Therapeutic amides
The invention provides compounds of the formula: wherein 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
X is F, Cl, or Br;
Y is hydrogen, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; and
Z is an amino acid, or Z is —NRaRb; where Ra and Rb together with the nitrogen to which they are attached are a pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepine, or 1,5-benzodiazepino;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 wherein Y is H, OH, or OMe, and X is Cl or Br.
3. The compound of claim 2 wherein Z is an amino acid.
4. The compound of claim 2 wherein Z is —NH—(CH 2 ) 2 —SO 3 H, —NH—CH 2 —CO 2 H, or —NH—CH(CH 3 )—CO 2 H.
5. The compound of claim 2 wherein Z is a nitrogen linked pyrrolidino, piperidino, morpholino, 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
6. The compound of claim 1 which is the (R) enantiomer.
7. The compound of claim 1 which is the (S) enantiomer.
8. A pharmaceutical composition comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
9. The pharmaceutical composition of claim 8 , wherein the pharmaceutical composition is formulated as a unit dosage form, wherein the unit dosage form is optionally formulated for oral administration or is formulated for administration by injection.
10. A compound of formula (I):
wherein
X is F, Cl, or Br;
Y is hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; and
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, 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-benzodiazepine, or 1,5-benzodiazepino;
or a pharmaceutically acceptable salt thereof.
11. The compound of claim 10 wherein Y is OH or OMe and X is Cl or Br.
12. The compound of claim 11 wherein Z is —NR a R b where R a and R b are each independently (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 Z is —NH 2 or —NHCH 3 .
14. The compound of claim 11 wherein Z is a nitrogen linked 1,3-benzodiazepino, 1,4-benzodiazepino, or 1,5-benzodiazepino.
15. The compound of claim 10 which is the (R) enantiomer.
16. The compound of claim 10 which is the (S) enantiomer.
17. A pharmaceutical composition comprising a compound of claim 10 and a pharmaceutically acceptable diluent or carrier.
18. The pharmaceutical composition of claim 17 , wherein the pharmaceutical composition is formulated as a unit dosage form, wherein the unit dosage form is optionally formulated for oral administration or is formulated for administration by injection.
19. A compound of formula (I):
wherein
X is F, Cl, or Br;
Y is hydrogen, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, or hexyloxy; and
Z is —NR a R b ; wherein 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-benzodiazepine, or 1,5-benzodiazepino;
or a pharmaceutically acceptable salt thereof.
20. The compound of claim 19 wherein Y is H, OH, or OMe, and X is Cl or Br.
21. The compound of claim 20 wherein Z is —NR a R b where R a and R b are each independently (C 1 -C 7 )alkyl, (C 1 -C 7 )alkanoyl, aryl, or aryl(C 1 -C 7 )alkyl.
22. The compound of claim 20 wherein Z is —NR a R b 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 19 which is the (R) enantiomer.
24. The compound of claim 19 which is the (S) enantiomer.
25. A pharmaceutical composition comprising a compound of claim 19 and a pharmaceutically acceptable diluent or carrier.
26. The pharmaceutical composition of claim 25 , wherein the pharmaceutical composition is formulated as a unit dosage form, wherein the unit dosage form is optionally formulated for oral administration or is formulated for administration by injection.
27. A composition comprising 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-quinolin-2-yloxy)phenoxy}propionylamino}acetic acid;
(R) (2-(4-(7-Bromo-2-quinolinyl)oxy)phenoxy)propionylamino ethanesulfonic acid; or
(R) {2-[4-(7-Bromo-quinolin-2-yloxy)-phenoxy]-propionylamino}acetic acid;
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable diluent or carrier.
28. The pharmaceutical composition of claim 27 , wherein the pharmaceutical composition is formulated as a unit dosage form, wherein the unit dosage form is optionally formulated for oral administration or is formulated for administration by injection.