WO2015096551A1 - 含有醚侧链的n-取代咪唑羧酸酯手性化合物、制备方法和用途 - Google Patents

含有醚侧链的n-取代咪唑羧酸酯手性化合物、制备方法和用途 Download PDF

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WO2015096551A1
WO2015096551A1 PCT/CN2014/089898 CN2014089898W WO2015096551A1 WO 2015096551 A1 WO2015096551 A1 WO 2015096551A1 CN 2014089898 W CN2014089898 W CN 2014089898W WO 2015096551 A1 WO2015096551 A1 WO 2015096551A1
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compound
formula
preparation
chiral
etomidate
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PCT/CN2014/089898
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French (fr)
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张文胜
杨俊�
刘进
唐磊
柯博文
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四川大学华西医院
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Priority to RU2016123144A priority Critical patent/RU2659784C2/ru
Priority to AU2014373186A priority patent/AU2014373186B2/en
Priority to JP2016539968A priority patent/JP2016540795A/ja
Priority to CA2933098A priority patent/CA2933098A1/en
Priority to SG11201605055SA priority patent/SG11201605055SA/en
Priority to EP14873468.4A priority patent/EP3088394B1/en
Priority to US15/107,415 priority patent/US9969695B2/en
Priority to KR1020167017220A priority patent/KR20160089516A/ko
Publication of WO2015096551A1 publication Critical patent/WO2015096551A1/zh
Priority to PH12016501246A priority patent/PH12016501246A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to an N-substituted imidazole carboxylate chiral compound containing an ether side chain, a preparation method and use thereof.
  • Etomidate is a long-established intravenous general anesthetic. It has a fast onset time and short maintenance time. It is an ideal intravenous general anesthetic. At the same time, it also has unique pharmacological characteristics with excellent cardiovascular stability.
  • the inhibition of body circulation in anesthesia is the smallest among the general anesthetics used in clinical practice, so it is especially suitable for patients with cardiac insufficiency (JFCotton, Anesthesiology 2009;111 :240).
  • the mechanism of anesthesia of etomidate has been clarified, mainly by binding to the central inhibitory receptor GABA A , making the receptor more sensitive to the inhibitory neurotransmitter GABA, thereby producing an anesthetic effect.
  • the inhibition of corticosteroids by etomidate is mainly achieved by inhibiting the activity of 11-beta hydroxylase, which is a key enzyme in the synthesis of corticosteroids.
  • This side effect of etomidate is related to the imidazole structure in the drug molecule.
  • One N atom in the imidazole ring can form a complex with the topological iron atom in the 11-beta hydroxylase, thereby enhancing the binding of the drug molecule to the enzyme molecule.
  • the curve shows that after a single injection of 3 mg / kg of etomidate, the minimum effective concentration of the anesthetic effect of plasma is 110 ng / ml, the time of the drug maintained above this concentration in plasma is only 8 min; The minimum inhibitory effect of ester on cortisol synthesis inhibition was 8 ng/ml, and the drug remained above this concentration in plasma for up to 8 h. This suggests that the administration of anesthetic dose of etomidate to patients will also inhibit cortisol synthesis for a longer period of time after the anesthetic effect disappears rapidly.
  • the present invention provides an N-substituted imidazole carboxylate chiral compound containing an ether side chain, and further provides a process for the preparation of the compound and its use, which can satisfactorily achieve the above object.
  • the N-substituted imidazole carboxylate chiral compound containing an ether side chain of the present invention includes the pharmaceutically acceptable salt compound of the chiral compound.
  • the structure of the N-substituted imidazole carboxylate compound is as shown in formula (I), wherein the chiral C* configuration is R type:
  • the pharmaceutically acceptable salt compound of the N-substituted imidazole carboxylate chiral compound may include a salt compound which is commonly used in pharmacy such as a hydrochloride, a hydrobromide or a trifluoroacetate.
  • the above compound of the present invention can be obtained by optically separating the compound of the compound, or can be directly prepared.
  • the basic preparation method can be carried out by substituting a N-substituted imidazolecarboxylic acid chiral compound of the formula (II) with a halide of the formula (III) under a polar aprotic solvent and basic conditions to obtain the formula (I).
  • the target compound wherein the chiral C* configuration in the formula is R and X is a halogen element.
