WO2017059827A1 - 依托咪酯衍生物及其中间体、制备方法和用途 - Google Patents

依托咪酯衍生物及其中间体、制备方法和用途 Download PDF

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WO2017059827A1
WO2017059827A1 PCT/CN2016/101696 CN2016101696W WO2017059827A1 WO 2017059827 A1 WO2017059827 A1 WO 2017059827A1 CN 2016101696 W CN2016101696 W CN 2016101696W WO 2017059827 A1 WO2017059827 A1 WO 2017059827A1
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group
compound
formula
etomidate
hydrogen
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PCT/CN2016/101696
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English (en)
French (fr)
Inventor
李勤耕
王涛
曾令国
张桂生
徐祥青
任亮
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江苏恩华络康药物研发有限公司
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Priority to JP2018537709A priority Critical patent/JP6983416B2/ja
Priority to ES16853130T priority patent/ES2913090T3/es
Priority to CA3001431A priority patent/CA3001431C/en
Priority to DK16853130.9T priority patent/DK3360863T3/da
Priority to EP16853130.9A priority patent/EP3360863B1/en
Priority to PL16853130.9T priority patent/PL3360863T3/pl
Priority to US15/767,009 priority patent/US10392352B2/en
Priority to CN201680059075.4A priority patent/CN108349906B/zh
Publication of WO2017059827A1 publication Critical patent/WO2017059827A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics

Definitions

  • the invention belongs to the field of medicine, and relates to an etomidate derivative or a pharmaceutically acceptable salt, polymorph or solvate thereof, a pharmaceutical composition and a kit comprising the etomidate derivative, and a An intermediate, a preparation method and a use of the etomidate derivative.
  • Etomidate chemical name R-(+)-1-(1-phenethyl)-1-hydro-imidazole-5-carboxylic acid ethyl ester, is an intravenous anesthetic drug characterized by rapid onset and action. Short time, rapid recovery, mild inhibition of cardiovascular and respiratory, clinically used for induction of anesthesia and outpatient anesthesia, its structure is as follows:
  • etomidate may exert an inhibitory effect on 11 ⁇ -hydroxylase while exerting anesthetic action, thereby reducing the secretion of cortisol and/or corticosterone, so the long-term use of etomidate is potentially fatal.
  • the present invention provides an etomidate derivative or a pharmaceutically acceptable salt, polymorph or solvate thereof.
  • the etomidate derivative of the invention not only has good anesthetic activity, fast onset and short duration of action, but also has no inhibitory effect on the secretion of cortisol and/or corticosterone, and thus has good anesthetic effect and safety.
  • the etomidate derivative of the present invention has the following formula I:
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • a pharmaceutical composition comprising the etomidate derivative of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and one or more pharmaceutically acceptable An acceptable carrier.
  • kits comprising the etomidate derivative of the invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, or a pharmaceutical composition of the invention.
  • the invention provides an etomidate derivative of the invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, for use in anesthesia.
  • the present invention provides the use of the etomidate derivative of the present invention or a pharmaceutically acceptable salt, polymorph or solvate thereof for the preparation of an anesthetic.
  • the invention provides an anesthesia method comprising administering an effective amount of an etomidate derivative of the invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof.
  • a process for the preparation of the etomidate derivative of the present invention which comprises: preparing the etomidate derivative from the compound of formula 2:
  • X and Y are each independently a halogen or hydrogen, provided that X and Y are not hydrogen at the same time.
  • the present invention provides an intermediate compound, or a salt, polymorph or solvate thereof, for use in the preparation of the etomidate derivative of the present invention, which has the following Equation 2:
  • X and Y are each independently a halogen or hydrogen, provided that X and Y are not hydrogen at the same time.
  • a ninth aspect of the invention there is provided a use of a compound of formula 2, or a salt, polymorph or solvate thereof, for the preparation of an etomidate derivative of the invention.
  • a process for the preparation of the etomidate derivative of the present invention which comprises: preparing the etomidate derivative from the compound of the formula 3:
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • the present invention provides an intermediate compound, or a salt, polymorph or solvate thereof, for use in the preparation of the etomidate derivative of the present invention, wherein the intermediate compound has The following formula 3:
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • the present invention provides the use of a compound of Formula 3, or a salt, polymorph or solvate thereof, for the preparation of the etomidate derivative of the present invention.
  • substituted means that one or more (eg, 1, 2, 3 or 4) hydrogens on a specified atom are replaced by the selection of the indicated group, provided that the The normal valence of the specified atom in the present case and the substitution forms a stable compound. Combinations of substituents and/or variables are permissible only if such combinations form stable compounds.
  • halogen as used herein means fluoro, chloro, bromo or iodo, preferably fluoro, chloro or bromo.
  • C 1-6 alkyl as used herein means a straight or branched saturated hydrocarbon group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, or different. Butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, etc., preferably methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl base.
  • C 2-6 alkenyl refers to a straight or branched chain unsaturated hydrocarbon group having at least one carbon to carbon double bond and having 2 to 6 carbon atoms, such as vinyl, 1-propenyl, 2 - Propenyl (allyl), isopropenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.
  • C 2-6 alkynyl refers to a straight or branched chain unsaturated hydrocarbon group having at least one carbon to carbon triple bond and having 2 to 6 carbon atoms, such as ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl and the like.
  • C 3-6 cycloalkyl refers to a saturated monocyclic hydrocarbon group having 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 6-10 aryl refers to an aromatic group having 6 to 10 carbon atoms, such as phenyl or naphthyl.
  • C1-6 alkoxy refers to a saturated monovalent hydrocarbon radical of the formula -OC 1-6 alkyl, wherein the term “ C1-6 alkyl” is as defined above, eg, methoxy, ethoxy Base, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, pentyloxy, isopentyloxy, n-hexyloxy and the like.
  • C 2-7 alkoxycarbonyl refers to a C 1-6 alkoxy group attached to the remainder of the molecule through a carbonyl bond, wherein the term “C 1-6 alkoxy” is as defined above.
  • salt refers to a salt of an acid with a nitrogen atom of an imidazole ring.
  • the acid refers to an inorganic or organic acid which is commonly used in the field of organic chemistry and which reacts with a nitrogen atom of an imidazole ring to form a salt.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid, nitric acid, and the like.
  • the organic acid includes, but is not limited to, formic acid, acetic acid, propionic acid, butyric acid, pivalic acid, trifluoroacetic acid, difluoroacetic acid, fluoroacetic acid, acetoacetic acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, trifluoromethyl Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonic acid and the like.
  • pharmaceutically acceptable salt refers to a salt of a pharmaceutically acceptable acid with a nitrogen atom of an imidazole ring.
  • pharmaceutically acceptable acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, propionic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, camphorsulfonate Acid, etc.
  • the compounds of the invention may exist in crystalline or polymorphic form, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • the compound of the present invention may exist in the form of a solvate thereof, particularly a hydrate, wherein the present invention
  • the compound of the formula contains a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
  • a polar solvent as a structural element of the crystal lattice of the compound, such as water, ethanol, isopropanol, ethyl acetate or acetone.
  • the amount of polar solvent, particularly water may be present in stoichiometric or non-stoichiometric ratios.
  • the etomidate derivative of the invention not only has good anesthetic activity, fast onset and short action time, but also has no inhibitory effect on the secretion of cortisol and/or corticosterone in animals, and thus has good anesthetic effect and safety. Sex.
  • the present invention provides an etomidate derivative of the following formula 1 or a pharmaceutically acceptable salt, polymorph or solvate thereof:
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • one of X, Y is a halogen and the other is hydrogen.
  • X, Y are each independently halogen.
  • X, Y are the same halogen.
  • X, Y are different halogens.
