WO2019158075A1 - 苯二氮卓衍生物盐酸盐与晶型、制备方法及其应用 - Google Patents

苯二氮卓衍生物盐酸盐与晶型、制备方法及其应用 Download PDF

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WO2019158075A1
WO2019158075A1 PCT/CN2019/074935 CN2019074935W WO2019158075A1 WO 2019158075 A1 WO2019158075 A1 WO 2019158075A1 CN 2019074935 W CN2019074935 W CN 2019074935W WO 2019158075 A1 WO2019158075 A1 WO 2019158075A1
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powder diffraction
ray powder
hcl
diffraction spectrum
hydrochloride
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PCT/CN2019/074935
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English (en)
French (fr)
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李勤耕
段衬
王涛
廖建
李长文
郝超
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江苏恩华络康药物研发有限公司
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Application filed by 江苏恩华络康药物研发有限公司 filed Critical 江苏恩华络康药物研发有限公司
Priority to CA3090913A priority patent/CA3090913C/en
Priority to KR1020207026112A priority patent/KR102647713B1/ko
Priority to AU2019222052A priority patent/AU2019222052B2/en
Priority to JP2020543143A priority patent/JP7410036B2/ja
Priority to MX2020008465A priority patent/MX2020008465A/es
Priority to SG11202007733SA priority patent/SG11202007733SA/en
Priority to CN201980012858.0A priority patent/CN111712501A/zh
Priority to US16/969,224 priority patent/US11708368B2/en
Priority to EA202091927A priority patent/EA202091927A1/ru
Priority to EP19754326.7A priority patent/EP3753940A4/en
Publication of WO2019158075A1 publication Critical patent/WO2019158075A1/zh
Priority to IL276611A priority patent/IL276611A/en

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    • 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
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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
    • 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
    • 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
    • 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
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the invention relates to a benzodiazepine derivative hydrochloride and a crystal form, a preparation method and application thereof.
  • Remazozolam (CNS 7056), a new generation of benzodiazepine derivatives based on midazolam, has received attention due to its rapid onset and recovery. As the research progressed, the shortcomings of remiazolam gradually emerged. In the Phase II clinical trial of ICU sedation, Ono found that hemodynamics was unstable after the patient was treated with remiazolam, and 10% of the patients had higher plasma concentrations than the normal range (PAION AG Analyst call Oct 14 2014).
  • WO 0069836 discloses remiazolam and its pharmaceutically acceptable salts, but does not disclose a process for the preparation of pharmaceutically acceptable salts.
  • CN104059071 and CN 103221414 disclose methods for preparing remazolyl besylate and p-toluenesulfonate and crystalline forms thereof.
  • PCT/CN2015/084770 discloses a process for the preparation of a series of benzodiazepine derivatives and sulfonates thereof which have good intravenous anesthetic effects.
  • organic sulfonic acids e.g., ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, etc.
  • organic sulfonic acid salt has the disadvantage that the benzodiazepine derivative needs to use the corresponding alcohol as a solvent when forming a salt, and if an organic sulfonic acid is used, there is a possibility of forming an organic sulfonate. For example, see the following reaction process:
  • R is a methyl group or an ethyl group
  • R 1 is a methyl group, an ethyl group, a phenyl group, a 4-methylphenyl group, a 4-hydroxyphenyl group or the like.
  • the organic sulfonate thus produced is highly genotoxic (ICH Harmonised Tripartite Guideline, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, Current Step 4 version, 23 June 2014). Therefore, the organic sulfonates of these benzodiazepine derivatives have the risk of forming potentially genotoxic substances during production, storage and use. Genotoxic substances are characterized by damage to human genetic material at very low concentrations, which in turn leads to genetic mutations and may contribute to tumorigenesis. Because of its strong toxicity, it poses a strong threat to the safety of medication. In recent years, more and more serious medical accidents have occurred in traces of genotoxic impurities found in listed drugs.
  • the ideal method is to change the sulfonate to an acid radical that has no or only a small risk of genotoxicity, such as Cl - .
  • R is methyl and its crystalline structure is substantially as shown in Figure 1, or may be characterized by one or more parameters substantially as shown in Tables 1-6.
  • R is ethyl and its crystalline structure is substantially as shown in Figure 2, or may be characterized by one or more parameters substantially as shown in Tables 7-12.
  • R is methyl and the content of chloride ion in the compound of formula I is from 6.71 to 7.52% (w/w). In another embodiment, R is ethyl and the content of chloride ion in the compound of Formula I is from 6.51 to 7.31% (w/w).
  • the X-ray powder diffraction spectrum has the following 2 theta values measured using CuKa radiation: about 6.81, 8.93, 13.39, 19.38, 21.23, 22.42, 24.20 , 27.31 ⁇ 0.2 degrees.
  • the X-ray powder diffraction spectrum may also have the following 2 theta values measured using CuKa radiation: about 8.11, 9.86, 14.73, 17.47, 23.03, 25.94, 28.31 ⁇ 0.2 degrees.
  • the crystalline form has an X-ray powder diffraction spectrum substantially as shown in FIG.
  • the X-ray powder diffraction spectrum has the following 2 theta values measured using CuKa radiation: about 6.80, 8.93, 9.87, 13.37, 14.69, 19.36, 20.76, 21.25, 22.19, 22.38, 23.06, 24.21, 25.93, 27.73 ⁇ 0.2 degrees.
  • the X-ray powder diffraction spectrum may also have the following 2 theta values measured using CuKa radiation: about 16.14, 17.48, 20.02, 25.17, 26.36, 28.30, 34.13 ⁇ 0.2 degrees.
  • the crystalline form has an X-ray powder diffraction spectrum substantially as shown in Figure 4.
  • the X-ray powder diffraction spectrum has the following 2 theta values measured using CuKa radiation: about 6.87, 7.38, 9.53, 13.65, 18.71, 22.13, 22.67. , 25.10, 27.25, 29.30 ⁇ 0.2 degrees.
  • the X-ray powder diffraction spectrum may also have the following 2 theta values measured using CuKa radiation: about 14.96, 15.43, 20.23, 20.67, 21.13, 23.52, 28.22, 31.26 ⁇ 0.2 degrees.
  • the crystalline form has an X-ray powder diffraction spectrum substantially as shown in one of Figures 5-8.
  • the X-ray powder diffraction spectrum has the following 2 theta values measured using CuKa radiation: about 7.41, 9.24, 12.71, 13.64, 15.06, 18.30, 18.72. , 21.59, 22.18, 25.74 ⁇ 0.2 degrees.
  • the X-ray powder diffraction spectrum may also have the following 2 theta values measured using CuKa radiation: about 9.52, 11.69, 20.90, 22.60, 23.65, 24.26, 26.40, 28.43, 29.35 ⁇ 0.2 degrees.
  • the crystalline form has an X-ray powder diffraction spectrum substantially as shown in FIG.
  • the X-ray powder diffraction spectrum has the following 2 theta values measured using CuKa radiation: about 6.84, 7.37, 9.53, 13.66, 22.63, 25.57, 29.28, 31.26 ⁇ 0.2 degrees.
  • the X-ray powder diffraction spectrum may also have the following 2 theta values measured using CuKa radiation: about 15.43, 19.07, 22.16, 34.25 ⁇ 0.2 degrees.
  • the crystalline form has an X-ray powder diffraction spectrum substantially as shown in one of Figures 10-13.
  • a process for the preparation of a crystalline form of the hydrochloride salt of a benzodiazepine derivative of the above formula I according to the present invention comprising the steps of: formula II ⁇ 1 or II ⁇ 2
  • the benzodiazepine derivative free base is dissolved in the organic solvent 1, and the HCl supply A in which [H + ] is equimolar to the free base is added, and the temperature is -20 to 60 ° C, preferably 1-10 to 30 ° C.
  • the salt after decolorization of the crude salt, is crystallized in the crystallization solvent 1 at a temperature of from -60 to 80 ° C, preferably from -20 to 60 ° C to obtain the hydrochloride salt of the benzodiazepine derivative of the formula I. Crystal form.
  • the organic solvent 1 is an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; an ester solvent such as methyl acetate, Ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate; ketone solvents such as acetone, methyl ethyl ketone; or a mixture thereof.
  • alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol
  • an ester solvent such as methyl acetate, Ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate
  • ketone solvents such as acetone, methyl ethyl ketone; or a mixture thereof.
  • the HCl supply A is an amino acid hydrochloride such as glycine hydrochloride, alanine hydrochloride, valine hydrochloride; HCl-anhydrous alcohol solution, ie Drying the alcohol solution of HCl gas, such as dry HCl-methanol solution, dry HCl-ethanol solution, dry HCl-isopropanol solution; or HCl solution B, such as acetyl chloride-methanol solution, acetyl chloride-ethanol solution, Propionyl chloride-ethanol solution, acetyl chloride-isopropanol solution.
  • amino acid hydrochloride such as glycine hydrochloride, alanine hydrochloride, valine hydrochloride
  • HCl-anhydrous alcohol solution ie Drying the alcohol solution of HCl gas, such as dry HCl-methanol solution, dry HCl-ethanol solution, dry HCl-isopropanol solution
  • HCl solution B such as
  • the HCl supply A is an amino acid hydrochloride
  • the crystalline form of the benzodiazepine derivative hydrochloride is 0% to 8% (w) /w).
  • the HCl supply A is a HCl-anhydrous alcohol solution or a solution B that can form HCl, and the benzodiazepine derivative free base and the HCl supply A (in The ratio (molar ratio) of the substance of [H + ] is 1:0.4 to 1; the HCl supply A is an amino acid hydrochloride, and the benzodiazepine derivative free base and amino acid hydrochloride The amount ratio (molar ratio) of the substance is 1:1 to 10.
  • the crystallization solvent 1 comprises an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol; an ether solvent such as diethyl ether or isopropyl Ether, dioxane, methyl tert-butyl ether; ester solvents such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate; ketone solvents such as acetone, methyl ethyl ketone; Alkane solvents such as n-pentane, hexane, heptane, petroleum ether; halogenated alkanes such as dichloromethane, chloroform, 1,2-dichloroethane; and combinations thereof.
  • an alcohol solvent such as methanol, ethanol, n-propanol, isopropanol, n-butano
  • a pharmaceutical composition comprising the crystalline form of the hydrochloride salt of the benzodiazepine derivative of the above formula I according to the present invention, and a pharmaceutically acceptable excipient, Carrier and / or other excipients.
  • Both the crystalline form and the pharmaceutical composition according to the present invention can be used as an intravenous anesthetic.
  • a method of anesthesia comprising intravenously administering to a subject in need thereof an effective amount of a crystal of a hydrochloride salt of a benzodiazepine derivative of the above formula I according to the present invention.
  • Type or a pharmaceutical composition comprising the crystalline form.
  • the crystal form of the hydrochloride salt of the benzodiazepine derivative provided by the invention can not only improve the stability of the benzodiazepine derivative, but also eliminate the production and storage of the benzodiazepine derivative sulfonate.
  • the process brings the possibility of strong toxic impurities of sulfonate esters, and has a more excellent anesthetic effect, which is more conducive to clinical use.
  • the present invention provides a benzodiazepine derivative hydrochloride of the formula I, the ratio of such a hydrochloride to the corresponding sulfonate: 1) good stability, difficulty in producing a hydrolyzate; 2) in production or long-term No significant toxicity of sulfonate esters during storage; 3) shorter duration of anesthesia and shorter walking time after waking, small individual differences, and important clinical significance.