  • the reaction process is as follows:
  • Said halogen element X is preferably Br or Cl
  • the reaction solvent is preferably DMF;
  • the base is preferably an inorganic base including an alkali metal hydroxide or carbonate.
  • the compound of the formula (I) has a salt-forming basic N atom in the structure, the compound of the formula (I) obtained as described above or obtained by other routes can be combined with a pharmaceutically acceptable acid group. The corresponding salt compound is obtained.
  • N-substituted imidazole carboxylate compounds of the above formula (I) of the present invention and salts thereof are capable of producing rapid and reversible pharmacological effects such as sedative hypnosis and/or anesthesia, and the single administration time is longer than that of the support.
  • the anesthetic effect of imidazole is more short-acting, the quality of recovery is better, and the inhibition of adrenocortical hormone can be significantly alleviated, and the recovery is rapid and thorough.
  • the corresponding S-type optical isomer (IV) of the compound of the formula (I) and the corresponding racemate (V) are significantly inferior in potency and safety range as the R of the above formula (I) of the present invention.
  • Type compounds including said pharmaceutically acceptable salts thereof. Therefore, the above-mentioned N-substituted imidazole carboxylate-based chiral compound or a pharmaceutically acceptable salt compound thereof is used for the preparation of sedative hypnosis and/or anesthesia for animals or humans by intravenous or extravascular route.
  • the central inhibitory drugs there are significant advantages, values and application prospects.
  • Figure 1 is a graph showing the ee value of the product of Example 1 (compound of formula (I)).
  • Figure 2 is a ee value detection map of the product of Example 3 (compound of formula (IV)).
  • Figure 3 is a ee value detection map of the product of Example 4 (compound of formula (V)).
  • Mass spectrometry mass spectrometer: API3000LC-Ms/Ms, ABI, USA, ionization mode: ESI.
  • ee value The compound of the formula (I) was placed in a methanol solution having a concentration of 1 mg/mL, and the mixture was diluted by 100 times. It was detected by high performance liquid chromatography using a chiral AD column, UV detector wavelength: 254 nm, mobile phase: 20% isopropanol-n-hexane, flow rate: 1 mL/min. The optical purity of the compound (I) was determined to be 100% (as shown in Fig. 1).
  • reaction solution was poured into 100 mL of cold water to obtain a clear solution, which was extracted with ethyl acetate three times (50 mL each time), and the organic layer was combined, dried over anhydrous sodium sulfate and filtered.
  • the crude product was purified by EtOAcjjjjjjj
  • ee value The compound of the formula (IV) was placed in a methanol solution having a concentration of 1 mg/mL, and the mixture was diluted by 100 times. It was detected by high performance liquid chromatography using a chiral AD column, UV detector wavelength: 254 nm, mobile phase: 20% isopropanol-n-hexane, flow rate: 1 mL/min. The optical purity of the compound (IV) was determined to be 99% (as shown in Fig. 2).
  • reaction solution was poured into 100 mL of cold water to obtain a clear solution, which was extracted with ethyl acetate three times (50 mL each time), and the organic layer was combined, dried over anhydrous sodium sulfate and filtered.
  • the crude product was purified by EtOAcjjjjjjj
  • ED 50 half effective amount
  • All three compounds were dissolved using DMSO as a solvent, and etomidate was used as a commercial preparation (B BRAUN, 20 mg/10 ml), the initial dose was 1 mg/kg, and the dose change ratio was 0.8, and the ED 50 of the three compounds of the formulae (I), (IV) and (V) and etomidate were determined.
  • the disappearance time of the rat righting reflex was greater than 30s as a positive indicator of the anesthetic effect of the drug. If the reflex did not disappear, it was considered invalid.
  • the test result produced 4 crosses and calculated the ED 50 value.
  • the onset time refers to the time from the end of the administration to the time when the test animal has a righting reflex, and does not include the administration time of 30 s;
  • # Maintenance time refers to the time when the righting reflex disappears until the test animal's righting reflex is restored.
  • Awakening time refers to the time when the righting reflex is restored to the full recovery of the test animal.
  • the test result produced 4 crosses and calculated the ED 50 value.
  • the results showed that the ED 50 of the three salts of the compound of the formula (I) and etomidate were 2.58 mg/kg, 3.09 mg/kg, 3.61 mg/kg and 1.06 mg/kg, respectively.