  • X, Y are each independently fluorine, chlorine, bromine or hydrogen, provided that X, Y are not hydrogen at the same time.
  • R 1 is C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • the etomidate derivative of the invention is selected from the group consisting of:
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising the etomidate derivative of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, and one or more pharmaceutically acceptable Carrier.
  • pharmaceutically acceptable carrier in the present invention is meant a diluent, adjuvant, excipient or vehicle with which the therapeutic agent is administered, and which is suitable for contacting humans and/or within the scope of sound medical judgment. Or the tissues of other animals without excessive toxicity, irritation, allergic reactions, or other problems or complications corresponding to a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, sterile liquids such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, minerals. Oil, sesame oil, etc. Water is an exemplary carrier when the pharmaceutical composition is administered intravenously. It is also possible to use physiological saline and an aqueous solution of glucose and glycerin as a liquid carrier, particularly for injection.
  • Suitable pharmaceutical excipients include starch, glucose, lactose, sucrose, gelatin, maltose, chalk, silica gel, sodium stearate, glyceryl monostearate, talc, sodium chloride, skimmed milk powder, glycerin, propylene glycol, water, Ethanol and the like.
  • the pharmaceutical composition may further contain a small amount of a wetting agent, an emulsifier or a pH buffering agent as needed.
  • compositions of the invention may be administered in a suitable route.
  • the pharmaceutical compositions of the invention are administered by parenteral route, for example by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes. More preferably, the pharmaceutical composition of the invention is administered by the intravenous route.
  • Another object of the present invention is to provide a kit comprising the etomidate derivative of the present invention or a pharmaceutically acceptable salt, polymorph or solvate thereof, or a pharmaceutical composition of the present invention.
  • a further object of the present invention is to provide an etomidate derivative of the present invention, or a pharmaceutically acceptable salt, polymorph or solvate thereof, for use in anesthesia, particularly intravenous anesthesia.
  • a further object of the present invention is to provide the use of the etomidate derivative of the present invention or a pharmaceutically acceptable salt, polymorph or solvate thereof for the preparation of an anesthetic.
  • the medicament is a medicament for administration by a parenteral route, for example by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes. More preferably, the drug is a drug that is administered by an intravenous route.
  • a further object of the present invention is to provide an anesthesia method comprising administering an effective amount of the etomidate derivative of the present invention or a pharmaceutically acceptable salt, polymorph or solvate thereof.
  • the administration is by parenteral route, for example by intravenous, intraarterial, subcutaneous, intraperitoneal, intramuscular or transdermal routes. More preferably, the administration is by intravenous route.
  • X and Y are each independently a halogen or hydrogen, provided that X and Y are not hydrogen at the same time.
  • one of X, Y is a halogen and the other is hydrogen.
  • X, Y are each independently halogen.
  • X, Y are the same halogen.
  • X, Y are different halogens.
  • X, Y are each independently fluorine, chlorine, bromine or hydrogen, provided that X, Y are not hydrogen at the same time.
  • the compound of formula 2 is selected from the group consisting of
  • the etomidate derivative of Formula 1 can be prepared from the compound of Formula 2 using the following Scheme A (condensation with an ester):
  • the condensing agent is a compound containing a carbodiimide structure, such as EDCI or DCC or the like.
  • the above reaction is carried out at a temperature of from 10 ° C to 50 ° C.
  • the molar ratio of the compound of Formula 2, R 1 OH and the condensing agent is 1: (1-10): (1-15).
  • the etomidate derivative of Formula 1 can be prepared from the compound of Formula 2 using the following Scheme B:
  • the halogenating agent is thionyl chloride, oxalyl chloride or a similar chemical reagent.
  • the alkaline agent is a nitrogen-containing organic reagent such as triethylamine, DMAP or the like.
  • the above reaction is carried out at a temperature of from -20 ° C to 50 ° C.
  • the molar ratio of the compound of formula 2 to R 1 OH is 1: (1-10).
  • the etomidate derivative of Formula 1 can be prepared from the compound of Formula 2 using the following Scheme C:
  • the H + is sulfuric acid, HCl or HBr or the like.
  • the above reaction is carried out at a temperature of from -10 °C to 60 °C.
  • the molar ratio of the compound of formula 2 to R 1 OH is 1: (5-20).
  • the etomidate derivative of Formula 1 can be prepared from the compound of Formula 2 using the following Scheme D:
  • the activator refers to an agent that activates an acyl group to facilitate an esterification reaction, such as ethyl chloroformate, benzyl chloroformate, and the like.
  • the above reaction is carried out at a temperature of from -20 ° C to 50 ° C.
  • the molar ratio of the compound of formula 2 to R 1 OH is 1: (1-10).
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • one of X, Y is a halogen and the other is hydrogen.
  • X, Y are each independently halogen.
  • X, Y are the same halogen.
  • X, Y are different halogens.
  • X, Y are each independently fluorine, chlorine, bromine or hydrogen, provided that X, Y are not hydrogen at the same time.
  • R 1 is C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • the compound of formula 3 is selected from the group consisting of
  • the etomidate derivative of Formula 1 can be prepared from the compound of Formula 3 using the following Scheme E:
  • the method of Route E is carried out in the presence of Ph 3 P and DEAD.
  • the above reaction is carried out at a temperature of from -20 ° C to 60 ° C.
  • the molar ratio of the compound of formula 3 to S-phenylethyl alcohol is 1: (1-10).
  • the compound of formula 1 can be prepared from the compound of formula 4-5, respectively, according to the following route F-G:
  • the compound of formula 1 can be prepared by reacting a compound of formula 4 with NCS or NBS.
  • the compound of formula 1 can be prepared by reacting a compound of formula 5 with NCS or NBS.
  • X and Y are each independently a halogen or hydrogen, provided that X and Y are not hydrogen at the same time.
  • one of X, Y is a halogen and the other is hydrogen.
  • X, Y are each independently halogen.
  • X, Y are the same halogen.
  • X, Y are different halogens.
  • X, Y are each independently fluorine, chlorine, bromine or hydrogen, provided that X, Y are not hydrogen at the same time.
  • the compound of formula 2 is selected from the group consisting of
  • the compound of Formula 2 can be obtained by hydrolysis of the etomidate derivative of Formula 1, and thus the compound of Formula 2 can also be used as an impurity control for the compound of Formula 1.
  • a further object of the present invention is to provide an intermediate compound for the preparation of the etomidate derivative of the present invention, which has the following formula 3:
  • X and Y are each independently halogen or hydrogen, provided that X and Y are not hydrogen at the same time;
  • R 1 is optionally one or more selected from the group consisting of halogen, hydroxy, amino, cyano, C 1-6 alkoxy, C 2-7 alkoxycarbonyl, C 3-6 cycloalkyl and C 6-10 A substituted C 1-6 alkyl group, a C 2-6 alkenyl group, a C 2-6 alkynyl group, a C 3-6 cycloalkyl group or a C 6-10 aryl group substituted with an aryl group.
  • one of X, Y is a halogen and the other is hydrogen.
  • X, Y are each independently halogen.
  • X, Y are the same halogen.
  • X, Y are different halogens.
  • X, Y are each independently fluorine, chlorine, bromine or hydrogen, provided that X, Y are not hydrogen at the same time.
  • R 1 is C 1-6 alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl or isobutyl.
  • the compound of formula 3 is selected from the group consisting of
  • the compound of the formula 3 can be produced by a commercially available raw material according to a conventional method, for example, the following It was prepared by the method reported: [1] Journal of Organic Chemistry, 2001 (20), 76, 8477-8482; [2] Journal of Medicine Chemistry, 2008 (7), 51, 2244-2253; [3] Journal of American Chemical Society, 1973, 95, 4619; [4] Journal of Organic Chemistry, 1984 (11), 49, 1951-1954.
