ANTI-INFLAMMATORY PHOSPHONATE COMPOUNDS
First Claim
Patent Images
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(Rx), N(O)(Rx), N(ORx), N(O)(ORx), or N(N(Rx)(Rx));
Y2 is independently a bond, O, N(Rx), N(O)(Rx), N(ORx), N(O)(ORx), N(N(Rx)(Rx)), —
S(O)M2—
, or —
S(O)M2—
S(O)M2—
; and
when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);
Rx is independently H, R1, R2, W3, a protecting group, or the formula;
wherein;
Ry 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 R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d;
R3a is F, Cl, Br, I, —
CN, N3 or —
NO2;
R3b is Y1;
R3c is —
Rx, —
N(Rx)(Rx), —
SRx, —
S(O)Rx, —
S(O)2Rx, —
S(O)(ORx), —
S(O)2(ORx), —
OC(Y)Rx, —
OC(Y1)ORx, —
OC(Y)(N(Rx)(Rx)), —
SC(Y)Rx, —
SC(Y1)ORx, —
SC(Y1)(N(Rx)(Rx)), —
N(Rx)C(Y1)Rx, —
N(Rx)C(Y1)ORx, or N(Rx)C(Y1)(N(Rx)(Rx));
R3d is —
C(Y1)Rx, —
C(Y1)ORx or —
C(Y1)(N(Rx)(Rx));
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, —
SOM2R5, or —
SOM2W5;
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.
0 Assignments
0 Petitions
Accused Products
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.
41 Citations
11 Claims
-
1. A conjugate of the formula:
-
[DRUG]-(A0)nnwherein; 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(Rx), N(O)(Rx), N(ORx), N(O)(ORx), or N(N(Rx)(Rx)); Y2 is independently a bond, O, N(Rx), N(O)(Rx), N(ORx), N(O)(ORx), N(N(Rx)(Rx)), —
S(O)M2—
, or —
S(O)M2—
S(O)M2—
; and
when Y2 joins two phosphorous atoms Y2 can also be C(R2)(R2);Rx is independently H, R1, R2, W3, a protecting group, or the formula; wherein; Ry 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 R3a, R3b, R3c or R3d, provided that when R3 is bound to a heteroatom, then R3 is R3c or R3d; R3a is F, Cl, Br, I, —
CN, N3 or —
NO2;R3b is Y1; R3c is —
Rx, —
N(Rx)(Rx), —
SRx, —
S(O)Rx, —
S(O)2Rx, —
S(O)(ORx), —
S(O)2(ORx), —
OC(Y)Rx, —
OC(Y1)ORx, —
OC(Y)(N(Rx)(Rx)), —
SC(Y)Rx, —
SC(Y1)ORx, —
SC(Y1)(N(Rx)(Rx)), —
N(Rx)C(Y1)Rx, —
N(Rx)C(Y1)ORx, or N(Rx)C(Y1)(N(Rx)(Rx));R3d is —
C(Y1)Rx, —
C(Y1)ORx or —
C(Y1)(N(Rx)(Rx));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, —
SOM2R5, or —
SOM2W5;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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11)
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 Y2b is O or N(Rx).
-
-
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 Y2b is O or N(Rx).
-
-
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; Y1a is O or S; Y2b is O or N(R2); and Y2c is O, N(Ry) 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.
Specification