  • four groups (the hydrochloride of the formula (I), the hydrobromide of the formula (I) are determined by tail vein administration using the respective three salts of the compound of the formula (I) and the 2 ED 50 of etomidate as the equivalent dose.
  • the onset time refers to the time from the end of the administration to the time when the test animal has a righting reflex, and does not include the administration time of 30 s;
  • # Maintenance time refers to the time when the righting reflex disappears until the test animal's righting reflex is restored.
  • Awakening time refers to the time when the righting reflex is restored to the full recovery of the test animal.
  • Table 4 shows the increase of corticosteroids after ACTH stimulation after administration of three salts of the compound of formula (I)

Abstract

含有醚侧链的N-取代咪唑羧酸酯手性化合物、制备方法和用途。所说化合物的结构如式（Ⅰ）所示。该化合物能够产生快速、可逆的全身麻醉效应。动物实验显示出快速、短效的药理特点，可作为一类速效、短效的全身***物使用，同时与依托咪酯相比能够降低对肾上腺皮质激素合成的抑制，苏醒恢复迅速而彻底，具有明显的优势和良好的应用前景。此化合物结构中唯一的手性碳必须是R型。此化合物结构中咪唑环上具有可酸化的N原子，因此该化合物及其可药用的盐类分子可以在制备作为经静脉或静脉外途径对动物或人产生镇静催眠和/或麻醉作用的中枢抑制性药物中应用。

Description

含有醚侧链的N-取代咪唑羧酸酯手性化合物、制备方法和用途 技术领域
本发明涉及一种含有醚侧链的N-取代咪唑羧酸酯手性化合物、制备方法和用途。
背景技术
依托咪酯，是一种上市已久的静脉全身***物，该药物的起效时间快，维持时间短，是一种比较理想的静脉全身***物。同时其还具有心血管稳定性十分出色的独特药理特点，对麻醉中机体循环的抑制在目前临床上使用的全身***中最小，因而特别适合心功能不全的手术患者(J.F.Cotton,Anesthesiology 2009；111:240)。依托咪酯的麻醉作用机制目前已经明确，主要通过与中枢的抑制性受体GABAA结合，使该受体对抑制性神经递质GABA更加敏感，从而产生麻醉作用。但深入的研究发现，依托咪酯对机体的皮质激素合成也具有抑制作用，特别是长时间的连续输注对皮质激素的抑制更加明显(S.S.Husain,Journal of medicinal chemistry 2006；49:4818-4825)。由于皮质激素的自身合成是机体抗炎的重要因素，因此这一缺点对术后病人的恢复不利，而且这种不利影响已逐渐被临床研究证实，导致了依托咪酯的使用率随这种认识的加深而逐渐降低，因为医务人员不希望使用了依托咪酯的病人在术后恢复中面临感染增加的危险。
依托咪酯对皮质激素的抑制主要通过抑制11-β羟化酶的活性来实现，该酶是皮质激素合成的关键酶。依托咪酯的这种副作用与药物分子中的咪唑结构有关，咪唑环中的一个N原子能够与11-β羟化酶中的拓扑铁原子形成络合，从而加强了药物分子与酶分子的结合，从而达到抑制11-β羟化酶的作用，而且其与11-β羟化酶的结合能力比其与GABAA受体的结合能力强100倍，这就为设计没有或具有较弱11-β羟化酶结合能力的咪唑类衍生物带来了挑战(Zolle IM,J Med Chem 2008；51:2244-53)。依托咪酯主要在肝脏代谢，随着药物代谢研究的进行，人们已绘制了依托咪酯的疗效与副作用的时间/效应曲线(Stuart A.Forman,Anesthesiology 2011；114(3):695-707)，该曲线表明，单次注射3mg/kg的依托咪酯后，其麻醉效应的血浆最低起效浓度为110ng/ml，药物在血浆中维持在这一浓度之上的时间只有8min；而依托咪酯对皮质激素合成抑制的最低起效浓度为8ng/ml，药物在血浆中维持在这一浓度之上的时间长达8h。这即表明，对患者给予麻醉剂量的依托咪酯，在麻醉效应快速消失后对皮质激素合成的抑制还将存在较长时间。