  • Figure 1 Single crystal molecular structure of an ethanolate of a compound of formula I wherein R is methyl;
  • Figure 2 Single crystal molecular structure of an ethanolate of the compound of formula I wherein R is ethyl;
  • the present invention provides a benzodiazepine derivative hydrochloride having the following crystal structure of the general formula I and an ethanolate thereof,
  • R is a methyl group or an ethyl group.
  • the content of chloride ion in the compound of formula I is from 6.71 to 7.52% (w/w).
  • the content of chloride ion in the compound of formula I is from 6.51 to 7.31% (w/w).
  • the benzodiazepine derivative hydrochlorides provided by the present invention are crystalline salts and provide their crystal structure and X-ray powder diffraction data and patterns.
  • R is methyl
  • the X-ray powder diffraction spectrum expressed in terms of 2 ⁇ angle is about 6.81, 8.93, 13.39, 19.38, 21.23, 22.42, 24.20, 27.31 ⁇ 0.2
  • the characteristic absorption can be further characterized by an X-ray powder diffraction spectrum at about 8.11, 9.86, 14.73, 17.47, 23.03, 25.94, 28.31 ⁇ 0.2 degrees 2 ⁇ , or by X-ray powder diffraction spectroscopy as shown in FIG.
  • R is methyl
  • the X-ray powder diffraction spectrum expressed in terms of 2 ⁇ angles is about 6.80, 8.93, 9.87, 13.37, 14.69, 19.36, 20.76, 21.25, 22.19, 22.38, 23.06, 24.21, 25.93, 27.73 ⁇ 0.2 have characteristic absorption, and may be used in X-ray powder diffraction spectra at about 16.14, 17.48, 20.02, 25.17, 26.36, 28.30, 34.13 ⁇ 0.2 degrees 2 ⁇ , or as shown in Figure 4.
  • the X-ray powder diffraction spectrum is further characterized.
  • R is ethyl, using Cu-K ⁇ radiation
  • the X-ray powder diffraction spectrum expressed in terms of 2 ⁇ angle is about 6.87, 7.38, 9.53, 13.65, 18.71, 22.13, 22.67, 25.10, 27.25, 29.30 ⁇ 0.2 characteristic absorption
  • X-ray powder diffraction spectra at about 14.96, 15.43, 20.23, 20.67, 21.13, 23.52, 28.22, 31.26 ⁇ 0.2 degrees 2 ⁇ or X-rays as shown in Figures 5-8 Powder diffraction spectra were further characterized.
  • R is ethyl
  • the X-ray powder diffraction spectrum expressed in 2 ⁇ angles is about 7.41, 9.24, 12.71, 13.64, 15.06, 18.30, 18.72, 21.59, 22.18, 25.74 ⁇ 0.2 characteristic absorption, X-ray powder diffraction spectrum at about 9.52, 11.69, 20.90, 22.60, 23.65, 24.26, 26.40, 28.43, 29.35 ⁇ 0.2 degrees 2 ⁇ or X-ray as shown in Figure 9 Powder diffraction spectra were further characterized.
  • R is ethyl
  • the X-ray powder diffraction spectrum expressed in terms of 2 ⁇ angle is about 6.84, 7.37, 9.53, 13.66, 22.63, 25.57, 29.28, 31.26 ⁇ 0.2
  • the characteristic absorption can be further characterized by an X-ray powder diffraction spectrum at about 15.43, 19.07, 22.16, 34.25 ⁇ 0.2 degrees 2 ⁇ or an X-ray powder diffraction spectrum as shown in Figures 10-13.
  • a process for preparing a benzodiazepine derivative hydrochloride and a crystal form thereof dissolving a benzodiazepine derivative free base in an organic solvent 1, and adding a benzodiazepine
  • the derivative free base is equimolar to the HCl supply A, and is salted at -20 to 60 ° C to obtain a crude product. After decolorization of the crude product, it is crystallized at -60-80 ° C in a crystallization solvent 1 to obtain a benzodiazepine derivative.
  • Hydrochloride dissolving a benzodiazepine derivative free base in an organic solvent 1, and adding a benzodiazepine
  • the derivative free base is equimolar to the HCl supply A, and is salted at -20 to 60 ° C to obtain a crude product. After decolorization of the crude product, it is crystallized at -60-80 ° C in a crystallization solvent 1 to obtain a benzodiazepine derivative.
  • the organic solvent 1 is an alcohol solvent (for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc.), an ester solvent (for example, methyl acetate, Ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, etc.), ketone solvents (such as acetone, methyl ethyl ketone, etc.), or mixtures thereof.
  • alcohol solvent for example, methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc.
  • an ester solvent for example, methyl acetate, Ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, etc.
  • ketone solvents such as acetone, methyl ethyl ketone, etc.
  • the HCl supply A is an amino acid hydrochloride (such as glycine hydrochloride, alanine hydrochloride, valine hydrochloride, etc.), HCl-anhydrous alcohol solution (ie An alcohol solution of HCl gas, such as a dry HCl-methanol solution, a dry HCl-ethanol solution, can be used to form a solution B of HCl (such as an acetyl chloride-methanol solution, an acetyl chloride-ethanol solution, etc.).
  • an amino acid hydrochloride such as glycine hydrochloride, alanine hydrochloride, valine hydrochloride, etc.
  • HCl-anhydrous alcohol solution ie
  • An alcohol solution of HCl gas such as a dry HCl-methanol solution, a dry HCl-ethanol solution, can be used to form a solution B of HCl (such as an acetyl chloride-methanol solution, an acetyl chlor
  • the amount of the amino acid contained in the benzodiazepine derivative hydrochloride is from 0% to 8% (w/w).
  • the ratio of the amount of the benzodiazepine derivative (in terms of the free base) to the amino acid hydrochloride is 1:1 to 10;
  • the HCl supply A is a HCl-anhydrous alcohol solution or a solution B which can form HCl
  • the ratio of the amount of the benzodiazepine derivative (in terms of the free base) to the acid (in terms of HCl) is 1:0.4 to 1.
  • the salt-forming temperature is -20 to 60 ° C, preferably -10 to 30 ° C; and the crystallization temperature is -60 to 80 ° C, preferably -20 to 60 ° C.
  • the crystallization solvent 1 includes an alcohol solvent (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, etc.), an ether solvent (e.g., diethyl ether, isopropyl) Ether, dioxane, methyl tert-butyl ether, diisopropyl ether, etc., ester solvents (such as methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, etc.), ketones Solvents (such as acetone, methyl ethyl ketone, etc.), alkane solvents (such as pentane, hexane, heptane, petroleum ether, etc.), halogenated alkanes (such as dichloromethane, chloroform, 1,2-dichloroe),
  • an alcohol solvent e
  • a benzodiazepine derivative hydrochloride of the present invention and a pharmaceutical composition which are useful as intravenous anesthetics.
  • the pharmaceutical composition comprises a crystalline form of the hydrochloride salt of a benzodiazepine derivative of the above formula I according to the invention, and optionally a pharmaceutically acceptable excipient, carrier and/or other excipient.
  • the excipient and/or carrier includes, for example, mannitol, sorbitol, xylitol, sucrose, lactose, glucose, dextrin, maltose, maltitol, maltodextrin, erythritol, trehalose, gluconic acid
  • mannitol sorbitol
  • xylitol sucrose, lactose, glucose, dextrin, maltose, maltitol, maltodextrin, erythritol, trehalose, gluconic acid
  • mannitol sorbitol
  • xylitol sucrose, lactose, glucose, dextrin, maltose, mal
  • the composition may also optionally include other excipients such as pH adjusting agents, stabilizers, analgesics, bacteriostats, and the like.
  • the pH adjusting agent includes, for example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, acetic acid, sodium dihydrogen phosphate, potassium dihydrogen phosphate, ammonium dihydrogen phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate, diammonium hydrogen phosphate, phosphoric acid.
  • the stabilizer includes, for example, sodium hydrogen sulfite, sodium metabisulfite, sodium sulfite, sodium thiosulfate, vitamin C, sodium thioglycolate, glycine, cysteine, disodium edetate, calcium edetate One or more of sodium and the like.
  • the analgesic agent includes, for example, one or more of benzyl alcohol, chlorobutanol, and the like.
  • the bacteriostatic agent includes, for example, one or more of benzyl alcohol, chlorobutanol, benzoic acid and salts thereof, sorbic acid and salts thereof, and parabens.
  • anesthesia method comprising intravenously administering to a patient a dose of a benzodiazepine derivative hydrochloride of the invention and a pharmaceutical composition.
  • benzodiazepine derivative hydrochloride of the present invention for the preparation of an intravenous anesthetic.
  • X-ray powder diffraction spectrum instrument model: Bruker D8FOCUS X-ray powder diffractometer; ray: Cu target; scanning mode: ⁇ /2 ⁇ ; scanning range: 3 to 60 °; voltage: 40 KV; current: 40 mA.
  • A-1 HCl-anhydrous alcohol solution as HCl supply A
  • the compound of the formula II-1 (1.8 g, 4 mmol) was dissolved in anhydrous methanol (6 ml) at 13 ° C, and then anhydrous methanol-HCl (HCl content 9.29%) was added dropwise 1.57 g (HCl molar amount) It is 4 mmol). The mixture was reacted for 0.5 h, then MTBE (54 ml) was added dropwise and then reacted for 0.5 h. The reaction mixture was filtered, and the filter cake was evaporated with 30 ml of anhydrous methanol.
  • A-2 using amino acid hydrochloride as HCl supply A
  • the target compound can be obtained by referring to the operation of Example 2 using the compound of the formula II-1 and the proline hydrochloride as a raw material (molar ratio: 1:1.5).
  • the target compound can be obtained by referring to the operation of Example 2 using the compound of the formula II-1 and the alanine hydrochloride as a raw material (molar ratio: 1:3).
  • A-3 Solution B which can generate HCl as HCl supply A
  • Example 1 The compound of the formula I obtained in Example 1 was recrystallized from ethanol and methyl tert-butyl ether, and allowed to stand at room temperature for 4 days, and crystals were collected. The obtained crystal was subjected to an X-ray single crystal diffraction experiment, and the crystal parameters thereof are shown in Tables 1-6 below.
  • Table 1 Crystal data and structure refinement data for the ethanolate of the compound of formula I wherein R is methyl
  • Atomic number x y z U(eq) Br(1) -4202(1) 8268(1) 6312(1) 20(1) O(1) 1797(2) 1562(2) 6318(1) 24(1) O(2) 3608(2) 1616(2) 7788(1) 24(1) N(1) 3120(2) 7198(2) 8336(1) 11(1) N(2) 5345(3) 6118(2) 8788(1) 14(1) N(3) 2920(3) 5605(2) 6571(1) 12(1) N(4) 2033(3) 7931(2) 4955(1) 16(1) C(1) -1864(3) 8033(2) 6918(2) 15(1) C(2) -744(3) 7443(2) 6369(2) 15(1) C(3) 940(3) 7172(2) 6826(2) 12(1) C(4) 1444(3) 7520(2) 7839(2) 12(1) C(5) 3750(3) 6139(2) 8272(2) 12(1) C(6) 5737(3) 7165(2) 9197(2) 17(1) C(7) 4366(3) 7865(2) 8929(2) 14(1) C(8) 4159(3) 9076(2) 9132(2) 19(1) C(9) 2771(3) 5267(2) 7635(2) 12(1) C(10) 2080(3) 6484(2) 6240(2)
  • U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
  • Solution B which can generate HCl as HCl supply A
  • the compound of the formula II-2 (1.38 g, 3 mmol) was dissolved in anhydrous ethanol (5 ml) at 13 ° C, and then a solution of acetyl chloride (3 mmol) in anhydrous ethanol (5 ml) was added dropwise thereto and reacted overnight. . Then, MTBE (45 ml) was added dropwise to the above reaction mixture, and reacted for 0.5 h, then filtered. The filter cake was dissolved in 30 ml of absolute ethanol and decolorized at 50 ° C for 0.5 h and then filtered. The filtrate was concentrated, and the residue was crystallised from anhydrous ethyl alcohol (12 ml).
