Anti-cancer phosphonate analogs

• US 20060079478A1
• Filed: 04/26/2004
• Published: 04/13/2006
• Est. Priority Date: 04/25/2003
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Sciences Inc.
• Inventors: Watkins, William J., Zhang, Lijun, Cho, Aesop, Fardis, Maria, Markevitch, David Y., Chong, Lee S., Kim, Choung U., Lin, Kuei-Ying, Boojamra, Constantine G., Ray, Adrian S., Prasad, Vidya K., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Chen, James M., Huang, Alan X., Oare, David A., Zhang, Jennifer R., Cannizzaro, Carina, Pyun, Hyung-Jung, Mackman, Richard L., Nelson, Peter H., Krawczyk, Steven
• Granted Patent: US 7,452,901 B2
• Time in Patent Office: Days
• US Class Current: 514/47
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/7076 containing purines, e.g. adenosine, adenylic acid
• CPC Class Codes: A61K 47/548 Phosphates or phosphonates, e.g. bone-seeking phospholipids A61K47/544
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: C07H 19/04 Heterocyclic radicals containing only nitrogen atoms as ring hetero atom

Abstract

The invention is related to phosphorus substituted anti-cancer 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-cancer 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 500-601 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;

Y 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 R 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 yl;

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 500-601; and

nn is 1, 2, or 3.

4. The conjugate of claim 2 which has any one of formulae 1-336

wherein:

one A⁰ is A¹X⁵⁰ is H F, or Cl; and

X⁵¹ is H or Cl.

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 2 which has the formula:

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

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

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

106. A method of inhibiting tumor growth in vitro or in vivo comprising the step of contacting a sample in need of such treatment with a conjugate as described in claim 1.

109. A method of treating the symptoms or effects of cancer in an animal which comprises administering to said animal a compound as described in claim 1 to the mammal.

110. A method of inhibiting neoplastic diseases, in a mammal in need of such treatment comprising administering to said animal a compound as described in claim 1 to the mammal.

19. The conjugate of claim 1 having the following formula:

168. The conjugate of claim 1 having the following formula:

203. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 168, or a pharmaceutically acceptable salt or solvate thereof;

and a pharmaceutically acceptable excipient.

204. The conjugate of claim 1 that has the following formula:

226. The conjugate of claim 1 having the following formula:

236. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 204 or a pharmaceutically acceptable salt or solvate thereof;

and a pharmaceutically acceptable excipient.

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)

91-101. -101. (canceled)

102. A compound of the formula MBF.

103. A compound of claim 102 selected from Table 100.

107-108. -108. (canceled)

111-118. -118. (canceled)

120-155. -155. (canceled)

156. A composition having the following formula:

157-166. -166. (canceled)

167. A pharmaceutical composition comprising a therapeutically effective amount of a conjugate of claim 119, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable carrier.

169-202. -202. (canceled)

205-225. -225. (canceled)

227-235. -235. (canceled)

237. A method of inhibiting tumor growth in vitro or in vivo comprising the step of contacting a sample in need of such treatment with a conjugate as described in claim 119.

238-239. -239. (canceled)

240. A method of treating the symptoms or effects of cancer in an animal which comprises administering to said animal a conjugate as described in claim 119.

241. A method of inhibiting neoplastic diseases, in a mammal in need of such treatment comprising administering to said animal a conjugate as described in claim 119.

242-244. -244. (canceled)