因此，在能够保留该药物的药理活性前提下，获得不会产生明显皮质激 素合成抑制的咪唑类全身***物，可降低咪唑类全身***物的副作用，从而使这类药物的应用范围更加广泛，是十分有意义的。
发明内容
鉴于上述情况，本发明提供了一种含有醚侧链的N-取代咪唑羧酸酯手性化合物，并进一步提供了该化合物的制备方法及其用途，可以满意地实现上述的目的。
本发明含有醚侧链的N-取代咪唑羧酸酯手性化合物，包括该手性化合物其药学中可接受的盐类化合物。所说的N-取代咪唑羧酸酯化合物的结构如式(Ⅰ)所示，其中的手性C*构型为R型：
Figure PCTCN2014089898-appb-000001
所说N-取代咪唑羧酸酯手性化合物的药学中可接受的盐类化合物，可包括如盐酸盐、氢溴酸盐、三氟醋酸盐等药学中常用的盐类化合物。
本发明上述化合物，可以由其混旋化合物经光学拆分后得到，也可以直接制备得到。其基本制备方法，可以采用在极性非质子溶剂和碱性条件下，以式(Ⅱ)的N-取代咪唑羧酸手性化合物与式(Ⅲ)的卤化物经取代反应后得到式(Ⅰ)目标化合物，式中的手性C*构型为R型，X为卤元素。反应过程如下：
Figure PCTCN2014089898-appb-000002
在上述制备方法的基础上，还可以单独或以任意结合方式采用的优选方式包括：
所说的卤元素X优选为Br或Cl；
所说的反应溶剂优选为DMF；
所说的碱优选为包括碱金属的氢氧化物或碳酸盐在内的无机碱。
由于式(Ⅰ)化合物结构中具有可成盐的碱性N原子，因此由上述制备得到的、或经其它途径得到的该式(Ⅰ)化合物，与药学中可接受的酸根结合后，即可得到相应的盐类化合物。
动物实验表明，本发明上述式(Ⅰ)结构的N-取代咪唑羧酸酯类化合物及其盐均能够产生快速、可逆的镇静催眠和/或麻醉等药理作用，单次给药维持时间比依托咪酯的麻醉效应更短效，苏醒质量更好，并且能显著减轻对肾上腺皮质激素的抑制，恢复迅速而彻底。与之相比，式(Ⅰ)化合物的对应S型光学异构体(Ⅳ)以及相应的消旋体(Ⅴ)在效价，安全范围方面均明显不如本发明的上述式(Ⅰ)的R型化合物(包括所说其药用盐)。因此，本发明上述的N-取代咪唑羧酸酯类手性化合物或其药学中可接受的盐类化合物，在用于制备作为经静脉或静脉外途径对动物或人产生镇静催眠和/或麻醉作用的中枢抑制性药物中，具有显著的优势、价值和应用前景。
Figure PCTCN2014089898-appb-000003
以下结合由附图所示实施例的具体实施方式，对本发明的上述内容再作进一步的详细说明。但不应将此理解为本发明上述主题的范围仅限于以下的实例。在不脱离本发明上述技术思想情况下，根据本领域普通技术知识和惯用手段做出的各种替换或变更，均应包括在本发明的范围内。
附图说明
图1是实施例1产物(式(Ⅰ)化合物)的ee值检测图谱。
图2是实施例3产物(式(Ⅳ)化合物)的ee值检测图谱。
图3是实施例4产物(式(Ⅴ)化合物)的ee值检测图谱。
具体实施方式
实施例1
本发明式(Ⅰ)化合物的制备：将式(Ⅱ)化合物(CAS:56649-48-0)(216mg,1mmol)、式(Ⅲ)化合物(CAS:6482-24-2)(278mg,2mmol)与无水碳酸钾(564mg,3mmol)混合于15mL N,N-二甲基甲酰胺，混合物于50℃搅拌反应过夜。次日将反应液冲入100mL冷水中得澄清溶液，使用乙酸乙酯萃取3次(每次50mL),合并有机层，用无水硫酸钠干燥过夜，过滤得滤液，减压蒸干溶剂得油状粗品，经硅胶柱纯化(展开剂：环己烷/乙酸乙酯＝3/2)得无色油状物150mg，产率54％。
1)核磁：仪器：BRUKER，TMS为内标。
1H-NMR(400MHz CDCl3)δ：1.862(3H,d,J＝7.2Hz),3.393(3H,s),3.645(3H,t,J＝4.8Hz),4.318～4.405(2H,m),6.348(1H,q,J＝7.2Hz),7.176～7.359(m,5H),7.742(s,1H),7.827(s,1H).