  • 1H-4-Chloro-imidazole-5-carboxylic acid ethyl ester 1H-4-chloro-imidazole-5-carboxylic acid (300 mg) was placed in ethanol (5 ml) with stirring at room temperature, and thionyl chloride was added ( The reaction was carried out under reduced pressure for 1 hr. The mixture was neutralized with an aqueous solution of sodium hydrogencarbonate, and the mixture was evaporated to ethyl ether.
  • R-1-(1-Phenylethyl)-1H-imidazole-5-carboxylic acid ethyl ester (488 mg, 2 mmol) and NCS (280 mg, 2.1 mmol) were dissolved in acetonitrile (20 ml) and warmed to reflux. Reaction for 12 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure.
  • R-1-(1-Phenylethyl)-1H-2-fluoro-imidazole-5-carboxylic acid (470 mg, 2 mmol) was placed in dry dichloromethane (10 mL) with EtOAc. Ml) and catalytic amount of DMF, remove the ice bath, react at room temperature for 12 hours, remove the solvent and excess oxalyl chloride by evaporation under reduced pressure to obtain R-1-(1-phenylethyl)-1H-2- Fluoro-imidazole-5-formyl chloride.
  • the anesthetic ED 50 and LD 50 values were determined by sequential method. Healthyly qualified KM mice (male) were injected at a uniform rate through the tail vein during the experimental administration and injected for 10 seconds. A preliminary pre-test was performed to find the approximate dose (dosing volume) that caused the anesthesia (or death) of the animal as an intermediate dose at the time of the formal experiment. A group spacing of 0.8 was used, and 2-3 dose groups were further set up and down. The disappearance or death of righting reflex is used as a judgment indicator for pharmacodynamics or toxicity. In the case of a formal experiment, administration is first started from an intermediate dose.
  • TI LD 50 / ED 50 .
  • the etomidate derivative of the present invention can exert an anesthetic effect on mice, and its anesthetic efficacy is similar to that of etomidate.
  • mice Male Kunming mice were divided into groups, 5 in each group, and the test drug was injected into the tail vein at a uniform rate, and the injection was completed in 10 seconds. The time (latency) and recovery time (duration) of disappearance of righting reflex in mice were recorded.
  • mice anesthesia incubation period The results of the mouse anesthesia incubation period and duration of the compound are shown in Table 2 below:
  • mice The anesthetic effect of the etomidate derivative of the present invention on mice is similar to that of etomidate, and the onset is rapid and the duration is short.
  • the degree of inhibition of rat corticosterone secretion by the etomidate derivative of the present invention was evaluated by the method reported in the literature Anesthesiolgy 2010; 112(3): 637-644 using etomidate as a positive control.
  • Rats were placed in the tube for 1 day, grouped (negative control group, 6 other groups of 8), and tail vein injection was administered with 0.2 mg/kg dexamethasone (concentration: 0.04 mg/mL, administration volume was 5 mL). /kg).
  • the baseline value of serum cortex (corticosterone C 0min , negative control) was determined by carotid blood sampling 2 h later.
  • 0.2 mg/kg dexamethasone and compounds 15, 16 and etomidate (positive control) were administered again.
  • 25 ⁇ g/kg of ACTH 1-24 (concentration: 5 ⁇ g/mL, administration volume: 5 mL/kg) was administered by tail vein injection. After 15 min, blood was taken from the carotid artery and the corticosterone concentration (corticosterone C 15 min ) was determined.
  • Table 4 The test results are shown in Table 4 below:
  • the etomidate derivative of the present invention has no inhibitory effect on corticosterone secretion in rats.
  • the compounds of the present invention not only have the advantages of etomidate-like (ie, have better anesthetic activity, fast onset, short duration of maintenance, and little effect on the cardiovascular system), but also do not inhibit cortisol and/or cortex.
