Etomidate analogues with improved pharmacokinetic and pharmacodynamic properties
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 ; 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,
R 1 is L 1 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 0-5;
each R 3 is independently halogen or R 2 ;
L 1 is unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted C 2 -C 10 alkenylene, or substituted or unsubstituted C 2 -C 10 alkynylene, wherein the backbone of alkylene may contain one or more heteroatoms;
T is H, a substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, nitrophenol, or cyclopropyl, wherein the backbone of alkyl may contain one or more heteroatoms; and
pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof,
provided that when R 1 is L 1 C(O)OT, R 2 is CH 3 , R 3 fluorine, n is 1, and T is CH 2 CH 3 .
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 at least one of R 2 , T and L 1 are further substituted with one or more electron withdrawing groups.
5. The compound of claim 4 , wherein said electron withdrawing group is a halogen.
6. The compound of claim 1 , wherein the compound contains two or more ester groups.
7. A compound according to formula (I):
wherein R 1 is L 1 C(O)OT, R 2 is CH 3 , R 3 is CH 2 CH 2 C(O)OCH 3 , n is 1, L 1 is a bond, and T is CH 2 CH 3 .
8. A compound according to Formula (I):
wherein R 1 is L 1 C(O)OT, R 2 is CH 2 CH 2 C(O)OCH 3 , n is 0, L 1 is a bond, and T is CH 2 CH 3 .
9. The compound of claim 1 , wherein R 1 is L 1 C(O)OT, R 2 is CH 3 , n is 0, L 1 is CH 2 CH 2 , and T is CH 2 CH 3 .
10. A pharmaceutical composition comprising a pharmaceutically effective amount of a compound according to formula (I)
wherein,
R 1 is L 1 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 0-5;
each R 3 is independently halogen or R 2 ;
L 1 is unsubstituted C 1 -C 10 alkylene, substituted or unsubstituted C 2 -C 10 alkenylene, or substituted or unsubstituted C 2 -C 10 alkynylene, wherein the backbone of alkylene may contain one or more heteroatoms;
T is H, a substituted or unsubstituted C 1 -C 10 alkyl, C 2 -C 10 alkenylene, C 2 -C 10 alkynylene, nitrophenol, or cyclopropyl, wherein the backbone of alkyl may contain one or more heteroatoms; and
pharmaceutically acceptable salts, stereoisomer mixtures, and enantiomers thereof,
provided that when R 1 is L 1 C(O)OT, R 2 is CH 3 , R 3 fluorine, n is 1, and T is CH 2 CH 3 , and
a pharmaceutically acceptable carrier.
11. A method for providing anesthesia to a mammal comprising administering to said mammal a compound of formula (I) according to claim 1 .
12. A method for providing anesthesia to a mammal comprising administering to said mammal a pharmaceutical composition according to claim 10 .
13. The method of claim 11 , wherein the administration step administers 0.01 to 100 mg/kg of the compound of formula (I).
14. The method of claim 11 , wherein said administering comprises: injection of a single effective dose of the compound of formula (I).
15. The method of claim 11 , wherein said administering comprises: continuous infusion of an effective dose of the compound of formula (I).
16. The method of claim 11 , wherein the method further comprises administering to the mammal an effective amount of a therapeutic agent selected from another sedative hypnotic agent, an analgesic agent, and a paralytic agent.