WO2019129216A1 - 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 - Google Patents

一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 Download PDF

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WO2019129216A1
WO2019129216A1 PCT/CN2018/124969 CN2018124969W WO2019129216A1 WO 2019129216 A1 WO2019129216 A1 WO 2019129216A1 CN 2018124969 W CN2018124969 W CN 2018124969W WO 2019129216 A1 WO2019129216 A1 WO 2019129216A1
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group
compound
acid
propionate
alkyl
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PCT/CN2018/124969
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English (en)
French (fr)
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漆又毛
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杭州奥默医药股份有限公司
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Priority to EP18894266.8A priority Critical patent/EP3730495B1/en
Priority to KR1020237003241A priority patent/KR20230035589A/ko
Priority to CN201880089128.6A priority patent/CN111727190B/zh
Priority to KR1020207021831A priority patent/KR102523309B1/ko
Priority to JP2020555285A priority patent/JP6976013B2/ja
Priority to CA3087298A priority patent/CA3087298C/en
Priority to US16/958,977 priority patent/US11919905B2/en
Priority to AU2018395101A priority patent/AU2018395101B2/en
Publication of WO2019129216A1 publication Critical patent/WO2019129216A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
    • C07D213/46—Oxygen atoms
    • C07D213/50—Ketonic radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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 invention belongs to the field of medicinal chemical industry and relates to a novel pyridyl imidazobenzodiazepine propionate compound and its synthesis and application in preparing intravenous anesthesia drugs.
  • Remimazol is a novel ultra-short-acting systemic sedative anesthetic that is a water-soluble BZ derivative that has a very high BZ receptor in the cerebral cortex, limbic system, midbrain, and brainstem spinal cord.
  • High affinity which can rapidly and transiently act on 4 subtypes of ⁇ -aminobutyric acid A (GABAA) receptor, but remimazol has a stronger affinity for this receptor ⁇ 1 subtype, which can promote GABA and The binding of the receptor, the increased frequency of Cl - channel opening, and more Cl - influx, lead to hyperpolarization of nerve cells, resulting in a neuroinhibitory effect.
  • GABAA ⁇ -aminobutyric acid A
  • the present invention provides a novel pyridyl imidazobenzodiazepine propionate compound 1 having the following structural formula:
  • R represents a variety of alkyl groups of a short carbon chain, trifluoromethyl, methoxy, nitro, fluoro, chloro, bromo, etc.;
  • R 1 represents various alkyl groups of a short carbon chain, trifluoromethyl, methoxy, nitro, fluorine, chlorine, bromine, etc.;
  • R 2 represents a pyridine ring in which the nitrogen is at the 2, 3 or 4 position;
  • R 3 represents a variety of alkyl groups of a short carbon chain
  • HX represents any acceptable pharmaceutically acceptable inorganic and organic acid, preferably p-toluenesulfonic acid.
  • R is selected from the group consisting of halogen, nitro, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy.
  • R 1 is selected from the group consisting of halogen, nitro, halogenated C1-C6 alkyl, C1-C6 alkyl, C1-C6 alkoxy.
  • the various alkyl groups of the short carbon chain are C1-C6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, positive A pentyl, isopentyl, neopentyl, n-hexyl, or the like.
  • the halogenated C1-C6 alkyl group is one or more (e.g., 2 or 3) halogen-substituted C1-C6 alkyl groups.
  • the halogen is selected from the group consisting of F, Cl, Br, I.
  • the halogenated C1-C6 alkyl group is a fluorinated C1-C6 alkyl group.
  • the halogenated C1-C6 alkyl group is preferably a trifluoromethyl group.
  • the C1-C6 alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, tert-butoxy, or the like.
  • R 2 is a pyridine ring having a nitrogen at the 2, 3 or 4 position.
  • R 3 is a C1-C6 alkyl group.
  • HX is a pharmaceutically acceptable acid selected from the group consisting of inorganic acids, organic acids, and amino acids.
  • the inorganic acid includes, but is not limited to, hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid.
  • the organic acid includes, but is not limited to, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, apple Acid, tartaric acid, citric acid, picric acid, benzoic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, benzenesulfonic acid, naphthalenesulfonic acid.
  • the organic acid is selected from the group consisting of p-toluenesulfonic acid, benzenesulfonic acid, preferably p-toluenesulfonic acid.
  • the amino acid includes, but is not limited to, citrulline, ornithine, arginine, lysine, proline, phenylalanine, aspartic acid, and glutamine. acid.
  • the amino acid has a configuration selected from the group consisting of racemic, D configuration, and L configuration.
  • R is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group;
  • R 1 is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy Halogenated C1-C6 alkoxy;
  • R 2 is a pyridine ring in which the nitrogen is at the 2, 3 or 4 position;
  • R 3 is a C1-C6 alkyl group
  • HX is a pharmaceutically acceptable acid selected from the group consisting of inorganic acids, organic acids, and amino acids.
  • R and R 1 are different.
  • R is F;
  • R 1 is C1-C6 alkyl; and
  • R 2 is a pyridine ring having a nitrogen at the 2-position;
  • R 3 is a C1-C6 alkyl group
  • HX is a pharmaceutically acceptable acid selected from the group consisting of inorganic acids, organic acids, and amino acids.
  • R is C1-C6 alkyl;
  • R 1 is F; and
  • R 2 is a pyridine ring having a nitrogen at the 3-position;
  • R 3 is a C1-C6 alkyl group
  • HX is a pharmaceutically acceptable acid selected from the group consisting of inorganic acids, organic acids, and amino acids.
  • the compound 1 is selected from the group consisting of
  • the present invention also provides a 2-(Boc-L-glutamic acid-5-acyl)amino-3,4-disubstituted benzoylpyridine 4 which can be used as an intermediate of the synthesis 1, and has the following structural formula :
  • R, R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a 2-(L-glutamic acid-5-acyl)amino-3,4-disubstituted benzoylpyridine salt 6, which has the following structural formula:
  • R, R 1 , R 2 , R 3 and HX are as described above.
  • the present invention also provides a 3,4-disubstituted benzodiazepine propionate 7, having the following structural formula:
  • R, R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a (R)-N-(3,4-disubstituted benzodiazepine propionate)amino-2-propanol 9 having the following structural formula:
  • R, R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a pyridyl imidazobenzodiazepine propionate compound 10 having the following structural formula:
  • R is selected from the group consisting of various alkyl groups of a short carbon chain, a trifluoromethyl group, a methoxy group, a nitro group, a fluorine group, a chlorine group, and a bromine group;
  • R 1 is selected from the group consisting of various alkyl groups of a short carbon chain, a trifluoromethyl group, a methoxy group, a nitro group, a fluorine group, a chlorine group, and a bromine group;
  • R 2 is a pyridine ring in which the nitrogen is at the 2, 3 or 4 position;
  • R 3 is a various alkyl group of a short carbon chain.
  • R is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy, halogenated C1-C6 alkoxy.
  • R 1 is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl , C1-C6 alkoxy, halogenated C1-C6 alkoxy.
  • the various alkyl groups of the short carbon chain are C1-C6 alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, positive A pentyl, isopentyl, neopentyl, n-hexyl, or the like.
  • the halogenated C1-C6 alkyl group is one or more (e.g., 2 or 3) halogen-substituted C1-C6 alkyl groups.
  • the halogen is selected from the group consisting of F, Cl, Br, I.
  • the halogenated C1-C6 alkyl group is a fluorinated C1-C6 alkyl group.
  • the halogenated C1-C6 alkyl group is preferably a trifluoromethyl group.
  • the C1-C6 alkoxy group is a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy Base, butoxy, isobutoxy, tert-butoxy, or the like.
  • R 2 is a pyridine ring having a nitrogen at the 2, 3 or 4 position.
  • R 3 is a C1-C6 alkyl group.
  • R is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, a C1-C6 alkoxy group, a halogenated C1-C6 alkoxy group;
  • R 1 is selected from the group consisting of halogen, nitro, C1-C6 alkyl, halogenated C1-C6 alkyl, C3-C8 cycloalkyl, halogenated C3-C8 cycloalkyl, C1-C6 alkoxy Halogenated C1-C6 alkoxy;
  • R 2 is a pyridine ring in which the nitrogen is at the 2, 3 or 4 position;
  • R 3 is a C1-C6 alkyl group.