  • the secretion of ketones has both good anesthetic effects and safety.

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Abstract

本发明公开了一种式1的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，包含所述依托咪酯衍生物的药物组合物和药盒，以及所述依托咪酯衍生物的中间体、制备方法和用途。所述依托咪酯衍生物不仅具有较好的麻醉活性、起效快且作用时间短，还对动物中皮质激素的分泌基本没有抑制作用，因而兼具良好的麻醉效应和安全性。

Description

依托咪酯衍生物及其中间体、制备方法和用途
相关申请的交叉引用
本申请要求2015年10月10日提交的中国专利申请第201510650913.2号的优先权，所述申请的公开内容援引加入本文。
技术领域
本发明属于医药领域，涉及一种依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，包含所述依托咪酯衍生物的药物组合物和药盒，以及所述依托咪酯衍生物的中间体、制备方法和用途。
背景技术
依托咪酯，化学名为R-(+)-1-(1-苯乙基)-1-氢-咪唑-5-甲酸乙酯，是一种静脉麻醉药物，其特点是起效快、作用时间短、恢复迅速、对心血管和呼吸的抑制作用轻微，临床主要用于诱导麻醉和门诊手术麻醉，其结构如下所示：
Figure PCTCN2016101696-appb-000001
然而，研究发现，依托咪酯在发挥麻醉作用的同时，可能对11β-羟化酶产生抑制作用，从而减少皮质醇和/或皮质酮的分泌，因此长时间使用依托咪酯具有潜在的致命危险。
为了克服依托咪酯的缺点，开发既保持依托咪酯的优点，又不像依托咪酯那样强烈抑制皮质醇和/或皮质酮的分泌的新药，药物化学家们进行了大量研究。例如，Cotten JF等人(Methoxycarbonyl-etomidate:A novel rapidly metabolized and ultra-short-acting etomidateanalogue that does not produce  prolonged adrenocortical suppression,Anesthesiology,2009,111:240-9)报道了式7的依托咪酯衍生物，这类依托咪酯衍生物对皮质醇和/或皮质酮的分泌具有较低的抑制作用，但同时其麻醉效应也成倍减弱；同样地，Laha,Joydev K等人(Synthesis of Fused Imidazoles,Pyrroles,and Indoles with a Defined Stereocenter α to Nitrogen Utilizing Mitsunobu Alkylation Followed by Palladium-Catalyzed Cyclization,Journal of Organic Chemistry,2011,vol.76,#20,p 8477-8482)公开了式8的Carboetomidate类依托咪酯衍生物，这类衍生物几乎不抑制皮质醇和/或皮质酮的分泌，但其也具有降低的麻醉活性且作用时间长。
Figure PCTCN2016101696-appb-000002
鉴于以上问题，开发兼具良好的麻醉效应和安全性的依托咪酯衍生物具有很大的现实意义。
发明内容
根据本发明的第一方面，本发明提供了一种依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物。本发明的依托咪酯衍生物不仅具有较好的麻醉活性、起效快且作用时间短，还对皮质醇和/或皮质酮的分泌基本没有抑制作用，因而兼具良好的麻醉效应和安全性。
本发明的依托咪酯衍生物具有如下通式I：
Figure PCTCN2016101696-appb-000003
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的第二方面，本发明提供了药物组合物，其包含本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物以及一种或多种药学上可接受的载体。
根据本发明的第三方面，本发明提供了药盒，其包含本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物或者本发明的药物组合物。
根据本发明的第四方面，本发明提供了本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，其用于麻醉。
根据本发明的第五方面，本发明提供了本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物用于制备麻醉药物的用途。
根据本发明的第六方面，本发明提供了麻醉方法，其包括给药有效量的本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物。
根据本发明的第七方面，本发明提供了一种制备本发明的依托咪酯衍生物的方法，其包括：以式2的化合物为原料制备所述依托咪酯衍生物：
Figure PCTCN2016101696-appb-000004
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢。
根据本发明的第八方面，本发明提供了一种用于制备本发明的依托咪酯衍生物的中间体化合物或其盐、多晶型物或溶剂合物，所述中间体化合物具有以下通式2：
Figure PCTCN2016101696-appb-000005
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢。
根据本发明的第九方面，本发明提供了式2的化合物或其盐、多晶型物或溶剂合物在制备本发明的依托咪酯衍生物中的用途。
根据本发明的第十方面，本发明提供了另一种制备本发明的依托咪酯衍生物的方法，其包括：以式3的化合物为原料制备所述依托咪酯衍生物：
Figure PCTCN2016101696-appb-000006
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的第十一方面，本发明提供了另一种用于制备本发明的依托咪酯衍生物的中间体化合物或其盐、多晶型物或溶剂合物，所述中间体化合物具有以下通式3：
Figure PCTCN2016101696-appb-000007
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的第十二方面，本发明提供了式3的化合物或其盐、多晶型物或溶剂合物在制备本发明的依托咪酯衍生物中的用途。
具体实施方式
定义
除非在下文中另有定义，本文中所用的所有技术术语和科学术语的含义意图与本领域技术人员通常所理解的相同。提及本文中使用的技术意图指在本领域中通常所理解的技术，包括那些对本领域技术人员显而易见的技术的变化或等效技术的替换。虽然相信以下术语对于本领域技术人员很好理解，但仍然阐述以下定义以更好地解释本发明。
本文所用的术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的要素或方法步骤。
本文所用的术语“取代的”指所指定的原子上的一个或多个(例如1个、2个、3个或4个)氢被从所指出的基团的选择代替，条件是未超过所指定的原子在当前情况下的正常原子价并且所述取代形成稳定的化合物。取代基和/或变量的组合仅仅当这种组合形成稳定的化合物时才是允许的。
本文所用的术语“任选地被……取代”是指可以被或不被特定的基团、原子团或部分取代。
本文所用的术语“卤素”是指氟、氯、溴或碘，优选为氟、氯或溴。
本文所用的术语“C1-6烷基”是指具有1-6个碳原子的直链或支链的饱和烃基，例如甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、异戊基、新戊基、正己基、异己基等，优选甲基、乙基、丙基、异丙基、正丁基或异丁基。
本文所用的术语“C2-6烯基”是指具有至少一个碳碳双键且具有2-6个碳 原子的直链或支链的不饱和烃基，例如乙烯基、1-丙烯基、2-丙烯基(烯丙基)、异丙烯基、2-甲基-1-丙烯基、1-丁烯基、2-丁烯基等。
本文所用的术语“C2-6炔基”是指具有至少一个碳碳三键且具有2-6个碳原子的直链或支链的不饱和烃基，例如乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基等。
本文所用的术语“C3-6环烷基”是指具有3-6个碳原子的饱和的单环烃基，例如环丙基、环丁基、环戊基、环己基等。
本文所用的术语“C6-10芳基”是指具有6-10个碳原子的芳族基团，例如苯基或萘基。
本文所用的术语“C1-6烷氧基”是指式-O-C1-6烷基的饱和一价烃基，其中术语“C1-6烷基”如上所定义，例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、戊氧基、异戊氧基、正己氧基等。
本文所用的术语“C2-7烷氧羰基”是指是指通过羰基键与分子的其余部分相连的C1-6烷氧基，其中术语“C1-6烷氧基”如上所定义，例如甲氧羰基、乙氧羰基、正丙氧羰基、异丙氧羰基、正丁氧羰基、异丁氧羰基、叔丁氧羰基、仲丁氧羰基、戊氧羰基、异戊氧羰基、正己氧羰基等。
