Treatment of pancreatic and related cancers with 5-acyl-6,7-Dihydrothieno[3,2-C]pyridines
Methods for inhibiting the growth of pancreatic cancer cells or other cancer cells driven by Sonic hedgehog are disclosed. The method involves exposing the cells to 5-acyl-6,7-dihydrothieno[3,2-c]pyridines of formula I
1. A method for treating a patient having an Shh-driven cancer comprising administering to said patient a therapeutically effective amount of a compound of formula:
or a pharmaceutically acceptable salt thereof;
wherein:
R 1 and R 2 are independently hydrogen, halogen, (C 1 -C 4 )hydrocarbyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro;
R 3 is (C 1 -C 10 )hydrocarbyl, (C 1 -C 6 )oxaalkyl, or heterocyclylalkyl;
R 4 is hydrogen, methyl, halomethyl, dihalomethyl, or trihalomethyl; and
A is phenyl or a 5- or 6-membered aromatic heterocycle;
wherein the cancer is pancreatic cancer, gastric cancer, colon cancer, prostate cancer, osteosarcoma, small cell lung cancer, medulloblastoma, basal cell carcinoma, liver cancer, or a urogenital tumor.
2. The method of claim 1 , wherein the cancer is pancreatic cancer, gastric cancer, colon cancer, prostate cancer, osteosarcoma, or small cell lung cancer.
3. The method of claim 1 , wherein A is pyrrolidine, furan, thiophene, or pyridine.
4. The method of claim 3 , wherein A is pyridine.
5. The method of claim 1 , wherein A is phenyl.
6. The method of claim 5 , wherein R 1 is halogen, (C 1 -C 4 )hydrocarbyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro ortho relative to the point of attachment of phenyl to the thieno[3,2-c]pyridine.
7. The method of claim 5 , wherein R 2 is halogen, (C 1 -C 4 )hydrocarbyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro para to the point of attachment of phenyl to the thieno[3,2-c]pyridine.
8. The method of claim 5 , wherein R 1 is halogen, (C 1 -C 4 )hydrocarbyl, (C 1 -C 4 )alkoxy, trifluoromethyl, trifluoromethoxy, cyano, or nitro meta relative to the point of attachment of phenyl to the thieno[3,2-c]pyridine.
9. The method of claim 5 , wherein R 1 is hydrogen and R 2 is hydrogen or methyl.
10. The method of claim 9 , wherein R 1 is hydrogen and R 2 is hydrogen.
11. The method of claim 1 , wherein R 1 is hydrogen or methyl, and R 2 is hydrogen, methyl, methoxy, chloro, or fluoro.
12. The method of claim 1 , wherein R 1 and R 2 are the same and are selected from the group consisting of hydrogen and halogen.
13. The method of claim 1 , wherein R 1 is hydrogen and R 2 is hydrogen or methyl.
14. The method of claim 13 , wherein R 1 is hydrogen and R 2 is hydrogen.
15. The method of claim 1 , wherein R 3 is (C 3 -C 6 )alkyl, (C 3 -C 6 )alkenyl, (C 3 -C 6 )cycloalkyl, (C 1 -C 6 )oxaalkyl, furanyl(C 1 -C 4 )alkyl, thienyl(C 1 -C 4 )alkyl, pyrrolyl(C 1 -C 4 )alkyl, pyrrolidinyl(C 1 -C 4 )alkyl, or tetrahydrofuranyl(C 1 -C 4 )alkyl.
16. The method of claim 15 , wherein R 3 is methoxyethyl, methoxypropyl, ethoxypropyl, isopropyl, cyclopropyl, allyl, or furanylmethyl.
17. The method of claim 1 , wherein R 3 is (C 1 -C 10 )alkyl.
18. The method of claim 17 , wherein R 3 is (C 3 -C 6 )alkyl.
19. The method of claim 1 , wherein R 4 is hydrogen.
20. The method of claim 1 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts thereof.