Tetrapeptide inhibitors of β-secretase

• US 7,169,759 B1
• Filed: 06/15/2000
• Issued: 01/30/2007
• Est. Priority Date: 06/15/1999
• Status: Expired due to Fees

• Current Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Original Assignee: Elan Pharmaceuticals Incorporated (Perrigo Company PLC)
• Inventors: Tung, Jay, John, Varghese, Fang, Lawrence, Mamo, Shumeye S.
• Primary Examiner(s): Campell; Bruce R.
• Assistant Examiner(s): TELLER, ROY R
• Application Number:
  US09/594,667
• Time in Patent Office: 2,420 Days
• Field of Search: 514/18, 530/387.9, 530/388.1, 530/388.26, 530/389.1, 530/389.2
• US Class Current: 514/17.8
• CPC Class Codes: A61K 38/07 Tetrapeptides

Abstract

Statine-derived peptide inhibitors of the β-secretase enzyme are provided which are useful in the treatment of Alzheimer'"'"'s disease and other diseases characterized by deposition of Aβ peptide in a mammal. The compounds of the invention provide useful methods of treatment by administration of these inhibitors to reduce Aβ peptide formation and pharmaceutical compositions.

Claims

1. A compound of formula 1

2. The compound of claim 1 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

3. The compound of claim 2 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

4. The compound of claim 1 wherein B is the group (i) wherein L is phenyl, x=1, z=0, Q is selected from a bond, —

CH₂— and

—

O—

CH₂—

, R′

is H and E is H or CH₃, and R is H or C₁–

C₅ alkyl.

5. The compound of claim 4 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid;

4-methylaminomethylbenzoic acid;

1-amino-1-(4-carboxyphenyl)ethane;

2-aminomethylbenzoxyacetic acid;

2-aminobenzoic acid and 4-aminobenzoic acid.

6. The compound of claim 1 wherein B is the group (ii) wherein y is from 2 to 6 inclusive, z=0 or 1 and R′

and E are both H and R is H or C_1-5 alkyl.

7. The compound of claim 6 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminopropanoic acid and glutamic acid.

8. The compound of claim 1 wherein B is the group (v) wherein x=1 and z=0.

9. The compound of claim 8 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

10. The compound of claim 1 wherein B is the group (v) wherein ring M is a 6-membered heterocycle having 1 to 2 atoms of N, z=0, Q is a bond or CH₂ and R is H or C₁–

C₅ alkyl.

11. The compound of claim 10 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

12. The compound of claim 1 wherein B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO₂, C(O)NH₂, C₁–

C₂ alkoxy and hydroxymethyl.

13. The compound of claim 12 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

14. The compound of claim 1 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

15. The compound of claim 1 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

16. The compound of claim 1 wherein R₁ is 2-propyl and R₂ is chosen from the group consisting of 2-methylpropyl and benzyl.

17. The compound of claim 16 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

18. The compound of claim 17 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

19. The compound of claim 16 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid, 4-methylaminomethylbenzoic acid1-amino-1-(4-carboxyphenyl)ethane, 2-aminomethylbenzoxyacetic acid, 2-aminobenzoic acid and 4-aminobenzoic acid.

20. The compound of claim 16 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminoporpanoic acid and glutamic acid.

21. The compound of claim 16 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

22. The compound of claim 16 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

23. The compound of claim 16 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

24. The compound of claim 16 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

25. The compound of claim 16 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

26. The compound of claim 1 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

27. The compound of claim 16 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

28. The compound of claim 17 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

29. The compound of claim 18 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

30. The compound of claim 19 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

31. The compound of claim 20 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

32. The compound of claim 21 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

33. The compound of claim 22 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

34. The compound of claim 23 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

35. The compound of claim 24 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

36. The compound of claim 25 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

37. The compound of claim 26 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

38. A method of slowing the progression of a disease state characterized by deposition of Aβ

peptide in a mammal comprising administering to a mammal in need thereof an effective amount of a compound of Formula 1

39. The method of claim 38 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

40. The method of claim 39 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

41. The method of claim 38 wherein B is the group (i) wherein L is phenyl, x=1, z=0, Q is selected from a bond, —

CH₂— and

—

O—

CH₂—

, R′

is H and E is H or CH₃, and R is H or C₁–

C₅ alkyl.

42. The method of claim 41 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid;

4-methylaminomethylbenzoic acid;

1-amino-1-(4-carboxyphenyl)ethane;

2-aminomethylbenzoxyacetic acid;

2-aminobenzoic acid and 4-aminobenzoic acid.

43. The method of claim 38 wherein B is the group (ii) wherein y is from 2 to 6 inclusive, z=0 or 1 and R′

and E are both H and R is H or C_1-5 alkyl.

44. The method of claim 43 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminopropanoic acid and glutamic acid.

45. The method of claim 38 wherein B is the group (v) wherein x=1 and z=0.

46. The method of claim 45 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

47. The method of claim 38 wherein B is the group (v) wherein ring M is a 6-membered heterocycle having 1 to 2 atoms of N, z=0, Q is a bond or CH₂ and R is H or C₁–

C₅ alkyl.

48. The method of claim 47 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

49. The method of claim 38 wherein B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO₂, C(O)NH₂, C₁–

C₂ alkoxy and hydroxymethyl.