本文所用的术语“盐”是指酸与咪唑环的氮原子所成的盐。其中所述酸是指有机化学领域中常用的可与咪唑环的氮原子反应形成盐的无机酸或有机酸。所述无机酸包括但不限于盐酸、氢溴酸、氢碘酸、硫酸、焦硫酸、磷酸、硝酸等。所述有机酸包括但不限于甲酸、乙酸、丙酸、丁酸、特戊酸、三氟乙酸、二氟乙酸、氟乙酸、乙酰乙酸、苯甲酸、甲磺酸、乙磺酸、三氟甲磺酸、苯磺酸、对甲苯磺酸、萘磺酸、樟脑磺酸等。
本文所用的术语“药学可接受的盐”是指可药用的酸与咪唑环的氮原子所成的盐。其中所述可药用的酸包括但不限于盐酸、氢溴酸、硫酸、磷酸、乙酸、丙酸、甲磺酸、乙磺酸、苯磺酸、对甲苯磺酸、萘磺酸、樟脑磺酸等。
本发明的化合物可以结晶形式或多晶型物形式存在，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
本发明的化合物可以其溶剂合物特别是水合物的形式存在，其中本发 明的化合物包含作为所述化合物晶格的结构要素的极性溶剂，例如水、乙醇、异丙醇、乙酸乙酯或丙酮。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
化合物
本发明的一个目的在于提供一种依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物。本发明的依托咪酯衍生物不仅具有较好的麻醉活性、起效快且作用时间短，还对动物中皮质醇和/或皮质酮的分泌基本没有抑制作用，因而兼具良好的麻醉效应和安全性。
具体而言，本发明提供具有如下通式1的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物：
Figure PCTCN2016101696-appb-000008
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的一个实施方案，X、Y之一为卤素，另一者为氢。
根据本发明的另一实施方案，X、Y各自独立地为卤素。
根据本发明的一个实施方案，X、Y为相同的卤素。
根据本发明的另一实施方案，X、Y为不同的卤素。
根据本发明的一个实施方案，X、Y各自独立地为氟、氯、溴或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，R1为C1-6烷基，例如甲基、乙基、丙基、异丙基、正丁基或异丁基。
根据本发明的一个实施方案，本发明的依托咪酯衍生物选自：
Figure PCTCN2016101696-appb-000009
药物组合物和药盒
本发明的另一目的在于提供药物组合物，其包含本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物以及一种或多种药学上可接受的载体。
本发明中的“药学上可接受的载体”是指与治疗剂一同给药的稀释剂、辅剂、赋形剂或媒介物，并且其在合理的医学判断的范围内适于接触人类和/或其它动物的组织而没有过度的毒性、刺激、过敏反应或与合理的益处/风险比相应的其它问题或并发症。
在本发明的药物组合物中可使用的药学上可接受的载体包括但不限于无菌液体，例如水和油，包括那些石油、动物、植物或合成来源的油，例如花生油、大豆油、矿物油、芝麻油等。当所述药物组合物通过静脉内给药时，水是示例性载体。还可以使用生理盐水和葡萄糖及甘油水溶液作为液体载体，特别是用于注射液。适合的药物赋形剂包括淀粉、葡萄糖、乳糖、蔗糖、明胶、麦芽糖、白垩、硅胶、硬脂酸钠、单硬脂酸甘油酯、滑石、氯化钠、脱脂奶粉、甘油、丙二醇、水、乙醇等。所述药物组合物还可以视需要包含少量的湿润剂、乳化剂或pH缓冲剂。
本发明的药物组合物可以适合的途径给药。优选地，本发明的药物组合物通过肠胃外途径，例如通过静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。更优选地，本发明的药物组合物通过静脉内途径给药。
本发明的另一目的在于提供药盒，其包含本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，或者本发明的药物组合物。
治疗方法和用途
本发明的又一目的在于提供本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，其用于麻醉，特别是静脉麻醉。
本发明的又一目的在于提供本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物用于制备麻醉药物的用途。优选地，所述药物为通过肠胃外途径，例如通过静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药的药物。更优选地，所述药物为通过静脉内途径给药的药物。
本发明的又一目的在于提供麻醉方法，其包括给药有效量的本发明的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物。优选地，所述给药为通过肠胃外途径，例如通过静脉内、动脉内、皮下、腹膜内、肌内或经皮途径给药。更优选地，所述给药为通过静脉内途径给药。
制备方法
本发明的又一目的在于提供一种制备本发明的依托咪酯衍生物的方法，其包括：以式2的化合物为原料制备所述依托咪酯衍生物：
Figure PCTCN2016101696-appb-000010
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，X、Y之一为卤素，另一者为氢。
根据本发明的另一实施方案，X、Y各自独立地为卤素。
根据本发明的一个实施方案，X、Y为相同的卤素。
根据本发明的另一实施方案，X、Y为不同的卤素。
根据本发明的一个实施方案，X、Y各自独立地为氟、氯、溴或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，所述式2的化合物选自：
Figure PCTCN2016101696-appb-000011
根据本发明的一个实施方案，可以按照以下路线A(与酯缩合)，以式2的化合物为原料制备式1的依托咪酯衍生物：
路线A
Figure PCTCN2016101696-appb-000012
其中X、Y和R1如上文中所定义。
根据本发明的一个实施方案，所述缩合剂为含有碳二亚胺结构的化合物，例如EDCI或DCC等。
优选地，上述反应在10℃至50℃的温度下进行。
优选地，式2的化合物、R1OH和缩合剂的摩尔比为1:(1-10):(1-15)。
根据本发明的另一实施方案，可以按照以下路线B，以式2的化合物为原料制备式1的依托咪酯衍生物：
路线B
Figure PCTCN2016101696-appb-000013
其中X、Y和R1如上文中所定义。
根据本发明的一个实施方案，所述卤化剂为氯化亚砜、草酰氯或类似的化学试剂。
根据本发明的一个实施方案，所述碱性试剂为含氮有机试剂，例如三乙胺、DMAP等。
优选地，上述反应在-20℃至50℃的温度下进行。
优选地，式2的化合物与R1OH的摩尔比为1:(1-10)。
根据本发明的另一实施方案，可以按照以下路线C，以式2的化合物为原料制备式1的依托咪酯衍生物：
路线C
Figure PCTCN2016101696-appb-000014
其中X、Y和R1如上文中所定义。
根据本发明的一个实施方案，所述H+为硫酸、HCl或HBr等。
优选地，上述反应在-10℃至60℃的温度下进行。
优选地，式2的化合物与R1OH的摩尔比为1:(5-20)。
根据本发明的另一实施方案，可以按照以下路线D，以式2的化合物为原料制备式1的依托咪酯衍生物：
路线D
Figure PCTCN2016101696-appb-000015
其中X、Y和R1如上文中所定义。
所述活化剂是指使酰基活化以便于发生酯化反应的试剂，例如氯甲酸乙酯、氯甲酸苄酯等。
优选地，上述反应在-20℃至50℃的温度下进行。
优选地，式2的化合物与R1OH的摩尔比为1:(1-10)。
本发明的又一目的在于提供另一种制备本发明的依托咪酯衍生物的方法，其包括：以式3的化合物为原料制备所述依托咪酯衍生物：
Figure PCTCN2016101696-appb-000016
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的一个实施方案，X、Y之一为卤素，另一者为氢。
根据本发明的另一实施方案，X、Y各自独立地为卤素。
根据本发明的一个实施方案，X、Y为相同的卤素。
根据本发明的另一实施方案，X、Y为不同的卤素。
根据本发明的一个实施方案，X、Y各自独立地为氟、氯、溴或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，R1为C1-6烷基，例如甲基、乙基、丙基、异丙基、正丁基或异丁基。
根据本发明的一个实施方案，所述式3的化合物选自：
Figure PCTCN2016101696-appb-000017
根据本发明的一个实施方案，可以按照以下路线E，以式3的化合物为原料制备式1的依托咪酯衍生物：
路线E
Figure PCTCN2016101696-appb-000018
其中X、Y和R1如上文中所定义。
根据本发明的一个实施方案，路线E的方法是在Ph3P和DEAD的存在下进行的。
