NH)NH2.

102. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55 to 101 , wherein X is 0.

103. The compound or ester, solvate, hydrate or pharmaceutical salt thereof of any one of claims 55 to 102, wherein Ri is H or alkyl.

104. The compound of claim' 55, wherein the compound is of formula I, wherein X is O, Ri is H, and R3, R2 and R4 are as set forth below:


ester, solvate, hydrate or pharmaceutical salt thereof.

The compound of claim' 55, wherein R3, R2 and R are as set forth below:




or an ester, solvate, hydrate or pharmaceutical salt thereof.

106. The compound of claim' 55, wherein the compound is of formula I, wherein X is 0, Ri is H, and R2 and R4 are as set forth below:

or an ester, solvate, hydrate or pharmaceutical salt thereof.

107. The compound of claim' 55, wherein the compound is of formula I, wherein X is 0, Ri is H, and R3, R2 and R are as set forth below:



or an ester, solvate, hydrate or pharmaceutical salt thereof.

108. The compound of any one of claims 55 to 107, wherein the compound is of formula la:


(la),

wherein Ri, R2, R3, R4 and X are as defined in any one of claims 55 to 107.

109. The compound of any one of claims 55 to 107, wherein the compound is of formula lb:

wherein Ri, F¾, R3, R4 and X are as defined in any one of claims 55 to 107.

110. A pharmaceutical composition comprising the compound, ester, solvate, hydrate or pharmaceutical salt thereof defined in any one of claims 55 to 109, and a pharmaceutically acceptable carrier.

111. A method of preventing or treating atherosclerosis or a symptom thereof comprising administering to a subject in need thereof a therapeutically effective amount of (i) the compound, ester, solvate, hydrate or pharmaceutical salt thereof defined in any one of claims 55 to 109 or (ii) the pharmaceutical composition defined in claim' 110.