  • the target product was obtained by crystallization at 20 ° C by the procedure of Example 7.
  • the X-ray powder diffraction pattern of the crystal is shown in Figure 6.
  • the theoretical value of chloride ion content is 7.24% (w/w), and the measured value is 7.21% (w/w).
  • the compound of the formula II-2 (1.38 g, 3 mmol) was dissolved in absolute ethanol (5 ml) at 13 ° C, and then anhydrous ethanol-HCl (HCl content 8.87%) 1.2 g (HCl molar amount) was added dropwise thereto. 3 mmol) and reacted for 0.5 h. Then MTBE (45 ml) was added dropwise to the reaction mixture, which was reacted for 0.5 h, then filtered. The filter cake was dissolved in 30 ml of absolute ethanol and decolorized at 50 ° C for 0.5 h, then filtered.
  • Example 12 Another batch of crystals of the compound of formula I wherein R is ethyl can be prepared.
  • the crystallographic X-ray powder diffraction pattern is shown in Figure 13.
  • the target product can be obtained by referring to the operation of Example 11.
  • the theoretical value of chloride ion content is 7.24% (w/w), and the measured value is 6.63% (w/w).
  • Example 9 The II-2 hydrochloride obtained in Example 9 was recrystallized from ethanol and methyl tert-butyl ether, and allowed to stand at room temperature for 4 days, and the crystals were collected for X-ray single crystal diffraction experiments. The crystal parameters were as shown in Table 7 below. -12 is shown.
  • Table 7 Crystal data and structure refinement data for the ethanolate of the compound of formula I wherein R is ethyl
  • Atomic number x y z U(eq) Br(1) -3552(1) 10601(1) 5747(1) 37(1) O(1) 4576(6) 4196(2) 6487(2) 73(1) N(1) 3579(4) 9375(2) 6716(1) 24(1) N(2) 5735(4) 8340(2) 6948(1) 28(1) O(3) 2760(4) 4013(2) 5838(1) 46(1) N(4) 2822(4) 9849(2) 5048(1) 31(1) N(3) 3572(4) 7810(2) 5886(1) 24(1) C(11) 2919(4) 8840(3) 5178(1) 23(1) C(7) 4778(5) 9987(3) 6995(1) 28(1) C(2) -125(4) 9623(2) 5794(1) 24(1) C(22) -855(5) 10674(3) 6501(1) 29(1) C(16) 3957(5) 6435(3) 6506(1) 28(1) C(3) 1528(4) 9324(2) 6006(1) 24(1) C(6) 6102(5) 9324(3) 7136(1) 31(1) C(4) 1938(4) 9694(2) 6478(1) 23(1) C(1) -1287(5) 10272(2) 6046(1) 27(1) C(5) 4197
  • U(eq) is defined as one third of the trace of the orthogonalized U ij tensor.
  • Example 16 Stability test of benzodiazepine derivative hydrochloride
  • the compound of the formula I prepared in the above examples was selected, packaged and subjected to accelerated stability test and long-term stability test under the conditions of 40 ° C, RH 75% and 25 ° C, and RH 60%, respectively, and the composition was examined for 6 months.
  • the degradation products (CNS-7054) were changed, and the results are shown in Table 13 below.
  • R is a methyl group or an ethyl group
  • A is benzenesulfonic acid or p-toluenesulfonic acid.
  • the benzodiazepine derivative hydrochloride provided by the present invention has good stability, does not form a degradation product (CNS-7054), and does not generate genotoxic impurities.
  • Example 17 Determination of ED 50 and LD 50 of benzodiazepine derivative hydrochloride KM mice
  • the therapeutic index of the benzodiazepine derivative hydrochloride provided by the present invention is not significantly different from that of the besylate salt, and the safety is good.
  • mice male and female, 20 in each group; the dose was 2*ED 50 , tail vein injection, 5 seconds continuous injection, recording the time (induction time) and recovery time of the mouse righting reflex disappeared (duration) and walking time.
  • the experimental results are shown in Table 16 below.
  • the benzodiazepine derivative in which R is an ethyl group is superior to the benzodiazepine derivative in which R is a methyl ester in the duration of anesthesia and walking time, and is statistically different.
  • R is an ethyl benzodiazepine derivative
  • the incidence of animal anesthesia for more than 10min, sulfonate is 35%, hydrochloride is 20%; animal walking time is more than 1min, the sulfonate is 50%, the hydrochloride is 15%, indicating that hydrochloric acid is more stable than the sulfonate pharmacokinetic properties, and is less affected by individual differences.
  • the benzodiazepine derivative hydrochloride provided by the present invention has more stable pharmacokinetic properties than the sulfonate, and is less affected by individual differences.

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Abstract

本发明提供具有如下式I的苯二氮卓类衍生物盐酸盐或其乙醇合物的晶体结构，(I) 其中，R为甲基或乙基。本发明还提供制备上述式I化合物的晶型的方法，以及包含所述晶型的药物组合物。

Description

苯二氮卓衍生物盐酸盐与晶型、制备方法及其应用
相关申请的交叉引用
本申请要求2018年2月13日提交的中国专利申请第201810151979.0号的优先权，其内容援引加入本文。
技术领域
本发明涉及苯二氮卓衍生物盐酸盐与晶型、制备方法及其应用。
发明背景
瑞马唑仑(remimazolam，CNS 7056)，是在咪达唑仑基础上改进的新一代苯二氮卓类衍生物，因起效和恢复快而被受关注。随着研究深入，瑞马唑仑的缺点逐渐显露出来。小野公司在ICU镇静的II期临床实验中发现，病人用瑞马唑仑后，血液动力学不稳定，其中10％病人血药浓度高于正常范围(PAION AG Analyst call Oct 14 2014)。
WO 0069836公开了瑞马唑仑及其可药用的盐，但未公开可药用的盐的制备方法。CN104059071和CN 103221414公开了瑞马唑仑苯磺酸盐及对甲苯磺酸盐的制备方法及其晶型。PCT/CN2015/084770公开了一系列苯二氮卓类衍生物和其磺酸盐的制备方法，这些衍生物具有较好的静脉麻醉作用。在公开的资料中，这类化合物都采用有机磺酸(如乙磺酸、苯磺酸、对甲苯磺酸等)与苯二氮卓类的碱基成盐以增加它们在水中的溶解度。但是，采用有机磺酸成盐具有如下缺点：苯二氮卓衍生物在成盐时需用相应的醇作溶媒，如果采用有机磺酸，则有形成有机磺酸酯的可能。例如，可参见以下反应过程：
Figure PCTCN2019074935-appb-000001
其中，R为甲基或乙基；R 1为甲基、乙基、苯基、4-甲基苯基、4-羟基苯基等。
