Phosphonate analogs for treating metabolic diseases

• US 20050227947A1
• Filed: 04/26/2004
• Published: 10/13/2005
• Est. Priority Date: 04/25/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Watkins, William J., Cho, Aesop, Fardis, Maria, Chong, Lee S., Chen, Xiaowu, Kirschberg, Thorsten, Chen, James M., Pyun, Hyung-Jung, Krawczyk, Steven
• Granted Patent: US 7,407,965 B2
• Time in Patent Office: Days
• US Class Current: 514/79
• CPC Class Codes: A61K 31/66 Phosphorus compounds
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00

Abstract

The invention is related to phosphorus substituted compounds with activity for treating metabolic diseases and/or disorders, e.g., diabetes and hypercholesterolemia, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

Claims

1. A conjugate comprising a compound having activity against a metabolic disease;

or a pharmaceutically acceptable salt or solvate thereof.

2. The conjugate of claim 1, or a pharmaceutically acceptable salt or solvate thereof, that is a compound of any one of formulae 500-523 substituted with one or more groups A⁰,

wherein:

A⁰ is A¹, A² or W³ with the proviso that the conjugate includes at least one A¹;

Y¹ is independently O, S, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), or N(N(R^x)(R^x));

Y² is independently a bond, O, N(R^x), N(O)(R^x), N(OR^x), N(O)(OR^x), N(N(R^x)(R^x)), —

S(O)_M2—

, or —

S(O)_M2—

S(O)_M2—

; and

when Y² joins two phosphorous atoms Y² can also be C(R²)(R²);

R^x is independently H, R¹, R², W³, a protecting group, or the formula;

wherein;

R^y is independently H, W³, R² or a protecting group;

R¹ is independently H or alkyl of 1 to 18 carbon atoms;

R² is independently H, R¹, R³ or R⁴ wherein each R⁴ is independently substituted with 0 to 3 R³ groups or taken together at a carbon atom, two R² groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R³ groups;

R³ is R^3a, R^3b, R^3c or R^3d, provided that when R³ is bound to a heteroatom, the R³ is R^3c or R^3d;

R^3a is F, Cl, Br, I, —

CN, N₃ or —

NO₂;

R^3b is Y¹;

R^3c is —

R^x, —

N(R^x)(R^x), —

SR^x, —

S(O)R^x, —

S(O)(OR^x), —

S(O)₂(OR^x), —

OC(Y¹)R^x, —

OC(Y¹)OR^x, OC(Y¹)(N(R^x)(R^x)), —

SC(Y¹)R^x, —

SC(Y¹)OR^x, —

SC(Y¹)(N(R^x)(R^x)), —

N(R^x)C(Y¹)R^x, —

N(R^x)C(Y¹)OR^x, or —

N(R^x)C(Y¹)(N(R^x)(R^x));

R^3d is —

C(Y¹)R^x, —

C(Y¹)OR^x or —

C(Y¹)(N(R^x)(R^x));

R⁴ is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;

R⁵ is R⁴ wherein each R⁴ is substituted with 0 to 3 R³ groups;

W² is W⁴ or W⁵;

W⁴ is R⁵, —

C(Y¹)R⁵, —

C(Y¹)W⁵, —

SO_M2R⁵, or —

SO_M2W⁵;

W⁵ is carbocycle or heterocycle wherein W⁵ is independently substituted with 0 to 3 R² groups;

W⁶ is W³ independently substituted with 1, 2, or 3 A³ groups;

M2 is 0, 1 or 2;

M12a is 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

M1a, M1c, and M1d are independently 0 or 1; and

M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12;

3. The conjugate of claim 2, or a pharmaceutically acceptable salt or solvate thereof, which has the formula:

[DRUG]−

(A⁰)_nn

wherein

DRUG is a compound of any one of formulae 500-523; and

nn is 1, 2, or 3.