  • R and R 1 are different.
  • R is F;
  • R 1 is C1-C6 alkyl; and
  • R 2 is a pyridine ring having a nitrogen at the 2-position;
  • R 3 is a C1-C6 alkyl group.
  • R is C1-C6 alkyl;
  • R 1 is F; and
  • R 2 is a pyridine ring having a nitrogen at the 3-position;
  • R 3 is a C1-C6 alkyl group.
  • the compound 10 is selected from the group consisting of
  • the invention also provides a preparation method of pyridyl imidazobenzodiazepine propionate compound 1, which is achieved by the following steps:
  • the starting material is an anthranilic acid pyridine 2 with various substituents at the 3,4 position and Boc-L-glutamic acid-5 ester 3 to form 2-(Boc-L-glutamic acid-5) in the presence of DCC.
  • Esteryl)amino-3,4-disubstituted benzoylpyridine 4 removal of Boc protecting group under the action of acid 5 to give 2-(L-glutamic acid-5-ester)amino-3,4-di Substituted benzoylpyridinium salt 6; intramolecular condensation in the presence of sodium bicarbonate to give 3,4-disubstituted benzodiazepine propionate 7; followed by (R)-1-amino-2- Propyl alcohol 8 reacts to form (R)-N-(3,4-disubstituted benzodiazepine propionate)amino-2-propanol 9; oxidative ring closure reaction with DMP gives pyridyl imidazobenz
  • R, R 1 , R 2 , R 3 , HX are as defined above;
  • DMP represents Dess-Martin oxidant Dess-Martin Periodinal.
  • the equivalent ratio of the compound 2, the compound 3 and the DCC reaction is 1:0.9 to 1.1:1 to 1.5.
  • the equivalent ratio of the reaction of the compound 6 with sodium hydrogencarbonate is 1:10-20.
  • the equivalent ratio of the reaction of the compound 7 and 8 is 1:2 to 3.
  • the equivalent ratio of the reaction of the compound 9 with DMP is 1:3-6, and the reaction temperature is between 30-60 °C.
  • the equivalent ratio of the reaction of the compound 10 with the acid 5 in the step is 1:1 to 2, preferably 1:1.
  • HX is preferably p-toluenesulfonic acid.
  • the invention also provides a pharmaceutical composition comprising:
  • the present invention also provides the use of the pyridyl imidazobenzodiazepine propionate compound 1 for the preparation of an intravenous anesthetic.
  • the invention also provides an anesthesia method comprising administering an anesthetic effective amount of Compound 1 and/or Compound 10 described above to a subject to be anesthetized.
  • the anesthesia method is for a treatment regimen selected from the group consisting of sedation, general anesthesia, and ICU sedation.
  • a series of target products 1, 4, 6, 7, 9 and 10 synthesized according to the above reaction were all new compounds, and their structures were characterized by 1H NMR and ESI-MS. According to the animal model test, the results showed that Compound 1 had obvious intravenous anesthetic activity, and the intravenous anesthetic activity of 1 was equivalent to the positive control drug remiazolam p-toluenesulfonate or remiazolam besylate.
  • Compound 1 can be significantly reduced in mouse model experiments, even overcoming the remazuron besylate or remiazolam p-toluenesulfonate as a common drug in preclinical animal experiments. Side effects such as limb shaking, head tilting, and angular arch reversal may have implications for further development into clinical medicine.
  • Figure 1 is the effect of single administration of Compound 1-2 in Example 27 on the total distance of spontaneous activity in mice.
  • Figure 2 is a graph showing the effect of single administration of Compound 1-2 on the number of spontaneous activity of mice in Example 27.
  • Figure 3 is a graph showing the effect of single administration of Compound 1-2 in Example 27 on the resting time of spontaneous activity in mice.
  • Figure 4 is a graph showing the effect of multiple administrations of Compound 1-2 in Example 27 on the total distance of spontaneous activity in mice.
  • Figure 5 is a graph showing the effect of multiple administrations of Compound 1-2 in Example 27 on the resting time of spontaneous activity in mice.
  • Figure 6 is a graph showing the effect of multiple administrations of Compound 1-2 in Example 27 on the number of spontaneous activity of mice.
  • anesthetic compound which is safe, fast acting and/or rapidly recovered by adjusting the structure of the compound.
  • R 1 and R monosubstituted Ruima alprazolam or a p-toluenesulfonate or benzenesulfonate
  • the inventors have found that in a dual position R and R may be substituted Obtain an anesthetic compound with higher anesthesia safety and better overall performance.
  • a compound using Br as a substituent has better biopenetrability and better targeting organ selectivity than a compound having one of the disubstituted ones at the R and R 1 positions. It is basically non-toxic.
  • R is F
  • R 1 is a C1-C6 alkyl group
  • R 2 is a pyridyl group having N at the 2-position (e.g., compound 1-2)
  • the compound has extremely excellent comprehensive anesthetic properties.
  • the inventors completed the present invention.
  • halogen means F, Cl, Br or I.
  • C1-C6 alkyl means a straight or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl Base, tert-butyl, neopentyl, pentylene, or the like.
  • C3-C8 cycloalkyl means a cyclic alkyl group having 3 to 8 carbon atoms in the ring, and includes, without limitation, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, and a ring. Hexyl, cycloheptyl, cyclooctyl and the like.
  • halo means substituted by halogen.
  • C1-C6 alkoxy means a straight or branched alkoxy group having 1 to 6 carbon atoms, and includes, without limitation, a methoxy group, an ethoxy group, a propoxy group, Isopropoxy and butoxy groups. It is preferably a C1-C4 alkoxy group.
  • substituted means that one or more hydrogen atoms on a particular group are replaced by a specific substituent.
  • Particular substituents are the substituents described above in the corresponding paragraphs, or the substituents which appear in the examples.
  • a substituted group may have a substituent selected from a particular group at any substitutable position of the group, and the substituents may be the same or different at each position.
  • substituents contemplated by the present invention are those that are stable or chemically achievable.
  • the substituents are, for example but not limited to, halogen, hydroxy, carboxy (-COOH), C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C8 cycloalkyl, 3- to 12-membered heterocyclic group, aryl group, heteroaryl group, C1-C8 aldehyde group, C2-C10 acyl group, C2-C10 ester group, amino group, C1-C6 alkoxy group, C1-C10 sulfonyl group and the like.
  • the present invention provides a novel pyridyl imidazobenzodiazepine propionate compound 1 having the following structural formula:
  • R, R 1 , R 2 , R 3 and HX are as defined above.
  • any one of R, R 1 , R 2 , R 3 and HX in the compound 1 is a group corresponding to the specific compound described in the present invention.
  • the present invention also provides a pyridyl imidazobenzodiazepine propionate compound 10 having the following structural formula:
  • R, R 1 , R 2 and R 3 are as defined above.
  • the preparation method of the compound 1 or the compound 10 of the present invention is more specifically described below, but these specific methods do not constitute any limitation to the present invention.
  • the compounds of the present invention may also be conveniently prepared by combining various synthetic methods described in the specification or known in the art, and such combinations are readily made by those skilled in the art to which the present invention pertains.
  • the preparation process of the compounds of the present invention is as follows, wherein the starting materials and reagents used are commercially available unless otherwise specified.
  • R, R 1 , R 2 , R 3 and HX are as defined above.
  • the invention also provides a pharmaceutical composition comprising:
  • the "anaesthetic effective amount” means that the amount of the compound is sufficient to achieve an anesthetic effect without causing serious side effects.
  • the "anaesthetic effective amount" is from 0.1 to 500 mg, preferably from 0.5 to 300 mg, more preferably from 1 to 200 mg, relative to a person having a body weight of 60 kg.
  • the "pharmaceutically acceptable carrier” means a substance including, but not limited to, the following group: water for injection, vegetable oil (such as sesame oil, soybean oil, etc.), sodium chloride, glycerin, glucose. Ethanol, polyethylene glycol, propylene glycol, and an appropriate amount of excipients, buffers, wetting agents or emulsifiers may also be added as needed.
  • the dosage form of the pharmaceutical composition includes, but is not limited to, an injection solution, a lyophilized powder needle.