13C-NMR(100MHz CDCl3)δ：22.30,55.48,59.15,63.53,70.48,122.39,126.36,128.08,128.93,138.63,140.02,141.20,160.26.
2)质谱：质谱仪：美国ABI公司API3000LC-Ms/Ms，电离方式：ESI。
(M+H).HRMS:for C15H18N2O3+H,calcd 275.1396,found 275.1396.
3)旋光值：将式(Ⅰ)化合物配制成浓度为1g/100mL的乙醇溶液，使用Polarimeter 341旋光仪测定其旋光值，[α]D 20＝+71.9°。
4)ee值：将式(Ⅰ)化合物配置成浓度为1mg/mL的甲醇溶液，稀释100倍进样。使用手性AD柱经高效液相色谱检测，紫外检测器波长：254nm检测，流动相：20％异丙醇－正己烷，流速：1mL/min。经测定，化合物(Ⅰ)的光学纯度达100％(如图1所示)。
实施例2
本发明式(Ⅰ)化合物的制备：将式(Ⅱ)化合物(CAS:56649-48-0)(216mg,1mmol)、式(Ⅲ)化合物(CAS:627-42-9)(188mg,2mmol)与无水碳酸钾(564mg,3mmol)混合于15mL N,N-二甲基甲酰胺，混合物于50℃搅拌反应过夜。次日将反应液冲入100mL冷水中得澄清溶液，使用乙酸乙酯萃取3次(每次50mL),合并有机层，用无水硫酸钠干燥过夜，过滤得滤液，减压蒸干溶剂得油状粗品，经硅胶柱纯化(展开剂：环己烷/乙酸乙酯＝3/2)得无色油状物120mg，产率43％。
实施例3
S型光学对应体化合物(Ⅳ)的制备：
将S-(-)-1-(1-苯乙基)-1-氢-咪唑-5-甲酸(CAS:56649-49-1)216mg,1mmol)、式(Ⅲ)化合物(CAS:627-42-9)(188mg,2mmol)与无水碳酸钾(564mg,3mmol)混合于15mL N,N-二甲基甲酰胺，混合物于50℃搅拌反应过夜。次日将反应液冲入100mL冷水中得澄清溶液，使用乙酸乙酯萃取3次(每次50mL)，合并有机层，用无水硫酸钠干燥过夜，过滤得滤液，减压蒸干溶剂得油状粗品，经硅胶柱纯化(展开剂：环己烷/乙酸乙酯＝3/2)得无色油状物170mg，产率61.2％。
1)核磁：仪器：BRUKER，TMS为内标。
1H-NMR(400MHz CDCl3)δ：1.859(3H,d,J＝7.2Hz),3.392(3H,s),3.644(3H,t,J＝4.8Hz),4.301～4.412(2H,m),6.342(1H,q,J＝7.2Hz),7.172～7.355(m,5H),7.728(s,1H),7.822(s,1H).
2)旋光值：将式(Ⅳ)化合物配制成浓度为1g/100mL的乙醇溶液，使用Polarimeter 341旋光仪测定其旋光值，为[α]D 20＝-69.3°。
3)ee值：将式(Ⅳ)化合物配置成浓度为1mg/mL的甲醇溶液，稀释100倍进样。使用手性AD柱经高效液相色谱检测，紫外检测器波长：254nm检测，流动相：20％异丙醇－正己烷，流速：1mL/min。经测定，化合物(Ⅳ)的光学纯度达99％(如图2所示)。
实施例4
对应的消旋体化合物(Ⅴ)的制备：
将(±)-1-(1-苯乙基)-1-氢-咪唑-5-甲酸(CAS:CAS:7036-56-8)216mg,1mmol)、式(Ⅲ)化合物(CAS:627-42-9)(188mg,2mmol)与无水碳酸钾(564mg,3mmol)混合于15mL N,N-二甲基甲酰胺，混合物于50℃搅拌反应过夜。次日将反应液冲入100mL冷水中得澄清溶液，使用乙酸乙酯萃取3次(每次50mL),合并有机层，用无水硫酸钠干燥过夜，过滤得滤液，减压蒸干溶剂得油状粗品，经硅胶柱纯化(展开剂：环己烷/乙酸乙酯＝3/2)得无色油状物177mg，产率63.7％。
1)核磁：仪器：BRUKER，TMS为内标。
1HNMR(300MHz CDCl3)δ：1.839(3H,d,J＝7.2Hz),3.384(3H,s),3.619(2H,t,J＝4.8Hz),4.284～4.388(2H,m),6.325(1H,q,J＝7.2Hz),7.151～7.344(m,5H),7.749(s,1H),7.806(s,1H).