4. The conjugate of claim 2 which has any one of formulae 1-51 wherein:

one A⁰ is A¹;

X⁵¹ and X⁵² are the same or different and each represents hydrogen or C₁-C₅ alkyl;

X⁵³ and X⁵⁴ are the same or different and each represents hydrogen, a C₁-C₅ alkyl group or a C₁-C₅ alkoxy group, or X⁵³ and X⁵⁴ together represent a C₁-C₄ alkylenedioxy group;

X⁵⁶ represents a —

CH₂—

, >

CO or >

CH—

OX⁵⁵ group;

X⁵⁵ represents hydrogen;

C₁-C₆ aliphatic acyl;

(C₅-C₇ cycloalkane)carbonyl;

benzoyl, benzoyl substituted with one to three substituents selected from the group of C₁-C₄ alkyl, C₁-C₄ alkoxy, hydroxy, halogen, nitro amino and di(C₁-C₄ alkyl)amino;

naphthoyl;

4-7 membered heterocyclic acyl wherein heterocyclic moiety has O, S or N hereto atoms;

phenyl(C₂-C₃)aliphatic acyl;

cinnamoyl;

(C₁-C₆ alkoxy)carbonyl;

or benzoyloxycarbonyl;

X⁵⁷ represents a hydrogen atom, an alkyl group, an acyl group, an aralkyl group, wherein the aryl moiety may be substituted of unsubstituted, or a substituted or unsubstituted aryl group;

X⁵⁸ represents hydrogen or 1 to 4 optional substituents selected from the group consisting of alkyl, alkoxy, aryl and halogen or X⁵⁸ represents two substituents on adjacent carbon atoms, which substituents together with the carbon atoms to which they are attached form a substituted or unsubstituted aryl group;

X⁵⁹ represents O, NX⁶⁰, CH₂O, CH₂NX⁶⁰;

X⁶⁰ represents H or lower alkyl with one or two carbons;

X⁶¹ is selected from 5 or 6 membered aromatic ring with zero, one, or two heteroatoms with substituents. The substituents of the aromatic ring can be hydrogen, halogen, alkyl and alkoxy of one to six carbon atoms, hydroxy, amino, acetylamino and phenyl, wherein the alkyl, alkoxy and phenyl radicals may be substituted by at least one member selected from the group consisting of halogen, lower alkyl and lower alkoxy;

X⁶² is selected from the group consisting of lower alkyl of one to four carbon atoms, lower alkenyl of one to four carbon atoms, cycloaliphatic and substituted cycloaliphatic, preferably cycloalkyl and substituted cycloalkyl wherein the cyclic ring contains five to eight carbon atoms preferably five to six carbon atoms, and may be substituted by lower alkyl or lower alkoxy;

X⁶³, X⁶⁴, and X⁶⁵ are independently selected from the group consisting of hydrogen halogen, alkyl and alkoxy of one to six carbon atoms, hydroxy, amino, acetylamino and phenyl, wherein the alkyl, alkoxy and phenyl radicals may be substituted by at least one member selected from the group consisting of halogen, lower alkyl and lower alkoxy;

X⁶⁶ is selected from the group consisting of O, NX⁶⁷, CH₂O, CH₂NX⁶⁷;

X⁶⁷ is selected from H or lower alkyl with one or two carbons; and

X⁶⁸ is selected from alkylene or alkenylene having from 3 to 6 carbon atoms, optionally substituted by up to 3 alkyl groups each having from 1 to 4 carbon atoms, or a phenyl radical;

or cycloalkylene alkyl having up to 3 carbon atoms in the alkyl moiety and from 5 to 7 ring carbon atoms, optionally substituted by up to 3 methyl groups.

5. The conjugate of claim 2 wherein A¹ is of the formula:

6. The conjugate of claim 2 wherein each A¹ is of the formula:

7. The conjugate of claim 2 wherein each A¹ is of the formula:

8. The conjugate of claim 2 wherein each A¹ is of the formula:

9. The conjugate of claim 2 wherein each A¹ is of the formula:

10. The conjugate of claim 2 wherein M12a is 1.

11. The conjugate of claim 2 wherein each A¹ is of the formula:

12. The conjugate of claim 2 wherein each A¹ is of the formula;

13. The conjugate of claim 2 wherein each A¹ is of the formula

14. The conjugate of claim 2 wherein each A¹ is of the formula:

15. The conjugate of claim 2 wherein each A¹ is of the formula:

16. The conjugate of claim 2 wherein each A¹ is of the formula;

17. The conjugate of claim 2 wherein each A¹ is of the formula:

18. The conjugate of claim 2 wherein each A² is of the formula:

19. The conjugate of claim 2 wherein each A² is of the formula:

20. The conjugate of claim 2 wherein each M12b is 1.

21. The conjugate of claim 20 where M12b is 0, Y² is a bond and W⁵ is a carbocycle or heterocycle where W⁵ is optionally and independently substituted with 1, 2, or 3 R² groups.