如此生成的有机磺酸酯具有很强的基因毒性(ICH Harmonised Tripartite Guideline，Assessment and Control of DNA Reactive(Mutagenic)Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk，Current Step 4 version，23 June 2014)。因此，这些苯二氮卓衍生物的有机磺酸盐在生产、储存和使用的时候，具有形成潜在基因毒性物质的风险。基因毒性物质特点是在很低浓度时即可造成人体遗传物质的损伤，进而导致基因突变并可能促使肿瘤发生。因其毒性较强，对用药的安全性产生了强烈的威胁，近年来也越来越多的出现在已上市药品中发现痕量的基因毒性杂质残留而发生严重的医疗事故。因此，各国的法规机构如ICH、FDA、EMA等都对基因毒性杂质有了更明确的要求，越来越多的药企在新药研发过程中着重关注基因毒性杂质的控制和检测。为避免有机磺酸酯带来的基因毒性的风险，理想的方法是将磺酸根改换为不具有或仅具有较小基因毒性风险的酸根，如Cl -。然而，这类苯二氮卓衍生物的碱基分子中存在多个碱性中心，采取通常单一氨基与强酸--盐酸成盐，会形成单盐与多盐的混合物，难以获得单盐酸盐，造成结晶困难，吸湿性强，稳定性差。
发明内容
根据本发明的一个方面，其提供具有如下式I的苯二氮卓类衍生物的盐酸盐或其乙醇合物的晶型，
Figure PCTCN2019074935-appb-000002
其中R为甲基或乙基；其中R为甲基时，所述晶型具有以下晶胞参数：
Figure PCTCN2019074935-appb-000003
Figure PCTCN2019074935-appb-000004
α＝90°，β＝96.904(1)°，γ＝90°；以及R为乙基时，所述晶型具有以下晶胞参数：
Figure PCTCN2019074935-appb-000005
α＝90°，β＝90°，γ＝90°。
在根据此方面的一个实施方案中，R为甲基，且其晶型结构基本上如图1所示，或者可以用基本上如表1‐6所示的一种或多种参数表征。在另一个实施方案中，R为乙基，且其晶型结构基本上如图2所示，或者可以用基本上如表7‐12所示的一种或多种参数表征。
在根据此方面的一个实施方案中，R为甲基，且式I化合物中氯离子的含量为6.71～7.52％(w/w)。在另一个实施方案中，R为乙基，且式I化合物中氯离子的含量为6.51～7.31％(w/w)。
在一个实施方案中，对于其中R为甲基的式I化合物的晶型，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.81、8.93、13.39、19.38、21.23、22.42、24.20、27.31±0.2度。所述X射线粉末衍射光谱还可具有使用CuKα辐射测量的以下2θ值：约8.11、9.86、14.73、17.47、23.03、25.94、28.31±0.2度。另外，所述晶型具有基本上如附图3所示的X‐射线粉末衍射光谱。
在另一个实施方案中，对于其中R为甲基的式I化合物的晶型，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.80、8.93、9.87、13.37、14.69、19.36、20.76、21.25、22.19、22.38、23.06、24.21、25.93、27.73±0.2度。所述X射线粉末衍射光谱还可具有使用CuKα辐射测量的以下2θ值：约16.14、17.48、20.02、25.17、26.36、28.30、34.13±0.2度。另外，所述晶型具有基本上如附图4所示的X‐射线粉末衍射光谱。
在一个实施方案中，对于其中R为乙基的式I化合物的晶型，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.87、7.38、9.53、13.65、18.71、22.13、22.67、25.10、27.25、29.30±0.2度。所述X射线粉末衍射光谱还可具有使用CuKα辐射测量的以下2θ值：约14.96、15.43、20.23、20.67、21.13、23.52、28.22、31.26±0.2度。另外，所述晶型具有基本上如附图5～8之一所示的X‐射线粉末衍射光谱。
在一个实施方案中，对于其中R为乙基的式I化合物的晶型，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约7.41、9.24、12.71、13.64、15.06、18.30、18.72、21.59、22.18、25.74±0.2度。所述X射线粉末衍射光谱还可具有使用CuKα辐射测量的以下2θ值：约9.52、11.69、20.90、22.60、23.65、24.26、26.40、28.43、29.35±0.2度。另外，所述晶型具有基本上如附图9所示的X‐射线粉末衍射光谱。
在另一个实施方案中，对于其中R为乙基的式I化合物的晶型，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.84、7.37、9.53、13.66、22.63、25.57、29.28、31.26±0.2度。所述X射线粉末衍射光谱还可具有使用CuKα辐射测量的以下2θ值：约15.43、19.07、22.16、34.25±0.2度。另外，所述晶型具有基本上如附图10～13之一所示的X‐射线粉末衍射光谱。
根据本发明的另一个方面，其提供制备根据本发明的上述式I的苯二氮卓类衍生物的盐 酸盐的晶型的方法，包括以下步骤：将以下式II‐1或II‐2的苯二氮卓衍生物游离碱溶于有机溶剂1中，加入其中[H +]与游离碱等摩尔的HCl供给物A，在‐20至60℃、优选‐10至30℃的温度下成盐，将该粗品盐脱色后，于‐60至80℃、优选‐20至60℃的温度下在结晶溶剂1中结晶，得到所述式I的苯并二氮杂卓衍生物的盐酸盐的晶型。
Figure PCTCN2019074935-appb-000006
在根据此方面的一个实施方案中，所述有机溶剂1为醇类溶剂，如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇；酯类溶剂，如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯；酮类溶剂，如丙酮、丁酮；或者它们的混合物。
在根据此方面的一个实施方案中，所述HCl供给物A为氨基酸盐酸盐，如甘氨酸盐酸盐、丙氨酸盐酸盐、缬氨酸盐酸盐；HCl‐无水醇溶液，即干燥HCl气体的醇类溶液，如干燥HCl‐甲醇溶液、干燥HCl‐乙醇溶液、干燥HCl‐异丙醇溶液；或可以生成HCl的溶液B，如乙酰氯‐甲醇溶液、乙酰氯‐乙醇溶液、丙酰氯‐乙醇溶液、乙酰氯‐异丙醇溶液。
在根据此方面的一个实施方案中，所述HCl供给物A为氨基酸盐酸盐，且所述苯二氮卓衍生物盐酸盐的晶型中含有的氨基酸量为0％～8％(w/w)。
在根据此方面的一个实施方案中，所述HCl供给物A为HCl‐无水醇溶液或者可以生成HCl的溶液B，且所述苯二氮卓衍生物游离碱与该HCl供给物A(以[H +]计)的物质的量比(摩尔比)为1:0.4～1；所述HCl供给物A为氨基酸盐酸盐，且所述苯二氮卓衍生物游离碱与氨基酸盐酸盐的物质的量比(摩尔比)为1:1～10。
在根据此方面的一个实施方案中，所述结晶溶剂1包括醇类溶剂，如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇；醚类溶剂，如乙醚、异丙醚、二氧六环、甲基叔丁基醚；酯类溶剂，如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯；酮类溶剂，如丙酮、丁酮；烷烃类溶剂，如正戊烷、己烷、庚烷、石油醚；卤代烷烃，如二氯甲烷、三氯甲烷、1,2‐二氯乙烷；以及它们的组合。
根据本发明的另一个方面，其提供一种药物组合物，包含根据本发明的上述式I的苯二氮卓类衍生物的盐酸盐的晶型、以及药物学可接受的赋形剂、载体和/或其他辅料。
根据本发明所述的晶型以及药物组合物，都可用作静脉麻醉药物。
根据本发明的再一个方面，其提供麻醉的方法，其包括向有此需要的个体静脉内给药有效量的根据本发明的上述式I的苯二氮卓类衍生物的盐酸盐的晶型，或者包含该晶型的药物组合物。
本发明提供的苯二氮卓类衍生物的盐酸盐的晶型，既可提高苯二氮卓类衍生物的稳定性，又可消除苯二氮卓类衍生物磺酸盐在生产和储存过程中带来磺酸酯类强基因毒性杂质的可能，且具有更为优异的麻醉效应，更有利于临床使用。
另外，本发明提供如式I的苯二氮卓类衍生物盐酸盐，这类盐酸盐与相应的磺酸盐比：1)稳定性好，不易产生水解产物；2)在生产或长期储存过程中不会产生磺酸酯类强基因毒性的杂质；3)麻醉持续时间和醒后开始行走时间更短，个体差异小，具有重要的临床意义。
以下将参考附图对本发明进行更为详细的说明。
附图说明
图1：其中R为甲基的式I化合物乙醇合物的单晶分子结构；
图2：其中R为乙基的式I化合物乙醇合物的单晶分子结构；
图3：其中R＝CH 3的式I化合物结晶(CNS-7056A2017120401)的X-射线粉末衍射图谱；
图4：其中R＝CH 3的式I化合物结晶(CNS-7056AG20171225)的X-射线粉末衍射图谱；
图5：其中R＝CH 2CH 3的式I化合物结晶(EL-001A2017120401)的X-射线粉末衍射图谱；
图6：其中R＝CH 2CH 3的式I化合物结晶(EL-001A2017120801)的X-射线粉末衍射图谱；
图7：其中R＝CH 2CH 3的式I化合物结晶(EL-001A20180105)的X-射线粉末衍射图谱；
图8：其中R＝CH 2CH 3的式I化合物结晶(EL-001A2018010801)的X-射线粉末衍射图谱；
图9：其中R＝CH 2CH 3的式I化合物结晶(EL-001A20180130)的X-射线粉末衍射图谱；
图10：其中R＝CH 2CH 3的式I化合物结晶(EL-001AG2017121801)的X-射线粉末衍射图谱；
图11：其中R＝CH 2CH 3的式I化合物结晶(EL-001AG2017122101)的X-射线粉末衍射图谱；
图12：其中R＝CH 2CH 3的式I化合物结晶(EL-001AG2017122702LJ)的X-射线粉末衍射图谱；以及
图13：其中R＝CH 2CH 3的式I化合物结晶(EL-001AG2018010201)的X-射线粉末衍射图谱。
具体实施方式
本发明提供苯二氮卓类衍生物盐酸盐具有如下的通式I和其乙醇合物的晶体结构，
Figure PCTCN2019074935-appb-000007
其中，R为甲基或乙基。
根据本发明的一个实施方案，R为甲基时，本发明提供的苯二氮卓盐酸盐乙醇合物结晶包含具有以下晶胞参数：
Figure PCTCN2019074935-appb-000008
α＝90°，β＝96.904(1)°，γ＝90°。也可以用其如图1的结构，表1所示的参数，表2、表3、表4所示的结构坐标以及表5、表6所示的键长和角度来进一步表征。
根据本发明的一个实施方案，R为乙基时，本发明提供的苯二氮卓盐酸盐乙醇合物结晶包含具有以下晶胞参数：
Figure PCTCN2019074935-appb-000009
α＝90°，β＝90°，γ＝90°。也可以用其如图2的结构，表7所示的结构参数，表8、表9、表10所示的结构坐标以及表11、表12所示的键长和角度来进一步表征。
根据本发明的一个实施方案，R为甲基时，式I化合物中氯离子的含量为6.71～7.52％(w/w)。
根据本发明的一个实施方案，R为乙基时，式I化合物中氯离子的含量为6.51～7.31％(w/w)。
本发明提供的苯二氮卓类衍生物盐酸盐为结晶盐，并提供它们的晶体结构及X-射线粉末衍射数据和图谱。
根据本发明的一个实施方案，R为甲基，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射光谱在约6.81、8.93、13.39、19.38、21.23、22.42、24.20、27.31±0.2有特征吸收，可以用位于约8.11、9.86、14.73、17.47、23.03、25.94、28.31±0.2度2θ的X-射线粉末衍射光谱，或如附图3所示的X-射线粉末衍射光谱进一步表征。
根据本发明的一个实施方案，R为甲基，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射光谱在约6.80、8.93、9.87、13.37、14.69、19.36、20.76、21.25、22.19、22.38、23.06、24.21、25.93、27.73±0.2有特征吸收，可以用位于约16.14、17.48、20.02、25.17、26.36、28.30、34.13±0.2度2θ的X-射线粉末衍射光谱，或如附图4所示的X-射线粉末衍射光谱进一步表征。
根据本发明的一个实施方案，R为乙基，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射光谱在约6.87、7.38、9.53、13.65、18.71、22.13、22.67、25.10、27.25、29.30±0.2有特征吸收，可以用位于约14.96、15.43、20.23、20.67、21.13、23.52、28.22、31.26±0.2度2θ的X-射线粉末衍射光谱或如附图5～8所示的X-射线粉末衍射光谱进一步表征。