优选地，上述反应在-20℃至60℃的温度下进行。
优选地，式3的化合物与S-苯乙醇的摩尔比为1:(1-10)。
本发明的又一目的在于提供其它制备本发明的依托咪酯衍生物的方法。例如，可以按照以下路线F-G，分别以式4-5的化合物为原料制备式1的化合物：
路线F
Figure PCTCN2016101696-appb-000019
例如，当X、Y同为氯或溴时，可通过使式4的化合物与NCS或NBS反应来制得式1的化合物。
路线G
Figure PCTCN2016101696-appb-000020
例如，当X、Y之一为氟或氯且另一者为溴时，可通过使式5的化合物与NCS或NBS反应来制得式1的化合物。
中间体化合物
本发明的又一目的在于提供一种用于制备本发明的依托咪酯衍生物的中间体化合物，所述中间体化合物具有以下通式2：
Figure PCTCN2016101696-appb-000021
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，X、Y之一为卤素，另一者为氢。
根据本发明的另一实施方案，X、Y各自独立地为卤素。
根据本发明的一个实施方案，X、Y为相同的卤素。
根据本发明的另一实施方案，X、Y为不同的卤素。
根据本发明的一个实施方案，X、Y各自独立地为氟、氯、溴或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，所述式2的化合物选自：
Figure PCTCN2016101696-appb-000022
式2的化合物可以由式1的依托咪酯衍生物水解得到，因而式2化合物还可作为式1化合物的杂质对照品。
路线H
Figure PCTCN2016101696-appb-000023
本发明的又一目的在于提供另一种用于制备本发明的依托咪酯衍生物的中间体化合物，所述中间体化合物具有以下通式3：
Figure PCTCN2016101696-appb-000024
其中，
X、Y各自独立地为卤素或氢，条件是X、Y不同时为氢；且
R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基。
根据本发明的一个实施方案，X、Y之一为卤素，另一者为氢。
根据本发明的另一实施方案，X、Y各自独立地为卤素。
根据本发明的一个实施方案，X、Y为相同的卤素。
根据本发明的另一实施方案，X、Y为不同的卤素。
根据本发明的一个实施方案，X、Y各自独立地为氟、氯、溴或氢，条件是X、Y不同时为氢。
根据本发明的一个实施方案，R1为C1-6烷基，例如甲基、乙基、丙基、异丙基、正丁基或异丁基。
根据本发明的一个实施方案，所述式3的化合物选自：
Figure PCTCN2016101696-appb-000025
式3的化合物可以按照常规方法以市售原料制得，例如可参照以下文 献所报道的方法而制得：[1]Journal of Organic Chemistry,2001(20),76,8477-8482；[2]Journal of Medicine Chemistry,2008(7),51,2244-2253；[3]Journal of American Chemical Society,1973,95,4619；[4]Journal of Organic Chemistry,1984(11),49,1951-1954。
实施例
为了使本发明的目的和技术方案更加清楚，以下结合具体实施例进一步阐述本发明。要说明的是：以下实施例只用于对本发明进行进一步的说明，而不能理解为对本发明保护范围的限制。本领域的技术人员根据本发明的上述内容做出的一些非本质的改进和调整均属于本发明的保护范围。并且，下列实施例中未提及的具体实验方法，均按照常规实验方法进行。
本文中的缩写具有以下含义：
NCS N-氯代丁二酰亚胺
NBS N-溴代丁二酰亚胺
Ph3P 三苯基膦
DEAD 偶氮二甲酸二乙酯
NaNO2 亚硝酸钠
THF 四氢呋喃
EDCI 1-乙基-(3-二甲基氨基丙基)碳酰二亚胺盐酸盐
DCC 二环己基碳二亚胺
DMF N,N-二甲基甲酰胺
DMAP 4-N,N-二甲氨基吡啶
HBF4 氟硼酸
ACTH1-24 促肾上腺皮质激素氨基末端活性肽
式3的化合物的制备
实施例1
1H-4-氯-咪唑-5-甲酸乙酯的制备
在室温下，将市售原料1H-4-氯-咪唑-5-甲酸(300mg)置于乙醇(5ml)中，加入氯化亚砜(0.5ml)，在回流条件下反应1小时。通过减压蒸发除去溶剂， 得到作为白色固体的1H-4-氯-咪唑-5-甲酸乙酯盐酸盐。于冰水浴中，加入饱和碳酸氢钠水溶液中和，用乙酸乙酯萃取，通过减压蒸发除去溶剂，得到标题化合物(290mg)。ESI[M+H]+＝175.53
实施例2
1H-4-氟-咪唑-5-甲酸甲酯的制备
在冰浴下，将1H-咪唑-4-氨基-5-甲酸甲酯(0.5g)溶于50％的HBF4溶液(12.5ml)中，加入含有NaNO2(0.28g)的水溶液(1ml)，在汞灯照射(234nm)下持续反应，直至没有氮气放出。在反应完成后，在冰浴下用1N的NaOH冰水溶液调节pH至6，用乙酸乙酯(20ml*3)萃取水层，合并有机层，用饱和食盐水洗涤有机层后，用无水硫酸钠干燥，过滤，减压浓缩。将残余物经柱色谱法(EA:PE＝1:1)分离，得到作为无色油状物的标题化合物(0.23g)。ESI[M+H]+＝145.08
按照实施例1或2的方法，由相应的市售原料制备得到化合物36-50。所制得的化合物36-50的质谱数据如下表所示：
化合物编号 ESI[M+H]+
36 210.01
37 224.02
38 224.03
39 223.97
40 240.41
41 238.01
42 254.43
43 173.14
44 189.59
45 189.57
46 234.04
47 312.94
48 191.13
49 163.07
50 284.88
式2的化合物的制备
实施例3
R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸(化合物32)的制备
冰浴搅拌下，将R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸甲酯(2.48g，10mmol)溶于甲醇(30ml)，滴加1N NaOH溶液，经TLC监测反应，在反应完全后，通过减压蒸发除去甲醇。将水层用1N HCl调节pH为5后，用乙酸乙酯萃取(25ml*3)，合并有机层，用饱和食盐水洗涤后，用无水硫酸钠干燥，过滤，浓缩，得到作为白色固体的标题化合物(2.22g，收率94.8％)。ESI[M+H]+＝235.18
按照实施例3的方法，由相应的原料制备得到化合物30-31和33-35。所制得的化合物30-31和33-35的质谱数据如下表所示：
化合物编号 ESI[M+H]+
30 251.65
31 235.19
33 253.21
34 269.64
35 314.09
式1的依托咪酯衍生物的制备
实施例4
R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸甲酯(化合物13)的制备
在-30℃下，将含有S-苯乙醇(122mg)的THF(2ml)滴入含有1H-2-氟-咪唑-5-甲酸甲酯(144mg)和Ph3P(325mg)的THF(3ml)中。然后，将含有DEAD(220mg)的THF(2ml)滴入反应液中。滴完后，将反应液升温至0℃。经TLC监测反应，反应完全后，通过减压蒸发除去溶剂。将残余物经柱色谱法(EA:PE＝1:3)分离，得到作为无色油状物的标题化合物(73mg)。ESI[M+H]+＝249.21
实施例5
R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸乙酯(化合物14)的制备
以1H-2-氟-咪唑-5-甲酸乙酯为原料，按照实施例4的方法制得标题化合物。ESI[M+H]+＝263.24
实施例6
R-1-(1-苯乙基)-1H-2,4-二氟-咪唑-5-甲酸乙酯(化合物18)的制备
以1H-2,4-二氟-咪唑-5-甲酸乙酯为原料，按照实施例4的方法制得标题化合物。ESI[M+H]+＝281.23
实施例7
R-1-(1-苯乙基)-1H-4-氯-咪唑-5-甲酸乙酯(化合物4)的制备
1)1H-4-氯-咪唑-5-甲酸乙酯：在室温搅拌下，将1H-4-氯-咪唑-5-甲酸(300mg)置于乙醇(5ml)中，加入氯化亚砜(0.5ml)，在回流条件下反应1小时，通过减压蒸发除去溶剂，得到作为白色固体的1H-4-氯-咪唑-5-甲酸乙酯盐酸盐。于冰水浴中，缓缓加入碳酸氢钠冰水溶液中和，用乙酸乙酯萃取，通过减压蒸发除去溶剂，制得1H-4-氯-咪唑-5-甲酸乙酯(280mg)。
2)以1H-4-氯-咪唑-5-甲酸乙酯为原料，按照实施例4的方法制得标题化合物。ESI[M+H]+＝279.69
实施例8
R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸甲酯(化合物15)的制备