22. The conjugate of claim 2 wherein each A² is of the formula:

23. The conjugate of claim 22 wherein M12a is 1.

24. The conjugate of claim 2 wherein each A² is selected from phenyl, substituted phenyl, benzyl, substituted benzyl, pyridyl and substituted pyridyl.

25. The conjugate of claim 2 wherein each A² is of the formula:

26. The conjugate of claim 2 wherein each A² is of the formula:

27. The conjugate of claim 26 wherein M12b is 1.

28. The conjugate of claim 2 wherein each A³ is of the formula:

29. The conjugate of claim 2 wherein each A³ is of the formula:

30. The conjugate of claim 2 wherein each A³ is of the formula:

31. The conjugate of claim 2 wherein each A³ is of the formula:

32. The conjugate of claim 2 wherein each A³ is of the formula:

33. The conjugate of claim 2 wherein each A³ is of the formula

34. The conjugate of claim 33 wherein M12d is 1.

35. The conjugate of claim 2 wherein each A³ is of the formula:

36. The conjugate of claim 2 wherein each A³ is of the formula:

37. The conjugate of claim 36 wherein W⁵ is a carbocycle.

38. The conjugate of claim 2 wherein each A³ is of the formula:

39. The conjugate of claim 38 wherein W⁵ is phenyl.

40. The conjugate of claim 39 wherein W12b is 1.

41. The conjugate of claim 2 wherein each A³ is of the formula:

42. The conjugate of claim 2 wherein each A³ is of the formula:

43. The conjugate of claim 2 wherein each A³ is of the formula:

44. The conjugate of claim 43 wherein R¹ is H.

45. The conjugate of claim 44 wherein M12d is 1.

46. The conjugate of claim 2 wherein each A³ is of the formula:

47. The conjugate of claim 2 wherein each A³ is of the formula:

48. The conjugate of claim 2 wherein each A³ is of the formula:

49. The conjugate of claim 2 wherein each A³ is of the formula:

50. The conjugate of claim 2 wherein each A³ is of the formula:

51. The conjugate of claim 2 wherein each A³ is of the formula:

52. The conjugate of claim 2 wherein each A³ is of the formula:

53. The conjugate of claim 2 wherein each A³ is of the formula:

54. The conjugate of claim 2 wherein each A³ is of the formula:

55. The conjugate of claim 2 wherein each A³ is of the formula:

56. The conjugate of claim 2 wherein each A³ is of the formula:

57. The conjugate of claim 2 wherein each A³ is of the formula:

58. The conjugate of claim 2 wherein each A³ is of the formula:

59. The conjugate of claim 2 wherein each A³ is of the formula:

60. The conjugate of claim 2 wherein each A³ is of the formula:

61. The conjugate of claim 2 wherein each A³ is of the formula:

62. The conjugate of claim 2 wherein each A³ is of the formula:

63. The conjugate of claim 3 wherein A⁰ is of the formula:

64. The conjugate of claim 1 which has the formula:

65. The conjugate of claim 64 wherein each R^x is of the formula:

66. The conjugate of claim 64 wherein each R^x is of the formula:

67. The conjugate of claim 64 wherein each R^x is of the formula:

68. The conjugate of claim 64 wherein each R^y is independently H or alkyl of 1 to 10 carbons.

69. The conjugate of claim 64 wherein each R^x is of the formula:

70. The conjugate of claim 64 wherein each R^x is of the formula:

71. The conjugate of claim 64 wherein each R^x is of the formula:

72. The conjugate of claim 64 wherein each Y¹ is O or S.

73. The conjugate of claim 64 wherein each Y² is O, N(R^y) or S.

74. The conjugate of claim 64 wherein nn is 1.

75. The conjugate of claim 64 wherein nn is 2.

76. The conjugate of claim 64 wherein nn is 3.

77. The conjugate of claim 64 wherein the a compound having activity against a metabolic disease is a compound of any one of formulae 500-523.

78. The conjugate of claim 77 wherein each L has a molecular weight of from about 20 daltons to about 400 daltons.

79. The conjugate of claim 77 wherein each L has a length of about 5 angstroms to about 300 angstroms.

80. The conjugate of claim 77 wherein each L separates the compound of any one of formulae 500-523 and the phosphorous of the phosphonate group by about 5 angstroms to about 200 angstroms, inclusive.

