Therapeutic amides
The invention provides compounds of the formula: wherein A, X, Y, and Z are as defined in the specification. The compounds are effective anti-tumor agents. The invention also provides pharmaceutical compositions comprising a compound of the above formula or a salt thereof, intermediates useful for preparing a compound of the above formula, and therapeutic methods comprising administering a compound of the above formula or a salt thereof to a mammal in need thereof.
1. A compound of formula (I):
wherein
A is N;
X is F, Cl, or Br;
Y is hydrogen, hydroxy, or (C 1 -C 7 )alkoxy; and
Z is —NH—(CH 2 ) 2 -SO 3 H, —NH—CH 2 —CO 2 H, —NH—CH(CH 3 )—CO 2 H, or a nitrogen linked pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino; or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein Y is H.
3. The compound of claim 1 , wherein Y is —OH.
4. The compound of claim 1 , wherein Y is —OMe.
5. The compound of claim 1 wherein X is —Cl.
6. The compound of claim 1 wherein X is —Br.
7. The compound of claim 1 wherein Z is —NH—(CH 2 ) 2 —SO 3 H.
8. The compound of claim 1 wherein Z is —NH—CH 2 —CO 2 H.
9. The compound of claim 1 wherein Z is —NH—CH(CH 3 )—CO 2 H.
10. The compound of claim 1 wherein Z is a nitrogen linked pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
11. A compound of formula (I):
wherein
A is N;
X is F, Cl, or Br;
Y is hydroxy; and
Z is an —NR a R b ;
where R a and R b are each independently hydrogen, (C 1 -C 7 )alkyl, (C 1 -C 7 )alkanoyl, aryl, aryl(C 1 -C 7 )alkyl, or where R a and R b together with the nitrogen to which they are attached are a pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino;
or a pharmaceutically acceptable salt thereof.
12. The compound of claim 11 wherein Z is —NR a R b where R a and R b are each independently hydrogen, (C 1 -C 7 )alkyl, (C 1 -C 7 )alkanoyl, aryl, or aryl(C 1 -C 7 )alkyl.
13. The compound of claim 11 wherein X is —Cl.
14. The compound of claim 11 wherein X is —Br.
15. The compound of claim 11 wherein Z is —NH 2 .
16. The compound of claim 11 wherein Z is —NHCH 3 .
17. The compound of claim 11 wherein Z is —N(CH 3 ) 2 .
18. The compound of claim 11 wherein Z is a nitrogen linked pyrrolidino, piperidino, or morpholino.
19. The compound of claim 11 wherein Z is a nitrogen linked 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
20. A compound of formula (I):
wherein
A is N;
X is F, Cl, or Br;
Y is hydrogen, hydroxy, or (C 1 -C 7 )alkoxy; and
Z is —NR a R b ;
where R a and R b are independently (C 1 -C 7 )alkanoyl, aryl, aryl(C 1 -C 7 )alkyl, or where R a and R b together with the nitrogen to which they are attached are a pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino;
or a pharmaceutically acceptable salt thereof.
21. The compound of claim 20 wherein Y is H.
22. The compound of claim 20 wherein Y is —OH.
23. The compound of claim 20 wherein Y is —OMe.
24. The compound of claim 20 wherein X is —Cl.
25. The compound of claim 20 wherein X is —Br.
26. The compound of claim 20 wherein R a and R b are independently (C 1 -C 7 )alkanoyl, aryl, or aryl(C 1 -C 7 )alkyl.
27. The compound of claim 20 wherein R a , and R b together with the nitrogen to which they are attached are pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
28. The compound
(2-(4-(7-Chloro-2-quinoxalinyl)oxy)propionylamino ethansulfonic acid;
{2-{4-(7-Chloro-quinoxalin-2-yloxy)-phenoxy}propionyl amino}acetic acid;
(R){2-{4-(7-Chloro-quinoxalin-2-yloxy)-phenoxy}propionyl amino}acetic acid;
or pharmaceutically acceptable salts thereof.
29. The compound of claim 1 which is the (R) enantiomer.
30. The compound of claim 1 which is the (S) enantiomer.
31. The compound of claim 1 wherein the compound is isolated and purified.
32. The compound of claim 31 , wherein the compound is a solid.
33. The compound of claim 31 , wherein the compound is a crystalline solid.
34. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
35. The pharmaceutical composition of claim 34 , wherein the pharmaceutical composition is formulated as a unit dosage form.
36. The pharmaceutical composition of claim 35 , wherein the unit dosage form is formulated for oral administration.
37. The pharmaceutical composition of claim 35 , wherein the unit dosage form is formulated for administration by injection.
38. A therapeutic method to treat cancer in a mammal, comprising administering to a mammal in need of such therapy an effective amount of a compound of claim 1 , wherein the cancer is selected from melanoma or breast cancer.
39. A therapeutic method to treat cancer in a mammal, comprising administering to a mammal in need of such therapy an effective amount of a pharmaceutical composition of claim 34 , wherein the cancer is selected from melanoma or breast cancer.
40. A therapeutic method to treat cancer in a mammal, comprising co-administering to a mammal in need of such therapy, an effective amount of a mixture of two or more compounds of claim 1 , wherein the cancer is selected from melanoma or breast cancer.
41. A therapeutic method to treat cancer in a mammal, comprising co-administering to a mammal in need of such therapy, an effective amount of a mixture of two or more pharmaceutical compositions of claim 34 , wherein the cancer is selected from melanoma or breast cancer.
42. A compound of claim 28 that is the (R) enantiomer.
43. A compound of claim 28 that is the (S) enantiomer.