Substituted pyrrolo[2,3-d]pyrimidines as antifolates
The present invention is directed to antifolate compounds having the structure wherein: X is CHR 9 or NR 9 ; Y 1 , Y 2 , and Y 3 independently are O or S; V 1 and V 2 independently are O, S, or NZ; Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl; R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)—alkynyl; as well as pharmaceutically acceptable esters, amides, salts, solvates, and prodrugs thereof. The compounds are useful in pharmaceutical compositions and in methods of treating multiple conditions, including abnormal cell proliferation, inflammatory diseases, asthma, and arthritis.
1. A compound according to the following formula
wherein:
X is CHR 9 or NR 9 ;
Y 1 , Y 2 , and Y 3 independently are O or S;
V 1 and V 2 independently are O, S, or NZ;
Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)—alkynyl; or
a pharmaceutically acceptable ester, amide, salt or enantiomer thereof.
2. A compound according to claim 1 , wherein the compound is in the form of a pharmaceutically acceptable salt.
3. A compound according to claim 2 , wherein the compound is in the form of an alkali metal salt.
4. A compound according to claim 3 , wherein the compound is in the form of a disodium salt.
5. A compound according to claim 2 , wherein one or both of R 1 and R 2 are replaced by a salt-forming cation.
6. A compound according to claim 5 , wherein the salt-forming cation comprises an alkali metal cation.
7. A compound according to claim 2 , wherein V 1 and V 2 are O, and R 1 and R 2 are both independently replaced by a salt-forming cation.
8. A compound according to claim 7 , wherein the salt-forming cation comprises an alkali metal cation.
9. A compound according to claim 1 having the following formula
wherein:
X is CHR 9 or NR 9 ;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 4 , R 5 , R 6 , R 7 , R 8 , and R 9 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)—alkynyl; or
a pharmaceutically acceptable ester, amide, salt or enantiomer thereof.
10. A compound according to claim 9 , wherein the compound is in the form of a pharmaceutically acceptable salt.
11. A compound according to claim 10 , wherein the compound is in the form of an alkali metal salt.
12. A compound according to claim 11 , wherein the compound is in the form of a disodium salt.
13. A compound according to claim 1 having the following formula
wherein:
X is CHR 9 or NR 9 ;
Y 1 , Y 2 , and Y 3 independently are O or S;
V 1 and V 2 independently are O, S, or NZ;
Z is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 1 and R 2 independently are H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, or alkaryl;
R 3 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, hydroxyl, or halo; and
R 9 is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, acyl, —C(O)-alkyl, —C(O)-alkenyl, or —C(O)-alkynyl; or
a pharmaceutically acceptable ester, amide, salt or enantiomer thereof.
14. A compound according to claim 13 , wherein the compound is in the form of a pharmaceutically acceptable salt.
15. A compound according to claim 14 , wherein the compound is in the form of an alkali metal salt.
16. A compound according to claim 15 , wherein the compound is in the form of a disodium salt.
17. A compound according to claim 14 , wherein one or more of R 1 , R 2 , and Z are replaced by a salt-forming cation.
18. A compound according to claim 17 , wherein the salt-forming cation comprises an alkali metal cation.
19. A compound according to claim 14 , wherein V 1 and V 2 are O, and R 1 and R 2 are both independently replaced by a salt-forming cation.
20. A compound according to claim 19 , wherein the salt-forming cation comprises an alkali metal cation.
21. A compound according to claim 1 having the following formula:
or a pharmaceutically acceptable ester, amide, salt or enantiomer thereof.
22. A compound according to claim 21 , wherein the compound is in the form of a pharmaceutically acceptable salt.
23. A compound according to claim 22 , wherein the compound is in the form of an alkali metal salt.
24. A compound according to claim 22 , wherein the compound is in the form of a disodium salt.
25. A compound according to claim 24 having the formula
or an enantiomer thereof.
26. A compound according to claim 21 , wherein the compound is enantiomerically pure for the (S) enantiomer.
27. A compound according to claim 26 , wherein the compound has an enantiomeric purity of at least about 80%.
28. A compound according to claim 26 , wherein the compound has an enantiomeric purity of at least about 95%.
29. A compound according to claim 21 , wherein the compound is enantiomerically pure for the (R) enantiomer.
30. A compound according to claim 29 , wherein the compound has an enantiomeric purity of at least about 80%.
31. A compound according to claim 29 , wherein the compound has an enantiomeric purity of at least about 95%.
32. A compound according to claim 25 , wherein the compound is enantiomerically pure for the (S) enantiomer.
33. A compound according to claim 32 , wherein the compound has an enantiomeric purity of at least about 80%.
34. A compound according to claim 32 , wherein the compound has an enantiomeric purity of at least about 95%.
35. A compound according to claim 25 , wherein the compound is enantiomerically pure for the (R) enantiomer.
36. A compound according to claim 35 , wherein the compound has an enantiomeric purity of at least about 80%.
37. A compound according to claim 35 , wherein the compound has an enantiomeric purity of at least about 95%.
38. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
39. A pharmaceutical composition comprising a compound according to claim 9 and a pharmaceutically acceptable carrier.
40. A pharmaceutical composition comprising a compound according to claim 13 and a pharmaceutically acceptable carrier.
41. A pharmaceutical composition comprising a compound according to claim 21 and a pharmaceutically acceptable carrier.
42. A pharmaceutical composition comprising a compound according to claim 25 and a pharmaceutically acceptable carrier.
43. A pharmaceutical composition comprising a compound according to claim 26 and a pharmaceutically acceptable carrier.
44. A pharmaceutical composition comprising a compound according to claim 29 and a pharmaceutically acceptable carrier.
45. A pharmaceutical composition comprising a compound according to claim 32 and a pharmaceutically acceptable carrier.
46. A pharmaceutical composition comprising a compound according to claim 35 and a pharmaceutically acceptable carrier.