Ketoconazole-derivative antagonist of human pregnane X receptor and uses thereof
View Patent ↗The application discloses ketoconazole derivatives that are antagonists of the human pregnane X receptor (PXR), methods of preparing the derivatives, uses of the derivatives with drug therapy, and methods of inhibiting tumor cell proliferation and multidrug resistance using inhibitors of PXR.
1. A compound having the formula:
wherein A is
where X is H, CHO, COCH 3 , CO—OCH 3 , CO—OC 2 H 5 , CONH 2 , CONHCH 3 , CONHC 2 H 5 , CSNHCH 3 , CH 2 CH 3 , COO—CH 3 , COO—C 2 H 5 , CH 3 , CH 2 —CH(CH 3 ) 2 , CO—NH—(CH 2 ) 2 CH 3 , CH(CH 3 ) 2 , (CH 2 ) 3 CH 3 , (CH 2 ) 2 CH 3 , SO 2 CH 3 , CH 2 C 6 H 5 , or SO 2 CH 2 C 6 H 5 ;
wherein B is methyl, ethyl, propyl, butyl, CH 2 (CH 2 ) n CH 2 CH 3 where n=0-10, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
wherein each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, F, Br, I, OCH 3 , OC 2 H 5 , O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, alkyl, or phenyl; and
wherein C is ethyl, propyl, butyl, CH 2 (CH 2 ) n CH 2 CH 3 where n=0-10, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,
wherein each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, F, Br, I, OCH 3 , OC 2 H 5 , O-alkyl, SH, S-alkyl, NH 2 , NH-alkyl, alkyl, or phenyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X is H, CHO or COCH 3 .
3. The compound of claim 1 , wherein A is
4. The compound of claim 1 , wherein B is CH 3 .
5. The compound of claim 1 , wherein C is
wherein each R 1 , R 2 , R 3 , R 4 and R 5 is independently H, F, Br or I.
6. The compound of claim 1 , wherein C is
wherein at least two of R 1 , R 2 , R 3 , R 4 and R 5 are F, Br or I, and the remainder are H.
7. The compound of claim 1 , wherein C is
wherein at least R 3 is F.
8. The compound of claim 1 having the structure:
9. A compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
10. A pharmaceutical composition for antagonizing the human pregnane X receptor (PXR) comprising the compound of claim 1 , and a pharmaceutically acceptable carrier or diluent.
11. The compound of claim 9 having the structure
or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition for antagonizing the human pregnane X receptor (PXR) comprising the compound of claim 9 , and a pharmaceutically acceptable carrier or diluent.
13. A compound having a structure selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A pharmaceutical composition for antagonizing the human pregnane X receptor (PXR) comprising the compound of claim 13 , and a pharmaceutically acceptable carrier or diluent.