1)1H-咪唑-4-氟-5-甲酸甲酯：在冰浴下，将1H-咪唑-4-氨基-5-甲酸甲酯(0.5g)溶于50％的HBF4溶液(12.5ml)中，加入含有NaNO2(0.28g)的水溶液(1ml)，在汞灯照射(234nm)下持续反应，直至没有氮气放出。在反应完成后，在冰浴下用1N的NaOH冰水溶液调节pH至6以上。将水层用乙酸乙酯(20ml*3)萃取，合并有机层，用饱和食盐水洗涤有机层后，用无水硫酸钠干燥，过滤，减压浓缩，将残余物经柱色谱法(EA:PE＝1:1)分离，得到作为无色油状物的1H-4-氟-咪唑-5-甲酸甲酯(0.23g)。
2)以1H-4-氟-咪唑-5-甲酸甲酯为原料，按照实施例4的方法制得标题化合物。ESI[M+H]+＝249.22
1H-NMR(DMSO，400MHz)1.73-1.84(t,3H)；3.68(s,3H)；6.13(q,1H),7.1–7.3(m,5H)。
F-NMRδ：-113.40(s)。
实施例9
R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸乙酯(化合物16)的制备
将含有S-苯乙醇(134mg，1.1mmol)的干燥THF(2ml)滴入含有1H-4-氟-咪唑-5-甲酸乙酯(158mg，1.1mmol)和Ph3P(340mg，1.3mmol)的干燥THF(3ml)中。然后，将含有DEAD(230mg，1.32mmol)的干燥THF(2ml)滴入反应液中。滴完后，将反应液缓慢升温至0℃。经TLC监测反应，反应完全后，通过减压蒸发除去溶剂。将残余物经柱色谱法(EA:PE＝1:3)分离，得到作为无色油状物的标题化合物(81mg，收率28％)。ESI[M+H]+＝263.24
1H-NMR(CD3Cl，400MHz)1.31(t,J＝7.1Hz,3H)；1.96(d,J＝7.2Hz,3H)；4.20–4.33(q,J＝7.1Hz,2H)；6.22-6.31(m,1H),7.16–7.38(m,5H)。
F-NMRδ：-113.40(s)。
以相应的式3的化合物为原料，按照实施例4-9的方法制备得到化合物1-3、5-12、17和19-29。
实施例10
R-1-(1-苯乙基)-1H-2-氯-咪唑-5-甲酸乙酯(化合物2)、R-1-(1-苯乙基)-1H-4-氯-咪唑-5-甲酸乙酯(化合物4)和R-1-(1-苯乙基)-1H-2,4-二氯-咪唑-5-甲酸乙酯(化合物6)的制备
在室温下，将R-1-(1-苯乙基)-1H-咪唑-5-甲酸乙酯(488mg，2mmol)和NCS(280mg，2.1mmol)溶于乙腈(20ml)，升温至回流，反应12h。反应完成后，通过减压蒸发除去溶剂。将残余物用色谱柱分离，分别得到R-1-(1-苯乙基)-1H-2-氯-咪唑-5-甲酸乙酯(80mg)，R-1-(1-苯乙基)-1H-4-氯-咪唑-5-甲酸乙酯(120mg)和R-1-(1-苯乙基)-1H-2,4-二氯-咪唑-5-甲酸乙酯(50mg)。
R-1-(1-苯乙基)-1H-2-氯-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl,400MHz)δ：1.30(t,J＝7.1Hz,3H)；2.00(d,J＝7.2Hz,3H)；4.22-4.38(q,J＝7.1Hz,2H)；6.25-6.38(m,1H),7.15-7.37(m,5H)；7.55(s,1H)。
ESI[M+H]+＝279.71。
R-1-(1-苯乙基)-1H-4-氯-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl,400MHz)δ：1.33(t,J＝7.1Hz,3H)；1.97(d,J＝7.2Hz,3H)；4.24-4.31(q,J＝7.1Hz,2H)；6.65-6.77(m,1H)；7.15-7.35(m,5H)；7.70 (s,1H)。
ESI[M+H]+＝279.70。
R-1-(1-苯乙基)-1H-2,4-二氯-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl,400MHz)δ：1.31(t,J＝7.1Hz,3H)；1.96(d,J＝7.2Hz,3H)；4.26-4.36(q,J＝7.1Hz,2H)；6.60-6.69(m,1H)；7.16-7.36(m,5H)。
ESI[M+H]+＝341.15。
实施例11
R-1-(1-苯乙基)-1H-2-溴-咪唑-5-甲酸乙酯(化合物7)、R-1-(1-苯乙基)-1H-4-溴-咪唑-5-甲酸乙酯(化合物10)和R-1-(1-苯乙基)-1-氢-2,4-二溴-咪唑-5-甲酸乙酯(化合物12)的制备
以R-1-(1-苯乙基)-1H-咪唑-5-甲酸乙酯为原料，并以NBS为溴代试剂，按照实施例10的方法制得标题化合物。
R-1-(1-苯乙基)-1H-2-溴-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl，400MHz)δ：1.30(t,J＝7.1Hz,3H)；2.00(d,J＝7.2Hz,3H)；4.22-4.38(q,J＝7.1Hz,2H)；6.26-6.40(m,1H),7.09-7.39(m,5H)；7.58(s,1H)。
ESI[M+H]+＝324.17。
R-1-(1-苯乙基)-1H-4-溴-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl，400MHz)δ：1.30(t,J＝7.1Hz,3H)；2.00(d,J＝7.2Hz,3H)；4.20-4.27(q,J＝7.1Hz,2H)；6.65-6.71(m,1H),7.36-7.12(m,5H)；7.75(s,1H)。
ESI[M+H]+＝324.18。
R-1-(1-苯乙基)-1H-2,4-二溴-咪唑-5-甲酸乙酯：
1H-NMR(CH3Cl，400MHz)δ：1.31(t,J＝7.1Hz,3H)；1.99(d,J＝7.1Hz,3H)；4.35-4.16(q,J＝7.1Hz,2H)；6.49-6.6(m,1H)；7.42-7.09(m,5H)。
ESI[M+H]+＝403.07。
实施例12
R-1-(1-苯乙基)-1H-2-氯-4-溴-咪唑-5-甲酸乙酯(化合物19)的制备
以R-1-(1-苯乙基)-1H-2-氯-咪唑-5-甲酸乙酯为原料，并以NBS为溴代试剂，按照实施例10的方法制得标题化合物。ESI[M+H]+＝358.61
实施例13
R-1-(1-苯乙基)-1H-2-氟-4-氯-咪唑-5-甲酸异丙酯(化合物24)的制备
以R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸异丙酯为原料，并以NCS为氯代试剂，按照实施例10的方法制得标题化合物。ESI[M+H]+＝356.19
实施例14
R-1-(1-苯乙基)-1H-2-氟-4-氯-咪唑-5-甲酸异丙酯(化合物25)的制备
在-20℃下，将R-1-(1-苯乙基)-1H-2-氟-4-氯-咪唑-5-甲酸(270mg，1mmol)和三乙胺(111mg，1.1mmol)溶于干燥的二氯甲烷(15ml)中。缓慢滴加含有氯甲酸乙酯(110mg，1mmol)的干燥二氯甲烷溶液(2ml)，在-20℃搅拌下反应1小时。过滤，在冰浴下向滤液中滴加异丙醇(0.5ml)，在冰浴下反应4小时。反应完成后，将反应液依次用0.1N HCl(5ml*2)、饱和NaHCO3溶液(10ml*2)和饱和食盐水(15ml*1)洗涤后，将有机层用无水硫酸钠干燥，过滤，减压浓缩。将残余物用柱色谱法纯化，得到作为无色油状物的标题化合物(280mg，收率90％)。ESI[M+H]+＝311.68
实施例15
R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸异丙酯(化合物26)的制备
在室温搅拌下，将R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸(234mg，1mmol)、EDCI(250mg，1.3mmol)和DMAP(12mg，0.1mmol)加入到干燥的二氯甲烷(10ml)后，缓慢滴加异丙醇(12mg，2mmol)。在室温搅拌下反应6小时，反应完成后，将反应液依次用0.1N HCl(5ml*2)、饱和NaHCO3(10ml*2)和饱和食盐水(15ml*1)洗涤后，用无水硫酸钠干燥有机层，过滤，减压浓缩。将残余物用柱色谱法纯化，得到作为无色油状物的标题化合物(248mg，收率90％)。ESI[M+H]+＝277.28
实施例16
R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸正丁酯(化合物27)的制备
以R-1-(1-苯乙基)-1H-4-氟-咪唑-5-甲酸和正丁醇为原料，按照实施例15的方法制得标题化合物。ESI[M+H]+＝291.31
实施例17
R-1-(1-苯乙基)-1H-2,4-二溴-咪唑-5-甲酸异丁酯(化合物28)的制备
以R-1-(1-苯乙基)-1H-2,4-二溴-咪唑-5-甲酸和异丁醇为原料，按照实施 例15的方法制得标题化合物。ESI[M+H]+＝431.09
实施例18
R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸正丁酯(化合物29)的制备