根据本发明的一个实施方案，R为乙基，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射光谱在约7.41、9.24、12.71、13.64、15.06、18.30、18.72、21.59、22.18、25.74±0.2有特征吸收，可以用位于约9.52、11.69、20.90、22.60、23.65、24.26、26.40、28.43、29.35±0.2度2θ的X-射线粉末衍射光谱或如附图9所示的X-射线粉末衍射光谱进一步表征。
根据本发明的一个实施方案，R为乙基，使用Cu-Kα辐射，以2θ角度表示的X-射线粉末衍射光谱在约6.84、7.37、9.53、13.66、22.63、25.57、29.28、31.26±0.2有特征吸收，可以用位于约15.43、19.07、22.16、34.25±0.2度2θ的X-射线粉末衍射光谱或如附图10～13所示的X-射线粉末衍射光谱进一步表征。
根据本发明的第二方面，其提供制备苯二氮卓衍生物盐酸盐及其晶型的制备方法：将苯并二氮卓衍生物游离碱溶于有机溶剂1，加入苯二氮卓类衍生物游离碱等摩尔的HCl供给物A，在-20～60℃成盐，得到粗品，粗品脱色后，于-60-80℃在结晶溶剂1中，结晶，得到苯二氮卓衍生物的盐酸盐。
根据本发明的一个实施方案，所述有机溶剂1为醇类溶剂(例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇等)、酯类溶剂(例如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯等)、酮类溶剂(例如丙酮、丁酮等)，或者它们的混合物。
根据本发明的一个实施方案，所述HCl供给物A为氨基酸盐酸盐(如甘氨酸盐酸盐、丙氨酸盐酸盐、缬氨酸盐酸盐等)、HCl-无水醇溶液(即干燥HCl气体的醇类溶液，如干燥HCl-甲醇溶液、干燥HCl-乙醇溶液)、可以生成HCl的溶液B(如乙酰氯-甲醇溶液、乙酰氯-乙醇溶液等)。
根据本发明的一个实施方案，当HCl供给物A为氨基酸盐酸盐时，苯二氮卓衍生物盐酸盐中含有的氨基酸量为0％～8％(w/w)。
根据本发明的一个实施方案，当HCl供给物A为氨基酸盐酸盐时，苯二氮卓衍生物(以游离碱计)与氨基酸盐酸盐的物质的量比为1:1～10；当HCl供给物A为HCl-无水醇溶液或者可以生成HCl的溶液B时，苯二氮卓衍生物(以游离碱计)与酸(以HCl计)物质的量比为1:0.4～1。
根据本发明的一个实施方案，所述成盐温度为-20～60℃，优选-10-30℃；结晶温度为 -60-80℃，优选-20-60℃。
根据本发明的一个实施方案，所述结晶溶剂1包括醇类溶剂(例如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇等)、醚类溶剂(例如乙醚、异丙醚、二氧六环、甲基叔丁基醚、异丙醚等)、酯类溶剂(例如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯等)、酮类溶剂(例如丙酮、丁酮等)、烷烃类溶剂(例如戊烷、己烷、庚烷、石油醚等)、卤代烷烃(如二氯甲烷、三氯甲烷、1,2-二氯乙烷等)以及它们的组合。
根据本发明的第三方面，其提供本发明的苯二氮卓类衍生物盐酸盐以及药物组合物，它们可用作静脉麻醉药物。
所述药物组合物包含根据本发明的上述式I的苯二氮卓类衍生物的盐酸盐的晶型、以及任选存在的药物学可接受的赋形剂、载体和/或其他辅料。所述赋型剂和/或载体例如包括：甘露醇、山梨醇、木糖醇、蔗糖、乳糖、葡萄糖、糊精、麦芽糖、麦芽糖醇、麦芽糖糊精、赤藓糖醇、海藻糖、葡萄糖酸钙、硫酸钙、氯化钠、甘氨酸、水解明胶、人血白蛋白等中的一种或多种。所述组合物还可选地包括其他辅料，如pH调节剂、稳定剂、止痛剂、抑菌剂等。所述pH调节剂例如包括：盐酸、硫酸、磷酸、柠檬酸、乙酸、磷酸二氢钠、磷酸二氢钾、磷酸二氢铵、磷酸氢二钠、磷酸氢二钾、磷酸氢二铵、磷酸钠、磷酸钾、磷酸铵、硫酸氢钠、硫酸氢钾、硫酸氢铵、碳酸氢钠、碳酸氢钾、碳酸钠、碳酸钾、氢氧化钠、氢氧化钾、氨水、枸橼酸、枸橼酸二氢钠、枸橼酸二氢钾、枸橼酸二氢铵、枸橼酸氢二钠、枸橼酸氢二钾、枸橼酸氢二铵、枸橼酸氢钾钠、枸橼酸钠、枸橼酸钾、枸橼酸铵、乳酸、乳酸钠、乳酸钾、乳酸铵、苹果酸、苹果酸钠、苹果酸钾、苹果酸、苹果酸氢钠、苹果酸氢钾、苹果酸氢铵、苹果酸钾钠、酒石酸、酒石酸氢钠、酒石酸氢钾、酒石酸氢铵、酒石酸钾钠、维生素C、维生素C钠、海藻酸、海藻酸钠、琥珀酸、琥珀钠、琥珀钾、琥珀酸铵、琥珀氢钠、琥珀氢钾、琥珀酸氢铵、琥珀酸钾钠、醋酸、醋酸钠、醋酸钾、醋酸铵、氨基酸及其盐类等中的一种或多种。所述稳定剂例如包括：亚硫酸氢钠、焦亚硫酸钠、亚硫酸钠、硫代硫酸钠、维生素C、巯基乙酸钠、甘氨酸、半胱氨酸、乙二胺四乙酸二钠、乙二胺四乙酸钙钠等中的一种或多种。所述止痛剂例如包括：苯甲醇、三氯叔丁醇等中的一种或多种。所述抑菌剂例如包括：苯甲醇、三氯叔丁醇、苯甲酸及其盐类、山梨酸及其盐类、尼泊金酯类等中的一种或多种。
根据本发明的第四方面，其提供麻醉方法，其包括向患者静脉内给药一定剂量的本发明的苯二氮卓类衍生物盐酸盐以及药物组合物。
根据本发明的第五方面，其提供本发明的苯二氮卓类衍生物盐酸盐在制备静脉麻醉药物中的用途。
为了使本发明的目的和技术方案更加清楚，下面对本发明的实施例进行详细的描述。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。
根据本发明的制备方法中涉及到的苯二氮卓类衍生物游离碱(式II-1、式II-2)的制备在PCT/CN2015/084770和WO0069836中都有公开，其整体内容在此并入作为参考。
Figure PCTCN2019074935-appb-000010
实验所用的测试仪器
X-射线粉末衍射谱：仪器型号：Bruker D8FOCUS X-射线粉末衍射仪；射线：Cu靶；扫描方式：θ/2θ；扫描范围：3～60°；电压：40KV；电流：40mA。
A.式II-1化合物的盐酸盐(其中R为甲基的式I化合物)的制备
A-1：以HCl-无水醇溶液作为HCl供给物A
实施例1：使用HCl-无水甲醇溶液
于13℃下，将式II-1的化合物(1.8g，4mmol)溶于无水甲醇(6ml)中，然后向其中滴加无水甲醇-HCl(HCl含量9.29％)1.57g(HCl摩尔量为4mmol)。该混合物反应0.5h，然后滴加MTBE(54ml)，并再反应0.5h。反应混合物进行过滤，滤饼用30ml无水甲醇溶清，于50℃脱色0.5h，然后过滤。滤液进行浓缩，而残余物用无水甲醇(14ml)在50℃溶清，滴加甲基叔丁基醚(7ml)，溶液浑浊，搅拌0.5h，滴加MTBE(98ml)，滴毕，降温至-10℃搅拌1h，过滤。滤饼用乙醚(30ml)打浆1.5h，然后过滤。滤饼进行干燥，得白色固体1.62g，收率90％，纯度：99.57％，m.p:173-175℃。氯离子含量理论值：7.45％(w/w)，实测值7.42％(w/w)。X-射线粉末衍射图谱见附图3。
A-2：以氨基酸盐酸盐作为HCl供给物A
实施例2：使用甘氨酸盐酸盐
60℃下，将甘氨酸盐酸盐(2.46g，22mmol)置于无水甲醇(50ml)中。在5min内向上述混合物中滴加含有式II-1化合物(5g，11mmol)的无水甲醇溶液(15ml)，并反应0.5h。该反应混合物降温至-20℃并在该温度下冷冻过夜，然后过滤。滤液进行浓缩，而残余物用无水甲醇(50ml)溶清，于55-60℃脱色0.5h，然后过滤。滤液进行浓缩，而残余物在60℃下用无水甲醇(20ml)溶清，向其中滴加甲基叔丁基醚(140ml)，滴毕，冷却至室温，并搅拌过夜，然后过滤。所得的固体进行干燥，得目标物。氯离子含量理论值：7.45％(w/w)，实测值7.38％(w/w)。X-射线粉末衍射图谱见附图4。
实施例3：使用缬氨酸盐酸盐
以式II-1化合物和缬氨酸盐酸盐为原料(摩尔比为1:1.5)，参照实施例2的操作，可以制得目标物。氯离子含量理论值：7.45％(w/w)，实测值6.94％(w/w)。
实施例4：使用丙氨酸盐酸盐
以式II-1化合物和丙氨酸盐酸盐为原料(摩尔比为1:3)，参照实施例2的操作，可以制得目标物。氯离子含量理论值：7.45％(w/w)，实测值6.81％(w/w)。
A-3：以可以生成HCl的溶液B作为HCl供给物A
实施例5：使用乙酰氯-无水甲醇溶液
以式II-1化合物和乙酰氯-无水甲醇溶液为原料(乙酰氯和式II-1化合物的摩尔比为1:1)，参照实施例1的操作，在20℃结晶，可制得目标物。氯离子含量理论值：7.45％(w/w)，实测值7.52％(w/w)。
实施列6：其中R为甲基的式I化合物的乙醇合物的单晶的制备与结构表征
将实施例1制得的式I化合物用乙醇和甲基叔丁基醚重结晶，于室温下静置4天，收集结晶。所得的晶体进行X-射线单晶衍射实验，其晶体参数如以下表1-6所示。
表1：其中R为甲基的式I化合物的乙醇合物的晶体数据和结构细化数据
Figure PCTCN2019074935-appb-000011
表2：其中R为甲基的式I化合物的乙醇合物的非氢原子坐标(x10 4)和等效各向同性位移参数
Figure PCTCN2019074935-appb-000012
数据
原子编号 x y z U(eq)
Br(1) -4202(1) 8268(1) 6312(1) 20(1)
O(1) 1797(2) 1562(2) 6318(1) 24(1)
O(2) 3608(2) 1616(2) 7788(1) 24(1)
N(1) 3120(2) 7198(2) 8336(1) 11(1)
N(2) 5345(3) 6118(2) 8788(1) 14(1)
N(3) 2920(3) 5605(2) 6571(1) 12(1)
N(4) 2033(3) 7931(2) 4955(1) 16(1)
C(1) -1864(3) 8033(2) 6918(2) 15(1)
C(2) -744(3) 7443(2) 6369(2) 15(1)
C(3) 940(3) 7172(2) 6826(2) 12(1)
C(4) 1444(3) 7520(2) 7839(2) 12(1)
C(5) 3750(3) 6139(2) 8272(2) 12(1)
C(6) 5737(3) 7165(2) 9197(2) 17(1)
C(7) 4366(3) 7865(2) 8929(2) 14(1)
C(8) 4159(3) 9076(2) 9132(2) 19(1)
C(9) 2771(3) 5267(2) 7635(2) 12(1)
C(10) 2080(3) 6484(2) 6240(2) 12(1)
C(11) 2264(3) 6836(2) 5168(2) 13(1)
C(12) 2297(3) 8259(3) 4006(2) 19(1)
C(13) 2764(3) 7536(2) 3271(2) 20(1)
C(14) 2999(3) 6408(2) 3507(2) 22(1)
C(15) 2745(3) 6053(2) 4475(2) 19(1)
C(16) 3417(3) 4067(2) 7808(2) 14(1)
C(17) 2268(3) 3324(3) 7070(2) 20(1)
C(18) 2680(3) 2085(2) 7127(2) 17(1)
C(19) 1984(4) 359(2) 6277(3) 29(1)
C(20) 324(3) 8166(2) 8354(2) 15(1)
C(21) -1338(3) 8426(2) 7891(2) 16(1)
Cl(1) 8473(1) 4573(1) 8670(1) 25(1)
O(3) 11847(2) 5057(2) 10155(1) 30(1)
C(22) 11733(4) 6161(3) 10571(2) 29(1)
C(23) 10127(4) 6328(3) 11098(2) 27(1)
注：U(eq)is defined as one third of the trace of the orthogonalized U ij tensor。
表3：其中R为甲基的式I化合物的乙醇合物的非氢原子各向异性位移参数
Figure PCTCN2019074935-appb-000013
数据
原子编号 U 11 U 22 U 33 U 23 U 13 U 12
Br(1) 10(1) 18(1) 30(1) 5(1) -2(1) 1(1)
O(1) 33(1) 10(1) 28(1) -4(1) -4(1) 2(1)
O(2) 25(1) 15(1) 30(1) 4(1) -2(1) 1(1)
N(1) 11(1) 10(1) 12(1) -1(1) 2(1) 0(1)
N(2) 12(1) 14(1) 16(1) 2(1) 0(1) 3(1)
