PHOSPHONATE COMPOUNDS HAVING IMMUNO-MODULATORY ACTIVITY
First Claim
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1. A conjugate of formula:
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[DRUG]-(A0)nn;
wherein;
DRUG is a compound of formula 546;
nn is 1, 2 or 3;
A0 is A1;
A1 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 H;
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(Y1)Rx, —
OC(Y1)ORx, —
OC(Y1)(N(Rx)(Rx)), —
SC(Y1)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 W1;
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; and
M12b is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12;
or a pharmaceutically acceptable salt or solvate thereof.
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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.
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Citations
11 Claims
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1. A conjugate of formula:
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[DRUG]-(A0)nn;wherein; DRUG is a compound of formula 546; nn is 1, 2 or 3; A0 is A1; A1 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 H; 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(Y1)Rx, —
OC(Y1)ORx, —
OC(Y1)(N(Rx)(Rx)), —
SC(Y1)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 W1; 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; and M12b 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)
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4. The conjugate of claim 1 wherein each A3 is of the formula:
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5. The conjugate of claim 1 wherein each A3 is of the formula:
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wherein; Y1a is O or S; and Y2a is O, N(Rx) or S.
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6. The conjugate of claim 1 wherein each A3 is of the formula:
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wherein Y2b is O or N(Rx).
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7. The conjugate of claim 1 wherein each A3 is of the formula:
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wherein; Y2b is O or N(Rx); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
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8. The conjugate of claim 1 wherein each A3 is of the formula:
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wherein; Y2b is O or N(Rx); and M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
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9. The conjugate of claim 1, wherein each A3 is of the formula:
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10. The conjugate of claim 1 wherein A0 is of the formula:
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wherein each R is independently alkyl.
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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