冰浴搅拌下，将R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酸(470mg，2mmol)置于干燥二氯甲烷(10ml)中，加入草酰氯(0.5ml)和催化量的DMF，撤去冰浴，在室温下反应12小时后，通过减压蒸发除去溶剂和过量的草酰氯，制得R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酰氯。
在冰浴搅拌下，将含有上一步制得的R-1-(1-苯乙基)-1H-2-氟-咪唑-5-甲酰氯的干燥二氯甲烷溶液(5ml)缓慢滴入到含有正丁醇(0.2ml)和DMAP(300mg，2.5mmol)的干燥二氯甲烷溶液(10ml)中，撤去冰浴，在室温下反应6小时。在反应完成后，将反应液依次用0.1N HCl(5ml*2)、饱和NaHCO3(10ml*2)和饱和食盐水(15ml*1)洗涤后，将有机层用无水硫酸钠干燥，过滤，减压浓缩。将残余物用柱色谱法纯化，得到作为无色油状物的标题化合物(550mg，收率95％)。ESI[M+H]+＝291.30
以相应的式2的化合物为原料，按照实施例14-18的方法制备得到化合物1-24。
所制得的化合物1、3、5、8、9、11、17、20-23的质谱数据如下表所示：
化合物编号 ESI[M+H]+
1 265.68
3 265.70
5 300.13
8 338.18
9 338.19
11 417.08
17 264.22
20 372.64
21 279.69
22 279.71
23 328.13
生物学实验例
实验例1
本发明的依托咪酯衍生物的小鼠ED50及LD50测试
实验药品与给药：
精密称定化合物14、15、16、18各5mg，放置于10ml离心管中。加入1ml空白乳液(20％大豆油空白乳剂)，在超声仪中超声数分钟。临用时用注射器抽吸，成5mg/ml均匀乳液。取依托咪酯脂肪乳注射液(市售，2mg/ml)作为对照品。对小鼠固定给药浓度，给药体积则根据实际情况而变化。
实验方法：
采用序贯法测定麻醉ED50及LD50值。取健康合格的KM小鼠(雄性)，实验给药时经尾静脉匀速注射，10秒钟注射完。实验前经初步预试找出能够导致动物麻醉(或死亡)的大致剂量(给药体积)，作为正式实验时的中间剂量。采用0.8的组间距，向上向下分别再设2-3个剂量组。以翻正反射消失或死亡作为药效或毒性的判断指标。正式实验时首先从中间剂量开始给药。若动物被麻醉，则降低一个剂量给药；若动物未被麻醉，则增大一个剂量给药，直到出现3-4个反复。采用序贯法aot425软件进行LD50及ED50的计算。TI的计算公式为：TI＝LD50/ED50。
实验结果：
化合物的小鼠LD50/ED50及TI指数测试结果见下表1：
表1.化合物的小鼠LD50/ED50及TI指数测试结果(n＝10-20)
化合物编号 LD50(mg/kg) ED50(mg/kg) TI
15 48.4(44.1-54.2) 2.0(1.8-2.3) 24
16 46.5(42.7-50.7) 2.0(1.8-2.3) 23
依托咪酯 50.3(46.6-55.8) 2.0(1.8-2.3) 25
结论：本发明的依托咪酯衍生物对小鼠可以发挥麻醉作用，其麻醉效力与依托咪酯相近。
实验例2：
本发明的依托咪酯衍生物的小鼠麻醉潜伏期及持续期测定
取雄性昆明种小鼠，分组，每组5只，尾静脉匀速注射受试药物，10秒钟注射完。记录小鼠翻正反射消失的时间(潜伏期)及恢复时间(持续期)。
化合物的小鼠麻醉潜伏期及持续期测定结果如下表2所示：
表2.化合物的麻醉潜伏期及持续期测定结果(小鼠，mg/kg，分组法n＝5)
化合物编号 剂量(mg/kg) 潜伏期(s) 持续期(s) 行走时间(s)
15 6(3*ED50) 5.90±0.88 83.60±29.13 68.80±30.10
16 6(3*ED50) 5.80±0.79 82.10±20.18 98.10±63.96
依托咪酯 6(3*ED50) 5.40±0.52 175.50±100.09 156.30±120.78
结论：本发明的依托咪酯衍生物对小鼠的麻醉作用与依托咪酯相近，起效迅速，且持续时间短。
另外，发明人在小鼠麻醉实验中还发现，本发明的化合物对小鼠血压和麻醉苏醒后续反应的影响更小。数据如下表3所示：
表3.化合物对小鼠血压和麻醉苏醒后续反应的影响
Figure PCTCN2016101696-appb-000026
实验例3
本发明的依托咪酯衍生物对大鼠皮质酮分泌的抑制程度试验
按照文献Anesthesiolgy 2010；112(3):637-644中报道的方法，以依托咪酯为阳性对照，评估本发明的依托咪酯衍生物对大鼠皮质酮分泌的抑制程度。
实验方法：
将大鼠置管恢复1天，分组(阴性对照组6只，其他每组8只)后，尾静脉注射给药0.2mg/kg地塞米松(浓度为0.04mg/mL，给药体积为5mL/kg)。 在2h后经颈动脉取血测定血清皮质的基础值(皮质酮C0min，阴性对照)。再次给药0.2mg/kg地塞米松和化合物15、16及依托咪酯(阳性对照)。之后立即尾静脉注射给药25μg/kg的ACTH1-24(浓度为5μg/mL，给药体积为5mL/kg)。15min后经颈动脉取血，测定皮质酮浓度(皮质酮C15min)。试验结果如下表4所示：
表4.化合物对大鼠皮质酮分泌的抑制程度
Figure PCTCN2016101696-appb-000027
与阴性对照组比较，*表示P<0.05，**表示P<0.001；
与阳性对照组比较，#表示P<0.001。
由以上结果，可以看出本发明的依托咪酯衍生物对大鼠的皮质酮分泌没有抑制作用。
综上，本发明的化合物不仅具有依托咪酯样的优点(即，具有较好的麻醉活性、起效快、维持时间短及对心血管系统影响小等)，还不抑制皮质醇和/或皮质酮的分泌，因而兼具良好的麻醉效应和安全性。

Claims (11)

  1. 式1的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物：
    Figure PCTCN2016101696-appb-100001
    其中，
    X、Y各自独立地为卤素(优选为氟、氯或溴)或氢，条件是X、Y不同时为氢；且
    R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基，优选为C1-6烷基，更优选为甲基、乙基、丙基、异丙基、正丁基或异丁基。
  2. 如权利要求1所述的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，所述依托咪酯衍生物选自：
    Figure PCTCN2016101696-appb-100002
    Figure PCTCN2016101696-appb-100003
  3. 药物组合物，其包含如权利要求1或2所述的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物以及一种或多种药学上可接受的载体。
  4. 药盒，其包含如权利要求1或2所述的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物，或者如权利要求3所述的药物组合物。
  5. 如权利要求1或2所述的依托咪酯衍生物或其药学上可接受的盐、多晶型物或溶剂合物用于制备麻醉药物、特别是静脉麻醉药物的用途。
  6. 制备如权利要求1所述的依托咪酯衍生物的方法，其包括：以式2的化合物为原料制备所述依托咪酯衍生物：
    Figure PCTCN2016101696-appb-100004
    其中，
    X、Y各自独立地为卤素(优选为氟、氯或溴)或氢，条件是X、Y不同时为氢。
  7. 如权利要求6所述的方法，其特征在于：所述式2的化合物选自：
    Figure PCTCN2016101696-appb-100005
  8. 式2的化合物或其盐、多晶型物或溶剂合物：
    Figure PCTCN2016101696-appb-100006
    其中，
    X、Y各自独立地为卤素(优选为氟、氯或溴)或氢，条件是X、Y不同时为氢。
  9. 如权利要求8所述的式2的化合物或其盐、多晶型物或溶剂合物，其特征在于：所述式2的化合物选自：
    Figure PCTCN2016101696-appb-100007
  10. 制备如权利要求1所述的依托咪酯衍生物的方法，其包括：以式3的化合物为原料制备所述依托咪酯衍生物：
    Figure PCTCN2016101696-appb-100008
    其中，
    X、Y各自独立地为卤素(优选为氟、氯或溴)或氢，条件是X、Y不同时为氢；且
    R1为任选地被一个或多个选自卤素、羟基、氨基、氰基、C1-6烷氧基、C2-7烷氧羰基、C3-6环烷基和C6-10芳基的取代基取代的C1-6烷基、C2-6烯基、C2-6炔基、C3-6环烷基或C6-10芳基，优选为C1-6烷基，更优选为甲基、乙基、丙基、异丙基、正丁基或异丁基。
  11. 如权利要求10所述的方法，其特征在于：所述式3的化合物选自：
    Figure PCTCN2016101696-appb-100009
    Figure PCTCN2016101696-appb-100010
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