81. The conjugate of claim 77 wherein each L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 2 to 25 carbon atoms, wherein one or more of the carbon atoms is optionally replaced by (—

O—

), and wherein the chain is optionally substituted on carbon with one or more substituents selected from (C₁-C₆)alkoxy, (C₃-C₆)cycloalkyl, (C₁-C₆)alkanoyl, (C₁-C₆)alkanoyloxy, (C₁C₆)alkoxycarbonyl, (C₁-C₆)alkylthio, azido, cyano, nitro, halo, hydroxy, oxo (═

O), carboxy, aryl, aryloxy, heteroaryl, and heteroaryloxy.

82. The conjugate of claim 77 wherein each L is of the formula W-A wherein A is (C₁C₂₄)alkylene, (C₂-C₂₄)alkenylene, (C₂-C₂₄)alkynylene, (C₃-C₈)cycloalkylene, (C₆-C₁₀)aryl or a combination thereof, wherein each W is —

N(R)C(═

O)—

, —

C(═

O)N(R)—

, —

OC(═

O)—

, —

C(═

O)O—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

N(R)—

, —

C(═

O)—

, —

N(R)C═

N(R)—

N(R)—

, —

C(R)═

N(R)—

, —

S(O)_M2—

N(R)—

, —

N(R)—

S(O)_M2—

, or a direct bond;

wherein each R is independently H or alkyl of 1 to 10 carbons.

83. The conjugate of claim 82 wherein each A is alkylene of 1 to 10 carbons.

84. The conjugate of claim 77 wherein each L is a divalent radical formed from a peptide.

85. The conjugate of claim 77 wherein each L is a divalent radical formed from an amino acid.

86. The conjugate of claim 77 wherein each L is a divalent radical formed from poly-L-glutamic acid, poly-L-aspartic acid, poly-L-histidine, poly-L-ornithine, poly-L-serine, poly-L-threonine, poly-L-tyrosine, poly-L-leucine, poly-L-lysine-L-phenylalanine, poly-L-lysine or poly-L-lysine-L-tyrosine.

87. The conjugate of claim 77 wherein each L is of the formula W—

(CH₂)_n wherein, n is between about 1 and about 10; and

W is —

N(R)C(═

O)—

, —

C(═

O)N(R)—

, —

OC(═

O)—

, —

C(═

O)O—

, —

O—

, —

S—

, —

S(O)—

, —

S(O)₂—

, —

C(═

O)—

, —

N(R)—

, —

N(R)C═

N(R)—

N(R)—

, —

C(R)═

N(R)—

, —

S(O)_M2—

N(R)—

, —

N(R)—

S(O)_M2—

, or a direct bond;

wherein each R is independently H or (C₁-C₆)alkyl.

88. The conjugate of claim 77 wherein each L is methylene, ethylene, or propylene.

89. The conjugate of claim 77 wherein each L is linked to P at a carbon atom of L.

90. The conjugate as described in claim 1, which is isolated and purified.

91. The conjugate of claim 1 which is not an anti-inflammatory compound.

92. The conjugate of claim 1 which is not an anti-infective.

93. The conjugate of claim 1 which is not a compound that is active against immune-mediated conditions.

94. The conjugate of claim 1 which is not a compound that is not an antimetabolite.

95. The conjugate of claim 1 which is not an antiviral agent.

96. The conjugate of claim 1 which is not a nucleoside.

97. The conjugate of claim 1 which is not a IMPDH inhibitor.

98. The conjugate of claim 1 which is not a kinase inhibitor.

99. The conjugate of claim 1 which is not a PNP inhibitor.

100. The conjugate of claim 2 which is not a substituted compound of any one of formula 519.

101. The conjugate of claim 2 which is not a substituted compound of formula 510.

103. The conjugate of claim 4 which is not a compound of formula 45.

106. A compound of claim 107 selected from Table 100.

107. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

108. A unit dosage form comprising a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof;

and a pharmaceutically acceptable excipient.

109. A method of treating metabolic disorder comprising administering to a mammal afflicted with a metabolic disorder, an amount of a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof.

110. The method of claim 109 wherein the mammal is a human.

111. A method of inhibiting cholesterol synthesis in a mammal, comprising administering a conjugate as described in claim 1, or a pharmaceutically acceptable salt or solvate thereof to the mammal.

112. The method of claim 111 wherein the conjugate is formulated with a pharmaceutically acceptable carrier.

113. The method of claim 112 wherein the formulation further comprises a second active ingredient.

102. The conjugate of 4 which is not a compound of any one of formulae 29-31.

104. An conjugate having activity against a metabolic disease described herein.

105. A compound of the formula MBF.