50. The method of claim 49 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

51. The method of claim 38 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

52. The method of claim 38 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

53. The method of claim 38 wherein R₁ is 2-propyl and R₂ is chosen from the group consisting of 2-methylpropyl and benzyl.

54. The method of claim 53 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

55. The method of claim 54 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

56. The method of claim 53 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid, 4-methylaminomethylbenzoic acid1-amino-1-(4-carboxyphenyl)ethane, 2-aminomethylbenzoxyacetic acid, 2-aminobenzoic acid and 4-aminobenzoic acid.

57. The method of claim 53 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminoporpanoic acid and glutamic acid.

58. The method of claim 53 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

59. The method of claim 53 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

60. The method of claim 53 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

61. The method of claim 53 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

62. The method of claim 53 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

63. The method of claim 38 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

64. The method of claim 43 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

65. The method of claim 44 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

66. The method of claim 45 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

67. The method of claim 46 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

68. The method of claim 47 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

69. The method of claim 48 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

70. The method of claim 49 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

71. The method of claim 50 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

72. The method of claim 51 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

73. The method of claim 52 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

74. The method of claim 53 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

75. A pharmaceutical composition comprising a compound of formula 1

76. The composition of claim 75 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

77. The composition of claim 76 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

78. The composition of claim 75 wherein B is the group (i) wherein L is phenyl, x=1, z=0,

Q is selected from a bond, —

CH₂— and

—

O—

CH₂—

, R′

is H and E is H or CH₃, and R is H or C₁–

C₅ alkyl.

79. The composition of claim 78 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid;

4-methylaminomethylbenzoic acid;

1-amino-1-(4-carboxyphenyl)ethane;

2-aminomethylbenzoxyacetic acid;

2-aminobenzoic acid and 4-aminobenzoic acid.

80. The composition of claim 75 wherein B is the group (ii) wherein y is from 2 to 6 inclusive, z=0 or 1 and R′

and E are both H and R is H or C_1-5 alkyl.

81. The composition of claim 80 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminopropanoic acid and glutamic acid.

82. The composition of claim 75 wherein B is the group (v) wherein x=1 and z=0.

83. The composition of claim 82 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

84. The composition of claim 75 wherein B is the group (v) wherein ring M is a 6-membered heterocycle having 1 to 2 atoms of N, z=0, Q is a bond or CH₂ and R is H or C₁–

C₅ alkyl.

85. The composition of claim 75 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

86. The composition of claim 75 wherein B is the group (iv) wherein L is phenyl and T is selected from the group consisting of H, OH, F, NO₂, C(O)NH₂, C₁–

C₂ alkoxy and hydroxymethyl.

87. The composition of claim 86 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

88. The composition of claim 75 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

89. The composition of claim 75 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

90. The composition of claim 75 wherein R₁ is 2-propyl and R₂ is chosen from the group consisting of 2-methylpropyl and benzyl.

91. The composition of claim 90 wherein B is the group (i) wherein L is cyclohexane, x=0, z=0 or 1, Q is —

CH₂—

or a bond and E and R′

are both H and R is H or C₁–

C₅ alkyl.

92. The composition of claim 91 wherein B is selected from the group consisting of 3,5-dicarboxycyclohexylamine, 3,4-dicarboxycyclohexylamine and 2,4-dicarboxycyclohexylamine and 2,5-dicarboxycyclohexylamine.

93. The composition of claim 90 wherein B is selected from the group consisting of 4-aminomethylbenzoic acid, 4-methylaminomethylbenzoic acid1-amino-1-(4-carboxyphenyl)ethane, 2-aminomethylbenzoxyacetic acid, 2-aminobenzoic acid and 4-aminobenzoic acid.

94. The composition of claim 90 wherein B is selected from the group consisting of 4-aminobutanoic acid-3-aminoporpanoic acid and glutamic acid.

95. The composition of claim 90 wherein B is selected from the group consisting of 3-aminofuran-2-one and 2-aminopentanedioic acid anhydride.

96. The composition of claim 90 wherein B is selected from the group consisting of 4-piperidineacetic acid and piperazine-4-carboxylic acid.

97. The composition of claim 90 wherein B is selected from the group consisting of 1-amino-2-(3-nitro-4-hydroxyphenyl)ethane, 4-fluorobenzenamine, and aminomethylbenzene-4-carboxamide.

98. The composition of claim 90 wherein B is selected from 2-aminomethylthiazole-5-carboxylic acid and phenylglycine.

99. The composition of claim 90 wherein B is selected from 3,5-dimethoxycyclohexylamine, 3,5-dihydroxymethylcyclohexylamine and 3,4,5-trimethoxycyclohexylamine.

100. The composition of claim 75 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

101. The composition of claim 90 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

102. The composition of claim 91 wherein R₃ is selected from the group consisting of phenyl and 2-methylthio ethyl and R4 is 2-propyl.

103. The composition of claim 92 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

104. The composition of claim 93 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

105. The composition of claim 94 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

106. The composition of claim 95 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

107. The composition of claim 96 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

108. The composition of claim 97 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

109. The composition of claim 98 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

110. The composition of claim 99 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.

111. The composition of claim 100 wherein R₃ is selected from the group consisting of phenyl and 2-methylthioethyl and R4 is 2-propyl.