N(3) 14(1) 10(1) 12(1) 1(1) 1(1) -1(1)
N(4) 17(1) 15(1) 16(1) 2(1) -1(1) -1(1)
C(1) 9(1) 14(2) 22(1) 2(1) 0(1) 0(1)
C(2) 16(1) 11(1) 16(1) 1(1) -1(1) -1(1)
C(3) 13(1) 8(1) 14(1) 0(1) 1(1) -1(1)
C(4) 10(1) 10(1) 14(1) 1(1) 1(1) 0(1)
C(5) 13(1) 10(1) 12(1) 1(1) 3(1) 1(1)
C(6) 16(1) 18(1) 15(1) 0(1) -2(1) -4(1)
C(7) 14(1) 16(1) 10(1) -1(1) 0(1) -2(1)
C(8) 20(1) 13(1) 22(1) -3(1) -1(1) -2(1)
C(9) 14(1) 11(1) 12(1) 1(1) 1(1) 1(1)
C(10) 12(1) 10(1) 14(1) -1(1) -1(1) -4(1)
C(11) 12(1) 13(1) 13(1) 0(1) -1(1) 0(1)
C(12) 19(1) 18(1) 21(1) 9(1) -1(1) -4(2)
C(13) 19(1) 26(1) 14(1) 6(1) 2(1) -2(1)
C(14) 26(1) 23(1) 16(1) -2(1) 4(1) 3(1)
C(15) 24(1) 16(1) 18(1) 1(1) 2(1) 3(1)
C(16) 16(1) 11(1) 16(1) 3(1) 1(1) 1(1)
C(17) 25(1) 9(1) 25(1) 0(1) -5(1) 3(1)
C(18) 16(1) 11(1) 24(1) 1(1) 5(1) -2(1)
C(19) 31(2) 11(1) 45(2) -5(1) -1(1) 3(1)
C(20) 17(1) 12(1) 15(1) -1(1) 3(1) -2(1)
C(21) 14(1) 11(1) 23(1) -2(1) 7(1) 2(1)
Cl(1) 16(1) 26(1) 32(1) -12(1) -1(1) 3(1)
O(3) 22(1) 40(1) 26(1) -5(1) -3(1) 9(1)
C(22) 34(2) 31(2) 22(1) 2(1) 7(1) -3(1)
C(23) 27(1) 26(2) 27(1) -3(1) 1(1) 2(1)
表4：其中R为甲基的式I化合物的乙醇合物的氢原子坐标(x10 4)和等效各向同性位移参数
Figure PCTCN2019074935-appb-000014
数据
氢原子编号 x y z U(eq)
H(2) 6024 5542 8856 17
H(2A) -1108 7227 5701 18
H(6) 6775 7361 9593 20
H(8A) 3702 9449 8512 28
H(8B) 5276 9392 9382 28
H(8C) 3364 9174 9632 28
H(9) 1536 5300 7748 15
H(12) 2155 9015 3840 23
H(13) 2919 7800 2625 24
H(14) 3320 5903 3026 26
H(15) 2893 5302 4658 23
H(16A) 4631 4008 7684 17
H(16B) 3331 3840 8506 17
H(17A) 1060 3427 7193 24
H(17B) 2364 3580 6382 24
H(19A) 1305 76 5673 44
H(19B) 1577 28 6868 44
H(19C) 3194 171 6262 44
H(20) 693 8423 9010 18
H(21) -2090 8859 8230 19
H(3) 10946 4916 9780 45
H(22A) 11727 6706 10026 35
H(22B) 12763 6299 11054 35
H(23A) 9102 6175 10629 40
H(23B) 10090 7089 11333 40
H(23C) 10164 5827 11669 40
表5：其中R为甲基的式I化合物的乙醇合物的键长
Figure PCTCN2019074935-appb-000015
和键角(°)数据
Figure PCTCN2019074935-appb-000016
Figure PCTCN2019074935-appb-000017
表6：其中R为甲基的式I化合物的乙醇合物的键扭角(°)数据
键 扭角(°) 键 扭角(°)
Br(1)-C(1)-C(2)-C(3) -174.59(17) N(2)-C(5)-C(9)-N(3) -102.1(3)
Br(1)-C(1)-C(21)-C(20) 174.62(19) N(2)-C(5)-C(9)-C(16) 19.0(3)
N(1)-C(4)-C(20)-C(21) -176.5(2) N(2)-C(6)-C(7)-N(1) -0.1(3)
N(1)-C(5)-C(9)-N(3) 71.7(3) N(2)-C(6)-C(7)-C(8) -176.9(2)
N(1)-C(5)-C(9)-C(16) -167.2(2) N(3)-C(9)-C(16)-C(17) -60.3(2)
N(3)-C(10)-C(11)-N(4) -153.5(2) C(1)-C(2)-C(3)-C(10) 176.7(2)
N(3)-C(10)-C(11)-C(15) 23.0(3) C(2)-C(1)-C(21)-C(20) -3.8(4)
N(4)-C(11)-C(15)-C(14) -0.2(4) C(2)-C(3)-C(4)-N(1) 176.6(2)
N(4)-C(12)-C(13)-C(14) -0.7(4) C(2)-C(3)-C(4)-C(20) -3.2(4)
C(1)-C(2)-C(3)-C(4) -0.4(3) C(2)-C(3)-C(10)-N(3) -130.2(3)
C(2)-C(3)-C(10)-C(11) 49.3(3) C(4)-N(1)-C(5)-C(9) 3.2(3)
C(3)-C(4)-C(20)-C(21) 3.3(4) C(4)-N(1)-C(7)-C(6) -178.4(2)
C(3)-C(10)-C(11)-N(4) 26.9(3) C(4)-N(1)-C(7)-C(8) -1.4(4)
C(3)-C(10)-C(11)-C(15) -156.5(2) C(4)-C(3)-C(10)-N(3) 46.7(4)
C(4)-N(1)-C(5)-N(2) 178.27(19) C(4)-C(3)-C(10)-C(11) -133.8(2)
C(4)-C(20)-C(21)-C(1) 0.2(4) C(5)-N(2)-C(6)-C(7) -0.4(3)
C(5)-N(1)-C(4)-C(3) -44.1(3) C(5)-C(9)-C(16)-C(17) -178.74(19)
C(5)-N(1)-C(4)-C(20) 135.7(2) C(6)-N(2)-C(5)-N(1) 0.7(3)
C(5)-N(1)-C(7)-C(6) 0.6(3) C(6)-N(2)-C(5)-C(9) 175.1(2)
C(5)-N(1)-C(7)-C(8) 177.6(2) C(7)-N(1)-C(4)-C(3) 134.8(2)
C(7)-N(1)-C(4)-C(20) -45.4(3) C(9)-C(16)-C(17)-C(18) -179.3(2)
C(7)-N(1)-C(5)-N(2) -0.8(2) C(10)-N(3)-C(9)-C(5) -70.0(2)
C(7)-N(1)-C(5)-C(9) -175.84(19) C(10)-N(3)-C(9)-C(16) 164.8(2)
C(9)-N(3)-C(10)-C(3) -1.6(4) C(10)-C(3)-C(4)-N(1) -0.3(3)
C(9)-N(3)-C(10)-C(11) 178.83(19) C(10)-C(3)-C(4)-C(20) 179.9(2)
C(10)-C(11)-C(15)-C(14) -176.5(2) C(13)-C(14)-C(15)-C(11) 0.1(4)
C(11)-N(4)-C(12)-C(13) 0.5(3) C(16)-C(17)-C(18)-O(1) -168.7(2)
C(12)-N(4)-C(11)-C(10) 176.34(19) C(16)-C(17)-C(18)-O(2) 12.9(4)
C(12)-N(4)-C(11)-C(15) -0.1(3) C(19)-O(1)-C(18)-O(2) 1.1(4)
C(12)-C(13)-C(14)-C(15) 0.3(4) C(19)-O(1)-C(18)-C(17) -177.4(2)
C(21)-C(1)-C(2)-C(3) 3.9(4)    
B：式II-2化合物的盐酸盐(其中R为乙基的式I化合物)的制备
B-1:以可以生成HCl的溶液B作为HCl供给物A
实施例7：使用乙酰氯-无水乙醇溶液
于13℃下，将式II-2的化合物(1.38g，3mmol)溶于无水乙醇(5ml)中，然后向其中滴加含乙酰氯(3mmol)的无水乙醇溶液(5ml)，反应过夜。接着向上述反应混合物中滴加MTBE(45ml)，并反应0.5h，然后过滤。滤饼用30ml无水乙醇溶清，并于50℃脱色0.5h，然后过滤。滤液进行浓缩，而残余物用无水乙醇(12ml)在50℃下溶清，然后向其中滴加MTBE(6ml)，溶液浑浊，并搅拌0.5h。向上述混合物中滴加MTBE(82ml)，滴毕，降温至-8℃并搅拌1h，然后过滤。滤饼用乙醚(25ml)打浆1.5h，然后过滤。滤饼进行干燥，得白色固体1.3g，收率92％，纯度：99.73％，m.p:160-163℃。氯离子含量理论值：7.24％(w/w)，实测值7.31％(w/w)。结晶的X-射线粉末衍射图谱见附图5。
实施例8：使用乙酰氯-异丙醇溶液
以式II-2化合物和乙酰氯-无水异丙醇溶液为原料(摩尔比为1:1)，参照实施例7的操作，在20℃结晶，可制得目标物。结晶的X-射线粉末衍射图谱见附图6。氯离子含量理论值：7.24％(w/w)，实测值7.21％(w/w)。
B-2：以HCl-无水醇溶液作为HCl供给物A
实施例9：使用HCl-无水乙醇溶液
于13℃下，将式II-2化合物(1.38g，3mmol)溶于无水乙醇(5ml)中，然后向其中滴加无水乙醇-HCl(HCl含量8.87％)1.2g(HCl摩尔量为3mmol)，并反应0.5h。接着向该反应混合物中滴加MTBE(45ml)，并反应0.5h，然后过滤。滤饼用30ml无水乙醇溶清，于50℃脱色0.5h，然后过滤。滤液进行浓缩，而残余物用无水乙醇(12ml)在50℃溶清，并向其中滴加MTBE(60ml)，溶液浑浊，搅拌0.5h，再向其中滴加MTBE(82ml)。滴毕，降温至-8℃搅拌1h，该混合物进行过滤，而滤饼用乙醚(25ml)打浆1.5h，然后过滤。滤饼进行干燥，得白色固体1.3g，收率92％，纯度：99.89％，m.p:162-165℃。氯离子含量理论值：7.24％(w/w)，实测值7.15％(w/w)。结晶的X-射线粉末衍射图谱见附图7。
参照实施例9的操作，可以制得另一批次的其中R为乙基的式I化合物的晶体，其结晶的X-射线粉末衍射图谱见附图8。
实施例10：使用HCl-无水乙醇溶液
参照实施例9的操作，结晶溶剂乙醇：甲基叔丁基醚＝1:7(v/v)，可以得到其中R为乙基的式I化合物的晶体。氯离子含量理论值：7.24％(w/w)，实测值7.19％(w/w)。其结晶的X-射线粉末衍射图谱见附图9。
B-3.以氨基酸盐酸盐作为HCl供给物A
实施例11：使用甘氨酸盐酸盐
60℃下，将甘氨酸盐酸(2.46g，22mmol)置于无水乙醇(50ml)中，然后在5min内向其中滴加含有式II-2化合物(5g，11mmol)的无水乙醇溶液(15ml)，并使其反应0.5h。该反应混合物降温至-20℃并冷冻过夜，然后过滤。滤液进行浓缩，而残余物用无水乙醇(50ml)溶清，于55-60℃脱色0.5h，过滤，滤液浓缩，残余物在60℃下用无水乙醇(20ml)溶清，滴加甲基叔丁基醚(140ml)，滴毕，冷却至室温，搅拌过夜，过滤。滤饼进行干燥，得目标物。氯离子含量理论值：7.24％(w/w)，实测值6.82％(w/w)。其结晶的X-射线粉末衍射图谱见附图10。
参照实施例11的操作，可以制得另一批次的其中R为乙基的式I化合物的晶体，其结晶的X-射线粉末衍射图谱见附图11。
实施例12：使用甘氨酸盐酸盐
