Anti-inflammatory phosphonate compounds

• US 20060199788A1
• Filed: 04/26/2004
• Published: 09/07/2006
• 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, Chen, James, Lin, Kuei-Ying, Ray, Adrian S., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Oare, David A., Hirschmann, Ralph F., Sherlock, Rosemarie, Zhang, Jennifer R., Cannizzaro, Carina, Pyun, Hyung-Jung, Mackman, Richard L., Nelson, Peter H., Chong, Lee, Gibbs, Craig
• Granted Patent: US 7,432,261 B2
• Time in Patent Office: Days
• US Class Current: 514/114
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• CPC Class Codes: C07F 9/4021 Esters of aromatic acids (P-C aromatic linkage)
• CPC Class Codes: C07F 9/46 Phosphinous acids [R2POH], [R2P(= O)H]: Thiophosphinous acids including[R2PSH]; [R2P(=S)H]; Aminophosphines [R2PNH2]; Derivatives thereof
• CPC Class Codes: C07F 9/572 Five-membered rings
• CPC Class Codes: C07F 9/5728 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65031 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/65038 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/650905 having the nitrogen atoms in the positions 1 and 2
• CPC Class Codes: C07F 9/6524 having four or more nitrogen atoms as the only ring hetero atoms
• CPC Class Codes: C07F 9/653 Five-membered rings
• CPC Class Codes: C07F 9/65515 the oxygen atom being part of a five-membered ring
• CPC Class Codes: C07F 9/65517 condensed with carbocyclic rings or carbocyclic ring systems
• CPC Class Codes: C07F 9/65583 each of the hetero rings containing nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07F 9/6561 containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings
• CPC Class Codes: C07F 9/65616 containing the ring system having three or more than three double bonds between ring members or between ring members and non-ring members, e.g. purine or analogs

Abstract

The invention is related to phosphorus substituted anti-inflammatory compounds, 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 anti-inflammatory 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 500-611 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;

M12cis 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;

X⁶⁶ is hydrogen or fluorine; and

X⁶⁷ is hydrogen, hydroxy, or acyloxy.

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 500-611; and

nn is 1, 2, or 3.

4. The conjugate of claim 2 which has any one of formulae 1-296 wherein:

one A⁰ is A¹;

X⁵⁰ is H or F;

X⁵¹ is H, hydroxy, or acyloxy;

X⁵² is NH₂ or EtC(O)N—

Na+;

X⁵³ is H, methyl, CF₃, or halo;

X⁵⁴ is H, halo, trifluoromethyl, (C₁-C₃)alkyl, cyano, or (C₁-C₃)alkoxy;

X⁵⁵ is H, F, Cl, Br, methyl, or trifluoromethyl;

X⁵⁶ is H, halo, trifluoromethyl, cyano, methyl;

X⁵⁷ is H, F, Cl, CF₃, cyano, methyl, or t-butyl;

X⁵⁸ is H or CH₂OH;

X⁵⁹ is H or F;

X⁶⁰ is H, trifluoromethyl, or cyano;

X⁶¹ is methoxy, ethoxy, propoxy, difluoromethoxy, trifluoromethoxy, vinyl, ethyl, methyl, propyl, butyl, cyclopropyl, N-methylamino, or N-formylamino;

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 H 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 as described in claim 1, which is isolated and purified.

121. A pharmaceutical composition comprising a pharmaceutical excipient and a conjugate as described claim 1.

122. A unit dosage form comprising a conjugate as described in claim 1;

and a pharmaceutically acceptable excipient.

123. A method for inhibiting inflammatory activity in vitro or in vivo comprising contacting a sample in need of such treatment with a conjugate as described in claim 1.

125. A method of treating inflammation in a mammal, comprising administering a conjugate 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)

91-118. -118. (canceled)

119. A compound of formula MBF.

120. The compound of claim 119 which is selected from Table 100.

124. (canceled)

126-127. -127. (canceled)