Phosphonate compounds having immuno-modulatory activity

• US 20060035866A1
• Filed: 04/26/2004
• Published: 02/16/2006
• 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., Ray, Adrian S., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Chen, James M., Huang, Alan X., Zhang, Jennifer R., Cannizzaro, Carina, Pyun, Hyung-Jung, Mackman, Richard L., Nelson, Peter H., Desai, Manoj
• Granted Patent: US 7,470,724 B2
• Time in Patent Office: Days
• US Class Current: 514/102
• CPC Class Codes: A61K 47/542 Carboxylic acids, e.g. a fatty acid or an amino acid
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544

Abstract

The invention is related to phosphonate substituted compounds having immuno-modulatory activity, 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 an immuno-modulatory compound linked to one or more phosphonate groups;

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 500-547 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, then 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)₂R^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;

W³ 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 500-547; and

nn is 1, 2, or 3.

4. The conjugate of claim 2 which has any one of formulae 1-151 wherein:

one A⁰ is A¹;

each X⁵⁰ is independently hydrogen, F, Cl, CF₃, CN, methyl, or tert-butyl;

X⁵¹ is hydrogen, halo, trifluoromethyl, (C1-C3)alkyl, cyano, or (C1-C3)alkoxy;

X⁵² is hydrogen, fluoro, chloro, bromo, methyl, or trifluoromethyl;

X⁵³ is —

O—

, or —

S—

;

X⁵⁴ and X⁵⁵ are independently selected from hydrogen or a C₁-C₁₈ acyl;

X⁵⁶ is hydrogen, a C₁-C₁₈ acyl, or

or X⁵⁴ is hydrogen and together X⁵⁵ and X⁵⁶ are

X⁵⁷ is H, amino, hydroxy, or a halogen selected from Cl and Br;

X⁵⁸ is hydrogen, F, Cl, CF3, cyano, methyl, or t-butyl;

X⁵⁹ is hydrogen, CH₂OH;

X⁶⁰ is CO(CH₂)₆CONMe(CH₂)₂SO₃H;

X⁶² is methyl, chloro, or trifluoromethyl;

X⁶³ is H, methyl, ethyl, cyclopropyl, vinyl, or trifluoromethyl;

X⁶⁴ is H, methyl, ethyl, cyclopropyl, chloro, vinyl, allyl, 3-methyl-1-buten-1-yl;

X⁶⁵ is hydrogen or F; and

Ar is aryl or heteroaryl.

28. 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:

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

38. 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:

46. 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:

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

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

90. The conjugate of claim 1, which is isolated and purified.

107. A pharmaceutical composition comprising a pharmaceutically acceptable excipient and a conjugate as described in claim 1.

108. A unit dosage form comprising a conjugate as described in claim 1 and a pharmaceutically acceptable excipient.

109. A method for inhibiting an immune response in vitro or in vivo comprising contacting a sample in need of such treatment with a conjugate as described in claim 1.

111. A method of modulating an immune response in a mammal, comprising administering a compound as described in claim 1 to the mammal.

5-27. -27. (canceled)

29-30. -30. (canceled)

32-34. -34. (canceled)

36-37. -37. (canceled)

39-41. -41. (canceled)

43-45. -45. (canceled)

47-51. -51. (canceled)

53-62. -62. (canceled)

65-89. -89. (canceled)

91-104. -104. (canceled)

105. A compound of the formula MBF.

106. A compound of claim 105 selected from Table 100.

110. (canceled)

112-114. -114. (canceled)