Etomidate analogues that do not inhibit adrenocortical steroid synthesis
The invention is directed to compounds according to formula (I): where R 1 is L 1 C(O)OT or L 1 C(O)OL 2 C(O)OT; R 2 is a substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl, or R 1 ; n is an integer from 0 to 5; each R 3 is independently halogen or R 2 ; R 4 and R 5 are independently H, halogen, CN or CF 3 ; L 1 and L 2 are each independently a bond, a substituted or unsubstituted C 1 -C 10 alkylene, C 2 -C 10 alkenylene, or C 2 -C 10 alkynylene; and T is H, a substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenyl, or C 2 -C 10 alkynyl, nitrophenol, or cyclopropyl. The invention is also directed to a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier, and to methods for providing anesthesia in mammals by administering such a pharmaceutical composition.
1. A method for providing anesthesia to a subject comprising administering to said subject a compound, or pharmaceutically acceptable salt thereof, of formula (I):
wherein:
R 1 is L 1 C(O)OL 2 C(O)OT;
R 2 is C 1 -C 10 alkyl;
n is an integer from 0-5;
each R 3 is independently halogen or R 2 ;
R 4 and R 5 are independently H, halogen, CN or CF 3 ;
L 1 is a bond or C 1 -C 10 alkylene;
L 2 is a bond or C 1 -C 10 alkylene;
T is H, a C 1 -C 10 alkyl, C 1 -C 10 alkyl substituted with an electron withdrawing group, C 2 -C 10 alkenyl, C 2 -C 10 alkenyl substituted with an electron withdrawing group, C 2 -C 10 alkynyl, C 2 -C 10 alkynyl substituted with an electron withdrawing group, nitrophenol, or cyclopropyl, wherein the backbone of the alkyl may contain one or more heteroatom.
2. The method of claim 1 , wherein T is selected from the group consisting of H, CH 3 , CH 2 CH 3 , CH 2 CH(OH)CH 3 and CH 2 CH 2 CH 3 .
3. The method of claim 1 , wherein R 2 is selected from the group consisting of CH 3 , CH 2 CH 3 , and CH 2 CH 2 CH 3 .
4. The method of claim 1 , wherein n is 0 or 1.
5. The method of claim 1 , wherein L 1 is a bond and L 2 is C 1-10 alkylene.
6. The method of claim 1 , wherein L 1 is a bond, R 2 is CH 3 and T is H, CH 3 , CH 2 CH 3 or CH 2 CH(OH)CH 3 .
7. The method of claim 1 , wherein R 4 and R 5 are each H.
8. The method of claim 1 , wherein the compound is
9. A method for providing anesthesia to a subject comprising administering to said subject a compound, or pharmaceutically acceptable salt thereof, of formula (I):
wherein:
R 1 is L 1 C(O)OT;
R 2 is C 1 -C 10 alkyl;
n is an integer from 0-5;
each R 3 is independently halogen or R 2 ;
R 4 and R 5 are independently H, halogen, CN or CF 3 ;
L 1 is a bond or C 1 -C 10 alkylene;
T is ethyl, propyl, isopropyl, cyclopropyl, n-butyl, neopentyl, n-hexyl, cyclohexyl, n-octyl, n-decyl, n-dodecyl, n-hexadecyl, CH 2 CH(OH)CH 3 , C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, or nitrophenol, wherein the backbone of the ethyl, propyl, isopropyl, n-butyl, neopentyl, n-hexyl, cyclohexy, n-octyl, n-decyl, or n-hexadecyl may contain one or more heteroatoms.
10. The method of claim 9 , wherein R 2 is selected from the group consisting of CH 3 , CH 2 CH 3 and CH 2 CH 2 CH 3 .
11. The method of claim 9 , wherein n is 0 or 1.
12. The method of claim 9 , wherein L 1 is a bond.
13. The method of claim 9 , wherein T is selected from the group consisting of CH 2 CH 3 , CH 2 CH(OH)CH 3 , and CH 2 CH 2 CH 3 .
14. The method of claim 9 , wherein one of R 4 and R 5 is H and the other is Br or CN.
15. The method of claim 9 , wherein the compound is selected from the group consisting of