N-substituted imidazole carboxylate compound, preparation method and use
An N-substituted imidazole carboxylate compound is of formula (I). In formula (I), C* is an R-type chiral carbon atom, R 1 and R 2 are independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl or isopropyl, or R 1 and R 2 form a C 2˜5 alkylenyl group; R 3 is a substituted or unsubstituted C 1-18 saturated or unsaturated aliphatic hydrocarbon or aromatic hydrocarbon, in which the aliphatic hydrocarbon comprises a straight chain, branched chain or cyclic aliphatic hydrocarbyl. The compound or pharmaceutically acceptable salts thereof can be used to prepare central inhibitory drugs that exert sedative, hypnotic and/or anesthetic effects on humans or animals, and can produce rapid and reversible anesthetic effects, and can be rapidly metabolized into an inactive etomidate acid, and after drug withdrawal, the wake-up quality is good; and the body's corticosteroid function can be rapidly recovered after a single administration or continuous administration.
1. An N-substituted imidazole carboxylate compound of formula (I) and a pharmaceutically acceptable salt thereof,
in formula (I), C* is an R-type chiral carbon atom, R 1 and R 2 are independently selected from H, methyl, ethyl, cyclopropyl, cyclobutyl, and isopropyl, or R 1 and R 2 form a C 2˜5 alkylenyl group; R 3 is a substituted or unsubstituted C 1-18 saturated or unsaturated aliphatic hydrocarbon or aromatic hydrocarbon, in which the aliphatic hydrocarbon comprises a straight chain, branched chain or cyclic aliphatic hydrocarbyl.
2. The N-substituted imidazole carboxylate compound according to claim 1 , wherein, in formula (I), R 3 is substituted by halogen, nitro, or aryl.
3. The N-substituted imidazole carboxylate compound according to claim 1 , wherein,
in formula (I), R 1 is hydrogen, R 2 is hydrogen, R 3 is methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, cyclobutyl, 3-methyl-2-butyl, phenyl, or p-bromophenyl; or
in formula (I), R 1 and R 2 form ethylene, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is methyl, R 2 is hydrogen, R 3 is methyl, ethyl, isopropyl, or sec-butyl; or
in formula (I), R 1 is methyl, R 2 is methyl, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is ethyl, R 2 is hydrogen, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is isopropyl, R 2 is hydrogen, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is cyclopropyl, R 2 is hydrogen, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is cyclobutyl, R 2 is hydrogen, R 3 is methyl, ethyl, or isopropyl; or
in formula (I), R 1 is hydrogen, R 2 is hydrogen, R 3 is difluoroethyl, hexafluoroisopropyl, trifluoroethyl or nitroethyl; or
in formula (I), R 1 is hydrogen, R 2 is hydrogen, R 3 is 2-methyl-3-buten-2-yl or isopentenyl.
4. The pharmaceutically acceptable salt according to claim 1 which is a sulfonate or a hydrochlorate of the compound of formula (I).
5. The preparative method of N-substituted imidazole carboxylate compound according to claim 1 , comprising:
reacting an N-substituted imidazole carboxylic compound of formula (II) and a halogenated compound of formula (III) in presence of a base:
wherein X is a halogen atom.
6. The preparative method according to claim 5 , wherein X is chlorine.
7. The preparative method according to claim 5 , wherein the base is selected from potassium carbonate, cesium carbonate, triethylamine, 1,8-diazabicycloundec-7-ene, and mixtures thereof.
8. The preparative method according to claim 5 , wherein the reaction is carried out in a polar aprotic solvent.
9. The preparative method according to claim 8 , wherein the polar aprotic solvent is N,N-dimethylformamide, dimethylsulfoxide, or acetonitrile.
10. The preparative method of the N-substituted imidazole carboxylate compound according to claim 1 , comprising reacting an N-substituted imidazole carboxylic compound of formula (IV) and a chloroformate compound of formula (V) to obtain the compound of formula (I):
wherein R 1 and R 2 form a C2-5 alkylenyl group.
11. A central inhibitory drug, comprising the N-substituted imidazole carboxylate compound and the pharmaceutically acceptable salt thereof according to claim 1 .
12. A method for inducing anesthetic effect in a subject in need thereof, comprising administering to the subject the N-substituted imidazole carboxylate compound and the pharmaceutically acceptable salt thereof according to claim 1 .