  • the administration of the pharmaceutical composition includes, but is not limited to, intravenous bolus injection, intravenous drip, subcutaneous injection, intraperitoneal injection, intramuscular injection, transdermal administration.
  • the pharmaceutical composition further comprises:
  • the second compound is different from Compound 1 or Compound 10 and may be a conventional anesthetic compound.
  • the second compound includes, but is not limited to, propofol, fentanyl, remifentanil, sufentanil, dexmedetomidine, etomidate, morphine, Dexazocine, pentazocine, oxycodone, ropivacaine, lidocaine, sevoflurane, isoflurane.
  • the present invention has the following main advantages:
  • the compound 1 and/or compound 10 has significant intravenous anesthetic activity
  • the compound 1 and/or the compound 10 is significantly reduced in the preclinical animal experiment or has substantially no side effects such as limb shaking, head tilting, and horn arch reversal;
  • the compound 1 and/or the compound 10 has the characteristics of high safety, rapid onset of action and/or rapid recovery, that is, having excellent comprehensive properties;
  • the compound 1 and/or the compound 10 enhance the compliance of the drug, and the number of spontaneous activity and rest time recovery of the mouse after the multiple administration of the compound 1-2 is better than that of propofol.
  • the raw material compound 1-D (3.5 g, 9.86 mmol, 1.0 eq) was weighed into a 100 ml three-necked flask, 40 ml of anhydrous tetrahydrofuran was added, stirred and dissolved, and the temperature was lowered to -18 ° C, and argon gas was protected; lithium diisopropylamide was weighed. (4.9ml, 9.86mmol, 1.0eq) was slowly added to the reaction solution continuously, the temperature was controlled between -10 ° C and -5 ° C, and then reacted at 0 ° C for 0.5 h; di-morpholinophosphoryl chloride (5.0) was weighed.
  • the compound 1-2 was obtained using p-toluenesulfonic acid as a starting material, and the yield was 87%.
  • the compound 1-3 was obtained using hydrochloric acid as a starting material, and the yield was 92%.
  • the compound 1-4 was obtained using 3-bromopyridine or p-toluenesulfonic acid as a starting material, and the yield was 85.3%.
  • the compound 1-5 was obtained using 4-bromopyridine or p-toluenesulfonic acid as a starting material, and the yield was 86%.
  • the compound 1-6 was obtained using 2-amino-5-bromo-4-methylbenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 84.5%.
  • the compound 1-8 was obtained using 2-amino-5-trifluoromethyl-4-methylbenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 84.7%.
  • the compound 1-11 was obtained using 2-amino-4,5-difluorobenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 84.2%.
  • the compound 1-12 was obtained using 2-amino-4,5-dichlorobenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 84.8%.
  • the compound 1-13 was obtained using 2-amino-4,5-dimethylbenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 86%.
  • the compound 1-14 was obtained by using 3-bromopyridine, 2-amino-5-fluoro-4-(trifluoromethyl)benzoic acid and p-toluenesulfonic acid as raw materials.
  • the rate is 82.5%.
  • the compound 1-15 was obtained using 4-fluoro-5-methoxybenzoic acid and p-toluenesulfonic acid as a starting material, and the yield was 83.6%.
  • ICR mice male, 18-25 g were given a single dose of the same dose (100 mg/kg) of the test drug via a rapid bolus injection in the tail vein, and the latency and duration of disappearance of the righting reflex of the mouse were recorded.
  • the experimental results are shown in the table below.
  • the anesthetic effect of the compound of the present invention is comparable to or superior to remazuron p-toluenesulfonate or remazolyl besylate.
  • ICR mice male, 18-25 g were randomized, and a single bolus of different doses of test drug was administered via a rapid bolus injection to record the lowest dose (acting dose) that caused the disappearance of righting reflexes and the dose that caused the animal to die. (lethal dose) and calculate the treatment window (lethal dose / onset dose).
  • the effective dose is reduced by 33.3%, the lethal dose is increased by 64%, and the therapeutic window is increased by 2.5 times.
  • the present invention provides an anesthetic compound which has both rapid onset, rapid recovery, high safety and minimal side effects.
  • Example 26 Effect of compound 1-2 multiple times (9 times) after i.v administration on the duration of disappearance of righting reflex in mice