2)ee值：将式(Ⅴ)化合物配置成浓度为1mg/mL的甲醇溶液，稀释100倍进样。使用手性AD柱经高效液相色谱检测，紫外检测器波长：254nm，流动相：20％异丙醇－正己烷，流速：1mL/min。经测定，化合物(Ⅴ)是R与S两种构型的等比混合物，即消旋体。
实施例5
将2g实施例1的产物溶于50mL无水***中，冰浴下通入过量HCl气体，析出大量白色沉淀，过滤后干燥得白色粉末1.97g，即式(Ⅰ)化合物的盐酸盐。核磁：仪器：BRUKER，TMS为内标。
1HNMR(300MHz D2O)δ：1.833(3H,d,J＝7.2Hz),3.378(3H,s),3.614(2H,t,J＝4.8Hz),4.281～4.392(2H,m),6.321(1H,q,J＝7.2Hz),7.333～7.452(m,5H),8.001(s,1H),9.908(s,1H).
实施例6
将2g实施例1的产物溶于50mL无水***中，冰浴下滴加10％的HBr醋酸溶液，析出大量白色沉淀，过滤后干燥得白色粉末2.12g，即式(Ⅰ)化合物的氢溴酸盐。核磁：仪器：BRUKER，TMS为内标。
1HNMR(300MHz D2O)δ：1.821(3H,d,J＝7.2Hz),3.358(3H,s),3.611(2H, t,J＝4.8Hz),4.282～4.398(2H,m),6.319(1H,q,J＝7.2Hz),7.343～7.467(m,5H),8.000(s,1H),9.907(s,1H).
实施例7(三氟醋酸盐实施例)
将2g实施例1的产物溶于50mL无水***中，冰浴下滴加等摩尔的三氟醋酸，析出大量白色沉淀，过滤后干燥得白色粉末1.87g，即式(Ⅰ)化合物的三氟醋酸盐。核磁：仪器：BRUKER，TMS为内标。
1HNMR(300MHz D2O)δ：1.842(3H,d,J＝7.2Hz),3.367(3H,s),3.609(2H,t,J＝4.8Hz),4.271～4.382(2H,m),6.331(1H,q,J＝7.2Hz),7.312～7.432(m,5H),8.011(s,1H),9.928(s,1H).
实施例8
以体重250～300g的雄性SD大鼠为实验动物，采用序贯法测定半数有效量(ED50)。三种化合物均使用DMSO作为溶剂溶解，依托咪酯使用市售制剂(B BRAUN,
Figure PCTCN2014089898-appb-000004
20mg/10ml)，起始剂量均为1mg/kg，剂量变化比例为0.8，测定式(Ⅰ)、(Ⅳ)、(Ⅴ)三种化合物和依托咪酯的ED50。以大鼠翻正反射消失时间大于30s作为药物产生麻醉效应的阳性指标，反射未消失则视为无效，试验结果产生4个交叉后计算ED50值。结果显示三种化合物和依托咪酯的ED50分别为2.10mg/kg、7.46mg/kg、10.38mg/kg和1.14mg/kg。随后使用这三种化合物和依托咪酯各自的2ED50作为等效剂量经尾静脉给药，测定四组(式(Ⅰ)、(Ⅳ)、(Ⅴ)三种化合物和依托咪酯，每组10只)在大鼠的初步药效。试验结果显示式(Ⅰ)和依托咪酯给药后立即起效，式(Ⅳ)、(Ⅴ)的起效时间略慢为1-2min，维持时间式(Ⅰ)和依托咪酯为5-6min，式(Ⅳ)、(Ⅴ)为10-20min。但是，式(Ⅳ)、(Ⅴ)在试验期间不良反应的种类和发生率明显增加。DMSO没有药理效应，也未观察到不良反应的发生。三种化合物和依托咪酯的麻醉起效时间、维持时间及不良反应的种类和发生率见表1。
表1三种化合物和依托咪酯的麻醉起效时间、维持时间和不良反应种类及发生率
Figure PCTCN2014089898-appb-000005
注：—：无药理效应；
*：起效时间是指给药结束至试验动物出现翻正反射的时间，不包含30s的给药时间；
