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 compound according to formula (I)
wherein:
(i)
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 a C 1 -C 10 alkylene;
L 2 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, nitrophenol, or cyclopropyl, 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 hetoeratoms; and
pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof; or
(ii)
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 a C 1 -C 10 alkylene;
L 2 is a bond, or a 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; and
pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof.
2. The compound of claim 1 , wherein said compound is present in the form of a pure enantiomer.
3. The compound of claim 2 , wherein said enantiomer is the R enantiomer.
4. The compound of claim 1 , wherein R 1 is L 1 C(O)OT and 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 .
5. The compound of claim 1 , wherein R 1 is L 1 C(O)OL 2 C(O)OT and 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 .
6. The compound 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 .
7. The compound of claim 1 , wherein n is 0 or 1.
8. The compound of claim 1 , wherein: (i) R 1 is L 1 CO 2 L 2 CO 2 T, R 2 is CH 3 , n is 0, L 1 is a bond, and T is H, CH 3 , CH 2 CH 3 , or CH 2 CH(OH)CH 3 ; or (ii) R 1 is L 1 CO 2 T, R 2 is CH 3 , n is 0, and T is CH 2 CH 3 , or CH 2 CH(OH)CH 3 .
9. The compound of claim 1 , wherein both R 4 and R 5 are H.
10. The compound of claim 1 , wherein at least one of R 4 and R 5 is H and the other is Br or CN.
11. The compound of claim 10 , wherein R 4 is H and R 5 is Br or CN.
12. The compound of claim 10 , wherein R 4 is Br or CN and R 5 is H.
13. The compound of claim 1 , wherein the compound of formula (I) is selected from the group consisting of
pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof.
14. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
15. A method for providing anesthesia to a subject comprising administering to said subject a pharmaceutical composition according to claim 14 .
16. The compound of claim 1 , wherein L 1 is a bond.