  • Each group of animals was given the corresponding drug solution according to the corresponding group tail vein injection (iv), 0.1ml / time / time, 9 consecutive injections (the mice in the drug-administered group were injected once every time the righting reflex disappeared and recovered), record Each time the corrective reflection disappears for a duration, the data is expressed as an average.
  • mice in each group were tested for autonomous activity, 10 min per mouse. Subsequently, each group of animals was given a single dose of the corresponding drug solution according to the corresponding group tail vein injection (i.v.), 0.1 ml/10 g body weight, and the spontaneous activity of the mice was measured immediately after administration, and the recording time was 50 min. Data are expressed as mean ⁇ standard deviation. Among them, propofol was administered at a dose of 20 mg/kg.
  • mice in the drug-administered group were injected once every time the righting reflex disappeared and recovered.
  • the spontaneous activity of the mice was measured and the recording time was 50 min. Data are expressed as mean ⁇ standard deviation.
  • mice in the propofol and compound 1-2 groups were significantly reduced within 10 min.
  • the total activity and activity times of the mice in each group were significantly decreased, and the rest time was significantly increased.
  • the positive drug propofol group recovered substantially after 40-45 minutes after administration (and similar to the blank group at the same time).
  • Compound 1-2 The mice in the 50 mg/kg group were able to return to normal levels 15 to 20 minutes after administration (similar to the blank group at the same time); the mice in the compound 1-275 mg/kg group were autonomously active.
  • mice in the compound 1-2 100mg/kg group had not recovered to normal level during the autonomic activity test period (50min) (similar to the blank group at the same time) See Figure 4-6 for details.

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Abstract

本发明公开了一种吡啶基咪唑并苯并二氮杂卓丙酸酯（化合物1）及其合成和应用。本发明还提供制备中间体。本发明提供的化合物1具有明显的静脉麻醉活性,静脉麻醉活性等同于阳性对照药瑞马唑仑对甲苯磺酸盐或者瑞马唑仑苯磺酸盐。此外化合物1在小鼠模型实验中可以明显降低，甚至克服了瑞马唑仑苯磺酸盐或者瑞马唑仑对甲苯磺酸盐作为在研药物在临床前动物实验中常见的四肢抖动，昂头，角弓反张等副作用，因此可在制备静脉麻醉药物中的应用。化合物1的结构通式如下，其中各基团和取代基的定义如说明书中所述。

Description

一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和应用 技术领域
本发明属医药化工领域，涉及一种新的吡啶基咪唑并苯并二氮杂卓丙酸酯化合物及其合成和在制备静脉麻醉药物中的应用。
背景技术
雷米马唑仑是一种新型的超短效全身镇静麻醉药，是一种水溶性BZ类衍生物，它对大脑皮质、边缘系统、中脑以及脑干脊髓中的BZ类受体具有很高的亲和力，能快速而短暂地作用于γ-氨基丁酸A(GABAA)受体的4个亚型，但雷米马唑仑对该受体α1亚型的亲和力更强，可促进GABA与受体的结合，Cl -通道开放频率增加，更多Cl -内流，导致神经细胞超极化，从而产生神经抑制效应。然后，经研究发现瑞马唑仑苯磺酸盐或者瑞马唑仑对甲苯磺酸盐作为在研药物在临床前动物实验中常见有四肢抖动，昂头，角弓反张等副作用，因此期望研发出一种更加安全的，新型超短效镇静麻醉药，用于以下临床治疗方案中的静脉给药：操作镇静，全身麻醉和ICU镇静。
发明内容
本发明提供了一种新的吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1，具有如下结构通式：
Figure PCTCN2018124969-appb-000001
其中R代表短碳链的各种烷基，三氟甲基，甲氧基，硝基，氟，氯，溴等；
R 1代表短碳链的各种烷基，三氟甲基，甲氧基，硝基，氟，氯，溴等；
R 2代表氮在2，3或者4位置的吡啶环；
R 3代表短碳链的各种烷基；
HX代表任何可接受的药用无机酸和有机酸，优选对甲苯磺酸。
在另一优选例中，R选自下组：卤素、硝基、卤代的C1-C6烷基、C1-C6烷基、C1-C6烷氧基。
在另一优选例中，R 1选自下组：卤素、硝基、卤代的C1-C6烷基、C1-C6烷基、C1-C6烷氧基。
在另一优选例中，所述短碳链的各种烷基为C1-C6烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、或类似基团。
在另一优选例中，所述卤代的C1-C6烷基为一个或多个(如2或3个)卤素取代的C1-C6烷基。
在另一优选例中，卤素选自下组：F、Cl、Br、I。
在另一优选例中，所述卤代的C1-C6烷基为氟代的C1-C6烷基。
在另一优选例中，所述卤代的C1-C6烷基优选为三氟甲基。
在另一优选例中，所述C1-C6烷氧基为包括1-6个碳原子的直链或支链的烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、或类似基团。
在另一优选例中，R 2为氮在2、3或4位置的吡啶环。
在另一优选例中，R 3为C1-C6烷基。
在另一优选例中，HX为选自下组的药学上可接受的酸：无机酸、有机酸、氨基酸。
在另一优选例中，所述无机酸包括(但并不限于)：盐酸、氢溴酸、氢氟酸、硫酸、硝酸、磷酸。
在另一优选例中，所述有机酸包括(但并不限于)：甲酸、乙酸、三氟乙酸、丙酸、草酸、丙二酸、琥珀酸、富马酸、马来酸、乳酸、苹果酸、酒石酸、柠檬酸、苦味酸、苯甲酸、甲磺酸、乙磺酸、对甲苯磺酸、苯磺酸、萘磺酸。
在另一优选例中，所述有机酸选自下组：对甲苯磺酸、苯磺酸，优选为对甲苯磺酸。
在另一优选例中，所述氨基酸包括(但并不限于)：瓜氨酸、鸟氨酸、精氨酸、赖氨酸、脯氨酸、苯丙氨酸、天冬氨酸、谷氨酸。
在另一优选例中，所述氨基酸具有选自下组的构型：外消旋、D构型、L构型。
在另一优选例中，R选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基；
R 1选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基；
R 2为氮在2、3或4位置的吡啶环；
R 3为C1-C6烷基；
HX为选自下组的药学上可接受的酸：无机酸、有机酸、氨基酸。
在另一优选例中，R和R 1不同。
在另一优选例中，R为F；R 1为C1-C6烷基；R 2为氮在2位置的吡啶环；
R 3为C1-C6烷基；
HX为选自下组的药学上可接受的酸：无机酸、有机酸、氨基酸。
在另一优选例中，R为C1-C6烷基；R 1为F；R 2为氮在3位置的吡啶环；
R 3为C1-C6烷基；
HX为选自下组的药学上可接受的酸：无机酸、有机酸、氨基酸。
在另一优选例中，所述化合物1选自下组：
Figure PCTCN2018124969-appb-000002
Figure PCTCN2018124969-appb-000003
本发明还提供了一种2-(Boc-L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶4，可作为合成1的中间体，具有如下结构通式：
Figure PCTCN2018124969-appb-000004
其中R、R 1、R 2、R 3如上所述。
本发明还提供了一种2-(L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶盐6，具有如下结构通式：
Figure PCTCN2018124969-appb-000005
其中R、R 1、R 2、R 3、HX如上所述。
本发明还提供了一种3，4-二取代基苯并二氮杂卓丙酸酯7，具有如下结构通式：
Figure PCTCN2018124969-appb-000006
其中R、R 1、R 2、R 3如上所述。
本发明还提供了一种(R)-N-(3，4-二取代基苯并二氮杂卓丙酸酯基)氨基-2-丙醇9，具有如下结构通式：
Figure PCTCN2018124969-appb-000007
其中R、R 1、R 2、R 3如上所述。
本发明还提供了一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物10，具有如下结构通式：
Figure PCTCN2018124969-appb-000008
其中，R选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
R 1选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
R 2为氮在2、3或者4位置的吡啶环；
R 3为短碳链的各种烷基。
在另一优选例中，R选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基。
在另一优选例中，R 1选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基。
在另一优选例中，所述短碳链的各种烷基为C1-C6烷基，如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、正戊基、异戊基、新戊基、正己基、或类似基团。
在另一优选例中，所述卤代的C1-C6烷基为一个或多个(如2或3个)卤素取代的C1-C6烷基。
在另一优选例中，卤素选自下组：F、Cl、Br、I。
在另一优选例中，所述卤代的C1-C6烷基为氟代的C1-C6烷基。
在另一优选例中，所述卤代的C1-C6烷基优选为三氟甲基。
在另一优选例中，所述C1-C6烷氧基为包括1-6个碳原子的直链或支链的烷氧基，例如甲氧基、乙氧基、丙氧基、异丙氧基、丁氧基、异丁氧基、叔丁氧基、或类似基团。
在另一优选例中，R 2为氮在2、3或4位置的吡啶环。
在另一优选例中，R 3为C1-C6烷基。
在另一优选例中，R选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基；
R 1选自下组：卤素、硝基、C1-C6烷基、卤代的C1-C6烷基、C3-C8环烷基、卤代的C3-C8环烷基、C1-C6烷氧基、卤代的C1-C6烷氧基；
R 2为氮在2、3或4位置的吡啶环；
R 3为C1-C6烷基。
在另一优选例中，R和R 1不同。
在另一优选例中，R为F；R 1为C1-C6烷基；R 2为氮在2位置的吡啶环；
R 3为C1-C6烷基。
在另一优选例中，R为C1-C6烷基；R 1为F；R 2为氮在3位置的吡啶环；
R 3为C1-C6烷基。
在另一优选例中，所述化合物10选自下组：
Figure PCTCN2018124969-appb-000009
Figure PCTCN2018124969-appb-000010
本发明还提供了一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1的制备方法，通过以下步骤实现：
起始原料采用3，4位上各种取代基的邻氨基苯甲酰吡啶2与Boc-L-谷氨酸-5酯3在DCC存在下生成2-(Boc-L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶4；在酸5的作用下脱除Boc保护基得到2-(L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶盐6；在碳酸氢钠存在下发生分子内缩合得到3，4-二取代基苯并二氮杂卓丙酸酯7；继而与(R)-1-氨基-2-丙醇8反应生成(R)-N-(3，4-二取代基苯并二氮杂卓丙酸酯基)氨基-2-丙醇9；与DMP发生氧化闭环反应得到吡啶基咪唑并苯并二氮杂卓丙酸酯10；经与酸5发生成盐反应获得目标产物吡啶基咪唑并苯并二氮杂卓丙酸酯盐化合物1。
反应式如下：
Figure PCTCN2018124969-appb-000011
其中R、R 1、R 2、R 3、HX如上所述；DMP代表戴斯－马丁氧化剂Dess-MartinPeriodinane。
所述的化合物2、化合物3与DCC反应的当量比为1：0.9～1.1：1～1.5。
所述的化合物6与碳酸氢钠反应的当量比为1:10～20。
所述的化合物7与8反应的当量比为1:2～3。
所述的化合物9与DMP反应的当量比为1:3～6，反应温度在30-60℃之间。
所述步骤中化合物10与酸5反应的当量比为1:1-2，优选为1:1。
HX优选对甲苯磺酸。
本发明还提供了一种药物组合物，所述药物组合物包含：
1)麻醉有效量的一种或多种上述化合物1和/或化合物10；和
2)药学上可接受的载体。
本发明还提供了所述的吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1的用途，用于制备静脉麻醉药物。
本发明还提供了一种麻醉方法，包括将麻醉有效量的上述化合物1和/或化合物10施用于待麻醉的受试者。
在另一优选例中，所述麻醉方法用于选自下组的治疗方案：操作镇静、全身麻醉、ICU镇静。
按上述反应合成的一系列目标产物1,4,6,7,9和10均为新化合物,其结构经1H NMR和ESI-MS表征。经动物模型试验研究，结果表明:化合物1有明显的静脉麻醉活性,其中1的静脉麻醉活性等同于阳性对照药瑞马唑仑对甲苯磺酸盐或者瑞马唑仑苯磺酸盐。
此外还惊喜的发现化合物1在小鼠模型实验中可以明显降低，甚至克服了瑞马唑仑苯磺酸盐或者瑞马唑仑对甲苯磺酸盐作为在研药物在临床前动物实验中常见的四肢抖动，昂头，角弓反张等副作用，因此可能具有进一步开发成临床药物的意义。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1是实施例27中化合物1-2单次给药对小鼠自主活动总路程的影响。
图2是实施例27中化合物1-2单次给药对小鼠自主活动活动次数的影响。
图3是实施例27中化合物1-2单次给药对小鼠自主活动休息时间的影响。
图4是实施例27中化合物1-2多次给药对小鼠自主活动总路程的影响。
图5是实施例27中化合物1-2多次给药对小鼠自主活动休息时间的影响。
图6是实施例27中化合物1-2多次给药对小鼠自主活动活动次数的影响。
具体实施方式
本发明人经过长期而深入的研究，通过调整化合物的结构意外地制备了一种安全性高、快速起效和/或快速恢复的麻醉用化合物。具体地，相比于现有的在R 和R 1位置单取代的瑞马唑仑(或其对甲苯磺酸盐或苯磺酸盐)，发明人发现在R和R 1位置进行双取代可获得麻醉安全性更高且综合性能更优的麻醉用化合物。进一步地，相比于在R和R 1位置双取代之一的取代基采用Br的化合物，采用F作为取代基之一的化合物具有更好的生物穿透性和更好的靶向器官选择性且基本无毒性。更进一步地，当R为F、R 1为C1-C6烷基且R 2为N在2位的吡啶基(如化合物1-2)时，所述化合物具有极其优异的综合麻醉性能。在此基础上，发明人完成了本发明。
术语
在本发明中，除非特别指出，所用术语具有本领域技术人员公知的一般含义。
在本发明中，术语“卤素”指F、Cl、Br或I。
在本发明中，“C1-C6烷基”是指包括1-6个碳原子的直链或支链的烷基，例如甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、新戊基、特戊基、或类似基团。
在本发明中，术语“C3-C8环烷基”是指在环上具有3至8个碳原子的环状烷基，非限制性地包括环丙基、环丁基、环戊基、环己基、环庚基、环辛基等。
在本发明中，术语“卤代”是指被卤素取代。
在本发明中，术语“C1-C6烷氧基”是指具有1至6个碳原子的直链或支链烷氧基，非限制性地包括甲氧基、乙氧基、丙氧基、异丙氧基和丁氧基等。优选为C1-C4烷氧基。
在本发明中，术语“取代”指特定的基团上的一个或多个氢原子被特定的取代基所取代。特定的取代基为在前文中相应描述的取代基，或各实施例中所出现的取代基。除非特别说明，某个取代的基团可以在该基团的任何可取代的位点上具有一个选自特定组的取代基，所述的取代基在各个位置上可以是相同或不同的。本领域技术人员应理解，本发明所预期的取代基的组合是那些稳定的或化学上可实现的组合。所述取代基例如(但并不限于)：卤素、羟基、羧基(-COOH)、C1-C6烷基、C2-C6烯基、C2-C6炔基、C3-C8环烷基、3-至12元杂环基、芳基、杂芳基、C1-C8醛基、C2-C10酰基、C2-C10酯基、氨基、C1-C6烷氧基、C1-C10磺酰基等。
化合物1
本发明提供了一种新的吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1，具有如下结构通式：
Figure PCTCN2018124969-appb-000012
其中R、R 1、R 2、R 3和HX如上文所定义。
在另一优选例中，所述化合物1中R、R 1、R 2、R 3和HX中任一个为本发明所述具体化合物中所对应的基团。
化合物10
本发明还提供了一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物10，具有如下结构通式：
Figure PCTCN2018124969-appb-000013
其中R、R 1、R 2、R 3如上文所定义。
制备方法
下面更具体地描述本发明化合物1或化合物10的制备方法，但这些具体方法不对本发明构成任何限制。本发明化合物还可以任选将在本说明书中描述的或本领域已知的各种合成方法组合起来而方便地制得，这样的组合可由本发明所属领域的技术人员容易地进行。
典型地，本发明化合物的制备工艺流程如下，其中所用原料和试剂如无特殊说明，均可通过商业途径购买。
Figure PCTCN2018124969-appb-000014
其中R、R 1、R 2、R 3和HX如上文所定义。
药物组合物和施用方法
本发明还提供了一种药物组合物，所述药物组合物包含：
1)麻醉有效量的一种或多种上述化合物1和/或化合物10；和
2)药学上可接受的载体。
在另一优选例中，所述“麻醉有效量”是指化合物的量足以实现麻醉效果，而不至于产生严重的副作用。
在另一优选例中，所述“麻醉有效量”为0.1-500mg，较佳地0.5-300mg，更佳地1-200mg，相对于体重为60kg的人。
在另一优选例中，所述“药学上可接受的载体”是指包括(但并不限于)下组的物质：注射用水、植物油(如麻油、豆油等)、氯化钠、甘油、葡萄糖、乙醇、聚乙二醇、丙二醇，还可以视需要加入适量的赋形剂、缓冲剂、润湿剂或乳化剂。
在另一优选例中，所述药物组合物的剂型包括(但并不限于)：注射液、冻干粉针。
在另一优选例中，所述药物组合物的施用方式包括(但并不限于)：静脉推注、静脉滴注、皮下注射、腹膜内注射、肌内注射、经皮给药。
在另一优选例中，所述药物组合物还包含：
3)麻醉有效量的第二化合物。
在另一优选例中，所述第二化合物不同于化合物1或化合物10，且可为现有的麻醉用化合物。
在另一优选例中，所述第二化合物包括(但并不限于)：丙泊酚、芬太尼、瑞芬太尼、舒芬太尼、右美托咪定、依托咪酯、吗啡、地佐辛、喷他佐辛、羟考酮、罗哌卡因、利多卡因、七氟烷、异氟烷。
相比于现有技术，本发明具有如下主要优点：
(1)所述化合物1和/或化合物10具有显著的静脉麻醉活性；
(2)所述化合物1和/或化合物10在临床前动物实验中显著降低或者基本未出现四肢抖动、昂头、角弓反张等副作用；
(3)所述化合物1和/或化合物10具有安全性高、快速起效和/或快速恢复的特点，即具有非常优异的综合性能；
(4)所述化合物1和/或化合物10增强了用药的顺应性，体现在多次给药化合物1-2后小鼠自主活动次数及休息时间恢复情况均好于丙泊酚。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
Figure PCTCN2018124969-appb-000015
-40℃下，向含有31.2ml(78.1mmol，4.0eq)正丁基锂(2.5M)和50ml无水乙醚的250ml三口瓶中加入2-溴吡啶8.2ml(85.9mmol，4.4eq)，然后反应液在-40℃下搅拌1小时；逐滴加入2-氨基-5-氟-4-甲基苯甲酸3.3g(19.53mmol，1.0eq)的40ml无水四氢呋喃溶液，升温至0℃，反应3小时，TLC跟踪反应进展；反应完全，将反应液倒入200ml冰水中，乙酸乙酯(100ml)提取，无水硫酸钠(50g)干燥，过滤，滤液减压浓缩(-0.08MPa，40℃)得到油状物，残留物过柱纯化(乙酸乙酯：石油醚＝1:20 to 1：6)得到3.59g黄色固体化合物1-A，收率80％。
该化合物H核磁共振谱(氘代甲醇)：δ2.33(CH3,s,3H)、6.96(CH,d,H)、7.58(CH,m,H)、7.82(CH,m,H)、7.94(CH,m,H)、8.10(CH,m,H)、8.75(CH,m,H)ppm。MS:m/z:231.09(M+1)。
实施例2
Figure PCTCN2018124969-appb-000016
称取化合物1-A(2.64g，11.5mmol，1.0eq)和Boc-L-谷氨酸-5-甲酯(3.3g，12.6mmol，1.1eq)于100ml三口瓶中，加入30ml无水二氯甲烷，搅拌溶解，冷却至0℃；逐滴加入含有二环己基亚胺(2.37g，11.5mmol，1.0eq)的10ml无水二氯甲烷溶液，加完后升温至室温下反应过夜，TLC跟踪反应进展；反应完全，过滤，滤饼用二氯甲烷(2*10ml)洗，合并滤液，过柱纯化(乙酸乙酯：石油醚＝1:20to1：3)得到5.17g黄色稠状液体化合物1-B，收率95％。
该化合物H核磁共振谱(氘代甲醇)：δ1.42(3CH3,s,9H)、2.28(CH2,m,2H)、2.33(CH3,m,3H)、2.35(CH2,m,2H)、3.61(CH3,s,3H)、4.60(CH,t,H)、7.81(CH,d,H)、7.82(CH,m,H)、7.83(CH,m,H)、7.94(CH,m,H)、8.10(CH,m,H)、8.75(CH,m,H)ppm。 MS:m/z:474.20(M+1)。
实施例3
Figure PCTCN2018124969-appb-000017
室温下，化合物1-B(5.6g，11.8mmol，1.0eq)溶于含有l0ml甲醇的100ml反应瓶中，连续缓慢加入(17ml，47.4mmol，4.0eq)自制的盐酸二氧六环(2.8M)，室温下反应3小时，原料转化完全，反应液(化合物1-C)直接用于下步反应。
该化合物H核磁共振谱(氘代甲醇)：δ2.33(CH3,m,3H)、2.35(CH2,m,2H)、2.76(CH2,m,2H)、3.61(CH3,s,3H)、4.58(CH,m,H)、7.81(CH,d,H)、7.82(CH,m,H)、7.83(CH,m,H)、7.94(CH,m,H)、8.10(CH,m,H)、8.31(CH,m,H)、8.75(CH,m,H)ppm。MS:m/z:410.13(M+1)。
实施例4
Figure PCTCN2018124969-appb-000018
室温下，称取碳酸氢钠(13.9g，165.2mmol，14.0eq)于100ml反应瓶中，加入乙腈37ml(甲醇：二氧六环：乙腈＝3：4：10)，快速搅拌下分4份加入化合物1-C反应液(11.8mmol，1.0eq)，室温下反应3小时，转化完全；加硅藻土(5.0g)滤液减压浓缩(-0.08MPa，45℃)得到浅灰白色固体，残留固体过柱纯化(乙酸乙酯：石油醚＝1:10 to 2：1)得到3.51g白色固体化合物1-D，两步收率83.8％。
该化合物H核磁共振谱(氘代甲醇)：δ2.33(CH3,m,3H)、2.35(CH2,m,2H)、2.38(CH2,m,2H)、3.61(CH3,s,3H)、4.14(CH,m,H)、7.40(CH,d,H)、7.74(CH,m,H)、7.79(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)、8.83(CH,m,H)ppm。MS:m/z:356.13(M+1)。
实施例5
Figure PCTCN2018124969-appb-000019
称取原料化合物1-D(3.5g，9.86mmol，1.0eq)于100ml三口瓶中，加入40ml无水四氢呋喃，搅拌溶解，降温至-18℃，氩气保护；量取二异丙基氨基锂(4.9ml，9.86mmol，1.0eq)连续缓慢加入反应液中，控温在-10℃到-5℃之间，然后在0℃下反应0.5h；称取二-吗啉代磷酰氯(5.0g，19.72mmol，2.0eq)在5分钟内分份连续缓慢加入反应液中，该混合物在-5℃到0℃之间反应1小时；称取(R)-1-氨基-2-丙醇(1.8g，24.06mmol，2.44eq)于50ml单口瓶中，加入7ml无水四氢呋喃，震荡均匀后连续缓慢加入反应液中，维持温度在-2℃到4℃之间，耗时约40分钟；滴加完毕，升温至室温下反应过夜；将反应液倒入冰水中淬灭，乙酸乙酯提取，合并有机相，无水硫酸钠干燥，过滤，减压浓缩(-0.08MPa，42℃)，残留物过柱纯化(乙酸乙酯：石油醚＝1:10to纯乙酸乙酯)得到3.05g橙黄色油状物化合物1-E，收率75％。
该化合物H核磁共振谱(氘代甲醇)：δ1.05(CH3,d,3H)、2.29(CH2,m,2H)、2.33(CH3,m,3H)、2.35(CH2,m,2H)、3.11(CH,m,H)、3.61(CH3,s,3H)、3.69；3.44(CH2,m,2H)、7.05(CH,d,H)、7.74(CH,m,H)、7.75(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:413.19(M+1)。
实施例6
Figure PCTCN2018124969-appb-000020
称取化合物1-E(1.5g，3.64mmol，1.0eq)溶于14ml丁酮中，温热至30℃，分4次加入戴斯-马丁氧化剂(5.41g，12.74mmol，3.5eq)，然后升温至45℃， TLC跟踪反应进展，直至原料转化完全；用饱和碳酸氢钠溶液淬灭反应液，乙酸乙酯提取，无水硫酸钠干燥，过滤，滤液减压浓缩(-0.08MPa，45℃)，残留物过柱纯化(乙酸乙酯：石油醚＝1:10to纯乙酸乙酯)得到1.12g棕黄色固体化合物1-F，收率78.7％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、3.61(CH3,s,3H)、4.32(CH2,m,2H)、7.31(CH,m,H)、7.33(CH,m,H)、7.69(2CH,m,2H)、7.74(CH,m,H)、7.75(CH,m,H)、7.79(CH,m,H)、7.83(CH,m,H)、7.89(2CH,m,2H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:393.16(M+1)。
实施例7
Figure PCTCN2018124969-appb-000021
向含有化合物1-F(0.25g，0.64mmol，1.0eq)的反应瓶中加入80mL无水乙醚，搅拌溶解，冷却至0℃，氩气保护；逐滴加入含有苯磺酸(0.1g，0.64mmol，1.0eq)的1.5ml无水乙酸乙酯，反应1小时，完全析出固体，TLC检测反应完全；过滤，滤饼真空干(-0.09MPa，20℃)得到0.31g类白色固体化合物1-1，收率88.9％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.33(CH,m,H)、7.69(2CH,m,2H)、7.74(CH,m,H)、7.75(CH,m,H)、7.79(CH,m,H)、7.83(CH,m,H)、7.89(2CH,m,2H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:551.17(M+1)。
实施例8
Figure PCTCN2018124969-appb-000022
参照实施例7化合物1-1的合成方法，采用对甲苯磺酸为原料得到化合物1-2，收率87％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.33(CH,m,H)、7.47(2CH,m,2H)、7.74(CH,m,H)、7.75(3CH,m,3H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:565.18(M+1)。
实施例9
Figure PCTCN2018124969-appb-000023
参照实施例7化合物1-1的合成方法，采用盐酸为原料得到化合物1-3，收率92％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.33(CH,m,H)、7.74(CH,m,H)、7.75(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:429.14(M+1)。
实施例10
Figure PCTCN2018124969-appb-000024
参照实施例7化合物1-1的合成方法，采用3-溴吡啶、对甲苯磺酸为原料得 到化合物1-4，收率85.3％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.33(CH,m,H)、7.47(2CH,m,2H)、7.58(CH,m,H)、7.75(3CH,m,3H)、8.30(CH,m,H)、8.75(CH,m,H)、9.07(CH,m,H)ppm。MS:m/z:565.18(M+1)。
实施例11
Figure PCTCN2018124969-appb-000025
参照实施例7化合物1-1的合成方法，采用4-溴吡啶、对甲苯磺酸为原料得到化合物1-5，收率86％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.33(CH,m,H)、7.47(2CH,m,2H)、7.75(3CH,m,3H)、7.98(2CH,m,2H)、8.64(2CH,m,2H)ppm。MS:m/z:565.18(M+1)。
实施例12
Figure PCTCN2018124969-appb-000026
参照实施例7化合物1-1的合成方法，采用2-氨基-5-溴-4-甲基苯甲酸、对甲苯磺酸为原料得到化合物1-6，收率84.5％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.24(CH,m,H)、7.31(CH,m,H)、7.47(2CH,m,2H)、7.75(2CH,m,2H)、7.74(CH,m,H)、7.79(CH,m,H)、7.86(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。 MS:m/z:625.10(M+1)。
实施例13
Figure PCTCN2018124969-appb-000027
参照实施例7化合物1-1的合成方法，采用2-氨基-5-硝基-4-甲基苯甲酸、对甲苯磺酸为原料得到化合物1-7，收率83％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.34(CH3,m,3H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,m,H)、7.47(2CH,m,2H)、7.75(2CH,m,2H)、7.61(CH,m,H)、7.74(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.47(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:592.18(M+1)。
实施例14
Figure PCTCN2018124969-appb-000028
参照实施例7化合物1-1的合成方法，采用2-氨基-5-三氟甲基-4-甲基苯甲酸、对甲苯磺酸为原料得到化合物1-8，收率84.7％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.29(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.28(CH,m,H)、7.31(CH,m,H)、7.47(2CH,m,2H)、7.75(2CH,m,2H)、7.74(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.00(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:615.18(M+1)。
实施例15
Figure PCTCN2018124969-appb-000029
参照实施例7化合物1-1的合成方法，采用2-氨基-5-甲氧基-4-甲基苯甲酸、对甲苯磺酸为原料得到化合物1-9，收率82.9％。
该化合物H核磁共振谱(氘代甲醇)：δ2.15(CH3,s,3H)、2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、3.61(CH3,s,3H)、3.72(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,d,H)、7.35(2CH,d,2H)、7.47(2CH,d,2H)、7.74(CH,m,H)、7.75(2CH,m,2H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:577.20(M+1)。
实施例16
Figure PCTCN2018124969-appb-000030
参照实施例7化合物1-1的合成方法，采用2-氨基-4,5-二甲氧基苯甲酸、对甲苯磺酸为原料得到化合物1-10，收率81.4％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、3.61(CH3,s,3H)、3.85(2CH3,d,6H)、4.32(CH,m,H)、7.09(CH,s,H)、7.31(CH,s,H)、7.40(CH,s,H)、7.47(2CH,d,2H)、7.75(2CH,m,2H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:593.20(M+1)。
实施例17
Figure PCTCN2018124969-appb-000031
参照实施例7化合物1-1的合成方法，采用2-氨基-4,5-二氟苯甲酸、对甲苯磺酸为原料得到化合物1-11，收率84.2％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.16(CH,m,H)、7.31(CH,s,H)、7.47(2CH,d,2H)、7.75(2CH,m,2H)、7.78(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:569.16(M+1)。
实施例18
Figure PCTCN2018124969-appb-000032
参照实施例7化合物1-1的合成方法，采用2-氨基-4,5-二氯苯甲酸、对甲苯磺酸为原料得到化合物1-12，收率84.8％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,s,H)、7.42(CH,s,H)、7.47(2CH,d,2H)、7.74(CH,d,H)、7.75(2CH,m,2H)、7.79(CH,m,H)、7.85(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:601.10(M+1)。
实施例19
Figure PCTCN2018124969-appb-000033
参照实施例7化合物1-1的合成方法，采用2-氨基-4,5-二甲基苯甲酸、对甲苯磺酸为原料得到化合物1-13，收率86％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.31(CH3,m,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、2.47(CH3,s,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.30(CH,d,H)、7.31(CH,d,H)、7.47(2CH,d,2H)、7.69(CH,m,H)、7.74(CH,m,H)、7.75(2CH,m,2H)、7.79(CH,m,H)、7.96(CH,m,H)、 8.71(CH,m,H)ppm。MS:m/z:561.21(M+1)。
实施例20
Figure PCTCN2018124969-appb-000034
参照实施例7化合物1-1的合成方法，采用3-溴吡啶、2-氨基-5-氟-4-(三氟甲基)苯甲酸、对甲苯磺酸为原料得到化合物1-14，收率82.5％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、3.61(CH3,s,3H)、4.32(CH,m,H)、7.31(CH,s,H)、7.47(2CH,d,2H)、7.58(CH,m,H)、7.64(CH,m,H)、7.73(CH,m,H)、7.75(2CH,m,2H)、8.30(CH,m,H)、8.75(CH,m,H)、9.07(CH,m,H)ppm。MS:m/z:619.16(M+1)。
实施例21
Figure PCTCN2018124969-appb-000035
参照实施例7化合物1-1的合成方法，采用4-氟-5-甲氧基苯甲酸、对甲苯磺酸为原料得到化合物1-15，收率83.6％。
该化合物H核磁共振谱(氘代甲醇)：δ2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、3.61(CH3,s,3H)、3.83(CH3,s,3H)、4.32(CH,m,H)、7.18(CH,s,H)、7.31(CH,s,H)、7.38(CH,s,H)、7.47(2CH,d,2H)、7.74(CH,m,H)、7.75(2CH,m,2H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:581.18(M+1)。
实施例22
Figure PCTCN2018124969-appb-000036
参照实施例7化合物1-1的合成方法，采用3-溴吡啶、Boc-L-谷氨酸-5-乙酯、2-氨基-4-氟-5-甲基苯甲酸、对甲苯磺酸为原料得到化合物1-16，收率87.3％。
该化合物H核磁共振谱(氘代甲醇)：δ1.07(CH3,s,3H)、2.23(CH3,s,3H)、2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,s,3H)、4.01(CH2,s,2H)、4.32(CH,m,H)、7.13(CH,d,H)、7.31(CH,s,H)、7.47(2CH,d,2H)、7.58(CH,t,H)、7.72(CH,m,H)、7.75(2CH,m,2H)、8.30(CH,m,H)、8.75(CH,m,H)、9.07(CH,m,H)ppm。MS:m/z:579.20(M+1)。
实施例23
Figure PCTCN2018124969-appb-000037
参照实施例7化合物1-1的合成方法，采用Boc-L-谷氨酸-5-乙酯、2-氨基-4-甲氧基-5-乙基苯甲酸、对甲苯磺酸为原料得到化合物1-17，收率81.5％。
该化合物H核磁共振谱(氘代甲醇)：δ1.07(CH3,m,3H)、1.12(CH3,m,3H)、2.23(CH3,s,3H)、2.33(CH2,m,2H)、2.35(CH2,m,2H)、2.43(CH3,m,3H)、2.50(CH2,m,2H)、3.72(CH3,s,3H)、4.01(CH2,m,2H)、4.32(CH,m,H)、7.09(CH,s,H)、7.31(CH,s,H)、7.47(2CH,d,2H)、7.74(CH,m,H)、7.75(2CH,m,2H)、7.78(CH,m,H)、7.79(CH,m,H)、7.96(CH,m,H)、8.71(CH,m,H)ppm。MS:m/z:605.24(M+1)。
药理活性及安全性评估
在进行手术和诊断操作期间，需要对麻醉药物的作用效果有良好的控制，从而保证手术的顺利实施，并在操作完成后尽快结束麻醉。良好的静脉麻醉药物应符合快速起效、快速恢复、安全性高的要求。
实施例24药物诱导小鼠翻正反射消失实验
ICR小鼠(雄性，18-25g经尾静脉快速推注单次给予相同剂量(100mg/kg)的受试药物后，记录小鼠翻正反射消失的潜伏期和持续期。其中，潜伏期指给药开始到动物翻正反射消失的时间，持续时间指翻正反射消失至恢复的时间。实验结果见下表。
表1小鼠翻正反射消失实验结果
化合物 潜伏期(min) 持续期(min)
瑞马唑仑(对甲苯磺酸盐) 0.73 9.43
瑞马唑仑(苯磺酸盐) 0.64 10.61
1-1 0.35 7.00
1-2 0.52 6.02
1-3 0.30 7.20
1-4 0.37 9.32
1-5 0.40 8.21
1-6 0.47 7.98
1-7 0.60 8.39
1-8 0.55 8.60
1-9 0.63 8.77
1-10 0.48 7.86
1-11 0.53 7.28
1-12 0.42 8.35
1-14 0.58 6.30
1-15 0.54 9.02
1-16 0.86 9.35
1-17 0.75 7.24
从表1可以看出，本发明的化合物麻醉作用效果与瑞马唑仑对甲苯磺酸盐或者瑞马唑仑苯磺酸盐相当或更优。
进一步地，相比于瑞马唑仑对甲苯磺酸盐或者瑞马唑仑苯磺酸盐，本发明大多数化合物具有起效更快、恢复更快的优点。
实施例25小鼠静脉给药起效剂量和致死剂量实验
将ICR小鼠(雄性，18-25g)随机分组，经尾静脉快速推注单次给予不同剂量的受试药物，记录导致翻正反射消失的最低剂量(起效剂量)和造成动物死亡的剂量(致死剂量)，并计算治疗窗(致死剂量/起效剂量)。
表2不同受试化合物的起效和致死剂量
Figure PCTCN2018124969-appb-000038
上表2的数据显示，在小鼠试验中，本发明的化合物安全窗口明显更大，并且麻醉过程平稳，未观察到四肢抖动、抽搐、角弓反张等不良作用，具有良好的安全性。
典型地，相比于瑞马唑仑(对甲苯磺酸盐)，以化合物1-2为例，其起效剂量降低33.3％，致死剂量则提高64％，治疗窗增加为2.5倍。
因此，本发明提供了一种兼具快速起效、快速恢复、安全性高且副作用极小的麻醉用化合物。
实施例26化合物1-2多次(9次)i.v给药后对小鼠翻正反射消失持续时间的影响
实验方法
各组动物按照相应组别尾静脉注射(i.v.)多次给予相应药液，0.1ml/只/次，连续注射9次(给药组小鼠每次翻正反射消失恢复时注射一次)，记录每次翻正反射消失持续时间，数据以平均值表示。
实验结果
静脉注射化合物1-2后，小鼠翻正反射消失持续时间具剂量依赖性，同时各剂量组小鼠随着给药次数的增加，翻正反射消失持续时间迅速延长，并在5-6次反复给药后到达稳态。单次给药后，化合物1-2的75mg/kg剂量组与丙泊酚组翻正反射消失持续期接近(表3)，但经过6-7次给药后，75mg/kg的化合物1-2翻正反射消失时间为丙泊酚组小鼠的65-70％，见表3和表4。
表3化合物1-2多次iv给药后翻正反射消失持续期的影响
Figure PCTCN2018124969-appb-000039
表4化合物1-2多次iv给药后翻正反射消失持续期的影响
Figure PCTCN2018124969-appb-000040
从表3和表4可知：丙泊酚和受试药物化合物1-2多次i.v给药均会延长小鼠的翻正反射持续时间，丙泊酚及不同剂量受试药物组小鼠翻正反射消失持续时间均在连续给药6-7次后达稳态。但化合物1-2各剂量组多次给药后的翻正反射消 失时间延长率显著低于丙泊酚，说明化合物1-2的蓄积作用低于丙泊酚，提示化合物1-2的安全性更高。
实施例27化合物1-2单次及多次(10次)i.v给药后对小鼠自主活动的影响
实验方法
单次给药
各组动物测定自主活动情况，每只小鼠10min。随后各组动物按照相应组别尾静脉注射(i.v.)单次给予相应药液，0.1ml/10g体重，给药后立即测定小鼠自主活动情况，记录时间为50min。数据以平均值±标准差表示。其中，丙泊酚的给药剂量为20mg/kg。
多次给药
各组动物按照相应组别尾静脉注射(i.v.)多次给予相应药液，0.1ml/只/次，连续注射十次(给药组小鼠每次翻正反射消失恢复时注射一次)后立即测定小鼠自主活动情况，记录时间为50min。数据以平均值±标准差表示。
实验结果
1、化合物1-2单次给药对小鼠自主活动的影响
各组小鼠给药前的自主活动未见差异，空白组小鼠的自主活动随探索时间的延长缓慢下降。单次阳性药丙泊酚组在注射5min的自主活动明显降低，同时该组小鼠在给药后5-10min均已清醒，给药15min后自主活动基本恢复，但后续自主活动无论在总路程、活动次数均低于空白对照组。小鼠单次注射不同剂量化合物1-2后测定小鼠自主活动，结果显示：注射10min内，50mg/kg-100mg/kg剂量组小鼠自主活动总路程与同时间点空白组相比明显降低，且呈现剂量依赖性。低剂量组化合物1-2(50mg/kg)小鼠给药15min后，自主活动恢复至正常水平；中剂量组化合物1-2(75mg/kg)小鼠给药35min后，自主活动恢复至正常水平；高剂量组化合物1-2(100mg/kg)在测试期内自主活动一直低于空白组，参见图1-3。
2、化合物1-2多次给药对小鼠自主活动的影响
在测试期间，空白组小鼠的自主活动随探索时间的延长缓慢下降。连续10次注射药物后，10min内丙泊酚及化合物1-2各剂量组的小鼠自主活动均明显降低，表现在各组小鼠活动总路程、活动次数显著降低，休息时间显著增加。阳性药丙泊酚组在给药后40-45min后自主活动基本恢复(和同时间空白组相近)。化合物1-2 50mg/kg组的小鼠自主活动于给药后15-20min即可恢复至正常水平(和同时间空白组相近)；化合物1-275mg/kg组的小鼠自主活动于给药后40-45min才恢复至正常水平(和同时间空白组相 近)；化合物1-2 100mg/kg组的小鼠自主活动测试期内(50min)尚未恢复至正常水平(和同时间空白组相近)；具体参见图4-6。
从图1-6可知：根据自主活动总路程、活动次数及休息时间，可知丙泊酚单次给药的自主活动恢复略快于受试药物，与化合物1-2低剂量组较接近。而丙泊酚多次给药后自主活动的恢复明显变缓，基本与受试药物75mg/kg恢复速度及程度相当，但受试药物75mg/kg组在活动次数及休息时间指标甚至好于丙泊酚20mg/kg。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (10)

  1. 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1，其特征在于，所述化合物1的结构通式如下：
    Figure PCTCN2018124969-appb-100001
    其中：
    R选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
    R 1选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
    R 2为氮在2、3或者4位置的吡啶环；
    R 3为短碳链的各种烷基；
    HX代表任何可接受的药用无机酸和有机酸。
  2. 如权利要求1所述的化合物1，其特征在于，所述短碳链的各种烷基为C1-C6烷基。
  3. 如权利要求1所述的化合物1，其特征在于，R和R 1不同。
  4. 如权利要求1所述的化合物1，其特征在于，R为F；R 1为C1-C6烷基；R 2为氮在2位置的吡啶环；
    R 3为C1-C6烷基。
  5. 如权利要求1所述的化合物1，其特征在于，R为C1-C6烷基；R 1为F；R 2为氮在3位置的吡啶环；
    R 3为C1-C6烷基。
  6. 如权利要求1所述的化合物1，其特征在于，所述化合物1选自下组：
    Figure PCTCN2018124969-appb-100002
    Figure PCTCN2018124969-appb-100003
  7. 一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物10，其特征在于，具有如下结构通式：
    Figure PCTCN2018124969-appb-100004
    其中，R选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
    R 1选自下组：短碳链的各种烷基、三氟甲基、甲氧基、硝基、氟、氯、溴；
    R 2为氮在2、3或者4位置的吡啶环；
    R 3为短碳链的各种烷基。
  8. 如权利要求1所述的一种吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1的制备方法，其特征在于，通过以下合成步骤实现：
    起始原料采用3，4位上各种取代基的邻氨基苯甲酰吡啶2与Boc-L-谷氨酸-5酯3在DCC存在下生成2-(Boc-L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶4；在酸5的作用下脱除Boc保护基得到2-(L-谷氨酸-5酯酰)氨基-3，4-二取代基苯甲酰吡啶盐6，在碳酸氢钠存在下发生分子内缩合得到3，4-二取代基苯并二氮杂卓丙酸酯7；继而与(R)-1-氨基-2-丙醇8反应生成(R)-N-(3，4-二取代基苯并二氮杂卓丙酸酯基)氨基-2-丙醇9，与DMP发生氧化闭环反应得到吡啶基咪唑并苯并二氮杂卓丙酸酯10，经与酸5发生成盐反应获得目标产物吡啶基咪唑并苯并二氮杂卓丙酸酯盐化合物1；
    合成反应路线如下：
    Figure PCTCN2018124969-appb-100005
    其中R、R 1、R 2、R 3、HX如权利要求1所述；DMP代表戴斯－马丁氧化剂。
  9. 一种药物组合物，其特征在于，所述药物组合物包含：
    1)麻醉有效量的一种或多种权利要求1所述的化合物1和/或权利要求7所述的化合物10；和
    2)药学上可接受的载体。
  10. 一种权利要求1所述的吡啶基咪唑并苯并二氮杂卓丙酸酯化合物1的用途，其特征在于，用于制备静脉麻醉药物。
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