60℃下，将甘氨酸盐酸(2.46g，22mmol)置于无水乙醇(50ml)中，然后在5min内，向其中滴加含有式II-2化合物(5g，11mmol)的无水乙醇溶液(15ml)，并反应0.5h。降温至-20℃并冷冻过夜，然后过滤。滤液进行浓缩，而残余物用无水乙醇(50ml)溶清，并于55-60℃脱色0.5h，然后过滤。滤液进行浓缩，而残余物在60℃下用无水乙醇(25ml)溶清，并向其中滴加乙酸乙酯(240ml)。滴毕，冷却至-40℃，搅拌2h，过滤。残余物在50℃下用无水乙醇(25ml)溶清，向其中滴加甲基叔丁基醚(150ml)，滴毕，降温至室温，搅拌1h，过滤。滤饼进行干燥，得目标物。氯离子含量理论值：7.24％(w/w)，实测值7.02％(w/w)。其结晶的X-射线粉末衍射图谱见附图12。
参照实施例12的操作，可以制得另一批次的其中R为乙基的式I化合物的晶体，其结晶的X-射线粉末衍射图谱见附图13。
实施例13：以缬氨酸盐酸盐制备其中R为乙基的式I化合物
以式II-2化合物和缬氨酸盐酸盐为原料(摩尔比为1:1.5)，参照实施例11的操作，以乙醇和异丙醚为结晶溶剂，于-10℃结晶，得目标物。氯离子含量理论值：7.24％(w/w)，实测值6.74％(w/w)。
实施例14：其中R为乙基的式I化合物的制备
以式II-2化合物和丙氨酸盐酸盐为原料(摩尔比为1:3)，参照实施例11的操作，可以制得目标物。氯离子含量理论值：7.24％(w/w)，实测值6.63％(w/w)。
实施例15：其中R为乙基的式I化合物的晶体的制备与结构表征
将实施例9制得的II-2盐酸盐用乙醇和甲基叔丁基醚重结晶，于室温静置4天，收集结晶，进行X-射线单晶衍射实验，晶体参数如以下表7-12所示。
表7：其中R为乙基的式I化合物的乙醇合物的晶体数据和结构细化数据
Figure PCTCN2019074935-appb-000018
表8：其中R为乙基的式I化合物的乙醇合物的非氢原子坐标(x10 4)和等效各向同性位移参数
Figure PCTCN2019074935-appb-000019
数据
原子编号 x y z U(eq)
Br(1) -3552(1) 10601(1) 5747(1) 37(1)
O(1) 4576(6) 4196(2) 6487(2) 73(1)
N(1) 3579(4) 9375(2) 6716(1) 24(1)
N(2) 5735(4) 8340(2) 6948(1) 28(1)
O(3) 2760(4) 4013(2) 5838(1) 46(1)
N(4) 2822(4) 9849(2) 5048(1) 31(1)
N(3) 3572(4) 7810(2) 5886(1) 24(1)
C(11) 2919(4) 8840(3) 5178(1) 23(1)
C(7) 4778(5) 9987(3) 6995(1) 28(1)
C(2) -125(4) 9623(2) 5794(1) 24(1)
C(22) -855(5) 10674(3) 6501(1) 29(1)
C(16) 3957(5) 6435(3) 6506(1) 28(1)
C(3) 1528(4) 9324(2) 6006(1) 24(1)
C(6) 6102(5) 9324(3) 7136(1) 31(1)
C(4) 1938(4) 9694(2) 6478(1) 23(1)
C(1) -1287(5) 10272(2) 6046(1) 27(1)
C(5) 4197(5) 8375(3) 6699(1) 25(1)
C(10) 2729(4) 8615(2) 5715(1) 24(1)
C(21) 759(5) 10376(3) 6721(1) 27(1)
C(8) 4561(5) 11133(3) 7077(1) 34(1)
C(15) 3156(5) 8029(3) 4848(1) 33(1)
C(14) 3266(6) 8272(3) 4351(1) 39(1)
C(9) 3279(4) 7547(2) 6409(1) 24(1)
C(12) 2931(5) 10065(3) 4565(1) 34(1)
C(18) 3569(6) 4567(3) 6194(1) 38(1)
C(13) 3142(5) 9305(3) 4208(1) 34(1)
C(17) 2968(5) 5690(3) 6167(1) 36(1)
C(19) 3152(8) 2898(3) 5820(2) 60(1)
C(20) 1904(10) 2421(3) 5460(2) 74(2)
O(2) 12010(4) 7592(3) 7610(1) 50(1)
C(23) 11583(7) 8592(3) 7804(2) 48(1)
C(24) 10366(10) 8548(4) 8231(2) 83(2)
Cl(1) 8848(1) 6748(1) 6988(1) 34(1)
注：U(eq)is defined as one third of the trace of the orthogonalized U ij tensor。
表9：其中R为乙基的式I化合物的乙醇合物非氢原子各向异性位移参数
Figure PCTCN2019074935-appb-000020
数据
原子编号 U 11 U 22 U 33 U 23 U 13 U 12
Br(1) 30(1) 42(1) 39(1) 4(1) -2(1) 9(1)
O(1) 88(3) 35(2) 96(3) 4(2) -51(2) 17(2)
N(1) 25(1) 27(1) 21(1) -2(1) -1(1) -6(1)
N(2) 25(1) 33(2) 27(1) 4(1) -2(1) 0(1)
O(3) 68(2) 21(1) 49(2) -3(1) -9(2) 12(1)
N(4) 42(2) 25(1) 25(1) 1(1) 2(1) -1(1)
N(3) 28(1) 23(1) 22(1) -1(1) 1(1) 2(1)
C(11) 21(2) 25(2) 23(1) -2(1) 0(1) 1(1)
C(7) 29(2) 36(2) 21(1) -5(1) 2(1) -8(2)
C(2) 26(2) 20(1) 26(1) 1(1) 1(1) -3(1)
C(22) 31(2) 23(2) 34(2) -3(1) 9(1) 0(1)
C(16) 26(2) 29(2) 30(2) 2(1) -3(1) 1(1)
C(3) 26(2) 21(1) 25(1) -2(1) 2(1) -2(1)
C(6) 27(2) 39(2) 27(1) -3(1) -4(1) -6(2)
C(4) 22(2) 24(2) 23(1) -2(1) 1(1) -2(1)
C(1) 24(2) 24(1) 34(2) 4(1) 4(1) -4(1)
C(5) 27(2) 28(2) 21(1) 0(1) 2(1) -1(1)
C(10) 26(2) 22(1) 24(1) -3(1) 1(1) -2(1)
C(21) 28(2) 27(2) 25(1) -5(1) 3(1) -3(1)
C(8) 32(2) 36(2) 34(2) -13(2) 2(2) -8(2)
C(15) 46(2) 27(2) 27(2) -4(1) 3(2) 8(2)
C(14) 50(2) 40(2) 26(2) -9(1) 1(2) 8(2)
C(9) 24(2) 25(2) 24(1) 2(1) 2(1) 2(1)
C(12) 44(2) 31(2) 27(2) 6(1) 0(2) -1(2)
C(18) 43(2) 25(2) 46(2) 3(2) -6(2) 5(2)
C(13) 33(2) 45(2) 24(1) 2(2) 0(1) -2(2)
C(17) 42(2) 22(2) 45(2) 2(2) -13(2) 3(2)
C(19) 85(4) 21(2) 73(3) -7(2) -4(3) 17(2)
C(20) 127(5) 24(2) 72(3) -10(2) -6(4) 4(3)
O(2) 37(2) 65(2) 47(2) -18(1) -12(1) 14(1)
C(23) 49(2) 43(2) 50(2) 4(2) 2(2) -7(2)
C(24) 116(5) 50(3) 81(4) -28(3) 49(4) -19(3)
Cl(1) 28(1) 42(1) 30(1) -4(1) 0(1) 0(1)
表10：其中R为乙基的式I化合物的乙醇合物氢原子坐标(x10 4)和等效各向同性位移参数
Figure PCTCN2019074935-appb-000021
数据
氢原子编号 x y z U(eq)
H(2) 6416 7778 6987 34
H(2A) -443 9376 5476 29
H(22) -1652 11149 6662 35
H(16A) 5278 6396 6444 34
H(16B) 3731 6240 6853 34
H(6) 7121 9503 7333 37
H(21) 1064 10636 7038 32
H(8A) 4204 11472 6768 51
H(8B) 5713 11430 7191 51
H(8C) 3623 11253 7326 51
H(15) 3242 7322 4958 40
H(14) 3424 7733 4113 47
H(9) 1950 7574 6480 29
H(12) 2860 10778 4464 41
H(13) 3200 9492 3870 41
H(17A) 1658 5721 6245 44
H(17B) 3123 5938 5825 44
H(19A) 2972 2579 6148 71
H(19B) 4425 2782 5718 71
H(20A) 2128 2722 5134 112
H(20B) 649 2563 5558 112
H(20C) 2105 1660 5449 112
H(2B) 11129 7368 7445 74
H(23A) 11005 9020 7544 57
H(23B) 12720 8948 7902 57
H(24A) 9274 8150 8145 124
H(24B) 10026 9262 8328 124
H(24C) 10986 8201 8506 124
表11：其中R为乙基的式I化合物的乙醇合物键长
Figure PCTCN2019074935-appb-000022
和键角(°)数据
Figure PCTCN2019074935-appb-000023
Figure PCTCN2019074935-appb-000024
表12：其中R为乙基的式I化合物的乙醇合物键扭角(°)数据
键 扭角(°) 键 扭角(°)
O(1)-C(18)-C(17)-C(16) 8.9(7) N(1)-C(5)-C(9)-C(16) -169.6(3)
N(1)-C(7)-C(6)-N(2) 0.3(4) N(2)-C(5)-C(9)-N(3) -105.1(4)
N(1)-C(4)-C(21)-C(22) -178.5(3) N(2)-C(5)-C(9)-C(16) 15.8(5)
N(1)-C(5)-C(9)-N(3) 69.5(4) O(3)-C(18)-C(17)-C(16) -172.3(3)
N(4)-C(11)-C(10)-N(3) -149.5(3) C(11)-N(4)-C(12)-C(13) -0.3(6)
N(4)-C(11)-C(10)-C(3) 32.4(4) C(11)-C(15)-C(14)-C(13) 0.3(6)
N(4)-C(11)-C(15)-C(14) -1.3(6) C(7)-N(1)-C(4)-C(3) 138.6(3)
N(4)-C(12)-C(13)-C(14) -0.7(6) C(7)-N(1)-C(4)-C(21) -41.4(4)
C(7)-N(1)-C(5)-N(2) -1.0(3) C(2)-C(3)-C(10)-N(3) -135.7(3)
C(7)-N(1)-C(5)-C(9) -176.7(3) C(2)-C(3)-C(10)-C(11) 42.2(4)
C(2)-C(3)-C(4)-N(1) 177.6(3) C(3)-C(2)-C(1)-Br(1) -177.5(2)
C(2)-C(3)-C(4)-C(21) -2.5(4) C(3)-C(2)-C(1)-C(22) 2.1(5)
C(3)-C(4)-C(21)-C(22) 1.6(5) C(4)-N(1)-C(7)-C(8) -2.6(5)
C(6)-N(2)-C(5)-N(1) 1.2(3) C(4)-N(1)-C(5)-N(2) 179.4(2)
C(6)-N(2)-C(5)-C(9) 176.4(3) C(4)-N(1)-C(5)-C(9) 3.7(4)
C(4)-N(1)-C(7)-C(6) -180.0(3) C(4)-C(3)-C(10)-N(3) 43.3(5)
