Phosphonate compounds having immuno-modulatory activity
View Patent ↗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.
1. A method for inhibiting an immune response in vitro comprising contacting a sample in need of such treatment with a conjugate or a pharmaceutically acceptable salt or solvate thereof wherein the conjugate is a compound of formula:
[DRUG]-(A 0 ) nn ;
wherein:
DRUG is a compound of formula 546:
wherein:
nn is 1, 2, or 3;
A 0 is A 1 ;
Y 1 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 ));
Y 2 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 Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is H;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 where each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 R 5 , or —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 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.
2. A method of treating rheumatoid arthritis in a mammal, comprising administering a conjugate or a pharmaceutically acceptable salt or solvate thereof, to the mammal wherein the conjugate is a compound of formula:
[DRUG]-(A 0 ) nn ;
wherein:
DRUG is a compound of formula 546:
wherein:
nn is 1, 2 or 3;
A 0 is A 1 ;
Y 1 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 ));
Y 2 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 )(R x )( R x )), —S(O) M2 —, or —S(O) M2 —: and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is H;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groupos form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O)(OR x ), —S(O) 2 (OR X ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )(N(R x )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 —C(Y 1 )W 5 —SO M2 R 5 or —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 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.
3. The method of claim 1 wherein Y 2 is O.
4. A method for inhibiting an immune response in vitro comprising contacting a sample in need of such treatment with a conjugate or a pharmaceutically acceptable salt or solvate thereof wherein the conjugate is a compound of formula:
[DRUG]-(A 0 ) nn ;
wherein:
DRUG is a compound of formula 546:
wherein:
nn is 1, 2 or 3;
A 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least on A 1 ;
Y 1 is independently O, S, N(R x ), N(O)(R x ), N(O)(OR x ), or N(N(R x )(R x ));
Y 2 is independently a bond, O, N(R x ), N(O)(R x ), N(O)(OR x ), N(N(R x )(R x )), —S(O) M2 , —, or —S(O) M2 —; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
wherein:
R y is independently H, W 3 , R 2 or a protecting group;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —CN, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N(R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x , —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )R x , —SC(Y 1 )OR x , —SC(Y 1 )(N(R x _l )(R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 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.
5. The method of claim 2 wherein Y 2 is O.
6. A method of treating rheumatiod arthritis in a mammal, comprising administering a conjugate or a pharmaceutically acceptable salt or solvate thereof, to the mammal wherein the conjugate is a compound of the formula:
[DRUG]-(A 0 ) nn ;
wherein:
DRUG is a compound of formula 546:
wherein:
nn is 1, 2 or 3;
A 0 is A 1 , A 2 or W 3 with the proviso that the conjugate includes at least one A 1 ;
Y 1 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 ));
Y 2 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 )), —A(O) M2 —, or —S(O) M2 —; and when Y 2 joins two phosphorous atoms Y 2 can also be C(R 2 )(R 2 );
R x is independently H, R 1 , R 2 , W 3 , a protecting group, or the formula:
wherein:
R y is independently H, W 3 R 2 or a protection group;
R 1 is independently H or alkyl of 1 to 18 carbon atoms;
R 2 is independently H, R 1 , R 3 or R 4 wherein each R 4 is independently substituted with 0 to 3 R 3 groups or taken together at a carbon atom, two R 2 groups form a ring of 3 to 8 carbons and the ring may be substituted with 0 to 3 R 3 groups;
R 3 is R 3a , R 3b , R 3c or R 3d , provided that when R 3 is bound to a heteroatom, then R 3 is R 3c or R 3d ;
R 3a is F, Cl, Br, I, —Cn, N 3 or —NO 2 ;
R 3b is Y 1 ;
R 3c is —R x , —N 9 R x )(R x ), —SR x , —S(O)R x , —S(O) 2 R x , —S(O)(OR x ), —S(O) 2 (OR x ), —OC(Y 1 )R x , —OC(Y 1 )OR x , —OC(Y 1 )(N(R x )(R x )), —SC(Y 1 )OR x , —SC(Y 1 )(N(R x (R x )), —N(R x )C(Y 1 )R x , —N(R x )C(Y 1 )OR x , or —N(R x )C(Y 1 )(N(R x )(R x ));
R 3d is —C(Y 1 )R x , —C(Y 1 )OR x or —C(Y 1 )(N(R x )(R x ));
R 4 is an alkyl of 1 to 18 carbon atoms, alkenyl of 2 to 18 carbon atoms, or alkynyl of 2 to 18 carbon atoms;
R 5 is R 4 wherein each R 4 is substituted with 0 to 3 R 3 groups;
W 3 is W 4 or W 5 ;
W 4 is R 5 , —C(Y 1 )R 5 , —C(Y 1 )W 5 , —SO M2 R 5 , or —SO M2 W 5 ;
W 5 is carbocycle wherein W 5 is independently substituted with 0 to 3 R 2 groups;
W 6 is W 3 independently substituted with 1, 2, or 3 A 3 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.
7. The method of claim 1 wherein each A 3 is of the formula:
8. The method of claim 1 wherein each A 3 is of the formula:
9. The method of claim 1 wherein each A 3 is of the formula:
wherein:
Y 1a is O or S; and
Y 2a is O, N(R x ) or S.
10. The method of claim 1 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
11. The method of claim 1 wherein each A 3 is of the formula:
wherein:
Y 2b is O or N(R x ); and
M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
12. The method of claim 1 wherein each A 3 is of the formula:
wherein:
Y 2b is O or N(R x ); and
M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
13. The method of claim 2 wherein each A 3 is of the formula:
14. The method of claim 2 wherein each A 3 is of the formula:
15. The method of claim 2 wherein each A 3 is of the formula:
wherein:
Y 1a is O or S; and
Y 2a is O, N(R x ) or S.
16. The method of claim 2 wherein each A 3 is of the formula:
wherein Y 2b is O or N(R x ).
17. The method of claim 2 wherein each A 3 is of the formula:
wherein:
Y 2b is O or N(R x ); and
M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
18. The method of claim 2 wherein each A 3 is of the formula:
wherein:
Y 2b is O or N(R x ); and
M12d is 1, 2, 3, 4, 5, 6, 7 or 8.
19. The method of claim 4 , wherein each A 3 is of the formula:
20. The method of claim 6 , wherein each A 3 is of the formula: