ANTI-INFLAMMATORY PHOSPHONATE COMPOUNDS

• US 20090247488A1
• Filed: 06/25/2008
• Published: 10/01/2009
• Est. Priority Date: 04/25/2003
• Status: Abandoned Application

• Current Assignee: Adrian S. Ray, Aesop Cho, Carina Cannizzaro, Christopher P. Lee, Craig Gibbs, David A. Oare, Hyung-Jung Pyun, James Chen, Jennifer R. Zhang, Kuei-Ying Lin, Lee Chong, Maria Fardis, Peter H. Nelson, Ralp F. Hirschmann, Richard L. Mackman, Rosemarie Sherlock, Sundaramoorthi Swaminathan, Thorsten Kirschberg, William J. Watkins, Xiaowu Chen
• Original Assignee: Adrian S. Ray, Aesop Cho, Carina Cannizzaro, Christopher P. Lee, Craig Gibbs, David A. Oare, Hyung-Jung Pyun, James Chen, Jennifer R. Zhang, Kuei-Ying Lin, Lee Chong, Maria Fardis, Peter H. Nelson, Ralp F. Hirschmann, Richard L. Mackman, Rosemarie Sherlock, Sundaramoorthi Swaminathan, Thorsten Kirschberg, William J. Watkins, Xiaowu Chen
• Inventors: Chen, James, Chong, Lee, Hirschmann, Ralp F., Gibbs, Craig, Watkins, William J., Cho, Aesop, Fardis, Maria, Lin, Kuei-Ying, Ray, Adrian S., Lee, Christopher P., Chen, Xiaowu, Swaminathan, Sundaramoorthi, Kirschberg, Thorsten, Oare, David A., Sherlock, Rosemarie, Zhang, Jennifer R., Cannizzaro, Carina, Pyun, Hyung-Jung, Mackman, Richard L., Nelson, Peter H.
• Application Number:
  US12/145,611
• Publication Number:
  US 20090247488A1
• Time in Patent Office: Days
• US Class Current: 514/85
• CPC Class Codes: A61K 31/675 having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
• CPC Class Codes: A61K 47/54 the modifying agent being an organic compound
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: C07D 237/14 Oxygen atoms
• CPC Class Codes: C07F 9/4006 Esters of acyclic acids which can have further substituents on alkyl
• 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 9/58 Pyridine rings
• CPC Class Codes: C07F 9/60 Quinoline or hydrogenated quinoline 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 9/6512 having the nitrogen atoms in positions 1 and 3
• 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 9/65586 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 of the formula:

[DRUG]-(A⁰)_nn

wherein;

DRUG is a compound of formula 556;

wherein;

nn is 1, 2, or 3;

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

A¹ is;

A² is;

A³ is;

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(Y)R^x, —

OC(Y¹)OR^x, —

OC(Y)(N(R^x)(R^x)), —

SC(Y)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 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;

or a pharmaceutically acceptable salt or solvate thereof.

2. The conjugate of claim 1 which is a compound of formula 103:

wherein;

A⁰ is A¹.

3. The conjugate of claim 1 wherein each A³ is of the formula:

4. The conjugate of claim 1 wherein each A³ is of the formula:

wherein Y^2b is O or N(R^x).

5. The conjugate of claim 1 wherein each A³ is of the formula:

6. The conjugate of claim 1 wherein each A³ is of the formula:

7. The conjugate of claim 1 wherein each A³ is of the formula:

wherein Y^2b is O or N(R^x).

8. The conjugate of claim 1 wherein each A³ is of the formula:

wherein the phenyl carbocycle is substituted with 0, 1, 2, or 3 R¹ groups.

9. The conjugate of claim 1 wherein each A³ is of the formula:

wherein;

Y^1a is O or S;

Y^2b is O or N(R²); and

Y^2c is O, N(R^y) or S.

10. The conjugate of claim 1 wherein A⁰ is of the formula:

wherein each R is independently alkyl.

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