C(4)-C(3)-C(10)-C(11) -138.8(3) C(5)-N(1)-C(7)-C(6) 0.4(3)
C(1)-C(2)-C(3)-C(4) 0.7(4) C(5)-N(1)-C(7)-C(8) 177.8(3)
C(1)-C(2)-C(3)-C(10) 179.8(3) C(5)-N(1)-C(4)-C(3) -41.9(4)
C(1)-C(22)-C(21)-C(4) 1.2(5) C(5)-N(1)-C(4)-C(21) 138.2(3)
C(5)-N(2)-C(6)-C(7) -0.9(4) C(10)-C(3)-C(4)-N(1) -1.4(5)
C(10)-N(3)-C(9)-C(16) 165.0(3) C(10)-C(3)-C(4)-C(21) 178.5(3)
C(10)-N(3)-C(9)-C(5) -70.5(4) C(21)-C(22)-C(1)-Br(1) 176.5(2)
C(10)-C(11)-C(15)-C(14) 177.9(3) C(21)-C(22)-C(1)-C(2) -3.1(5)
C(8)-C(7)-C(6)-N(2) -176.9(3) C(9)-N(3)-C(10)-C(11) -175.9(3)
C(15)-C(11)-C(10)-N(3) 31.3(5) C(9)-N(3)-C(10)-C(3) 2.0(5)
C(15)-C(11)-C(10)-C(3) -146.8(3) C(9)-C(16)-C(17)-C(18) 176.3(3)
C(15)-C(14)-C(13)-C(12) 0.6(6) C(12)-N(4)-C(11)-C(10) -177.9(3)
C(12)-N(4)-C(11)-C(15) 1.3(6) C(17)-C(16)-C(9)-C(5) -177.2(3)
C(18)-O(3)-C(19)-C(20) 170.6(4) C(19)-O(3)-C(18)-O(1) 0.6(7)
C(17)-C(16)-C(9)-N(3) -57.7(4) C(19)-O(3)-C(18)-C(17) -178.2(4)
实施例16：苯二氮卓衍生物盐酸盐稳定性实验
选取在上述实施例中制备的式I化合物，包装后放置在40℃、RH75％和25℃、RH60％两个条件下进行加速稳定性试验和长期稳定性试验，分别考察组合物在6个月内的降解产物(CNS-7054)变化情况，结果如下表13所示。
表13：苯二氮卓衍生物盐酸盐稳定性实验数据
Figure PCTCN2019074935-appb-000025
另外，使用根据现有技术的磺酸盐制成的冻干制剂，在加速实验和长期实验中，均有部分降解为羧酸(CNS-7054)并释放出醇，变化情况见下表14。
Figure PCTCN2019074935-appb-000026
其中R为甲基或乙基；A为苯磺酸、对甲苯磺酸。
表14：苯二氮卓衍生物磺酸盐稳定性实验数据
Figure PCTCN2019074935-appb-000027
由以上数据，可以看出本发明提供的苯二氮卓类衍生物盐酸盐，稳定性好，不会生成降解产物(CNS-7054)，不会生成具有基因毒性的杂质。
实施例17：苯二氮卓衍生物盐酸盐KM种小鼠ED 50和LD 50的测定
采用序贯法测定苯二氮卓衍生物盐酸盐KM种小鼠催眠ED 50及LD 50值。取健康合格的雄性KM种小鼠，n＝10～20。通过尾静脉注射药物，5秒钟匀速注完；实验前经初步预试找出能导致动物催眠(或死亡)的大致剂量，作为正式实验时的中间剂量，采用0.8的组间距，往上往下分别再设2-3个剂量组。正式实验时首先从中间剂量开始给药，当动物被麻倒(或死亡)时，则降低一个剂量给药，若动物未被麻倒(或死亡)，至增大一个剂量给药，至到出现3-4个反复为至，分别以翻正反射消失或死亡为指标测定ED 50值及LD 50值。通过LD 50及ED 50值计算治疗指数(TI指数＝ED 50/LD 50)。实验结果如下表15所示。
表15：苯二氮卓衍生物盐酸盐KM种小鼠ED 50和LD 50数据
Figure PCTCN2019074935-appb-000028
由以上数据，可以看出本发明提供的苯二氮卓衍生物盐酸盐的治疗指数较苯磺酸盐没有 明显差异，安全性良好。
实施例18：苯二氮卓衍生物盐酸盐与磺酸盐KM种小鼠2*ED 50麻醉药效学实验(n＝20)
KM种小鼠，雌雄各半，每组20只；给药剂量为2*ED 50，尾静脉注射，5秒钟匀速注完，记录小鼠翻正反射消失的时间(诱导时间)、恢复时间(持续期)和行走时间。实验结果如下表16所示。
表16：苯二氮卓衍生物盐酸盐与磺酸盐KM种小鼠2*ED 50麻醉药效学实验数据
Figure PCTCN2019074935-appb-000029
由以上数据，可以看出：
1、R为乙基的苯二氮卓衍生物在麻醉持续时间和行走时间均优于R为甲酯的苯二氮卓衍生物，且有统计学差异。
2、R为乙基的苯二氮卓衍生物，动物麻醉时间超过10min的发生率，磺酸盐为35％，盐酸盐为20％；动物行走时间超过1min的发生率，磺酸盐为50％，盐酸盐为15％，说明盐酸较磺酸盐药代动力学性质更稳定，受个体差异影响小。
3、R为甲基的苯二氮卓衍生物，动物麻醉时间超过10min的发生率，磺酸盐为45％，盐酸盐为25％；动物行走时间超过1min的发生率，磺酸盐为85％，盐酸盐为40％，说明盐酸较磺酸盐药代动力学性质更稳定，受个体差异影响小。
总结：本发明提供的苯二氮卓衍生物盐酸盐较磺酸盐具有更稳定的药代动力学性质，受个体差异的影响小。

Claims (18)

  1. 具有如下式I的苯二氮卓类衍生物的盐酸盐或其乙醇合物的晶型，
    Figure PCTCN2019074935-appb-100001
    其中R为甲基或乙基；其中R为甲基时，所述晶型具有以下晶胞参数：
    Figure PCTCN2019074935-appb-100002
    Figure PCTCN2019074935-appb-100003
    α＝90°，β＝96.904(1)°，γ＝90°；以及R为乙基时，所述晶型具有以下晶胞参数：
    Figure PCTCN2019074935-appb-100004
    α＝90°，β＝90°，γ＝90°。
  2. 如权利要求1所述的晶型，其中R为甲基，且其晶型结构基本上如图1所示，或者可以用基本上如表1‐6所示的一种或多种参数表征；以及其中R为乙基，且其晶型结构基本上如图2所示，或者可以用基本上如表7‐12所示的一种或多种参数表征。
  3. 如权利要求1所述的晶型，其中R为甲基，且式I化合物中氯离子的含量为6.71～7.52％(w/w)；以及其中R为乙基，且式I化合物中氯离子的含量为6.51～7.31％(w/w)。
  4. 如权利要求1所述的晶型，其中R为甲基，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.81、8.93、13.39、19.38、21.23、22.42、24.20、27.31±0.2度；或者所述X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约8.11、9.86、14.73、17.47、23.03、25.94、28.31±0.2度；或者所述晶型具有基本上如附图3所示的X‐射线粉末衍射光谱。
  5. 如权利要求1所述的晶型，其中R为甲基，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.80、8.93、9.87、13.37、14.69、19.36、20.76、21.25、22.19、22.38、23.06、24.21、25.93、27.73±0.2度；或者所述X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约16.14、17.48、20.02、25.17、26.36、28.30、34.13±0.2度；或者所述晶型具有基本上如附图4所示的X‐射线粉末衍射光谱。
  6. 如权利要求1所述的晶型，其中R为乙基，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.87、7.38、9.53、13.65、18.71、22.13、22.67、25.10、27.25、29.30±0.2度；或者所述X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约14.96、15.43、20.23、20.67、21.13、23.52、28.22、31.26±0.2度；或者所述晶型具有基本上如附图5～8之一所示的X‐射线粉末衍射光谱。
  7. 如权利要求1所述的晶型，其中R为乙基，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约7.41、9.24、12.71、13.64、15.06、18.30、18.72、21.59、22.18、25.74±0.2度；或者所述X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约9.52、11.69、20.90、22.60、23.65、24.26、26.40、28.43、29.35±0.2度；或者所述晶型具有基本上如附图9所示的X‐射线粉末衍射光谱。
  8. 如权利要求1所述的晶型，其中R为乙基，其X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约6.84、7.37、9.53、13.66、22.63、25.57、29.28、31.26±0.2度；或者所述X射线粉末衍射光谱具有使用CuKα辐射测量的以下2θ值：约15.43、19.07、22.16、34.25±0.2度；或者所述晶型具有基本上如附图10～13之一所示的X‐射线粉末衍射光谱。
  9. 制备如权利要求1‐8之一所述的晶型的方法，包括以下步骤：将以下式II‐1或II‐2的苯二氮卓衍生物游离碱溶于有机溶剂1中，加入其中[H +]与游离碱等摩尔的HCl供给物A，在‐20～60℃成盐，将该粗品盐脱色后，于‐60‐80℃在结晶溶剂1中结晶，得到所述式I的苯并二氮杂卓衍生物的盐酸盐的晶型。
    Figure PCTCN2019074935-appb-100005
  10. 如权利要求9所述的方法，其中所述有机溶剂1为醇类溶剂，如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇；酯类溶剂，如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯；酮类溶剂，如丙酮、丁酮；或者它们的混合物。
  11. 如权利要求9所述的方法，其中所述HCl供给物A为氨基酸盐酸盐，如甘氨酸盐酸盐、丙氨酸盐酸盐、缬氨酸盐酸盐；HCl‐无水醇溶液，即干燥HCl气体的醇类溶液，如干燥HCl‐甲醇溶液、干燥HCl‐乙醇溶液、干燥HCl‐异丙醇溶液；或可以生成HCl的溶液B，如乙酰氯‐甲醇溶液、乙酰氯‐乙醇溶液、丙酰氯‐乙醇溶液、乙酰氯‐异丙醇溶液。
  12. 如权利要求11所述的方法，其中所述HCl供给物A为氨基酸盐酸盐，且所述苯二氮卓衍生物盐酸盐的晶型中含有的氨基酸量为0％～8％(w/w)。
  13. 如权利要求11所述的方法，其中所述HCl供给物A为HCl‐无水醇溶液或者可以生成HCl的溶液B，且所述苯二氮卓衍生物游离碱与该HCl供给物A(以[H +]计)的物质的量比(摩尔比)为1:0.4～1；所述HCl供给物A为氨基酸盐酸盐，且所述苯二氮卓衍生物游离碱与氨基酸盐酸盐的物质的量比(摩尔比)为1:1～10。
  14. 如权利要求9所述的方法，其中所述成盐温度为‐10至30℃；以及所述结晶温度为‐20至60℃。
  15. 如权利要求9所述的方法，其中所述结晶溶剂1包括醇类溶剂，如甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇；醚类溶剂，如乙醚、异丙醚、二氧六环、甲基叔丁基醚；酯类溶剂，如乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸异丙酯、乙酸丁酯；酮类溶剂，如丙酮、丁酮；烷烃类溶剂，如正戊烷、己烷、庚烷、石油醚；卤代烷烃，如二氯甲烷、三氯甲烷、1,2‐二氯乙烷；以及它们的组合。
  16. 药物组合物，其包含如权利要求1‐8之一所述的晶型、以及药物学可接受的赋形剂、载体和/或其他辅料。
  17. 如权利要求1‐8之一所述的晶型或如权利要求16所述的药物组合物，其是用作静脉麻醉药物。
  18. 如权利要求1‐8之一所述的晶型在制备静脉麻醉药物中的用途。
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