#：维持时间是指翻正反射消失至试验动物翻正反射恢复的时间。
▲：苏醒时间是指翻正反射恢复至试验动物完全恢复的时间。
上述动物实验结果表明，本发明R型的式(Ⅰ)化合物与依托咪酯一样表现出良好的镇静催眠和全身麻醉效果，而其S型对映异构体式(Ⅳ)化合物和消旋体式(Ⅴ)化合物则表现出效价降低、起效时间延长、维持时间延长、不良反应种类和发生率明显增加。
实施例9
以体重250～300g的雄性SD大鼠为实验动物，采用序贯法测定半数有效量(ED50)。三种化合物的盐酸盐均使用生理盐水作为溶剂溶解，依托咪酯仍使用市售制剂(B BRAUN,
Figure PCTCN2014089898-appb-000006
20mg/10ml)，起始剂量均为1mg/kg，剂量变化比例仍为0.8，测定式(Ⅰ)的盐酸盐、式(Ⅰ)的氢溴酸盐、式(Ⅰ)的三氟醋酸盐和依托咪酯的ED50。以大鼠翻正反射消失时间大于30s作为药物产生麻醉效应的阳性指标，反射未消失则视为无效，试验结果产生4个交叉后计算ED50值。结果显示式(Ⅰ)化合物的三种盐和依托咪酯的ED50分别为2.58mg/kg、3.09mg/kg、3.61mg/kg和1.06mg/kg。随后使用式(Ⅰ)化合物的这三种盐和依托咪酯各自的2ED50作为等效剂量经尾静脉给药，测定四组(式(Ⅰ)的盐酸盐、式(Ⅰ)的氢溴酸盐、式(Ⅰ)的三氟醋酸盐和依托咪酯，每组10只)在大鼠的初步药效。试验结果显示式(Ⅰ)的盐酸盐、式(Ⅰ)的氢溴酸盐、式(Ⅰ)的三氟醋酸盐和依托咪酯给药后均能立即起效，其维持时间分别为5-7min、5-6min、4-7min和4-8 min。苏醒时间也均在5-10min。在试验期间不良反应的种类和发生率各组之间没有明显差异。DMSO没有药理效应，也未观察到不良反应的发生。三种盐和依托咪酯的麻醉起效时间、维持时间及不良反应的种类和发生率见表2。表2三种化合物盐酸盐和依托咪酯的麻醉起效时间、维持时间和不良反应种类及发生率
Figure PCTCN2014089898-appb-000007
注：—：无药理效应；
*：起效时间是指给药结束至试验动物出现翻正反射的时间，不包含30s的给药时间；
#：维持时间是指翻正反射消失至试验动物翻正反射恢复的时间。
▲：苏醒时间是指翻正反射恢复至试验动物完全恢复的时间。
上述动物实验结果表明，本发明R型的式(Ⅰ)化合物的盐酸盐、氢溴酸盐、三氟醋酸盐与依托咪酯一样能表现出良好的镇静催眠和全身麻醉效果。
实施例10
选用雄性Beagle犬(10±2kg)作为受试动物，通过ELISA试剂盒以及酶标仪读数器对给药后的Beagle犬血清中皮质酮、皮质醇含量进行测定。20只Beagle犬随机分为五组，每组4只，分别给予***(0.01mg/kg)后将动物体内肾上腺皮质水平降至基线水平，将此时皮质醇与皮质酮水平作为基础值(Baseline)。随后给予等效剂量(2ED50)的(Ⅰ)化合物(2.88mg/kg)、(Ⅳ)化合物(5.66mg/kg)和(Ⅴ)化合物(4.12mg/kg)和阳性对照药物依托咪酯
Figure PCTCN2014089898-appb-000008
(0.8mg/kg)以及等体积溶媒DMSO。10min后给予ACTH(促肾上腺皮质激素)刺激，促使动物体内的皮质水平提高，于给予ACTH后1h测定动物体内的两种皮质激素浓度，计算皮质水平峰值与基础值之比，即得到皮质激素被提高的倍数，倍数越大说明药物对皮质激素的抑制越轻。依托咪酯、式(Ⅰ)、(Ⅳ)、(Ⅴ)化合物及DMSO给药后经ACTH刺激后皮质激素提高的倍数见表3。
表3三种化合物给药后经ACTH刺激后的皮质激素提高情况
Figure PCTCN2014089898-appb-000009
