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 CH;
X is F, Cl, or Br;
Y is hydrogen, hydroxy, or (C 1 –C 7 )alkoxy; and
Z is an amino acid, or heterocycle;
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 any of claims 1 to 4 wherein X is —Cl.
6. The compound of any of claims 1 to 4 wherein X is —Br.
7. The compound of any of claims 1 to 6 wherein Z is an amino acid.
8. The compound of any of claims 1 to 6 wherein Z is —NH—(CH 2 ) 2 —SO 3 H.
9. The compound of any of claims 1 to 6 wherein Z is —NH—CH 2 —CO 2 H.
10. The compound of any of claims 1 to 6 wherein Z is —NH—CH(CH 3 )—CO 2 H.
11. The compound of any of claims 1 to 6 wherein Z is a nitrogen linked pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
12. A compound of formula (I):
wherein
A is CH;
X is F, Cl, or Br;
Y is hydroxy, or (C 1 –C 7 )alkoxy; and
Z is an —NR a R b ;
where R a and R b is 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.
13. The compound of claim 12 , wherein Y is —OH.
14. The compound of claim 12 , wherein Y is —OMe.
15. The compound of any of claims 12 to 14 wherein X is —Cl.
16. The compound of any of claims 12 to 14 wherein X is —Br.
17. The compound of any of claims 12 to 16 wherein Z is —NR a R b .
18. The compound of any of claims 12 to 16 wherein Z is —NH 2 .
19. The compound of any of claims 12 to 16 wherein Z is —NHCH 3 .
20. The compound of any of claims 12 to 16 wherein Z is a nitrogen linked 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
21. A compound of formula (I):
wherein
A is CH;
X is F, Cl, or Br;
Y is hydrogen, hydroxy, or (C 1 –C 7 )alkoxy; and
Z is —NR a R b ;
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.
22. The compound of claim 21 wherein R a and R b are each 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.
23. The compound of claim 21 or 22 wherein Y is H.
24. The compound of claim 21 or 22 wherein Y is —OH.
25. The compound of claim 21 or 22 wherein Y is —OMe.
26. The compound of any of claims 21 to 25 wherein X is —Cl.
27. The compound of any of claims 21 to 25 wherein X is —Br.
28. The compound of any of claims 21 to 27 wherein Z is —NR a R b .
29. The compound of any of claims 21 to 27 wherein Z is a nitrogen linked pyrrolidino, piperidino, or morpholino.
30. The compound of any of claims 21 to 27 wherein Z is a nitrogen linked 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
31. The compound
2-{4-((7-Bromo-2-quinolinyl)oxy)phenoxy}propionmethylamide;
2-{4-((7-Chloro-2-quinolinyl)oxy)phenoxy}propiondimethylamide;
2-{4-((7-Bromo-2-quinolinyl)oxy)phenoxy}propionylamino ethanesulfonic acid;
{2-{4-(7-Bromo-2-quinolin-2-yloxy)phenoxy}propionylamino}ecetic acid;
(R) (2-(4-(7-Bromo-2-quinolinyl)oxy)phenoxy)propionylamino ethanesulfonic acid;
(R) {2-[4-(7-Bromo-quinolin-2-yloxy)-phenoxy]propionylamino}acetic acid;
or pharmaceutically acceptable salts thereof.
32. The compound of any of claims 1 to 30 or 31 which is the (R) enantiomer.
33. The compound of any of claims 1 to 30 or 31 which is the (S) enantiomer.
34. The compound of any of claims 1 to 30 or 31 to 33 , wherein the compound is isolated and purified.
35. The compound of claim 34 , wherein the compound is a solid.
36. The compound of claim 34 , wherein the compound is a crystalline solid.
37. A pharmaceutical composition comprising a compound any one of claims 1 to 30 or 31 to 36 and a pharmaceutically acceptable diluent or carrier.
38. The pharmaceutical composition of claim 37 , wherein the pharmaceutical composition is formulated as a unit dosage form.
39. The pharmaceutical composition of claim 38 , wherein the unit dosage form is formulated for oral administration.
40. The pharmaceutical composition of claim 38 , wherein the unit dosage form is formulated for administration by injection.