上述实验显示：依托咪酯能够严重抑制肾上腺皮质激素的自身合成，使得受试动物的皮质水平不能被ACTH刺激而提高；而式(Ⅰ)化合物组的动物虽然经ACTH刺激后皮质激素的提高不如空白组，但已经明显高于阳性药物依托咪酯组。因此，式(Ⅰ)化合物对皮质激素的抑制较之对照药物依托咪酯已经明显降低。式(Ⅰ)化合物与式(Ⅳ)、(Ⅴ)化合物相比，对肾上腺皮质激素的抑制效应也明显降低。
实施例11
选用雄性Beagle犬(10±2kg)作为受试动物，通过ELISA试剂盒以及酶标仪读数器对给药后的Beagle犬血清中皮质酮、皮质醇含量进行测定。20只Beagle犬随机分为五组，每组4只，分别给予***(0.01mg/kg)后将动物体内肾上腺皮质水平降至基线水平，将此时皮质醇与皮质酮水平作为基础值(Baseline)。随后给予等效剂量(2ED50)的式(Ⅰ)化合物的盐酸盐(3.62mg/kg)、氢溴酸盐(3.86mg/kg)、三氟醋酸盐(4.66mg/kg)和阳性对照药物依托咪酯
Figure PCTCN2014089898-appb-000010
(0.9mg/kg)以及等体积溶媒DMSO。10min后给予ACTH(促肾上腺皮质激素)刺激，促使动物体内的皮质水平提高，于给予ACTH后1h测定动物体内的两种皮质激素浓度，计算皮质水平峰值与基础值之比，即得到皮质激素被提高的倍数，倍数越大说明药物对皮质激素的抑制越轻。依托咪酯、式(Ⅰ)化合物的三种盐及DMSO给药后经ACTH刺激后皮质激素提高的倍数见表4。
表4式(Ⅰ)化合物的三种盐给药后经ACTH刺激后的皮质激素提高情况
Figure PCTCN2014089898-appb-000011
上述实验显示：依托咪酯仍能够严重抑制肾上腺皮质激素的自身合成，使得受试动物的皮质水平不能被ACTH刺激而提高；而式(Ⅰ)化合物的盐酸盐、氢溴酸盐、三氟醋酸盐组的动物虽然经ACTH刺激后皮质激素的提高不如空白组，但已经明显高于阳性药物依托咪酯组。因此，式(Ⅰ)化合物的盐对皮质激素的抑制效应较之对照药物依托咪酯已经明显降低。

Claims (8)

  1. 含有醚侧链的N-取代咪唑羧酸酯手性化合物或其药学中可接受的盐类化合物，所说的N-取代咪唑羧酸酯化合物的结构如式(Ⅰ)所示，其中的手性C*构型为R型：
    Figure PCTCN2014089898-appb-100001
  2. 权利要求1所述的化合物，其特征是所说的药学中可接受的盐类化合物包括盐酸盐、氢溴酸盐、三氟醋酸盐等。
  3. 权利要求1所述化合物的制备方法，其特征是在极性非质子溶剂和碱性条件下，以式(Ⅱ)的N-取代咪唑羧酸手性化合物与式(Ⅲ)的卤化物经下列取代反应后得到式(Ⅰ)目标化合物，式中的手性C*构型为R型，X为卤元素，反应过程如下：
    Figure PCTCN2014089898-appb-100002
  4. 权利要求3的制备方法，其特征是所说的卤元素X为Br或Cl。
  5. 权利要求3的制备方法，其特征是所说的反应溶剂为DMF。
  6. 权利要求3的制备方法，其特征是所说的碱为包括碱金属的氢氧化物或碳酸盐在内的无机碱。
  7. 权利要求1或2所述含有醚侧链的N-取代咪唑羧酸酯手性化合物的药学中可接受盐类化合物的制备方法，其特征是由式(Ⅰ)化合物与药学中可接受的酸根结合后可得到相应的盐类化合物。
  8. 权利要求1所述的N-取代咪唑羧酸酯类手性化合物或其药学中可接受的盐类化合物在制备作为经静脉或静脉外途径对动物或人产生镇静催眠和/或麻醉作用的中枢抑制性药物中的应用。
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